USE OF ADVISORY COMMITTEES BY THE
FOOD AND DRUG ADMINISTRATION
(PART 2)
HEARINGS
BEFORE A
SUBCOMMITTEE OF THE
COMMITTEE ON
GOVERNMENT OPERATIONS
HOUSE OF REPRESENTATIVES
NINETY-FOURTH CONGRESS
FIRST SESSION
APRIL 23: MAT 9 AND 12, 1975
Printed for the use of the Committee oh Government Oiierntions
1\/G.
U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 1975
For sale by the Superintendent of Documents, U.S. Government Printing Office
Washington, D.C. 20402 - Price $3.40
NORTHEASTERN UNIVERSITY SCHOOL of LAW LIBRARY
COMMITTEE ON GOVERNMENT OPERATIONS
JACK BROOKS, Texas, Chairman
L. H. FOUNTAIN, North Carolina
JOHN E. MOSS, California
DANTE B. FASCELL, Florida
TORBERT H. MACDONALD, Massachusetts
WILLIAM S. MOORHEAD, Pennsylvania
WM. J. RANDALL, Missouri
BENJAMIN S. ROSENTHAL, New York
JIM WRIGHT, Texas
FERN AND J. ST GERMAIN, Rhode Island
FLOYD V. HICKS, Washington
DON FUQUA, Florida
JOHN CONYERS, Jr., Michigan
BELLA S. ABZUG, New York
JAMES V. STANTON, Ohio
LEO J. RYAN, California
CARD1SS COLLINS, Illinois
JOHN L. BURTON, California
RICHARDSON PRE YE R, North Carolina
MICHAEL HARRINGTON, Massachusetts
ROBERT F. DRINAN, Massachusetts
EDWARD MEZVINSKY, Iowa
BARBARA JORDAN, Texas
GLENN ENGLISH, Oklahoma
ELLIOTT H. LEV1TAS, Georgia
DAVID W. EVANS, Indiana
ANTHONY MOFFETT, Connecticut
ANDREW MAGUIRE, New Jersey
LES ASP1N, Wisconsin
FRANK HORTON, New York
JOHN N. ERLENBORN, Illinois
JOHN W. WYDLER, New York
CLARENCE J. BROWN, Ohio
GILBERT GUDE, Maryland
PAUL N. McCLOSKEY, Jr., California
SAM STEIGER, Arizona
GARRY BROWN, Michigan
CHARLES THONE, Nebraska
ALAN STEELMAN, Texas
JOEL PRITCHARD, Washington
EDWIN B. FORSYTHE, New Jersey
ROBERT W. KASTEN, Jr., Wisconsin
WILLIS D. GRADISON, Jr., Ohio
William M. Jones, (lateral Counsel
John E. Moore, Staff Administrator
William H. Copenhaver, Associate Counsel
Lyn.ne Higginbotham, Clerk
J. P. Carlson, Minority Counsel
Intergovernmental Relations and Human Resources Subcommittee
L. H. FOUNTAIN, North Carolina, Chairman
DON FUQUA, Florida JOHN W. WYDLER, New York
EDWARD MEZVINSKY, Iowa CLARENCE J. BROWN, Ohio
BARBARA JORDAN, Texas ROBERT W. KASTEN, Jr., Wisconsin
JOHN L. BURTON, California
ROBERT F. DRINAN, Massachusetts
GLENN ENGLISH, Oklahoma
ELLIOTT H. LEVITAS, Georgia
EX OFFICIO
JACK BROOKS, Texas
FRANK HORTON, New York
Delphis C. Goldberg, Professional Staff Member
James R. Naughton, Counsel
Gilbert S. Goldhammer, Consultant
Pamela Welch, Secretary
(U)
a
CONTENTS
(SEE PP. — TO — FOR CONTENTS LISTED BY
SUBJECT MATTER)
Hearings held on — Pa £e
April 23 1
May 9 53
May 12 111
Statement of Alexander M. Schmidt, M.D., Commissioner of Food and
Drugs, Food and Drug Administration, Department of Health, Edu-
cation, and Welfare; accompanied by J. Richard Crout, M. D., Director,
Bureau of Drugs; Peter B. Hutt, Chief Counsel; Robert C. Wetherell,
Jr., Director, Office of Legislative Services; Robert G. Pinco, Chief,
Division of OTC Evaluation; John Jennings, M.D., Associate Com-
missioner for Medical Devices and Diagnostic Products ; Mark Novitch,
M.D., Deputy Associate Commissioner for Medical Affairs; and Gary
L. Yingling, Associate Chief Counsel for Enforcement 2, 54, 111
Letters, statements, etc., submitted for the record by —
Fountain, Hon. L. H, a Representative in Congress from the State of
North Carolina, and chairman, Intergovernmental Relations and
Human Resources Subcommittee:
April 8, 1975, letter from Clealand F. Baker, Burroughs Wellcome
Co. to J. Richard Crout, M.D., FDA, replying to March 4, 1975,
letter re marketing of products without premarket FDA
clearance 9 1-92
August 8, 1972, letter from Gerald F. Myer, Office of Legislative
Services, FDA, to Dr. Delphis C. Goldberg, subcommittee
professional staff member, re status of litigation on drug Ornex_ 85-86
Ayerst Laboratories' Epitrate drug recall letter of February 26,
'1971 76
Bibliography of papers on granulomas associated with the ap-
plication or inhalation of zirconyl compounds 20
December 11, 1972, letter from Franz J. Ingelfinger, M.D., to
Henry E. Simmons, M.D., M.P.H., Director, Bureau of Drugs,
FDA, re panel meeting of December 8 and 9, 1972 179-180
Excerpts from the British Medical Journal — Letter to the
editor, by G. H. Jennings, entitled "Alka-Seltzer and Hae-
matemesis," 16:475, 1963; and article, by G. H. Jennings,
entitled "Causal Influences in Haematemesis and Malaena,"
Gut, 6:1-13, 1965 227-247
Excerpts from the Federal Register concerning the FDA OTC
Antacid Review Panel: January 5, 1972, request for data and
information on safety and effectiveness; April 5, 1973; and
June 4, 1974 121-122, 183-185.214-216,222-224
Excerpt from the Code of Federal Regulations, title 21, chapter
I, entitled "Part 330— Over-the-Counter (OTC) Human Drugs
Which Are Generally Recognized as Safe and Effective and
Not Misbranded" 5-10
FDA Talk Paper of October 10, 1973, Gillette Co. recall letter
on certain Right Guard products 17
Federal Register notice 1 of September 7, 1973, entitled "Over-
the-Counter Antiperspirant Drug Products and Over-the-
Counter Topical Antibiotic Drugs" 10-13
Informal ion from FDA OTC Antacid Review Panel meetings of:
May 8, 1972, second meeting; September, 7 to 9, 1972, fifth
meeting; December 8 and 9, 1972, sixth meeting; January 9,
1973, telephone conference call; and verbatim transcripts from
December 8 and 9, 1972, meetings 122-123,
126-129, 143-144, 146-149, 160-168, 188
IV
-ubmitted for the record by — Continued
L EL — C :.:inued
Information froni FDA Review P:\nel
5s of: I 10, 1 974; A . - - i 9, 1974: Oct
31 and I r 2. 1974: December 16 and 17. 1974: January
"": and verbatim transcript of March 24. 1975 Pase
- Lsess 15-16.19.21-.- . • ■
Jui; 8 J " .r.dum re Rx status of cyclizine and mechzine
from Peter Barton E sui FDA Bureau of
Dm_- L. Tingling. 5T( staff,
July > i — bant to the Director :" r
Regulat ry Affairs, re si I is :' ral preparations containing
ehloreyclizine, cychzine. or meclizine 1 IS— 119
June IS. 1971. memorandum to Henrv E. Simmons. M.D..
M.P.H. E J. Finkel. M.D.. D
Dire. _- - t:Pod phyUum: A potentially
s ] .vith memo record on pharmacology
opinion on hazards and actions of podophyllum; and letter
from Mary A. McEniry to Director. FDA OiC Products
Rev. . phyliurn containing drags 113-115
June 20, 1972. letter ::ible from Paul A. Bry.
M.D DESI Project Office, Bureau of Dru r
abbreviated new drug application for Secret
fcer 1 Dr. E. William Ros g I hairman,
TC Drug Review Panel from Rober: W.
. group vice president. Gillette North America, re
panel's November 1974 and January 1975 classification of
- II 57 " v
March 25, 1975 - - r S midf
..mending withdrawal of all zirconium-containing anti-
- Is from interstate commerce 35
March 2$ 75, hairman
d the market without
approved NDA's, and compliance with the I
" 16. 1975. letter from Chair:
r Schmidt, and Dr. Schmidt's July 3. 1975, reply r
J of podophyllum from the formulation of Carter's
s- 115-118
May 17 " letter from Chief Counsel Peter B. Hutt, FDA, to
lourt citations to support F I
on panel report 175-176
from Chairman 1 missioner
mder M. Schmidt, FDA. re Mnv 17. 1975. letter from
Chief Counsel Peter B. Hut:. FDA____ . 176-177
Memorandum to FDA, from 1 Eary K. Brueh,
itive of Bureau of Drugs FDA OT1
ting of the FDA OTI - irant
ion Alert _ 72-74
- received by Gary L.
FDA. - L: December 22. 72 randum on
FDA
- d the final proposed draft report:
22, 1972, di ft i Miles 1
- :. . 72 randum, sul
i draft report of FI .
>2, 1972; and
3, 1973,
_ ifdnger 191-199
_• 27, 197 ment on aei
23-29
tacid Review Panel's dr
anm I -
and 213-21 4.220-221
__PP___\_Y_X
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USE OF ADVISORY COMMITTEES BY THE FOOD AND
DRUG ADMINISTRATION
(Part 2)
WEDNESDAY, APRIL 23, 1975
House of Representatives,
Intergovernmental Relations
and Human Resources Subcommittee
of the Committee on Government Operations,
Washington, D.C.
The subcommittee met, pursuant to notice, at 10 a.m., in room
2247, Rayburn House Office Building, Hon. L. H. Fountain (chairman
of the subcommittee) presiding.
Present: Representatives L. H. Fountain, Don Fuqua, Robert F.
Drinan, Glenn English, Elliott H. Levitas, and John W. Wydler.
Also present: Delphis C. Goldberg, professional staff member;
Gilbert S. Goldhammer, consultant; and Richard L. Thompson,
minority professional staff, Committee on Government Operations.
Mr. Fountain. The subcommittee will come to order.
The record will show a quorum is present for the purpose of taking
testimony.
This hearing is intended to complete the record developed in hear-
ings held during March, April, and May of last year on FDA's use
of advisory committees and FDA's compliance with the requirements
of the Federal Advisory Committee Act, This will probabty be the
final subcommittee hearing on this subject prior to completion of a
report now in preparation. The subcommittee's investigation and
hearings have disclosed a number of serious deficiencies which will
be fully discussed in the report. However, I am pleased to say that
the agency has acknowledged some of these deficiencies and has taken
steps to correct them.
Last year the subcommittee examined the role of advisory commit-
tees in FDA actions concerning a number of drugs, including pro-
pranolol for angina pectoris, Depo Provera as an injectable contra-
ceptive, and DES as a "morning after" contraceptive, These sub-
committee hearings, and our related oversight activities, have resulted
in regulatory actions that should significantly enhance the public's
health protection.
We plan now to examine the role of several advisory review panels
in evaluating over-the-counter drugs, specifically the work of the OTC
antacid and antiperspii ant review panels, and, if time permits, the
antimicrobial panel. We will also examine recent advisory committee
deliberations on the safety of the Dalkon shield, an intrauterine con-
traceptive device, that was discussed in subcommittee hearings held
in May and June 1973.
(1)
While I recognize that FDA has previously testified before Senate
committees on some of these matters, our inquiry relates to different
aspects and is based upon new information with respect to the drugs
and panels concerned. We will avoid unnecessary duplication.
Our witnesses include those FDA officials who are most familiar
with the functioning of the advisory panels involved in this hearing.
We will begin with an examination of the advisory role of the anti-
perspirant review panel, with special emphasis on its review of aerosol
spray antiperspirant preparations containing zirconium compounds.
We have with us today Alexander M. Schmidt, M.D., Commis-
sioner of Food and Drugs, Food and Drug Administration ; J. Richard
Crout, M.D., Director, Bureau of Drugs; Mr. Peter B. Hutt, Chief
Counsel; Mr. Robert C. Wetherell, Jr., Director, Office of Legislative
Services; Mr. Robert G. Pinco, Chief, Division of OTC Evaluation;
Dr. John Jennings, Associate Commissioner for Medical Affairs;
and Mr. David M. Link, Acting Director, Bureau of Medical Devices
and Diagnostic Products.
We want to welcome 3^011 and your colleagues, Dr. Schmidt; we
appreciate your presence and your willingness to cooperate in the
hearings.
I understand that you have a brief statement you would like to
make preparatory to questioning.
You may proceed at this point.
STATEMENT OF ALEXANDER M. SCHMIDT, M.D., COMMISSIONER OE
EOOD AND DRUGS, FOOD AND DRUG ADMINISTRATION, DEPART-
MENT OE HEALTH, EDUCATION, AND WELFARE; ACCOMPANIED
BY J. RICHARD CROUT, M.D., DIRECTOR, BUREAU OF DRUGS;
PETER BARTON HUTT, CHIEF COUNSEL; ROBERT C. WETHERELL,
JR., DIRECTOR, OFFICE OF LEGISLATIVE SERVICES; ROBERT G.
PINCO, CHIEF, DIVISION OF OTC EVALUATION; JOHN JENNINGS,
M.D., ASSOCIATE COMMISSIONER FOR MEDICAL AFFAIRS; AND
DAVID M. LINK, ACTING DIRECTOR, BUREAU OF MEDICAL DE-
VICES AND DIAGNOSTIC PRODUCTS
Dr. Schmidt. Thank you, Mr. Chairman. I also have with me Mr.
Robert Pinco, Chief, Division of OTC Evaluation.
Mr. Fountain. Nice to have you with us.
Dr. Schmidt. Behind me are Dr. John Jennings and Mr. David
Link, Director of the Bureau of Medical Devices. If necessary they
can contribute to our session this morning.
I did want to make just two or three points which I think are impor-
tant in a brief statement.
We are pleased to be here this morning and believe this is an impor-
tant subject.
I understand from your letter of invitation that today's inquiry
will turn to the review we are conducting of over-the-counter drugs,
and the role played therein of advisory committees, or, as they are
known in this case, OTC panels.
To me, this is an excellent area for discussion, as the role of advisory
committees in the OTC review typifies what I think to be the most
positive aspects of the use of advisory committees by a Federal agency.
First, through the use of the OTC panels, FDA and the American
people benefit in a number of important ways. Perhaps most important
is the trust in the entire OTC review process that has been engendered
by our use of advisory panels, operating in an open fashion. Through
the process we have established, the public and the industry
can observe and participate in the review and evaluation. In a real
sense, the OTC review is not a Federal agency dictating, ex cathedra,
how the American public and the American industry must behave.
Instead, we have found a way to work together that engenders trust
in the process and in the outcome, through involvement by the con-
cerned parties, including the public. This enables the agency to take
definitive action on the basis of the panel reports with a minimum
of challenge on nonsubstantive issues, and a minimum of very costly,
time-consuming, legal challenges.
We have now had enough experience with the OTC review to know
that it is sound and is working very well, indeed.
Second, we have evolved a process that enables us to tackle a
herculean job in a practical period of time. Two aspects of the OTC
review would have given the agency, acting alone, much trouble:
the immensity of the task— hundreds of thousands of products to
review and evaluate, and the great variety of products, calling for a
tremendous range of expertise. We have been able to call on literally
scores of experts from across the country who in turn have called on
dozens of other experts from around the world, who, among them all,
have been exceptionally knowledgeable in the many subject areas
of the review.
Third, the educational value of the process has been incalculable.
The OTC review has been an open national forum, allowing many
people to come and see us, see what we do, see how we do it, and why.
The}^ have helped us, made suggestions for our improvement, told
others and the general public about us, about our work, and about
OTC drugs. Just the newspaper coverage of the problems uncovered
by the review so far has educated many people to the fact that OTC
drugs are drugs not candy. The regulatory monographs will, I believe,
turn out to be of great and lasting value to all parts of the health care
sj^stem, from drug manufacturers to medical and nursing students
learning about rational self-therapy.
Lastly, the output of the OTC panels becomes the input to the
FDA, so that in the last analysis, no agency authority or responsi-
bility is abridged. I am ultimately responsible for everything that
happens, and in this case, I bear that responsibility with a great
amount of equanimity, because of the excellence of the panels.
So, in short, we are happ}^ to discuss a very sound process that has
been working well, and which, to my mind, illustrates the best of
the advisory committee process, working well with our agency staff.
Mr. Fountain. Thank you very much, Dr. Schmidt. As has been
our usual procedure, when a question is asked, if it happens to fall
within the province of one of your assistants, do not hesitate to desig-
nate that person to answer the question.
The first topic to be considered is the work of FDA's antiperspirant
advisory review panel. The reason we have chosen to look at this
particular panel is that both FDA and the panel have had under
consideration for some time questions concerning the safety of several
nationally advertised underarm antiperspirant aerosol sprays con-
taining the chemical, zirconium.
I believe the principal products of this type currently on the market
are Sure and Secret. Is this correct?
Dr. Schmidt. Yes.
Mr. Fountain. These deodorants are apparently widely used
by the adult and, perhaps, also by the teenage population. The safety
of their long-term use now appears to be in doubt. If that is so, it is
imperative that these safety questions be resolved promptly. I want
to stress that it is not the intention of this subcommittee to express
any view at this time on the safety of these preparations. They may
be entirely safe, or they may be harmful — we do not know. However,
in our oversight role, we are obligated to get the facts necessary
to determine whether or not FDA has taken appropriate action to
protect the public health and to fulfill its obligations under the laws
that it enforces. We are particularly interested in the nature and
extent of the advisory panel participation in this matter.
We also need to know how FDA is using the panel's advice in
discharging its regulatory obligations.
Before we get too deeply into the hearing, I want to explain that the
background concerning FDA's regulation of zirconium antiperspirants
of the aerosol spray type can be developed most comprehensively and
effectively, in my opinion, by exploring the functioning of the FDA's
antiperspirant panel in its consideration of the zirconium aerosols,
as reflected in the minutes of the panel's meetings.
This will entail a chronological development of the facts and my
reading into the record pertinent and significant portions of the
minutes. However, I plan to intersperse this with questions intended
to clarify points or make them more understandable to the sub-
committee and the public, or to bring out the applicable requirements
of the law.
I would, therefore, ask that the subcommittee members defer
their questioning of the witnesses until a satisfactory background
record has been developed. I believe that it may take about 20 minutes
for me to do that.
In order that we may fully understand the role of the OTC anti-
perspirant review panel, Doctor, will you explain briefly FDA's,
purpose in creating this panel?
Dr. Schmidt. The purpose in creating the panel was simply to
serve as a group of knowledgeable experts with a wide variety of
experience and expertise to review the available literature on safety
and efficacy of OTC products on the market, and based on their
review to report to the Food and Drug Administration their reviews
on the safety, efficacy, and proper conditions under which these
products are used and can be used as OTC drugs safely.
The panel was further charged to render a report conveying their
views fully and the reasons behind their views to the agency to be
used as the basis for the evolution, then, of what I term a regulatory
monograph. In brief that is the purpose of the panel.
Mr. Fountain. FDA's regulations relating to the establishment of
this and other OTC drug review panels appear in title 21 of the
Code of Federal Regulations, as revised June 1, 1974, at pages 231
through 236 of part 141 to part 599.
I am placing these pages, which are self-explanatory, into the record.
[The material referred to follows :]
Code of Federal Regulations — Chapter I — Food and Drug
Administration
P\rt 330— Over-the-Counter (OTC) Human Drugs Which Are Generally
Recognized as Safe and Effective and Not Misbranded
subpart a — general provisions
Sec.
330.1 General conditions for general recognition as safe, effective and not
misbranded.
330.5 Drug categories.
SUBPART B ADMINISTRATIVE PROCEDURES
330.10 Procedures for classifying OTC drugs as generally recognized as safe and
effective and not misbranded, and for establishing monographs.
330.11 NDA deviations from applicable monograph.
330.12 Status of over-the-counter (OTC) drugs previously reviewed under the
Drug Efficacy Study (DESI).
Authority: Sees. 502, 503, 505, 601, 52 Stat. 1051, 1052, 1053, 1055, as amended
(21 U.S.C. 352, 353, 355, 371) (5 U.S.C. 554), unless otherwise noted.
Source: 39 FR 11741, Mar. 29, 1974, unless otherwise noted.
SUBPART A GENERAL PROVISIONS
§ 330.1 General conditions for general recognition as safe, effective and not
misbranded.
An over-the-counter (OTC) drug listed in this subchapter is generally recog-
nized as safe and effective and is not misbranded if it meets each of the conditions
contained in this part and each of the conditions contained in any applicable mono-
graph. Any product which fails to conform to each of the conditions contained
in this part and in an applicable monograph is liable to regulatory action.
(a) The product is manufactured in compliance with current good manufac-
turing practices, as established by Part 133 of this chapter.
(b) The establishment (s) in which the drug product is manufactured is regis-
tered, and the drug product is listed, in compliance with Part 132 of this. chapter.
It is requested but not required that the number assigned to the product pursu-
ant to Part 132 of this chapter appear on all drug labels and in all drug labeling.
If this number is used, it shall be placed in the manner set forth in Part 132 of
(c) The product is labeled in compliance with Chapter V of the act and § 1.100
et seq. of this chapter. For purposes of § 1.102a(b) of this chapter, the statement
of identity of the product shall be the term or phrase used in the applicable
monograph established in this part.
(d) The advertising for the product prescribes, recommends, or suggests its
use onlv under the conditions stated in the labeling.
(e) The product contains only suitable inactive ingredients which are safe in
the amounts administered and do not interfere with the effectiveness of the
preparation or with suitable tests or assays to determine if the product meets
its professed standards of identity,. strength, quality, and purity. Color addi-
tives may be used only in accordance with section 706 of the act and Parts 8
and 9 of this chapter.
(f) The product container and container components meet the requirements
of § 133.9 of this chapter.
(g) The labeling contains the general warning: "Keep this and all drugs out
of the reach of children. In case of accidental overdose, contact a physician
immediately." The Food and Drug Administration will grant an exemption
from this general warning where appropriate upon petition.
(h) Where no maximum daily dosage limit for an active ingredient is estab-
lished in this part, it is used in a product at a level that does not exceed the
amount reasonably required to achieve its intended effect.
(i) The labeling for any drug for which an applicable monograph requires a drug
interaction warning contains the following warning: "Warning: Do not take this
product concurrently with a prescription drug except on the advice of a physician.'
(j) It is recommended that the labeling of the product contain the quantita-
tive amount of each active ingredient, expressed in terms of the dosage unit
stated in the directions for use (e.g., tablet, teaspoonful).
§330.5 Drug categories.
Monographs promulgated pursuant to the provisions of this part' shall be es-
tablished in this Part 330 and following parts and shall cover the following desig-
nated categories:
(a) Antacids.
(b) Laxatives.
(c) Antidiarrheal products.
(d) Emetics.
(e) Antiemetics.
(f) Antiperspirants.
(g) Sunburn prevention and treatment products,
(h) Vitamin-mineral products.
(i) Antimicrobial products,
(j) Dandruff products,
(k) Oral hygiene aids.
(1) Hemorrhoidal products,
(m) Hematinics.
(n) Bronchodilator and antiasthmatic products,
(o) Analgesics.
(p) Sedatives and sleep aids,
(q) Stimulants,
(r) Antitussives,
(s) Allergy treatment products.
(t) Cold remedies,
(u) Antirheumatic products.
(v) Ophthalmic products,
(w) Contraceptive products.
(x) Miscellaneous dermatologic products.
(y) Dentifrices and dental products such as analgesics, antiseptics, etc.
(z) Miscellaneous (all other OTC drugs not falling within one of the above
therapeutic categories.)
SUBPART B ADMINISTRATIVE PROCEDURES
§ 330.10 Procedures for classifying OTC drugs as generally recognized as safe
and effective and not misbranded, and for establishing monographs.
For purposes of classifying over-the-counter (OTC) drugs as drugs generally
recognized among qualified experts as safe and effective for use and as not mis-
branded drugs, the following regulations shall apply:
(a) Procedure for establishing OTC drug monographs — (1) Advisory review panels.
The Commissioner shall appoint advisory review panels of qualified experts to
evaluate the safety and effectiveness of OTC drugs, to review OTC drug labeling,
and to advise him on the promulgation of monographs establishing conditions
under which OTC drugs are generally recognized as safe and effective and not
misbranded. A single advisory review panel shall be established for each designated
category of OTC drugs and every OTC drug category will be considered by a
panel. The members of a panel shall be qualified experts (appointed by the Com-
missioner) and may include persons from lists submitted by organizations repre-
senting professional, consumer, and industry interests. The Commissioner shall
designate the chairman of each panel. Summary minutes of all meetings shall
be made.
(2) Request, for data and views. The Commissioner will publish a notice in the
Federal Register requesting interested persons to submit, for review and eval-
uation by an advisory review panel, published and unpublished data and infor-
mation pertinent to a designated category of OTC drugs. Data and information
submitted pursuant to a published notice, and falling within the confidentiality
provisions of 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331 (j), shall be handled
by the advisory review panel and the Food and Drug Administration as confi-
dential until publication of a proposed monograph and the full report (s) of the
panel. Thirtv days thereafter such data and information shall be made publicly
available and may be viewed at the office of the Hearing Clerk of the Food and
Drug Administration, except to the extent that the person submitting it demon-
strates that it still falls within the confidentiality provisions of one or more of
those statutes. To be considered, eight copies of the data and/or views on any
marketed drug within the class must be submitted, preferably bound, indexed,
and on standard sized paper (approximately 8M> x 11 inches). When requested,
abbreviated submissions should be sent. All submissions must be in the following
format :
OTC Drug Review Information
I. Label (s) and all labeling (preferably mounted and filed with the other data —
facsimile labeling is acceptable in lieu of actual container labeling).
II. A statement setting forth the quantities of active ingredients of the drug.
III. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
IV. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the
safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as
to the safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to
the safety of the finished drug product.
5. Pertinent medical and scientific literature.
V. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination of
the efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on
the efficacy of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on
the efficacy of the finished drug product.
5. Pertinent medical and scientific literature.
VI. A summary of the data and views setting forth the medical rationale and
purpose (or lack thereof) for the drug and its ingredients and the scientific basis
(or lack thereof) for the conclusion that the drug and its ingredients have been
proven safe and effective for the intended use. If there is an absence of controlled
studies in the material submitted, an explanation as to why such studies are
not considered necessary must be included.
(3) Deliberations of an advisory review panel. An advisory review panel will
meet as often and for as long as is appropriate to review the data submitted to it
and to prepare a report containing its conclusions and recommendations to the
Commissioner with respect to the safety and effectiveness of the drugs in a des-
ignated category of OTC drugs. A panel may consult any individual or group.
Any interested person may request an opportunity to present oral views to the
panel; such request may be granted or denied by the panel. Such requests for oral
presentations should be in written form including a summarization of the data
to be presented to the panel. Any interested person may present written data and
views which shall be considered by the panel. This information shall be presented
to the panel in the format set forth in paragraph (a) (2) of this section and within
the time period established for the drug category in the notice for review by a
panel.
(4) Standards for safely, effectiveness, and labeling. The advisory review panel,
in reviewing the data submitted to it and preparing its conclusions and recom-
mendations, and the Commissioner, in reviewing the conclusions and recommen-
dations of the panel and the published proposed, tentative, and final monographs,
shall apply the following standards to determine general recognition that a cate-
gory of OTC drugs is safe and effective and not misbranded:
(i) Safety means a low incidence of adverse reactions or significant side ef-
fects under adequate directions for use and warnings against unsafe use as well
as low potential for harm which may result from abuse under conditions of wide-
spread availability. Proof of safety shall consist of adequate tests by methods
reasonably applicable to show the drug is safe under the prescribed, recommended,
or suggested conditions of use. This proof shall include results of significant
human experience during marketing. General recognition of safety shall ordinarily
be based upon published studies which may be corroborated by unpublished
studies and other data.
(ii) Effectiveness means a reasonable expectation that, in a significant propor-
tion of the target population, the pharmacological effect of the drug, when used
under adequate directions for use and warnings against unsafe use, will provide
clinically significant relief of the type claimed. Proof of effectiveness shall con-
sist of controlled clinical investigations as defined in § 314.111(a) (5) (ii) of this
chapter, unless this requirement is waived on the basis of a showing that it is not
reasonably applicable to the drug or essential to the validity of the investigation
and that an alternative method of investigation is adequate to substantiate ef-
fectiveness. Investigations may be corroborated by partially controlled or un-
controlled studies, documented clinical studies by qualified experts, and reports of
significant human experience during marketing. Isolated case reports, random ex-
perience, and reports lacking the details which permit scientific evaluation will
not be considered. General recognition of effectiveness shall ordinarily be based
upon published studies which may be corroborated by unpublished studies and
other data.
(iii) The benefit-to-risk ratio of a drug shall be considered in determining safety
and effectiveness.
(iv) An OTC drug may combine two or more safe and effective active ingredi-
ents and may be generally recognized as safe and effective when each active in-
gredient makes a contribution to the claimed effect(s); when combining of the
active ingredients does not decrease the safety or effectiveness of any of the
individual active ingredients; and when the combination, when used under ade-
quate directions for use and warnings against unsafe use, provides rational con-
current therapy for a significant proportion of the target population.
(v) Labeling shall be clear and truthful in all respects and may not be false or
misleading in any particular. It shall state the intended uses and results of the
product; adequate directions for proper use; and warnings against unsafe use,
side effects, and adverse reactions in such terms as to render them likely to be
read and understood by the ordinary individual, including individuals of low
comprehension, under customary conditions of purchase and use
(vi) A drug shall be permitted" for OTC sale and use by the laity unless, because
of its toxicity or other potential for harmful effect or because of the method or col-
lateral measures necessary to its use, it may safely be sold and used only under the
supervision of a practitioner licensed by law to administer such drugs.
(5) Advisory review panel report to the Commissioner. An advisory review panel
shall submit to the Commissioner a report containing its conclusions and recom-
mendatious with respect to the conditions under which OTC drugs falling within
the category covered by the panel are generally recognized as safe
and effective and not misbranded. Included within this report shall be:
(i) A recommended monograph or monographs covering the category of OTC
drugs and establishing conditions under which the drugs involved are generally
recognized as safe and effective and not misbranded. This monograph may include
any conditions relating to active ingredients, labeling indications, warnings and
adequate directions for use, prescription or OTC status, and any other conditions
necessary and appropriate for the safety and effectiveness of drugs covered by the
monograph.
(ii) A statement of all active ingredients, labeling claims or other statements, or
other conditions reviewed and excluded from the monograph on the basis of the
panel's determination that they would result in the drug's not being generally
recognized as safe and effective or would result in misbranding.
(iii) A statement of all active ingredients, labeling claims or other statements, or
other conditions rsviewed and excluded from the monograph on the basis of the
panel's determination that the available data are insufficient to classify such
condition under either paragraph (a) (5) (i) or (ii) of this section and for which
further testing is therefore required. The report may recommend the type of
further testing required and the time period within which it might reasonably be
concluded.
(6) Proposed monograph. After reviewing the conclusions and recommendations
of the advisory review panel, the Commissioner shall publish in the Federal
Register a proposed order containing:
(i) A monograph or monographs establishing conditions under which a category
of OTC drugs is generally recognized as safe and effective and not misbranded.
(ii) A statement of the conditions excluded from the monograph on the basis of
the Commissioner's determination that they would result in the drug's not being
generally recognized as safe and effective or would result in misbranding.
(iii) A statement of the conditions excluded from the monograph on the basis
of the Commissioner's determination that the available data are insufficient to
classify such conditions under either paragraph (a)(6) (i) or (ii) of this section.
(iv)The full report(s) of the panel to the Commissioner.
The proposed order shall specify a reasonable period of time within which con-
ditions falling within paragraph (a) (6) (iii) of this section may be continued in
marketed products while the data necessary to support them are being obtained
for evaluation by the Food and Drug Administration. The summary minutes of
the panel meetings shall be made available to interested persons upon request.
Any interested person may, within 60 days after publication of the proposed
order in the Federal Register, file with the Hearing Clerk of the Food and Drug
Administration written comments in quint uplic'ate. Comments may be accom-
panied by a memorandum or brief in support thereof. All comments may be
reviewed at the office of the Hearing Clerk during regular working hours, Monday
through Friday. Within 30 days after the final day for submission of comments,
reply comments may be filed with the Hearing Clerk; these comments shall be
utilized to reply to comments made by other interested persons and not to reiterate
a position. The Commissioner may satisfy this requirement by publishing in the
Federal Register a proposed order summarizing the full report of the advisory
review panel, containing its conclusions and recommendations, to obtain full
public comment before undertaking his own evaluation and decision on the
matters involved.
(7) Tentative final monograph. After reviewing all comments and reply comments,
the Commissioner shall publish in "the Federal Register a tentative order
containing a monograph establishing conditions under which a category of OTC
drugs is generally recognized as safe and effective and not misbranded. Within
30 days, any interested party may file with the Hearing Clerk of the Food and
Drug Administration written objections specifying with particularity the omission -
or additions requested. These objections are to be supported by a brief statement
of the grounds therefor. A request for an oral hearing may accompany such
objections.
(8) Oral hearing before the Commissioner. After reviewing objections filed in
response to the tentative final monograph, the Commissioner, if he finds reason-
able grounds in support thereof, shall by notice in the Federal Register schedule
an oral hearing. The notice scheduling an oral hearing shall specify the length of
the hearing and how the time shall be divided among the parties requesting the
hearing. The hearing shall be conducted by the Commissioner and may not be
delegated.
10
(9) Final monograph. After reviewing the objections and considering the argu-
ments made at any oral hearing, the Commissioner shall publish in the Federal
Register a final order containing a monograph establishing conditions under
which a category of OTC drugs is generally recognized as safe and effective and
not misbranded. The monograph shall become effective as specified in the order.
(10) Court appeal. The monograph contained in the final order constitutes final
agency action from which appeal lies to the courts. The Food and Drug Admin-
istration will request consolidation of all appeals in a single court. Upon court
appeal, the Commissioner may, at his discretion, stay the effective date for part
or all of the monograph pending appeal and final court adjudication.
(11) Amendment of monographs. The Commissioner may propose on his own
initiative to amend or repeal any monograph established pursuant to this section.
Any interested person may petition the Commissioner for such proposal. A peti-
tion shall set forth the action requested and a detailed statement of the grounds in
support of such action. After review of a petition, the Commissioner may deny
the petition if he finds a lack of safety or effectiveness employing the standards
in paragraph (a) (4) of this section (in which case the appeal provisions of para-
graph (a) (10) of this section shall apply) or he may publish a proposed amendment
or repeal in the Federal Register if he finds general recognition of safety and
effectiveness employing the standards in paragraph (a) (4) of this section (in which
case the provisions of paragraph (a) (6), (7), (8), and (9) of this section shall
apply). A new-drug application may be submitted in lieu of or in addition to a
petition under this paragraph.
(b) Regulatory action. Any product which fails to conform to an applicable
monograph after its effective date is liable to regulatory action.
§ 330.11 NDA deviations from applicable monograph.
A new-drug application requesting approval of an OTC drug deviating in any
respect from a monograph that has become final shall be in, the form required
by § 314.1(a)(2) of this chapter, but shall include a statement that the product
meets all conditions of the applicable monograph except for the deviation for
which approval is requested and may omit all information except that pertinent
to the deviation.
Mr. Fountain. These regulations provide for the establishment of
advisory panels to review OTC drugs, and for the promulgation of
monographs for classes of drugs which apparently will serve as a basis
for determining whether OTC drugs on the market are generally
recognized as safe and effective and are not misbranded.
Is that description correct?
Mr. Hutt. Yes, sir. The only thing I would clarify is the use of the
word "apparently." The regulations say that any product which fails
to conform to an applicable monograph after its effective date is liable
to regulatoiy action.
Mr. Fountain. I am also inserting into the record a notice which
appeared in the September 7, 1973, Federal Register announcing an
intended safety and efficacy review of OTC antiperspirants. The notice
requested interested persons to submit to FDA by November 9, 1973,
their safety and effectiveness data and other information for anti-
perspirant chemical entities, including zirconium compounds, for
stiKty b}^ the review panel.
[The document referred to follows :]
[Federal Register, Vol. 3S, No. 173— Friday, Sept. 7, 1973]
Over-the-Counter Antiperspirant Drug Products and Over-the-Counter
Topical Antibiotic Drugs
safety and efficacy review; request for data and information
The FDA is undertaking a review of all over-the-counter (OTC) drug products
for human use currently marketed in the United States, to determine that these
OTC products are safe and effective for their labeled indications. This review
will utilize expert panels working with FDA personnel.
11
A notice outlining procedures for this review was published in the Federal
Register of May 11, 1972 (37 FR 9464).
To facilitate this review and a determination as to whether an OTC drug for
human use is generally recognized as safe and effective and not misbranded under
its recommended conditions of use, and to provide all interested persons an
opportunity to present for the consideration of the reviewing experts the best
data and information available to support the stated claims for all dosage forms
of antiperspirant drug products and topical antibiotic drugs, the administration
invites submission of data, published and unpublished, and other information
pertinent to all active ingredients in such preparations.
FDA is aware that the following is not a complete list, but only representative
of the kinds of active ingredients used in such products. FDA has conducted a
literature search on each of them.
I. ANTIPERSPIRANTS
Aluminum Chlorhydroxide Aluminum Hydroxy Lactate
Aluminum Chloride Sodium Aluminum Lactate
Aluminum Formate Aluminum Salts, General
Aluminum Hydroxide Zinc Peroxide
Aluminum Phenolsulfonate Zinc Phenolsulfonate (Zinc Sulfocar-
(Aluminum bolate)
Sulfocarbolate) Zinc Salts, General
Aluminum Sulfate Zirconyl Hydroxychloride
II. TOPICAL ANTIBIOTICS
Bacitracin Gramicidin
Neomycin Tyrothricin
Polymyxin
FDA's literature search on antiperspirants covered the United States of America
literature and other leading English language literature published since 1950
from the following sources:
Medlars (NLM and SUNY).
FDA Clinical Experience Abstracts.
Quarterly Cumulative Index Medicus.
Current List of Medical Literature.
Index Medicus.
JAMA Subject Index.
DeHaen Drugs in Use.
International Pharmaceutical Abstracts.
Excerpta Medica.
Abstracts of World Medicine.
Biological Abstracts.
Chemical Abstracts.
FDA's literature search on topical antibiotics covered the United States of
America literature and other leading English language literature published since
1905 from the following sources:
Medlars (SUNY).
FDA Clinical Experience Abstracts.
DeHaen Drugs in Use.
RINGDOC.
The bibliographies of the literature searches are available to interested persons.
Interested persons are also invited to submit data on any other active ingre-
dients used in antiperspirant or topical antibiotic drugs.
The FDA is aware that safety data on these ingredients may be available as a
result of testing related to nondrug products, such as cosmetics. All interested
parties are encouraged to submit at this time all available safety data for these
ingredients, so that the conclusions reached will reflect the best information
available.
This panel is not charged with reviewing the safety or effectiveness of the use
of these ingredients in nondrug products such as cosmetics (e.g., deodorants for
which no drug claims are made). However, the conclusions of the panel with
respect to these ingredients for drug use may be utilized by the Food and Drug
Administration in determining whether their use in cosmetics can continue to be
justified. Thus, although the report and monograph prepared by this panel will
cover only OTC drug use, the conclusions may well have a direct and substantial
impact on all uses of these ingredients in consumer products.
12
To be considered, eight copies of the data and/or views must be submitted,
preferably bound, indexed, and on standard size paper (approximately 8}i by 11
inches). All submissions must be in the format described below:
OTC DRUG REVIEW INFORMATION
I. Label (s) and all labeling (preferably mounted and filed with the other data —
facsimile labeling is acceptable in lieu of actual container labeling).
II. A statement setting forth the quantities of active ingredients of the drug.
III. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
IV. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to
the safety of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to
the safety of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination as to the
safety of the finished product.
5. Pertinent medical and scientific literature.
V. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on the
efficacy of each individual active component.
5. Pertinent medical and scientific literature.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on the
efficacy of combinations of the individual active components.
5. Pertinent medical and scientific literature.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports.
4. Pertinent marketing experiences that may influence a determination on the
efficacy of the finished drug product.
5. Pertinent medical and scientific literature.
VI. A summary of the data and views setting forth the medical rationale and
purpose (or lack thereof) for the drug and its ingredients and the scientific basis
(or lack thereof) for the conclusion that the drug and its ingredients have been
proven safe and effective for the intended use. If there is an absence of controlled
studies in the material submitted, an explanation as to why such studies are not
considered necessary must be included.
13
VII. If the submission is by a manufacturer, a statement signed by the person
responsible for such submission, that to the best of his knowledge it includes
unfavorable information, as well as any favorable information, known to him
pertinent to an evaluation of the safety, effectiveness, and labeling of such a
product. Thus, if any type of scientific data is submitted, a balanced submission
of favorable and unfavorable data must be submitted. The same would be true
of any other pertinent data or information submitted, such as consumer surveys
or marketing results.
In order to avoid duplication, interested persons should not in their submissions
include published literature listed in the FDA literature search. An abstract of
all such literature will be provided to the panel. Upon request, the panel will be
provided with the complete article. Interested persons may, of course, refer to
such literature in their submissions by citation.
Submissions or requests for copies of the bibliographies of the FDA literature
searches should be forwarded to:
Food and Drug Administration
Bureau of Drugs
OTC Drug Products Evaluation Staff (BD-109)
5600 Fishers Lane
Rockville, Maryland 20852
Data and information must be submitted on or before November 9, 1973.
Dated August 29, 1973.
Sam D. Fine,
Associate Commissioner for Compliance.
[FR Doc. 73-19007 Filed 9-6-73; 8:45 a.m.]
Mr. Fountain. FDA has provided the subcommittee with the
minutes of all meetings of the panel, beginning with the first meeting
on March 15, 1974, and going through the eighth meeting on January
30 and 31, 1975. The minutes of that last meeting held on or about
March 25, 1975, have not been furnished.
Have the minutes of that meeting been prepared?
Mr. Pinco. The panel will take them up this week.
Mr. Fountain. And the}^ will be made available soon thereafter?
Mr. Pinco. Yes.
Mr. Fountain. We have been using the terms "antiperspirants"
and "antiperspirant deodorants." What do these terms mean?
Dr. Schmidt. An antiperspirant is commonty thought to be a prod-
uct which inhibits the secretion of the glands and cuts down on the
volume, if you like, of perspiration. The deodorant is commonly
thought to protect against the odors which evolve from the interaction
of bacteria and products from the skin as well as perspiration.
These can be separable terms, but they are commonly used synony-
mously in the case of underarm preparations which generally both
inhibit perspiration, the volume of it, and inhibit the development of
the typical odor.
Mr. Fountain. How long have zirconium compounds been used in
antiperspirant deodorants and in aerosol spray antiperspirants?
Dr. Schmidt. Aerosol antiperspirants, themselves as a class are
fairly new. I believe zirconium has been used in them for about 4
years.
Mr. Fountain. As defined by the Federal Food, Drug, and Cosmetic
Act, are zirconium antiperspirant deodorants classified as drugs or
cosmetics?
Mr. Hutt. They are classified as drugs. Deodorants have always
been classified by the Food and Drug Administration and the Federal
Trade Commission as cosmetics, but antiperspirants are classified as
drugs.
14
Mr. Fountain. Are any of them covered by approved new drug
applications?
Mr. Hutt. The aerosol products?
Mr. Fountain. Yes, those containing zirconium.
Mr. Hutt. No, sir.
Mr. Fountain. Are there any aerosol antiperspirants on the market
which do not contain zirconium compounds?
Dr. Schmidt. Yes.
Mr. Fountain. Will you tell us what they are?
Dr. Schmidt. There is a wide variety.
Mr. Fountain. Just a few examples.
Dr. Schmidt. All of the aerosols, w-hich are numerous, except Sure,
Secret and a new Arrid which also is being test marketed and contains
zirconium. They also contain other antiperspirants, principally the
aluminum compounds.
Mr. Fountain. Has the OTC antiperspirant review panel given
any indication that the nonzirconium aerosol antiperspirants are not
generally recognized as safe?
Dr. Schmidt. I would like to make a general statement here. The
panel's work, like that of any other group, has all different kinds of
processes going on which groups in general have. Until the panel
has completed either a segment of its activity or all of their activities
by promulgating its report, it is not fair, proper, nor even possible
to say what it has done or is doing. The panel is in the middle of its
process right now and will be taking up antiperspirants in general
in its next few meetings, so it is not possible for me to state, nor would
I want to second-guess, the panel on what its opinions will be.
Mr. Fountain. The answer is no, they have not given any indication
that nonzirconium antiperspirants are not generally recognized as
safe?
Dr. Schmidt. That statement is true but misleading in that it
implies more than would be the case. They have not done either.
Mr. Fountain. I am talking about up to this date.
Dr. Schmidt. To this date they have made no statement about
antiperspirants.
Mr. Fountain. What about aluminum compounds?
Dr. Schmidt. Other than zirconium?
Mr. Fountain. What about aluminum compounds?
Dr. Schmidt. They are in the process of evaluating those.
Mr. Fountain. What advantages, if any, do zirconium-containing
aerosol antiperspirants have over those which do not contain zirconium
compounds, if you know?
Dr. Schmidt. There is a conventional wisdom, but again I am
awaiting a report from the panel to me on the zirconium-containing
products. Until I see that and evaluate it, I cannot answer the
question. .
Mr. Hutt. There is a legal problem here which, I think, 1 should
state. It would be improper for the Commissioner to prejudge any
of the issues of safety and effectiveness which may arise out of this
panel. If he were to do so, he would be forced to disqualify himself
from later considering any report that panel might issue. I would
hope we would not get into areas today of trying to decide safety
and effectiveness or labeling issues which are pending before the
panel and which will ultimately come to the Commissioner.
15
Mr. Fountain. As I read the law, if a drug is not general!}- recog-
nized as safe among experts qualified by scientific training and ex-
perience to evaluate the safety of drugs for the conditions for which
it is to be used, it is a new drug. Is that interpretation of the law
correct?
Mr. Hutt. Yes, sir, with certain exceptions under the grandfather
clause which certainly do not apply to these products.
Mr. Fountain. We understand that.
As a new drug, it may not be marketed commercially in interstate
commerce until a new drug application for it has been filed with,
and approved by, FDA. Is that correct?
Mr. Hutt. That is correct, Of course, the purpose of the OTC
drug review is to decide which are new drugs.
Mr. Fountain. What is the legal status of stocks of a new drug
which have been shipped from one State to another without an
approved new drug application? Are such stocks legal or illegal?
Mr. Hutt. Illegal.
Mr. Fountain. Would they be subject to seizure under the Federal
Food, Drug, and Cosmetic Act?
Mr. Hutt. They would be subject to injunction, seizure, and to
criminal action against the corporation and the individual who shipped
them.
Mr. Fountain. You have taken such regulatory actions?
Mr. Hutt. Yes, sir, in the past, against other products, but not
these.
Mr. Fountain. When FDA decides that a new drug must be re-
moved from the market because an NDA for the drug has not been
filed, must FDA prove that the drug is unsafe, in the event the removal
action is challenged in court?
Mr. Hutt. No, sir. We must prove that it is not generally recognized
as safe or not generally recognized as effective. We have the burden
of proof of establishing that it is a new drug.
Mr. Fountain. Returning to the subject of antiperspirants, the
subcommittee has examined the minutes of all of the meetings held
by the antiperspirant review panel through January 1975. Those
minutes, in my opinion, provide an adequate chronology of events in
the panel's review of zirconium-containing antiperspirants. I believe
we should take the time to develop the information contained in them
as an authentic source of the facts in this matter.
The minutes disclose that aerosol antiperspirants containing zir-
conium compounds were first discussed by the panel during its third
meeting on July 9 and 10, 1974. I am placing pages 1, 2, and 3 of the
minutes of that meeting into the record. They cover the remarks to
the panel by Prof. Joseph Page of Georgetown University Law
School, Washington, D.C.
[The information referred to follows:]
The FDA OTC Antiperspirant Panel met for the third time on July 9-10, 1974
at the Parklawn Building. All members attended except Dr. Charles Evans.
Open. Session— July 9, 1074—9:00-10:00 a.m.
Professor Joseph Page of Georgetown University appeared before the Panel
and also provided them a written statement of his views. Professor Page reviewed
the statement of the OTC Antimicrobial Panel which presents their concern about
the regulation of antimicrobial soaps as drugs and cosmetics where the active
ingredients are the same.
16
Professor Page was concerned that ingredients classified in Category II by
the Panel or moved in the future from Category III to Category II might escape
regulation by "hiding" under Cosmetic labeling.
He stressed his view that some ingredients placed in Category II by the Panel
when labeled in antiperspirants as "drugs" would be regulated; however, if a
product were relabeled only as a deodorant, there might not be sufficient evidence
of toxicity to allow the FDA to make the judgment that cosmetics containing it
are adulterated or misbranded.
Professor Page felt that the Antimicrobial I Panel's language had gone about
as far as possible in their statement that as long as the ingredients of these prod-
ucts are effectively regulated, the Panel is not concerned whether they be classified
as cosmetics or as drugs. They stated that, if a regulation can be promulgated
imposing the kind of testing requirements recommended in their report upon all
cosmetics containing antimicrobial ingredients at levels higher than necessary for
preservative use, the Panel's concerns would be met. The Panel also recommended
to the Food and Drug Administration that if this is not possible that they would
urge Congress to furnish the necessary authority.
Professor Page felt that it is very likely that the Antiperspirant Panel will be
faced with many of these same distinctions between cosmetic and drug definitions
in reviewing labeling where the same ingredients are labeled as deodorants and
antiperspirants.
In discussion with the Panel, the point was strongly made that the distinction
between and definitions of a drug and cosmetic had been extensively discussed
with the FDA legal counsel and that the Panel was proceeding on the basis of
that discussion. The Panel had concluded from their discussion that their concern
should be for the safety and effectiveness of the ingredients and that they need
not be overly involved with definitions.
In discussing a second subject, Professor Page voiced his concern about the
widespread advertising and sale of antiperspirants containing zirconium salts or
zirconyl compounds. He reflected on the earlier marketing, in the 60's, of roll-on
products containing zirconium salts which were shown to produce topical granu-
lomas in the axilla. He told the Panel that he was not sure that these products
had been adequately tested for safety of the aerosolized zirconium salts.
He stressed that for the product referred to, no NDA was submitted and that
as far as he knew no submission on the product had been made to the OTC Panel.
He reflected that one aerosol antiperspirant had been removed from the market
and praised the responsible behavior of the manufacturer. He urged the Panel to
review the information at hand on zirconium salts in liquid and aerosol formula-
tions and try to determine if the review of these products should be undertaken
immediately in the event that there is really a hazard to the public. A Panel
member was designated to review the literature and communicate with experts
to determine whether an immediate review by the Panel is required as was sug-
gested by Professor Page's presentation. The industry liaison member of the
Panel was asked to communicate the Panel's request for data to the companies
involved.
Closed Session — July 9-10, 1974
The Chairman began with a review of activities from Panel members who are
working on a series of subcommittees of the Panel; primarily, organizing data
and screening material for review by the entire Panel. The sub committee planning
the review of aerosol toxicity is collecting data and has requested all pertinent
data on zircomd-ahuninum chlorhydroxide combinations in aerosol antiperspirants
from manufacturers of these products and from the FDA. This group distributed
copies of some references to the entire Panel. They are concentrating on the
acquisition of material concerning particle size, dose-response data, determination
of animal species for testing and the appropriate design of such tests.
Mr. Fountain. Two sentences appearing at page 3 of the minutes
reflect Professor Page's views, as follows:
He reflected that one aerosol antiperspirant had been removed from the market
and praised the responsible behavior of the manufacturer. He urged the panel
to review the information at hand on zirconium salts in liquid and aerosol formula-
tions and try to determine if the review of these products should be undertaken
immediately in the event that there is really a hazard to the public.
Would you identify the aerosol antiperspirant that Professor Page
said had been removed from the market and its manufacturer?
17
Dr. Schmidt. That was Gillette which had marketed a zirconium-
containing product which had been termed "extra-strength". It was a
trade name already marketed, Right Guard. This was an extra-
strength Right Guard.
Mr. Fountain. In this connection I am placing into the record
FDA's October 10, 1973, Talk Paper describing Gillette's recall of
Right Guard. I think I saw some on my table in the bathroom this
morning in my own apartment.
Mr. Hutt. Mr. Chairman, it is not the Right Guard that you would
have had on your shelf this morning, to my knowledge, unless it
somehow escaped detection. That brand name has been used for
aluminum products and also for the zirconium product. It is the
aluminum product you had on your shelf. The zirconium product has
been withdrawn from the market by the company.
Mr. Fountain. I have no idea.
Mr. Hutt. The active ingredients are on the label.
Mr. Fountain. As with most consumers, I have not paid much
attention to the label. Perhaps I depend on you to protect me.
[The document referred to follows:]
FDA Talk Paper l
Rockville, Md., October 10,1973.
GILLETTE COMPANY RECALL
The Gillette recall of October 1, 1973 has generated considerable discussion
within the industry about products with similar formulation. The following is
provided to aid in responding to queries.
The Gillette Company has provided FDA with the preliminary data used by
the Company in deciding to recall Right Guard Extra-Strength Anti-Perspirant,
and Soft and'Dri Extra-Strength Anti-Perspirant. This data showed inflammations
in the lungs of monkeys subjected to repeated high level exposure. Both products-
are new, but only the Right Guard Extra-Strength product reached retail outlets.
Other Right Guard and Soft and Dri Aerosol Anti-Perspirant preparations are
not involved in this recall.
Gillette's study also included a competitive product, Procter & Gamble's
Sure Anti-Perspirant. While some lung inflamation was observed in monkeys
tested with Sure, the results were not the same as with the two Gillette products.
The formulations of the Procter & Gamble product and the Gillette products are
somewhat different. Procter & Gamble has conducted similar studies on Sure.
These studies will be provided to FDA shortly. The data now available to FDA
does not indicate the need for regulatory action. FDA has, however, assigned
a special team to expedite the evaluation of all data to determine if a question
of safety exists which would require action on similar products.
In addition, FDA has underway a comprehensive program to identify and
evaluate the safety of all OTC and Rx aerosol drug products on the market.
Mr. Fountain. Of significance, I think, is this statement appearing
in the Talk Paper :
The Gillette Co. has provided FDA with the preliminary data * * *. This data
showed inflammations in the lungs of monkeys subjected to repeated high level
exposure.
According to the minutes of the July 9 and 10 meeting, Dr. Page
also told the panel :
* * * Professor Page voiced his concern about the widespread advertising and
sale of antiperspirants containing zirconium salts or zirconyl compounds. He
reflected on the earlier marketing, in the sixties, of roll-on products containing
1 FDA Talk Papers are issued by the FDA Press Office to provide guidance to FDA
personnel in responding to requests for information on subjects of current interest. They
are subject to change as more information or data becomes available.
18
zirconium salts which were shown to produce topical granulomas in the axilla. He
told the Panel that he was not sure that these products had been adequately
tested for safety of the aerosolized zirconium salts. He stressed that for the product
referred to, no NDA was submitted and that as far as he knew no submission on
the product had been made to the OTC Panel.
Is it true, as the minutes state, no NDA's have been submitted
for these aerosol zirconium antiperspirant sprays now on the market?
Dr. Schmidt. Yes, sir.
Mr. Fountain. Is it also true, as the minutes state, that as of
July 9, 1974, the firms marketing those sprays had made no submis-
sions on the products for panel consideration?
Mr. Htjtt. I cannot state. Perhaps Mr. Pinco can do this.
Mr. Pinco. There are two points. I understand there was a submis-
sion, an abbreviated new drug application, back in 1972 with regard
to the Sure product. That was stayed pending OTC review.
Mr. Fountain. Was that an aerosol?
Mr. Pinco. Yes. I believe it was Sure antiperspirant aerosol. I
cannot give the date we received it but we can check on that and give
it to you.
Mr. Fountain. Will you check that and submit it for the record.
Mr. Pinco. Yes, sir.
[Note. — See pp. 53-55 for further discussion and document on this.]
Mr. Fountain. The minutes should cover this. Have you checked
those out?
Mr. Pinco. That would not be in the minutes. My understanding is
that the Sure product was covered by a submission when the call for
data went out. That submission was not subsequently made as a
special submission at a later date. However, we will check that. We
are going on memory here.
Mr. Goldhammer. In my investigation I was informed that the
manufacturer of Sure — Procter & Gamble — had not made a sub-
mission; and that a later opportunity was given. Their submission was
made at a later date, but not at the time of the call for data, which, I
believe, might have been in May.
Mr. Pinco. Mr. Goldhammer, we will have to check that. Our
recollection was they made some earlier submission. We may be
wrong. It is entirety possible it could have come in later.
[Note.- — FDA subsequently advised the subcommittee that the
Sure and Secret submission to the OTC panel was made in August
1974.]
Mr. Fountain. The minutes of the review panel meeting of July 9
and 10, 1974, also disclose that the panel acted on Dr. Page's request.
It designated a panel member to review the literature and com-
municate with experts to determine whether an immediate panel
review of the subject was required. The minutes of the review panel's
fourth meeting on August 8 and 9, 1974, disclose that the designated
panel member reported to the panel on his review of the literature on
zirconium in antiperspirants. I am placing the cover sheet and pages
9 and 10 of the minutes into the hearing record. I think they summarize
the panel's observations after discussing the available data.
19
[The information follows:]
SUMMARY MINUTES— FDA— OTC ANTIPERSPIRANT PANEL
[Fourth Meeting, Parklawn Building, Rockville, Md., August 8-9, 1974]
Chairman. — E. William Rosenberg, M.D.
Executive Secretary. — Mary K. Bruch.
Panel Members:
J. Weslev Clayton, Ph. D.
Charles Evans, M.D., Ph. D.
Zenona Mally, M.D.
Jane Rosenzweig, M.D.
Robert Scheuplein, M.D.
Eli Shelter, Ph. D.
Industrial Liaison. — CTFA — Robert Giovacchini, Ph. D.
Consumer Liaison. — Consumer Federation of America — Marsha Gardner.
FDA Representatives. — Bureau of Foods:
Leonard J. Trilling, M.D.
Mr. Heinz Eiermann.
OTC Staff:
Panel Administrator — Lee Geismar.
Drug Information Analyst — Gary Trosclair.
1. We know from the past medical literature and experience that sodium
zirconium lactate can cause skin granulomas and granuloma formation in the lungs.
2. A variety of granuloma formations have been seen in animals and some in
humans from zirconium oxide which is present in poison ivy remedies.
3. A presently marketed antiperspirant contains zirconium oxychloride (zir-
conium chlorhydrate) as part of a complex with aluminum chlorhydrate. The
manufacturer has conducted short-term studies in animals and claims no toxic
effects were found. Topical granulomas have been produced in individuals who
previously reacted to sodium zirconium lactate with one element of the complex,
zirconium oxychloride.
4. Complete complaint files have been requested from the manufacturer of the
marketed product containing zirconium oxychloride. The product complaints
received by the FDA are also being examined.
5. One manufacturer has voluntarily recalled two products containing zirconium
oxychloride after a granulomatous response was noted in monkeys who. were
exposed to the product in inhalation tests. This test was repeated in monkeys and
the same response was elicited again.
6. The Panel has received data from inhalation studies in monkeys for dif-
ferent formulations which do not produce granulomatous lesions under the test
conditions.
The Panel felt that many questions raised by their discussion can be resolved
in open discussion with recognized experts. They also decided as a result of their
discussion and review of the "data they presently have to alter the course of their
review and consider zirconyl-containing antiperspirants including aerosols as
soon as scheduling will permit.
Mr. Gary Yingling, a representative from the FDA Legal Counsel's Office,
was asked by the Panel to clarify some regulatory points raised by their discussions.
Mr. Yingling revealed that an ingredient which has not been marketed in the
United States cannot be marketed through OTC monograph amendment pro-
cedures but must be regulated through the IND/NDA procedures. Tins would
also apply to new ingredients never previously marketed.
Mr. Gary Yingling reviewed the three categories and the procedures to be
followed by FDA and the manufacturers subsequent to final categorization by the
Panel. The consequences of placement in Category II and timing of NDA applica-
tion, if it is required, were reviewed. Mr. Yingling told the Panel that a product
containing a Category II ingredient would be removed from the market unless
there were an approved NDA at the specified time period when the provisions of
the monograph became final. * * *
20
Mr. Fountain. If you gentlemen feel anything else should go in,
•don't hesitate to let us know.
On page 10 the minutes state:
The panel felt that many questions raised by their discussion can be resolved
in open discussion with recognized experts. They also decided as a result of their
discussion and review of the data they presently have to alter the course of their
review and consider zirconyl-containihg antiperspirants including aerosols as soon
as scheduling will permit.
The word "zirconyl" in this quote is different from zirconium
which I have been using. I am informed, however, the two words are
essentially interchangeable in this context. Is that right?
Dr. Schmidt. Well, yes and no. They both indicate the base zir-
conium. There is some discussion about different chemical complexes
which zirconium can enter into and whether or not there are different
safety aspects to zirconium in one particular complex as opposed to
another or just elemental substance.
Mr. Fountain. I am also placing into the record pages 13 and 14
of the minutes which contain a bibliography of papers mostly on
granulomas associated with the application or inhalation of zirconyl
compounds.
[The material referred to follows:]
References
(1) Baler, G. R., "Granulomas from Topical Zirconium in Poison Ivy Derma-
titis," Archives of Dermatology, 91: 145-148, 1965.
(2) Epstein, W. L., and J. R. Allen, "Granulomatous Hypersensitivity After
Use of Zirconium-Containing Poison Oak Lotions," Journal of the American
Medical Association, 190: 162-164, 1964.
(3) Epstein, W. L., et al., "The Organized Epithelioid Cell Granuloma: Differ-
entiation of Allergic (zirconium) from Colloidal (silica) Types," American Journal
of Pathology, 43: 391-404, 1963.
(4) Epstein, W. L., "Contribution of the Pathogenesis of Zirconium Granu-
lomas in Man," The Journal of Investigative Dermatology, 34: 183-188, 1960.
(5) Kozikowski, E. S., "Granuloma of the Axillae," American Medical Associa-
tion Archives of Dermatology, 75: 892, 1957.
(6) Lowe, I. A., "Granulomas of the Axillae Caused by Deodorant," American
Medical Association Archives of Dermatology, 75: 765-767, 1957.
(7) Nevins, M. A., et al., "Pulmonary Granulomatosis: Two Cases Associated
With Inhalation of Cosmetic Aerosols," Journal of the American Medical Associa-
tion, 193(4): 286-271, 1965.
(8) Pinkus, H., and I. Botvenick, "Deodorant Stick Eruption (Zirconium
Granuloma) of Axillae," American. Medical Association Archives of Dermatology,
75: 736-737, 1951.
(9) Prior, J. T., et al., "Pathological Changes Associated with Deodorant Prep-
arations Containing Sodium Zirconium Lactate: An Experimental Study," The
Journal of Investigative Dermatology, 29: 450-463, 1957.
(10) Prior, J. T., et al., "Pathological Changes Associated with the Inhalation
of Sodium Zirconium Lactate," Archives of Environmental Health, 1: 297-300, 1960.
(11) Rubin, L. S., and A. H. Slepyan, L. F. Weber and I. Neuhauser, "Granu-
lomas of the Axillae Caused by Deodorants," Journal of the American Medical
Association, 162:953-956, 1956.
(12) Sheard, C, Jr., et al., "Granulomatous Reactions to Deodorant Sticks,"
J (>ur>ial of the American Medical Association, 164: 1085-1087, 1957.
(13) Shelly, W. B., and Hurley, H. J., "The Allergic Origin of Zirconium Deo-
dorant Granulomas," The British Journal of Dermatology, 70:75-101, 1958.
(14) Thomas, K. G., et al., "Relative Hazards for Inhaled Zr and Nb Particles
Formed Under Various Thermal Conditions," Proceedings of the Society for Ex-
perimental Biology and Medicine," 138: 228-234, 1971.
Mr. Fountain. The panel's fifth meeting was held on September 19
through 21, 1974. Zirconyl antiperspirants were not discussed at this
21
meeting apparent^. However, the last two sentences of the minutes
of that" meeting indicate that the panel agreed to discuss granuloma
production with zirconium compounds in both topical and aerosol
antiperspirants at its sixth meeting.
The minutes of the panel's sixth meeting on October 31 to Novem-
ber 2, 1974, are lengthy, consisting of some 47 pages. They describe
presentations made by a number of experts in granuloma formation,
and the action of zirconyl antiperspirants. Representatives of Procter
& Gamble and their consultants also made presentations to the panel.
I am placing into the record the cover sheet and pages 43 through 47
of those minutes which cover the panel's discussions.
[The information follows:]
Summary Minutes of the OTC Panel on Antiperspirant Drug Products
[Sixth Meeting, October 31-November 2, 1974, Parklawn Building, Rockville, Md.
Panel Members:
E. William Rosenberg, M.D., Chairman.
Zenona Mallv, M.D.
Charles Evans, M.D., Ph. D.
Jane Rosenzweig, M.D.
Eli Shelter, Ph. D.
Robert Scheplein, Ph. D.
J. Wesley Clayton, Ph. D. (Absent November 2).
Liaison Members:
Consumer. — Ms. Marsha Gardner.
Industry. — Robert Giovacchini, Ph. D.
FDA Staff Members:
Mary K. Bruch, Executive Secretary — Division Anti-Infective Drug
Products.
Lee Geismar, Panel Administrator— OTC Staff.
Joe Hussion, R.Ph., Drug Information Analyst — OTC Staff.
Gary L. Yingling, Esq., General Counsel's Office.
J. Richard Crout, M.D., Director, Bureau of Drugs.
CLOSED SESSIONS
short closed session was held on Friday afternoon. The views of Panel mem-
were surveyed. Some felt strongly that zirconium aerosols should be in Cate-
A
bers . .
gory II and gave their reasoning for their view of the highly disproportionate
risk/benefit determination. Other members felt the situation was very serious but
expressed the view that perhaps better testing would answer their concerns, pro-
vided such tests could be successfully done. Members asked for a clarification of
the meaning of safetv, effectiveness and risk/benefit ratio. Mr. Yingling of Coun-
sel's Office provided this and responded to requests to explain the consequence of
Category II and III placement. Most members asked for the evening to sort their
thoughts before a final determination. -
A second closed session was held at 8:30 a.m. on Saturday, November 2, 1974
at the United Inn in Bethesda, Maryland. Members" again discussed their views,
constructing risk and benefit lists. The vote on a motion to categorize zirconium
containing aerosol antiperspirants in category II was 6 to (one Panel member
was absent), but later voted to make the vote unanimous.
The potential toxicity of these ingredients in antiperspirants was of such con-
cern that the Panel voted unanimously to request that the normal course of the
designated review process be interrupted. They agreed to prepare a statement to
present to the Commissioner in the immediate future detailing the reasoning
supporting their vote as to why it is inappropriate for the products to remain on
the market and requesting that this be published in the Federal Register. They
did not intend to suggest or recommend a recall.
22
- A vote was also taken on a motion to categorize zirconium chlorhydrate in
cream, liquid or pad (where application is directly on the skin and not aerosolized)
into Category I on the basis of safety. Effectiveness is yet to be reviewed.
The following statement includes the Panel's supporting reasons for their
action. This is in draft form and will be revised.
The benefits of aerosol application appear negligible or nil; in fact, the effec-
tiveness as deduced from laboratory test appears comparable or less when the
zirconium complex is applied as an aerosol than it is when applied as a liquid or
cream. The only benefit is perhaps the illusory increment in the ease of applica-
tion. Balanced against this, are what we consider the following risks:
1. Zirconium salts are well known to produce granulomas in the skin of some
sensitized subjects (Publication by W. Epstein). While these subjects were all
made allergic by the sodium zirconium salt, it has been shown that zirconium
chlorhydrate (Ref. — adopted name, CTFA Dictionary) is capable of eliciting a
granulomatous response in already sensitized human subjects (Procter and
Gamble submission to OTC Review).
2. Manufacturers of marketed aerosol products containing zirconium chlor-
hvdrate as a part of a complex or mixture were unable to prove that simple
zirconium chlorhydrate (same as zirconium hydroxy chloride) is not liberated
upon deposition in contact with lung tissue (statement to OTC Panel by Procter
and Gamble, November 1, 1974).
3. Testing of presently marketed aerosol antiperspirants containing zirconium
chlorhydrate was inadequate in both quantity and quality to demonstrate the
absence of granulomatogenic properties according to recognized experts (state-
ment of Dr. Boros to OTC Panel, November 1, 1974).
4. At least one major manufacturer who tested an aerosol of this general class
(a differently compounded complex of zirconium and aluminum chlorhydrate)
discovered at least 20 incidences of pathologic changes in monkey lungs. These
alterations were described by authorities as consistent with early changes of a
granulomatous nature.
5. Granulomatous diseases of the lung (sarcoid-like or sarcoid diseases) are
notoriously difficult to diagnose and may cause few or no symptions until quite
advanced. According to one manufactuer of zirconium-containing antiperspirants,
some one hundred million Americans have used the product at least once. If this
product should turn out to have even a modest granulomatogenic potential, the
problems it would cause are of enormous magnitude, both in numbers and in
possible seriousness in those affected.
6. Experts in the field of aerosol toxicology have pointed out that some par-
ticulate matter can remain suspended in the air for several hours after use. Be-
cause aerosol antiperspirants are used in small bathrooms, which are subsequently
used by other members of the family (including children, pregnant women and
persons with impaired pulmonary status), the risk would be magnified. Moreover,
since zirconium induced granulomas appear in some instances to be produced by
mechanisms of delayed hypersensitivity, even minute exposure to this secondary
source might be enough to evoke disease.
7. Certain granulomatous diseases of the lung (berylliosis and silicosis) are
worse when associated with other pulmonary irritant disorders, such as infection
or cigarette smoking. The precise etiology of such multi-f actorially induced diseases
has been in the past, difficult to elucidate by epidemiologic means. If the Panel
is to wait for clear-cut epidemiologic evidence of the causative role of zirconium
salts in producing lung disease, substantial numbers of persons may be exposed
to risk before the issue is settled.
8. In addition, the nearly ubiquitous distribution of these products will make
epidemiologic studies even more difficult.
9. Epithelioid cells and giant cells are a characteristic of previously reported
zirconium granulomas. Recent studies of the epithelioid cell and giant cell show
substantial DNA turnover and abnormal mitotic figures whose biological potential
in unknown.
Suggestions were made during the scientific presentation in the open session
that the toxicity of other aerosol antiperspirants be reviewed soon. This subject
will be initiated'at the Panel's next meeting on December 1G and 17.
Prepared by: Mary K. Bruch, Executive Secretary.
Mr. Fountain. Of particular significance is the following excerpt
from the minutes at page 43 :
23
A short closed session was held on Friday afternoon. The views of panel members
were surveyed. Some felt strongly that zirconium aerosols should be in category
jj * * *_
I have been informed that in the OTC drug reviews category II
is reserved for those drugs or drug ingredients not generally recognized
as safe or effective among qualified experts. Is that definition correct?
Mr. Pinco. That is correct, Mr. Fountain.
Mr. Fountain. And category II drugs, therefore, would be new
drugs requiring a new drug application. Is that correct?
Mr. Pinco. Yes, sir.
Mr. Fountain. What other categories are there for antiperspirant
ingredients classified by the review panel, Doctor?
Dr. Schmidt. Category I, of course, are those ingredients which
can be termed as safe and effective under the conditions specified.
Category III is one in which there are no data sufficient to make a
judgment and for which additional data are required.
Mr. Fountain. Page 44 of the minutes of the panel's sixth meeting
indicates :
A second closed session was held at 8:30 a.m. on Saturday, November 2, 1974,
at the United Inn in Bethesda, Md. Members again discussed their views, con-
structing risk and benefit lists. The vote on a motion to categorize zirconium
containing aerosol antiperspirants in category II was 6 to (one panel member
was absent), but later voted to make the vote unanimous.
The minutes also state at page 44, and again I quote:
The potential toxicity of these ingredients in antiperspirants was of such
concern that the Panel voted unanimously to request that the normal course of
the designated review process be interrupted. They agreed to prepare a statement
to present to the Commissioner in the immediate future detailing the reasoning
supporting their vote as to why it is inappropriate for the products to remain
an the market and requesting that this be published in the Federal Register. They
did not intend to suggest or recommend a recall.
On November 27 the panel issued a 21-page statement to set forth
its position on aerosol antiperspirants containing zirconium, and I
am placing a copy of that statement in the record.
[The statement referred to follows:]
Statement of the Panel on Aerosol Antiperspirants Containing
Zirconium, November 27, 1974
i. introduction
Consumer groups (Ref. 1) requested the Panel to pay particular attention to
the safety questions raised by the use of certain zirconium-containing compounds
in aerosol antiperspirants. The background of their request was the documented
record that certain other zirconium compounds had previously caused granu-
lomatous disease of the skin when used as antiperspirants and poison ivy remedies
(Shelly and Hurley, Ref. 2).
Because some aerosolized particles are known to reach the lungs, and because
the lung is one of the organs of the body especially prone to granulomatous
disease, the Panel decided to assess the risk to the lungs of presently marketed
zirconium-containing aerosol antiperspirants.
This report is a statement of our present position after discussing this problem
at both open and closed meetings. It includes an analysis of the benefit to risk
considerations as we believe them to apply here.
II. SAFETY OF ZIRCONIUM PRODUCTS
(a) Nature of the Granuloma
Since its tendency to induce granulomas is the basis for the Panel's concern
about zirconium, we will summarize very briefly what is meant by the term,
24
granuloma. The granuloma (Ref. 3) is considered to be a distinctive form of
inflammatory reaction which results when cells of the mononuclear phagocyte
system encounter some substance they are unable to eliminate effectively.
The cells of the mononuclear phagocyte system are scavenger cells, widely
dispersed throughout the body. It is now recognized that they are all derived
from a common precursor (source) cell in the bone marrow. Depending on where
they are located in the body, they take on different appearances and are called
by different names. These locations and names include circulating blood (mono-
cytes), connective tissue (histiocytes), liver (Kupffer cells), lungs (alveolar
macrophages), lymph nodes (free and fixed macrophages), bone marrow (macro-
phages), serous cavity (pleural and peritoneal macrophages). The osteoclast (bone
tissue) and the microglial cells of the nervous system are probably also cells of
this type.
As long as these cells are effectively able to remove foreign substances from
their respective tissue no unusual cell accumulation occurs. It is thought that in
at least three instances this effective elimination of foreign substances is impaired
and cells derived from mononuclear phagocytes accumulate. The term granuloma
is used for the lesion produced by those accumulated cells.
One such instance occurs when the foreign substance has low biological activity
for which there is no effective mechanism of elimination. Here the mononuclear
phagocytic cells become stuffed with material that resists the cell's degradative
enzyme system. These cells are immobile, resistant, long-lived macrophages
which do not divide. These cells store the offending substance, often over a pro-
longed period. The granuloma thus formed is metabolically relatively inactive
and has been termed, a "low turnover" granuloma.
A different form of granuloma occurs in two other instances. In one of these,
the foreign substance is toxic to the scavenger cell and damages it, releasing
further toxic material into the tissue. In the other, the foreign substance acts as
an allergen and brings cells of the body's immune system into play. In both of
these cases, when the foreign substance is toxic or when it acts as an allergen,
the resulting granuloma is characterized by a metabolically very active deriva-
tive of the mononuclear phagocyte called the epithelioid cell and also a form called
the giant cell. Such granulomas are now termed, "high turnover" granulomas.
Unlike the low turnover granulomas in whose cells the offending agent is
easily found, the cells of the high turnover granulomas usually do not reveal the
presence of the causative agent. The epithelioid cell granuloma has thus been
more difficult to study and understand. More recently, however, it has been
found that present techniques of immunology have helped to clarify the nature
of high turnover granulomas caused by immune mechanisms (Ref. 3).
Of considerable interest is the recent observation that the mononuclear phago-
cytic cells of the granuloma produce a substance which acts as a stimulant to
nearby connective tissue fibroblast cells. These fibroblasts are stimulated to pro-
duce more collagen, the basic fiber of connective tissue.
This effect of granuloma cells on fibroblasts would seem to explain the tendency
of chronic granulomatous disease of the lung to result in a condition called pul-
monary fibrosis. In this condition the required mobility of the breathing process
is interfered with by excessive amounts of connective tissue in the lung.
In current medical practice, a substantial amount of recognized granulomatous
disease is of unknown cause. The term sarcoidosis is applied to one group of
granulomatous changes whose cause is unknown but in which the clinical course
often conforms to a recognizable pattern. Known causes of granulomatous disease
are the bacterial products of the tuberculosis and leprosy bacilli, and some forms
or compounds of metallic chemicals such as silicon, beryllium, and zirconium.
(b) Zirconium Compounds Are Cause of Granuloma
(i) Clinical experience
Shelly and Hurley ( lief. 2) provide a concise review of the experience of Ameri-
can dermatologists with the granulomas that were first noted soon after sodium
zirconium lactate was introduced as an antiperspirant ingredient in the 1950s. At
that time the zirconium compound was formulated in a stick that was rubbed on
the underarm skin. A characteristic underarm eruption of small, indolent flesh-
colored papules appeared, often occurring in linear streaks. The streaks suggested
that the lesions followed introduction of the compound into the deeper parts of
the skin through breaks in the skin caused by shaving nicks. The individual lesions
resembled those seen in different distributions over the body in the disease called
sarcoidosis. Biopsies of the lesions also revealed a resemblance to the lesions of
sarcoidosis, the so called epithelioid cell granuloma (Refs. 4 through 10).
25
Several years later a different zirconium salt, zirconium oxide, was introduced
for use on the skin, this time as the treatment for poison ivy dermatitis. Again,
the areas of skin treated with the zirconium oxide cream broke out with small
papules which when biopsied revealed epithelioid cell granulomas (Refs. 11
through 15).
(ii) Mechanisms of zirconium-induced granulomas
It was shortly established (Ref. 10) that the zirconium-induced granuloma of
skin was the result of an allergic or hypersensitivity mechanism. These observa-
tions were later extended by Epstein (Ref. 16). The presence of an allergic mecha-
nism which caused zirconium-induced granulomas would explain the epithelioid
cell nature of the lesion, the fact that only some of those exposed to the product
developed lesions, the minute quantities required to elicit a response, and the in-
ability of investigators to find measurable quantities of zirconium in the lesion.
(Hi) Specificity of zirconium hypersensitivity
An important question is the one of how general is the tendency of zirconium-
containing compounds to produce granulomas. Clinical experience had shown that
two such compounds, sodium zirconium lactate and zirconium oxide, would
produce granulomas in the skin of sensitized individuals.
(An organized investigation, in which many different zirconium compounds of
different chemical types could be tested has not been accomplished. This is
because it has heretofore not been possible to induce a zirconium granuloma in a
laboratory animal and testing in man has until lately been limited to techniques
in which the investigator injects the test compound" into the patient's skin and
waits for the granuloma to develop. Such tests are obviously not suitable for large
scale screening studies. Recent advances in the immunologic studies of granuloma
formation suggest at least two possible avenues of study. These would include ( 1)
attempts to utilize techniques used to study schistosome hypersensitivity in labora-
tory animals, and (2) non-invasive tests in which white cells from patients with
known hypersensitivity to zirconium could be tested in vitro to different zirconium
compounds (Refs. 3 and 17 through 22). We will refer to these possible methods
of study later in this statement.)
Neither sodium zirconium lactate nor zirconium oxide are constituents of the
zirconium-containing spray antiperspirants under review. The OTC products
contain zirconium in the form of zirconium chlorhydrate which is then complexed
with either aluminum chlorhydrate alone or with aluminum chlorhydrate plus
glycine. Obviously it is the potential of these latter complexes to produce gran-
uloma that most concerns the Panel.
Epstein (Ref. 3) performed a limited number of skin tests on subjects known
to form skin granulomas when injected with sodium zirconium lactate. In one
such patient he found that a skin test with a saline solution of zirconium chlor-
hydrate and also with a complex of zirconium chlorhydrate and glycine resulted
iii a skin granuloma comparable to those elicited by sodium zirconium lactate.
In the same skin test report, however, Epstein stated that a specific complex of
zirconium chlorhydrate, aluminum chlorhydrate, and glycine did not elicit a
granulomatous response.
Epstein later reported (Ref. 3) that he was able to produce the zirconium-
induced granulomas in two of three zirconium-sensitized subjects when tested
with each of the following products: zirconium chlorhydrate, a complex of zir-
conium chlorhydrate and glycine, and a complex of zirconium chlorhydrate and
aluminum acetate. Again the specific complex of zirconium chlorhydrate, alumi-
num chlorhydrate and glycine did not produce positive skin tests.
The evidence thus shows clearly that at least three zirconium compounds will
induce epithelioid cell high turnover granulomas in man. These are sodium zir-
conium lactate, zirconium oxide, and zirconium chlorhydrate. Zirconium chlor-
hydrate, it must be noted, is the specific zirconium-containing moiety included
in each of the antiperspirant complexes under review.
Claims of safety based on Epstein's negative findings with skin tests of a
specific complex of zirconium chlorhydrate, aluminum chlorhydrate and glycine
are not considered adequate by the Panel. In order for Epstein's test to demon-
strate safety of the complex it would have to be established that the complex
remains permanently intact and will not break down in the body into its con-
stituent parts, one of which, zirconium chlorhydrate, is a known allergen. No evi-
dence was provided to the Panel of the metabolic fate of the various zirconium-
containing antiperspirants after exposure to the degradative mechanisms of the
body.
26
No substantial evidence was presented that zirconium-containing complexes
could not break down in the body to release zirconium chlorhydrate.
(c) Zirconium in the Lung
The Panel, even though it has evidence of zirconium-induced skin granulomas,
does not have indisputable evidence of granulomas induced by zirconium in the
lung. The potential problems of such lung disease, however, appear extremely
serious to the Panel.
(i) Access to the human lungs
Data presented to the Panel (Ref . 3) show that in four different tests, 48, 59,
67 and 63 percent respectively, of the zirconium-containing particles released
from an antiperspirant aerosol product were less than 5.5 microns in size. In-
haled particles of that size can gain "direct access to alveoli" according to Bern-
stein, Hatch and Gross, and Natusch and Wallace (Refs. 23 through 26). Bern-
stein also states that such particles cannot be extruded from alveoli and can cause
foreign body reactions.
(ii) Fate of inhaled particles
We come now to the critical question of what happens to these zirconium com-
plexes which have access to the alveolar macrophages. (It will be recalled that the
alveolar macrophage is a term used for the mononuclear phagocytic cell that is
found in the lung. Such mononuclear macrophages are entirely capable of under-
going transformation into the types of cells characteristic of a granuloma.)
(a) On the one hand there is the possibility that the complex of either zirconium
chlorhydrate and aluminum chlorhydrate or the specific complex of zirconium
chlorhydrate, aluminum chlorhydrate and glycine will, after deposition in the
lung, undergo a process of degradation as a result of metabolic activity. Should this
occur, it is likely that one of the breakdown products of that process will be zir-
conium chlorhydrate. As noted earlier, zirconium chlorhydrate is capable of elicit-
ing a hypersensitivity granulomatous response in sensitized subjects. Thus, should
it happen that the various complexes which contain zirconium chlorhydrate are
broken down in the lung, it can be anticipated that some number of those exposed
persons will exhibit an allergic type of granulomatous response to that zirconium
chlorhydrate.
Despite repeated questions from the Panel at its open meeting on November 1,
1974, representatives of industry were unable to state what the metabolic fate
of the various zirconium chlorhydrate-containing complexes in the lung would be.
They had no information to show the fate of inhaled particles left in contact with
lung surface.
(b) The second possibility, which was implied by manufacturers of one such
complex was that their complex (zirconium chlorhydrate, aluminum chlorhydrate,
glycine) was uniquely stable and was unlikely to break down in the lung. If this
were in fact to be the case, we are still left with the question of how the body is
to dispose of this unusual heavy metal complex that is now being brought to its
lung surface. Comparable situations exist in industry where certain dusts, long
thought to be inert, are now known to produce disease. These include the black
lung of coal dust which typically occurs after 20 to 30 years of exposure to coal
dust, silicosis which may occur only after a lapse of 20 years, and pulmonary effects
of exposure to metallic iron ore, and tin (Ref. 27). For many years, it was thought
that exposure to such inert dusts was harmless. It is now recognized they are not
harmless and that pulmonary fibrosis may sometimes result from continued
exposure to these dusts. Admittedly there is a vast individual variation and sus-
ceptibility to disease development as a result of exposure to such dusts. The
way in which a person breathes, the effectiveness of the clearing action of his
mucosal cilia, and the effectiveness of his alveolar macrophage function may all
play a part. Also involved may be the presence or absence of cigarette smoking
or other particulate contaminants in the air. In any case, the continued exposure
of alveolar macrophages to even an inert heavy metal complex cannot be regarded
as harmless, especially since the zirconium-containing complexes in question have
been available in inhalant form only for the past four years and it is perhaps too
early for the long term effects to have been documented by case reports.
(iii) Zirconium in the lungs of animals
Mogilezskaja (Ref. 28) reported on the effect of zirconium-containing aerosols
in rats. She found that soluble salts of zirconium produced tissue damage in the
lungs characteristic of a low-grade chronic irritation. The insoluble products did
not produce obvious inflammation but did seem to provoke an increase of the
fibrogenic reaction in the lung.
27
In 1960 Prior et al. found that when 6 albino rabbits were subjected to a 44
percent sodium zirconium lactate mist daily (at 20 minute intervals) for six weeks,
all developed either bronchiolar abscesses with lobular type pneumonia or lung
(peribronchial) granulomas (Ref. 29). Some animals developed granulomas in the
liver, tongue and ear cartilage. All six control animals subjected to a similar path-
ological examination at the end of six weeks were free from clinical disease and
granulomas.
There is further experience based on inhalation tests in monkeys of an antiper-
spirant complex composed of aluminum chlorhydrate and zirconium chlorhydrate.
The results of those tests showed that all animals exposed developed either slight
or mild degrees of exudative bronchiolitis. These results raised serious issues because
the test described was a routine 90-day type of toxicologic test, which was not
specifically designed to look for a tendency to produce granulomas. Such a short
term test (lasting 90 days) would not be expected to reveal the kinds of long-term
changes the Panel is concerned about.
(d) Statements from Industry Supporting the Safety of Zirconium
The Panel invited representatives of industry to present data supporting
the safety of zirconium containing antiperspirants. The summary of their state-
ments, and our analysis of them are as follows:
(i) The complex of zirconium chlorhydrate, aluminum chlorhydrate, and
glycine has been used on the skin for 16 years (since 1958) with approximately
468 million units having been sold in various forms. No documented reports of
granulomatous skin disease (such as quickly followed the marketing of sodium
zirconium lactate sticks) have been made.
The Panel agrees that the marketing experience of the creams and liquids are
reassuring about their safety and feels the creams and liquids are generally
regarded as safe. The fact that the cream is safe, however, does not necessarily
mean that an inhaled spray would also be safe, for the following reasons: (a)
only small amounts of zirconium enter the skin, mostly through nicks and cuts,
while a significant portion of inhaled spray particles can reach the lungs, (b)
The ability of the skin and lung to rid themselves of foreign particles differs.
(c) Metabolic degradation of foreign particles may differ. in the two sites, (d) Dif-
fuse fibrosis of the skin as a reaction to foreign substances is not a recognized
clinical entity while pulmonary fibrosis due to a wide variety of chronically inhaled
particles is a' well known and very serious disorder.
(ii) The complex of zirconium chlorhydrate, aluminum chlorhydrate and
glycine has been sold in aerosol spray form for 4 years and have been used by
millions of persons.
This mass distribution of a product, apparently lacking adequate safety testing,
did not reassure the Panel even though there were not a large number of reported
cases of clinical disease. Despite the fact that the particle size distribution of the
spray product makes it almost certain that some of the zirconium-containing
complex reaches the lung, the Panel was given no information about how much
reaches the lung, how it is either stored, degraded, or eliminated, or its final fate
in the body. Furthermore, a period of 4 years would not be long enough to reveal
a tendency to promote fibrosis; experience with other inhalation-induced diseases
shows that it is not rare for a 20 year period to elapse before obvious symptoms
begin to appear. The Panel was not satisfied by examination of one product's
complaint record. The Panel was told that during a 5-month period in 1973,
some 247 consumer complaints were received by one manufacturer including
over 30 complaints of respiratory distress. The manufacturer was unable to tell
us what sort of medical follow-up was made on any of these cases and it appeared,
in fact, that none had been made at all, except by FDA inspectors. Such follow-up
could have included, as a minimum, the taking of chest X-rays on these patients;
zirconium in the lung is radio-opaque and in some instances will produce shadows.
(iii) The complex of zirconium chlorhydrate, aluminum chlorhydrate and
glycine is chemically stable at body pH and unlikely to break apart.
'Even if it remained intact, that complex might produce a low turnover granu-
loma with late onset pulmonary fibrosis in sonic subjects. The pulmonary macro-
phage, moreover, is known to produce many degradative enzymes (Ref. 30).
Until the antiperspirant complex is exposed to comparable enzymes, the Panel
cannot know that it will remain intact in the lung.
(iv) Even in patients known to form allergic granulomas from sodium zirconium
lactate, skin tests with zirconium chlorhydrate, aluminum chlorhydrate and
glycine complex were consistently negative.
: In those same subjects, however, skin tests with plain zirconium chlorhydrate
(part of the complex), zirconium chlorhydrate, and glycine, and zirconium chlor-
55-495—75 3
28
hydrate and aluminum acetate all produced allergic granulomas. Since various
combinations of the elements of the zirconium chlorhydrate, aluminum acetate
and glycine complex result in a granulomatous response, the Panel, as noted
earlier, has yet to receive adequate scientific evidence that zirconium chlorhydrate
will not be liberated in the lung from the complex by the action of degradative
enzymes within the alveolar macrophage.
(v) In tests where one manufacturer of a zirconium chlorhydrate, aluminum
chlorhydrate aerosol antiperspirant (since withdrawn from sale) found toxic
changes in the lungs of test monkeys, a parallel test with a product containing a
complex of zirconium chlorhydrate, aluminum chlorhydrate, and glycine pro-
duced no such changes.
The test described was a routine toxicologic test, not one designed specifically
to look for a tendency to produce granulomas over a prolonged period of time.
As noted previously, standard 90-day tests would not be expected to reveal the
kinds of changes the Panel is concerned about. Furthermore, the fact that the
similar product did produce changes serious enough to provoke a voluntary product
recall, suggests the existence of a narrow margin between safety and toxicity with
inhaled zirconium particles. Again, should the complex product be broken down
by alveolar macrophages, it is likely a complex similar to the one causing changes
iii the monkeys lungs would be liberated.
(<?) Data Necessary to Prove Zirconium Spray Safe
Because millions of Americans have already used zirconium in antiperspirant
aerosols, the Panel is concerned that the following safety information was
unavailable.
(i) No data exist concerning the fate of zirconium antiperspirant complex
once it gets to the lungs. Such animal tests could be done with present technology
and would include: (a) analysis for zirconium compounds in animal lungs after
specific periods of time (i.e., 90 days, 180 days, 360 days), (b) tests to see if
zirconium is transported to the regional lymph nodes, (c) tests for zirconium in
the liver, bones, other body organs as well as excreta.
(ii) No data exist to show the absence of a potential for zirconium-containing
aerosols to produce pulmonary fibrosis after very prolonged use. Rodents should
be exposed to lifetime inhalation tests. Beagle dogs and monkeys could be ex-
posed to tests for periods of two years or more. Pulmonary function tests could
be done on test animals and controls.
(iii) More sophisticated methods than those available to Epstein for assessing
the immunologic hazards of marketed products now exist.
Specifically, techniques which have proven capable of inducing granuloma
in animals should be applied to zirconium (Refs. 17 through 22). An animal
species sensitive to the zirconium compounds which have been shown to react
in man must be utilized. Both cutaneous and pulmonary allergic response to
zirconium compounds should be produced. Prolonged exposure to zirconium
compounds that have been found reactive in man should be used in various
doses and time schedules. Because allergic responses sometimes are facilitated
more by intermittent exposure of variable intensity than by continuous heavy
exposure, lifetime observation of such sensitized animals to candidate zirconium
compounds would be required in order to allow for the influence of changes with
normal aging. Negative reactions with large numbers of animals in this kind of
test would be highly desirable before inhalation of any zirconium compounds
can be regarded as fully safe. Also it is now possible to remove white blood cells
from persons known to be allergic to zirconium and to test those cells with different
zirconium compounds and zirconium complexes. Such testing is done in vitro
and does not require that human subjects be repeatedly skin tested and their
immune resistance repeatedly challenged by potential sensitizers. Using such
i)i vitro techniques, it can be expected that investigators will be able to perform
much more extensive tests than can be done directly on patients (Ref. 22).
III. BENEFITS FROM ZIRCONIUM AEROSOL ANTIPERSPIRANTS
There is no available evidence that the addition of zirconium to the usual
aluminum-containing antiperspirant has any unique benefit. The most that has
been claimed for the zirconium-containing aerosol antiperspirants is that they are
somewhat more effective in reducing underarm perspiration than comparable
aerosols containing aluminum chlorhydrate as the active ingredient.
The differences, however, appear to be slight. Also, it appears that levels of per-
spiration control quite comparable to those achieved by the zirconium-containing
aerosols can be achieved with zirconium creams, roll-ons or aluminum roll-ons or
lotions — products totally lacking in potential for pulmonary toxicity.
29
IV. BENEFIT VERSUS RISK OP ZIRCONIUM AEROSOL ANTIPERSPIRANTS
In reviewing the benefit from the use of zirconium antiperspirant aerosols, it
was pointed out that quite comparable, if not identical reductions in the amount
of underarm perspiration may be achieved by products without zirconium's
potential for producing serious lung disease.
Whether or not the ability to limit underarm perspiration is a matter of impor-
tance to the American public is not a question the Panel chooses to discuss here.
The Panel is satisfied, however, that the American public believes that products
sold for this purpose are of proven safety and would not knowingly assume even a
modest risk of lung disease from their use.
Further complication of the use of these products comes from the fact that
exposure to these aerosols when delivered from propellant aerosols cannot be con-
fined solely to the individual user. These products are usually used in bathrooms
which may be small and poorly ventilated and which are used by other members
of the family within a time period while significant amounts of the product remain
in the air. It has been estimated that more than 25 percent of the particles from
aerosolized antiperspirant products are 3 microns or less. Particles in this size
range would remain suspended in an unventilated room for hours (a 3 micron
spherical particle of unit density would settle at a velocity of approximately 0.4
meters per hour).
At this point in time the analysis of benefit to risk considerations lead the
Panel to feel that zirconium compounds should not be sold for use in aerosol anti-
perspirants until the questions raised about their safety are adequately answered.
A further question is whether the sale of these agents should be permitted pend-
ing resolution of these safety questions. Here again, benefit to risk considerations
must be weighed. On the one hand are the slight to negligible increments of under-
arm perspiration control available to users of these products. On the other side is
the chance of producing lung disease where the population at risk may approach
100 million. Should zirconium-containing aerosol antiperspirants turn out to
carry a health hazard, the magnitude of the problem could be considerable. In
this connection the Panel would note that tests of the sort suggested earlier in
this statement have been feasible for several years and could have been done.
V. PLAN OP THE PANEL
The Panel feels this statement should be made known to all interested parties.
The Panel will accept comment on this statement at an open meeting on Decem-
ber 16, 1974 at the Parklawn Building in Rockville, Maryland.
Mr. Fountain. Of significance, I think, is the following excerpt
which appears at page 19:
There is no available evidence that the addition of zirconium to the usual
aluminum-containing antiperspirant has any unique benefit * * *. Also, it appears
that levels of perspiration control quite comparable to those achieved by the
zirconium-containing aerosols can be achieved with zirconium creams, roll-ons
or aluminum roll-ons or lotions — products totally lacking in potential for pul-
monary toxicity.
At pages 20 and 21 the panel made the following statement:
At this point in time the analysis of benefit to risk considerations lead the panel
to feel that zirconium compounds should not be sold for use in aerosol anti-
perspirants until the questions raised about their safety are adequately
answered. * * *
On the one hand are the slight to negligible increments of underarm perspiration
control available to users of these products. On the other side is the chance of
producing lung disease where the population at risk may approach 100 million.
Should zirconium-containing aerosol antiperspirants turn out to carry a health
hazard, the magnitude of the problem could be considerable. In this connection
the panel would note that tests of the sort suggested earlier in this statement
have been feasible for several years and could have been done.
The panel held its seventh meeting on December 16 and 17, 1974,
to hear the industry response to the panel's November 27, 1974, state-
ment from which I quoted. The committee heard presentations by
experts and industry representatives. I am inserting into the hearing
30
record the cover sheet and pages 35 and 36 of the minutes of the closed
sessions of the meeting which state:
The panel made no decisions but wanted to take the time until the next meeting
to review the data presented to them in light of their previous review and the
presentations made at their October/November meeting.
[The information follows :]
Summary Minutes of the OTC Panel on Antiperspirant Drug Products
[Seventh Meeting, December 16 and 17, 1974, Parklawn Building, Rockville, Md.]
Panel Members:
E. William Rosenberg, M.D., Chairman.
Zenona Mally, M.D.
Charles Evans, M.D., Ph. D.
Jane Rosenzweig, M.D.
Eli Shelter, Ph. D.
Pobert Scheuplein, Ph. D.
J. Wesley Clayton, Ph. D.
Liaison Members:
Consumer. — Ms. Marsha Gardner.
Industry. — Norman Estrin, Ph. D. (acting).
FDA Staff Members:
Mary K. Bruch, Executive Secretary — Division Anti-Infective Drug
Products,
Michael Kennedy, Panel Administrator — OTC Staff (acting in absence of
Lee Geismar).
Joe Hussion, Drug Information Analyst — OTC Staff.
Gary Yingling, General Counsel's Office.
CLOSED SESSIONS DECEMBER 16-17, 1974
Brief closed sessions were held at the end of the open session on both days.
Discussion of the material presented to the Panel, the importance of the data,
apparent inconsistencies in data and design of the experiments were the major
elements of discussion. The Panel made no decisions but wanted to take the time
until the next meeting to review the data presented to them in light of their pre-
vious review and the presentations made at their October/November meeting.
(Prepared by: Mary K. Bruch, Executive Secretary.)
Mr. Thompson. In the November 27 report which you mentioned
there is a statement where they said the advisory panel feels some
zirconium-based chemicals produce skin irritations and other prob-
lems while others did not, at least on the basis of available informa-
tion. They mentioned one complex, if that is the proper term, which
consists of zirconium chlorhydrate, aluminum chlorhydrate, and
glycine.
For the sake of the nonscientists, is it possible that one complex
containing zirconium could produce difficulties and another com-
plex containing zirconium could not?
Dr. Schmidt. That is a hypothetical question. The answer to that
would be "yes."
Mr. Thompson. Are there any products which have shown a lesser
degree of either external or internal irritation than, say, the product
removed from the market voluntarily?
Dr. Schmidt. I am sorry that I cannot answer that. I do not have
that information. Whether or not the panel has any sound information
in that area which they will provide, I do not know at this point.
Mr. Thompson. Are you grading various zirconium compounds
being developed?
31
Dr. Schmidt. It is my understanding that the panel has talked
about this sort of thing and the types of studies that could be or
should be done. I think sound experimentation could be done to get
at the answer to the question.
Mr. Goldhammer. I would like to attempt to get some clarification
concerning those zircoiryl complexes. In my review of the minutes I
detected that there was considerable doubt about the knowledge of
the composition of these complexes. As a matter of fact, there was
some suggestion that perhaps the doubts about the composition were
so great that there were questions as to whether the uniformity of the
product could be guaranteed.
If a product's composition is not established precisel}-, and if
there are doubts about the ability of the manufacturer to make a
uniform product of the same composition, would that fact alone
throw a drug into the category of new drug?
Mr. Pinco. That is such a hypothetical question in terms of scope
that I do not feel that I could responsibly answer it. The difficulty we
are getting into here, both with Mr. Thompson's questions and
your question, are the specifics of this OTC review panel's work on
ongoing processes.
While we can discuss the process, I think to discuss the specifics of
any product or series of products or compounds would be highly im-
proper for us at this stage because we do not have the report of the
panel which we can discuss in detail at this moment. We have not
received it nor reviewed it. I would have to beg off from that question
at this time.
Mr. Goldhammer. The Food and Drug Administration has its
experts in chemistry, some of whom are highly qualified. Have your
own biochemists and experts in the manufacture of drugs and in then
control made their own independent appraisal of whether the compo-
sition of these complexes has been established?
I am talking about the zirconyl complex.
Mr. Pinco. I am not aware our Bureau of^Drugs has conducted
that type of in-depth review.
Dr. Crout. No, because that stage of the process has not yet
occurred.
Mr. Pinco. That would occur normally after we have received the
report and evaluated internally as to what we may or may not wish
to do with respect to it.
Mr. Goldhammer. I got the impression that there were some
doubts about whether or not the composition of the zirconyl complexes
had been established. Are there such doubts?
Dr. Schmidt. What you are doing is pointing out one of the great
values of the OTC review and the use of the experts on those panels.
This is precisely their purpose. You have made a good point, and that
is that this process is very helpful and very important. We will now
be able to take whatever appropriate action is indicated by their
report.
Mr. Goldhammer. My question was whether there are such doubts.
Mr. Pinco. We cannot comment on that at this stage without
receiving their report and review.
Mr. Fountain. Are there doubts by others, other than yourselves?
32
Mr. Pinco. If the report states that the panel has doubts, then
apparently that is true. If it does not, then we would have no way of
knowing. I think the minutes would have to speak for themselves,
Mr. Chairman.
Mr. Fountain. The panel's eighth meeting was held on January 30
and 31, 1975. I am placing into the record the cover sheet and pages
19 and 20 of the minutes of that meeting which reflect the decisions
reached.
[The information follows :]
Summary Minutes of the OTC Panel on Antiperspirant Drug Products
[Eighth Meeting, January 30-31, 1975, Parklawn Building, Rockville, Md.]
Panel Members:
E. William Rosenberg, M.D., Chairman.
Zenona Mally, M.D.
Jane Rosenzweig, M.D.
Eli Shefter, Ph. D.
Robert Scheuplein, Ph. D.
J. Wesley Clayton, Ph. D.
Liaison Members:
Consumer.— -Ms. Marsha Gardner.
Industry. — Robert Giovacchini, Ph. D.
FDA Staff Members:
Mary K. Bruch, Executive Secretary — Division Anti-Infective Drug
Products.
Lee Geismar, Panel Administrator— OTC Division.
Joe Hussion, Drug Information Analyst — OTC Division.
Gary Yingling, General Counsel's Office.
Peter Hutt, General Counsel's Office.
Decisions reported herein are provisional in nature and may be modified or
revised in subsequent meetings of the Panel or in their final complete report to
the Commissioner.
Whenever there is a lack of unanimity on any given point, the vote will be given.
Regulations do not permit voting by the Liaison Members, Consultants, or FDA
Staff Members.
Adopted: March 25, 1975.
Lee Geismar,
for E. William Rosenberg, M.D.,
Chairman.
The OTC Antiperspirant Panel made the following decision: "All zirconium-
containing aerosol antiperspirants/deodorants be placed in Category II."
Our decision was made for the following reasons :
1. Unnecessary incidence of bronchial and respiratory distress.
2. Unnecessary burden of zirconium particles on respiratory and gastrointestinal
tract.
3. Likelihood of retention of zirconium particles in the lung.
4. Insufficient evidence that zirconium-containing particles in the body are
not altered into substances of probable antigenicity.
5. Insufficient evidence of safety of long-term exposure to zirconium-containing
aerosols.
6. Our assessment as to benefit-to-risk-ratio: Comparable degrees of respiration
control are achievable with other preparations which are generally recognized
as having less potential for harm.
7. The chemical and physical complexities of zirconium-containing antiper-
spirant formulations preclude its being identified in a generic manner and there-
fore each company's product should be evaluated separately. The Panel believes
the IND/NDA procedure would be required to achieve this.
The Panel believes that the major risks associated with the products, discussed
above, are primarily those of long-term use. We do not believe users of these
products are in imminent danger, since, at this time, we do not have documented
cases of serious clinical disease. We see no need to suggest a product recall.
33
The continued marketing of these products should be permitted contingent
upon the vigorous pursuit of safety testing by industry. The Panel plans to pro-
vide guidelines for those tests it considers essential.
(Prepared by: Lee Geismar for Mary K. Bruch.)
Mr. Fountain. These pages indicate that the panel once again
decided: "All zirconium-containing aerosol antiperspirants/deodorants
be placed in category II."
Category II are those not generally recognized as safe. Is that right?
Dr. Schmidt. Yes, sir.
Mr. Fountain. Among the reasons listed for the decision are:
"unnecessary incidence of bronchial and respiratory distress, unneces-
sary burden' of zirconium particles on respiratory and gastrointestinal
tract, likelihood of retention of zirconium particles in the lungs." On
the benefit-to-risk ratio: "Comparable degrees of perspiration control
are achievable with other preparations which are generally recognized
as having less potential for harm."
At page 20 of the minutes the panel is reported to have indicated
that it saw no need to suggest a product recall and that the continued
marketing of these products could be permitted contingent upon the
vigorous pursuit of safety testing by industry.
This recommendation appears to be inconsistent with the decision
to place the zirconium aerosol antiperspirant in category II. I wonder
whether you can enlighten us as to the implications of this recom-
mendation. Does it mean that the panel is recommending that inter-
state shipments of these antiperspirants be permitted to continue,
notwithstanding the fact that the panel did not recognize them to be
safe?
Dr. Schmidt. I think at this point it would be wise for Mr. Hutt
to review briefly the implications of category II and what process
we invoke in that case.
Mr. Hutt. Mr. Chairman
Mr. Fountain. That is a legal question and that is what you will
answer.
Mr. Hutt. Yes.
The process set out in the regulations governing the OTC drug
review which }^ou have placed into the record includes several stages.
The first stage is the panel's review and recommendations to the
Commissioner. Those recommendations are then placed in the Federal
Register as a proposed monograph with time for public comment.
After the time for public comment the Commissioner publishes a
tentative final monograph and provides an opportunity for any
interested person to request an oral hearing before the Commissioner
which, I might add, may not be delegated by him.
After that oral hearing, if one is justified, a final monograph is
published. At that point, on the effective date of that final monograph,
we implement the decision and recommendations all at one time
according to the effective date set out in the monograph.
We are at the first stage with zirconium, not at the end stage. The
issue we put, and which is still pending before the antiperspirant
panel, can be broken down into several parts.
The first part is whether it is in category I, II or III. The second
part is, if it is in category II, is that a decision Avhich should be taken
out of the normal process and implemented immediately or should it
34
be handled in the course of the normal process set out in the regula-
tions and thus implemented when the final monograph is promulgated?
You must recall that part of due process of law is permitting people
who are affected adversely by a decision to comment upon it and
pursue their administrative and judicial remedies.
What these minutes state is that, as of that meeting, and I em-
phasize as of that meeting, the panel had concluded that there was
not sufficient hazard thej^ could determine to justify taking _ the
zirconium aerosol issue out of the ordinary course of the adminis-
trative process and handle it on an expedited basis.
That, as you know, was not the end of the matter. We are uncertain
at this moment exactly what will happen, but as of that moment
that was their recommendation.
I would like to emphasize they were not sajdng that as of the final
date of the monograph, if it were to be in category II, that it should
stay on the market. That is not what that statement says.
Mr. Fountain. Then you are saying that that recommendation is
not necessarily inconsistent with the decision to place the zirconium
aerosol antiperspirants in category II?
Dr. Schmidt. Just a point I believe is important. It is realty not a
recommendation. W T hat you have there are minutes of meetings. If
one traces through minutes of meetings one finds many times a con-
clusion at one meeting which is reversed at the next meeting and
reversed at the next meeting.
You are not dealing with recommendations but you are dealing
with minutes of meetings. I do not have a recommendation from
that panel yet.
Mr. Fountain. You are dealing with expressions of opinion at the
time the members participate?
Dr. Schmidt. That is right.
Mr. Hutt. In any event, to answer the other question, Mr. Chair-
man, that is clearly not inconsistent with an interim conclusion
eventually to recommend class II to the Commissioner. It was a
conclusion expressed at that moment that they should not make an
immediate recommendation of expedited action.
Mr. Fountain. The most recent meeting of the review panel, as
you know, was held on March 24 and 25 of this year. As we learned
earlier today, the minutes of that meeting have not been prepared.
However, I am informed that at the termination of the meeting on
March 25, 1975, the panel chairman, Dr. Rosenberg, wrote in long-
hand a two-paragraph statement of the panel's decision which he
personalty delivered to the Commissioner.
Is that correct, Doctor?
Dr. Schmidt. That is correct.
Mr. Fountain. I am placing in the record a copy of the doctor's
statement which was obtained from FDA. I have been informed that
this is not a copy of the statement delivered by the panel's chairman
to the Commissioner but rather a longhand rewrite of the original by
an FDA employee assigned to work with the panel. I shall read the
panel's statement in full inasmuch as it is short.
and this is written in longhand—
The antiperspirant panel,
recommends to the Commissioner that he take action to withdraw all zirconium-
containing aerosol antiperspirants from interstate commerce (unanimous vote) .
35
The recommendation is based on the November 27, 1974 statement augmented
bv subsequent present at inn and submissions, further review of additional litera-
ture, and a review of the tvpes and extent of studies required to adequately
demonstrate the safety of the zirconium-containing aerosol antiperspirants.
[The statement referred to follows:]
L March 25, 1975.
The Antiperspirant Panel recommends to the Commissioner that he take action
to withdraw all zirconium-containing aerosol antiperspirants from Interstate
Commerce. [Unanimous vote.]
The recommendation is based on the November 27, 1974 statement augmented
bv subsequent presentations and submissions, further review of additional
literature, and a review of the types and extent of studies required to adequately
demonstrate the safety of the zirconium-containing aerosol antiperspirants.
Mr. Fountain. This now brings us up to date on the panel's review
of this matter and its decisions.
It is my understanding that FDA has asked the panel to prepare a
report to 'back up its decision and that the panel will meet, probably
tomorrow and Friday, to consider and finalize its report to the Com-
missioner. Is that correct?
Dr. Schmidt. Yes, sir.
Mr. Fountain. Since the background has now been adequately
developed, I yield to Mr. Thompson, if he has questions at this time.
Mr. Thompson. I would like to go back to the minutes of the
January 30-31, 1975, meeting and enter the statement the chairman
just read from the March 25 meeting.
I quote from the bottom of page 19 and the top of page 20 from
those minutes of the January meeting in which the minutes state:
We do not believe users of these products are in imminent danger since at this
time we do not have documented cases of serious clinical studies.
In the March statement which the chairman read, there is no
support to back the recommendation. The recommendation is made,
period, and as you stated, Mr. Hutt, that is almost a hypothetical
recommendation until it goes through the complete process.
I wonder whether you would comment within the limits of the re-
straints you have stated, on the blanket nature of the March recom-
mendation in that it deals with all products which are zirconium based,
in light of the fact that some information seems to indicate there is a
distinction according to the zirconium-based complex? Also comment
on whether the FDA would examine individual products which I
believe is the recommendation the panel made in one of its earlier
sessions.
Dr. Schmidt. The panel dealt with a wide variety of experimental
data of varying quality. They evaluated this data and they inter-
preted the data, went through a process of reasoning, and came out
with conclusions.
I have two principal concerns always when the agency takes an
action. One is for the quality of the evidence upon which conclusions
are based. The other is the due process we followed.
We have asked the panel to lay out all of these issues, to lay out not
just their conclusions but to lay out the evidence on which they base
the conclusions and their reasoning by which they went with regard
to the evidence.
I understand some of the issues you are now asking about are in-
volved in what was just quoted, subsequent presentations, submissions,
36
further review, and so on, which I charged them to deliver to me in
organized fashion on March 25.
Until I see that and look at that, I am unable to say anything more.
Mr. Thompson. After the November report which has also been
referred to, and at the January meeting, in the minutes provided the
subcommittee, it was stated in the minutes of February 4, 1975 :
The chemical and physical complexity of zirconium-containing formulations
preclude its being identified in a generic manner, and therefore each product
should be evaluated separately.
Recognizing again what you have just said in your own qualifica-
tions, is" that a likely option which the FDA will be able to proceed
upon?
Dr. Schmidt. Again, I really do not have any evidence before me
which would make possible a reasonable statement by me, Certainly,
what you now have is the best possible information and that is the
minutes of an expert group.
Mr. Thompson. Thank you, Mr. Chairman.
Mr. Fountain. I am a little confused, Doctor. I think what you are
requesting is a logical thing. However, as I recall it, and I believe the
record will back me up, during our hearings on propranolol, you stated
that you were not concerned with the details relating to the advisory
committee's discussions and reasoning, but were concerned primarily
with the panel's recommendations. How do you reconcile those two
statements?
Dr. Schmidt. That is really very simple. I said a few moments ago
that when one reads the minutes of meetings of a group one can find
that at one meeting they feel this way and then they may hear addi-
tional evidence, they may do some reading, and they may change their
minds later. I said at that time that I make my decisions based upon
what I said just a few moments ago.
The final report of the group, when they have completed their
investigation and discussion, tested their theses and find some wanting
and some quite firm, then they render a report. Then at that time,
I ask them to lay out not just their conclusions but to lay out their
evidence and their reasoning behind those conclusions in the final
report.
I am not interested in the details that take place during the process
of evolving what I must have at the end, which is the evidence,
rationale, and conclusions. Therefore, in no way are these statements
of mine inconsistent or illogical.
Mr. Fountain. Did you require this kind of detailed report in
connection with propranolol?
Dr. Schmidt. Yes, sir. When we take an action
Mr. Fountain. Before you made a decision?
Mr. Hutt. No; we did not.
Dr. Schmidt [continuing]. I may not be sure of what action you
are talking about.
Mr. Fountain. There was no report. Is that right?
Mr. Hutt. Mr. Chairman, there was no report at that time. One
of the things we have done in the OTC drug review, obviously, is
to build on our past experience. We do recognize the need for detailed
reports at this time and are improving across the board on all of this.
37
Probably the most detailed reports we have ever required have
been in the OTC drug review. I doubt we could ever meet the standard
of the OTC drug review in any of the prescription drug areas because
it is quite a different process.
Mr. Fountain. Doctor, even though the March 25, 1975, statement
by the chairman of the panel, backed by a unanimous vote, clearly
recommends to you that action be taken to withdraw all zirconium-
containing aerosol antiperspirants from interstate commerce, you
still want, in addition, a report on the basis upon which they made
this recommendation. Is that what 1 understand you to be saying?
Dr. Schmidt. Absolutely.
Mr. Thompson. And more detail?
Dr. Schmidt. I must have the reasoning and the evidence behind
the recommendation.
Mr. Goldhammer. Mr. Hutt, you indicated you are constantly
improving your handling of the advisory committees.
Mr. Hutt. Hopefully.
Mr. Goldhammer/ However, in your January 1972 proposed
regulations setting up the OTC panel's review and the monographs,
those proposed regulations, and the approved and finalized regulations
in May of 1972, provided for these reports.
I believe that the propranolol, the DES, and the Depo Provera
matters were handled after the May 1972 publication of your OTC
review regulations. However, there were no reports in any of these
cases; there was simply a vote. There was an executive secretary of
the advisory committee there and minutes were prepared. Aside
from that, there was no request for a formal report in any of these
instances.
Dr. Crout. I agree with that. The OTC panel system was begun
in a formalized way and with a relatively stylized mission. Each
one of those panels is to produce a report, and the process for doing
this was well thought out ahead of time, and it is in the regulations.
The other advisory committee system which we operate in the
Bureau of Drugs began substantially more informally, had many more
developmental problems, considered different issues at each meeting,
and there is no question that in its earlier days had problems with
identifying exactly what were the recommendations of the committee.
That has been a recognized flaw and has been corrected by the pro-
cedural regulations which will be out next month.
We are going to a system of requiring all of those committees'
recommendations be in the form of written reports. The written report
may be separate from the minutesw it may be included in the minutes.
However, that is the purpose of solving the precise problem.
Mr. Fountain. As I understand it, you have not made a firm
decision as to what to do about zirconium aerosol antiperspirants. Is
the reason you have not done so because you are awaiting this report?
Mr. Hutt. That is correct.
Mr. Fountain. Is the crux of the matter the question of whether
zirconyl aerosols are generally recognized as safe among qualified
experts?
Mr. Hutt. Yes, sir.
Mr. Fountain. Is the phrase "not generally recognized as safe"
synonymous with the phrase "found to be unsafe"?
38
Mr. Hutt. I would say no, Mr. Chairman.
Mr. Fountain. In other words, if a drug is not generally recognized
as safe by qualified experts, that does not necessarily mean that the
drug has been found to be unsafe?
Mr. Hutt. No. The phrase "general recognition of safety" is not
synonymous with safety, with proof of safety. You can have proof
of safety and not general recognition of safety. The statute recognizes
that distinction itself.
Mr. Fountain. I think we understand that. I wanted that explana-
tion in the record.
In other words, we can have a situation where a drug may be quite
safe, but where the safety has not yet gained general recognition
among the qualified experts.
Mr. Hutt. Yes, sir.
Mr. Fountain. A lack of recognition of safety may be due to the
fact that sufficient information concerning the action of the drug, or its
composition, is not available. Is that a correct statement?
Mr. Hutt. Yes, sir. The Supreme Court has particularly pointed out
in one of the cases it handed down in June of 1973 that general recogni-
tion of safety must ordinarily, and I emphasize "ordinarily," be
based upon widely available published literature. That is carried over
in our OTC drug regulations.
Mr. Fountain. Under those circumstances, the law requires that
a new drug application must be filed with and approved by FDA
for that drug if it is to be legally shipped in interstate commerced
Is that right?
Mr. Hutt. Yes, sir.
Mr. Fountain. On June 10, 1970, the subcommittee held a hearing
on cyclamate sweeteners at which Mr. Goodrich, then FDA's General
Counsel, appeared as a witness. He was questioned on the legal con-
struction of the term "not generally recognized as safe." He said at
page 10 of that hearing:
We are still involved, Mr. Chairman, in a good deal of litigation over the exact
meaning of that term, both from the standpoint of the new drug law and food
additives. But the cases we have so far — and I think they are mostly good,
because we won most of them — are that where there is genuine difference of
opinion among responsible experts, the product cannot be generally recognized
as safe.
Do you agree with Mr. Goodrich's interpretation?
Mr. Hutt. Indeed I do.
Mr. Fountain. Mr. Goodrich added:
A product can only be generally recognized as safe, say some of the courts, if
there is in the open literature a source of data to which experts could turn to
determine whether or not the product has been tested adequately and shown to be
safe.
Would you agree with that?
Mr. Hutt. I would, Mr. Chairman, and since then the Supreme
Court has affirmed that position. That position appears in our
regulations.
Air. Fountain. With respect to zirconyl aerosols, is there a source of
data to which experts can turn to determine whether or not zirconyl
aerosols have been tested adequately and shown to be safe?
39
Mr. Hutt. That is one of the issues before the panel, Mr. Chairman.
We could not comment on that at this time. That gets iuto the sub-
stance of whatever recommendations they may or may not be making.
Mr. Fountain. Does FDA have such source of information at its
disposal?
Mr. Hutt. I am not sure any of us have ever looked into that issue.
Dr. Crout. Not independently of the OTC review because that is
what the OTC review was set up for. Any information which we have
in our files on an OTC product we attempt to see is submitted to an
OTC panel.
The OTC review is meant to be the focal point for the review of all
issues concerned with OTC drugs.
Mr. Fountain. Of course, you have already testified that no NDA
ever has been filed, so you do not have information in support of that.
Dr. Crout. We have toxicological data given to us by Gillette, but
that has been given to the panel. They are evaluating that as part of
their total information.
Mr. Fountain. As I review the record and the minutes, and T ap-
preciate your request for details in support of the recommendation, it
appeal's they have three times recommended that this be withdrawn.
Dr. Schmidt. No.
Mr. Hutt. They have tentatively categorized it category II. That
is correct, Mr. Fountain. They have not recommended it be with-
drawn. They have come up with a tentative conclusion which ma}- be
in subsequent recommendations.
Mr. Fountain. They did recommend that in the letter which was
hand delivered to j^ou, did they not?
Dr. Schmidt. Yes, sir. However, the second paragraph of that is
important. The second paragraph cites that the recommendation is
based on the November statement augmented by a number of things.
Part of what it was augmented by was their discussion held just prior
to the chairman's coming up to see me. I cannot base mjr actions on
squishy oral reports.
Mr. Hutt. Mr. Chairman, the chairman of the panel, Dr. Kosen-
berg, fully agreed with the need for a report. He simply wished the
Commissioner to know that the report would be forthcoming. That
was not an issue.
Mr. Fuqua. There was never a formal decision made by the
panel?
Dr. Schmidt. The formal decision was made by the panel on that
date, which was March 25. The substance of their decision was con-
veyed to me. They said this wouM be followed by the inform a lion
which I required.
Mr. Fuqua. This is the report they gave you, then?
Dr. Schmidt. Yes.
Mr. Fountain. Before you arrived, Air. Fuqua, Dr. Schmidt had
stated, notwithstanding that, he wanted a full report giving the rea-
sons for their recommendation and all of the evidence^ the literature,
and. so forth, which they had examined in support of that recommen-
dation.
Mr. Fuqua. Thank you. That seems reasonable from this lian l-
written report.
40
Mr. Goldhammer. If I may clarify a point.
Mr. Fountain. Yes, Mr. Goldhammer.
Mr. Goldhammer. Mr. Hutt, you agree with Mr. Goodrich that
all you have to do is to establish a substantial difference of opinion,
and if there is not
Mr. Hutt. Yes.
Mr. Goldhammer. Let me finish. If there is not in the literature
sufficient information to establish safety, or if the test data is not
available to establish safety, then the experts are justified in saying,
"I just can't recognize it as safe." It ma} r be absolutely safe, but the
information is not available upon which they can make such a deci-
sion; therefore, they do not recognize it as safe.
That is a fair statement to make, is it not, Dr. Crout? If you do not
have the information it may be safe then you cannot recognize it as
safe. Is that right?
Dr. Schmidt. This is what the panel is for.
Mr. Goldhammer. If I may continue. I want the record to show
my reasoning. The panel has indicated on three occasions that there
is no recognition of safety among the qualified experts, and in Novem-
ber they published a report where they specified why they came to
that conclusion. Why do you need another report? Is it not enough
for them to tell you that there is not enough information around upon
which they can make a determination, and, therefore, it is not gen-
erally recognized as safe?
Mr. Hutt. No.
Dr. Schmidt. The answer is no. I would read from page 21 of that
report :
The panel feels this statement should be made known to all interested parties.
The panel will accept comment on this statement at an open meeting on December
16, 1974, at the Parklawn Building, Rockville, Md.
The purpose of tins statement was to invite comment on their
position at that time.
Mr. Hutt. Mr. Goldhammer, on top of that, the question of dif-
ference of opinion is a very tricky one in litigation. We have never had
a court case in which any court has accepted an expert going on the
witness stand and saying, "I do not think this is generally recognized as
safe" and then shutting up and saying nothing further. He has always
given the reasons. He has pointed out the lack of literature, or the
specific literature and has discussed the problem.
In short, on the stand, in testimony, he has given the very kind of
report we are asking for here. So the answer to your question of whether
it is enough simply to say there is a difference of opinion is that it is
not enough. There must be a scientific basis for that difference of
opinion, and if there is, then that is quite sufficient. I would agree
with that.
Mr. Goldhammer. Dr. Schmidt, it is true, is it not, that they heard
additional data from the manufacturer after the November report of
the review panel. And in January, after considering that, they said
nothing new has been given to them; it is still category II. Is that not
correct?
Dr. Schmidt. Well, that was in their minutes, but
Mr. Goldhammer. Were the minutes inaccurate?
41
Dr. Schmidt. No; I said it was in their minutes but it is not a report
to me.
Mr. Goldhammer. You have the minutes available. This is an
official document filed with FDA?
Dr. Schmidt. Yes.
Mr. Hutt. We are back into the middle of the process issue. The
question you are apparently raising is: Should we, whenever any of
the 17 panels in the midst of its deliberations come up with an interim
conclusion in its minutes that something should be placed in category
II, take that out from the panel, expedite it, immediate!}' go ahead
and implement it? The answer is no, unless there is a recommendation
by the panel to expedite it for good sound reasons.
* Mr. Fountain. We shall pursue this further.
Mr. Fuqua. It would seem to me that, based on this as a recom-
mendation to the Commissioner, you would have to defend any
position that the Commissioner would take in removing a product
from the market in what could develop into litigation by whomever
was involved. Is that not true?
Mr. Hutt. Yes, sir.
Mr. Fuqua. As you pointed out you would have to justify to a
judge in an injunctive proceeding the reason the Commissioner took
those actions. Is that not correct?
Mr. Hutt. Yes, that would be true for direct court action or when
going through a proposed regulation. However, it would be the same
thing ultimately.
Mr. Fuqua. You still would have to justify what you did and you
would need information from expert panels because this is a topic
requiring technical expertise. You would need some type of informa-
tion to support whatever you did.
Mr. Hutt. Without question.
Mr. Fuqua. Could you tell me the makeup of the panel? I assumed
some pathologists or dermatologists were present? What was the
professional makeup; not necessarily the names?
Mr. Hutt. We have that information. There was an attempt in this
panel, as in all panels, to have a variety of different medical disciplines.
Mr. Fuqua. It is my understanding you are dealing with an anti-
perspirant. This would deal with a rash and other types of effects. I
assume you would need a dermatologist on there. I understand one
of the points made was not the rash but some inflammation which
developed in the lungs of monkeys. Is this right?
Mr. Hutt. We have a toxicologist who was on the committee. We
could provide for the record the curriculum vitae of each of the seven
members of the panel. There is another important point. The panel
consists of all M.D.'s, Ph. D. combinations, or one Ph. D., in all fields.
In addition, the panel sought out experts in pulmonariasis, inhalation
toxicology, and so on, from all around the world. They did gather the
world's expertise in this area and had the input of those experts.
Mr. Fuqua. Regarding the point in question?
Mr. Hutt. Yes. I would suggest, Mr. Fuqua, we submit for the
record at least a brief curriculum vitae not only of the panel members
but of the outside experts who came in and participated at the one
particular meeting.
Mr. Fuqua. That would be very helpful.
42
Thank }^ou, Mr. Chairman.
[The curriculums vitae referred to may be found in the appendix
at pp. 293-309. No curriculums vitae of the outside experts referred
to were submitted by FDA.]
Mr. Fountain. As I understand it, if it is a new drug, all you have
to establish to the court is that it is not generally recognized as safe.
Mr. Hutt. Mr. Chairman, the Government has the burden of proof
of establishing it is a new drug.
Mr. Fountain. Right.
Mr. Hutt. That would require us to prove the various things to
which Mr. Goldhammer earlier made reference. We have the burden
of proof of establishing that in court .
Mr. Fountain. Mr. Goodrich also testified, and I quote from page
10 of the June 10, 1970, hearing:
The criteria I would apply from a legal standpoint is that if there were a responsi-
ble scientific opinion contrary to the belief in safety that that could not be generally
recognized as safe, even though the vast majority may believe the product
safe. * * * This is the kind of thing that was involved in some of our litiga-
tion. * * *
Do you agree with that opinion?
Mr. Hutt. I might take one slight disagreement. If, for example,
one person testified one way and 10 the other way— we have never
had one of those cases and Mr. Goodrich was not saying that we did —
then it might well be that you could conclude it was generally recog-
nized as safe.
What he was referring to was the normal case where we have
either a clear 50-50 division of opinion or something close to that.
Certainly wherever you have a substantial body of opinion on both
sides, then it would not be generally recognized as safe, again assuming
that those who say it is not recognized as safe give good, sound scien-
tific reasoning for their position.
Mr. Fountain. I think the hearing record should reflect how FDA
proved in court that a given drug was not generally recognized as
safe or effective among qualified experts. I believe the "not-generally-
recognized-as-safe" concept is now pretty well established by court
decisions; is it not?
Mr. Hutt. Yes. There are still some different court opinions but
I believe it is fair to sa}^ that the method by which we go about estab-
lishing that is fairly well known.
Mr. Fountain. In fact, the courts apparently are not reluctant to
study cases involving new drug charges on the basis of affidavits
alone, without testimony from witnesses.
Mr. Hutt. That depends on the court. Some are reluctant and some-
are not.
Mr. Fountain. A case in point is the "Trim Cigarette" case, with
which you may be familiar.
Mr. Hutt. That is a very, very old case. It was probably the
first general recognition-of-safety case.
Mr. Fountain. A more recent one is the Second Circuit Court of
Appeals February 1968 decision in the AMP case, which affirmed the
summary judgment of the lower court declaring AMP's ligatures and
inserting instruments to he new drugs. That case turned, in part, as
I understand it, on whether AMP's products were generally recognized
as safe. As 3011 know, each side submitted an expert's affidavit. The
43
expert for the Government was Dr. William J. Gyarfus, a medical
officer in FDA's Bureau of Drugs. He expressed his judgment that
the ligatures were not generally recognized as safe since the}^ remain
implanted in the body and long-term toxicity studies would be
required.
AMP submitted an affidavit of a professor of surgery and chairman
of the department at the Medical College of South Carolina, who
attested to his experience and studies of the AMP ligatures and
ligating instruments and expressed his view that they were safe.
The court in that case observed, and I quote :
On the basis of those two affidavits we must conclude that AMP's products
are not generally recognized among experts qualified by scientific training and
experience to evaluate the safety and effectiveness of drugs, as safe and effective
for use under the conditions prescribed, recommended, or suggested in the labeling
thereof and are therefore new drugs within the meaning of section 201 (p) of the
act. This is, we think, an appropriate case for summary judgment.
Are you familiar with that case? Do you agree with the court's
interpretation?
Mr. Hutt. I agree with the court's interpretation there. The
difficulty we have had, Mr. Chairman, is that other courts have gone
the other way. They have said affidavits are not sufficient for summary
judgment and have required a full trial with many witnesses and
experts, even on trivial products.
Mr. Fountain. This was a court of appeals.
Mr. Hutt. Yes, but that does not mean every district court in the
country will see the matter the same way.
Mr. Fountain. Are you waiting for every district court in the coun-
try to see things the same wa}^ before you make a decision?
Mr. Hutt. No. We go ahead frequently, but it means that when the
district court refuses to go along with us we have a major important
piece of litigation which may take a year to conclude. This happened,
for example, when we seized Excedrin PM as a new drug. We asked
for summanr judgment. We got turned down. The case still has not
gone to trial. That was over 4 years ago.
Mr. Fountain. As you probably recall, AMP contended, and
again I quote from the decision:
The defendant's motion for summary judgment should not have been granted
because there remained an issue as to the safety and efficacy of AMP's products.
The court of appeals answered that contention b}^ declaring:
The safety of the product is not what is at issue here. The question is whether
there is general recognition among qualified experts of the products' safety and
effectiveness — if there is not, the products must be submitted to the Secretary
of Health, Education, and Welfare for a, determination as to safetj^, adequacy
of testing, and so forth.
Do you agree with that?
Mr. Hutt. Again, I agree with all you are saying because you are
quoting from cases favorable to the Food and Drug Administration.
I should point out you are not quoting from cases which have gone
the other way.
Mr. Fountain. How many have gone the other way?
Mr. Hutt. I could not give you
Mr. Fountain. Can you give us some estimate for the record?
Mr. Goldhammer. Name one.
44
Mr. Hutt. The Excedrin PM case is a clear one. The issue is not
whether I agree as a lawyer with what you have said, or, indeed,
whether certain courts of appeal have said that. When we are in a
district court and it rules against us and holds we must have a trial,
we cannot at that time take an interlocutory appeal to the U.S. court
of appeals. We must litigate that case in that district court.
On top of that, I am sure you realize that in many of the trivial
cases we have had — for example, one brought against a product called
Vice Spice, a fake aphrodisiac — containing paprika, where we had to
get affidavits from the chairman of the department of pharmacology
at Michigan Medical School — it is very difficult to go to busy, impor-
tant people to get an affidavit of that kind.
We have brought cases against hangover remedies, products such
as Xerac Acne Gel — certainly not the most important cases. On each
occasion we have had to go out and get a number of affidavits from
busy and important people. On some occasions we have been unable
to convince them to take their time to do that. These are terribly
time-consuming pieces of litigation, which is why we pursued the
OTC drug review rather than continuing what was a formidable and,
indeed, impossible task on a case-by-case basis.
Air. Fountain. I can appreciate the point of view you express and
that it may not be important what your personal opinion is, except as
it results in a decision by the Commissioner. However, you do not
always have to await court action before you reach a decision on the
basis of the law that certain actions should be taken by FDA. You are
not saying you await court decisions to make a decision yourself.
Air/ Hutt. I am sorry. We bring those cases. What I am saying is
that our resources are limited. As we told the Supreme Court, we
could bring no more than at most perhaps 10, or at the maximum, 15
of those cases per year, contrasted with the 200,000 over-the-counter
drug products on the market today. There is no way we could ever
catch up with those b}^ litigation.
Moreover, there is an even more serious problem. In our Xerac
Acne Gel case, we won on the basis of affidavits in the district court.
When we got to the U.S. court of appeals, the compam>- informed
us, at the point of time when we were briefing that case in the court
of appeals, that they had changed the formula.
This would have meant that even if we had won the case in the
court of appeals, which I assume we would have done, they would
have had a new product back on the market and we would have had
to start another seizure action. That could keep up through all
eternity. Thus, the individual case-by-case approach is literally
useless in the real world.
This is why we gave up on what was a very ineffective means of
enforcement, * a means which was not only ineffective in terms of
actual results but using a great amount of our resources. We went,
instead, to a highly effective means of rulemaking, namely, the OTC
drug review.
Mr. Goldhammer. You said there are over 200,000 OTC products
on the market. I do not dispute that figure of 200,000.
You said if you tackled them all on a case-by-case basis you would
be bogged down. I would agree with that if all those products were
violative. However, are they all violative?
45
Mr. Hutt. We are finding, in terms of proper labeling as well as
general recognition of safety and effectiveness, that every over-the-
counter drug product in this country will be affected by the OTC
review.
In that sense one can say they are all technically in violation of
what good, modern medical science thinks should be proper indications
for use, warnings against misuse, formulations, dosage regimens, and
so forth.
If we were to go about reformulating and relabeling all over-the-
counter drug products in the country on the basis of litigation alone,
it could not be done. We would all have to agree with that.
If we do it by rulemaking, on the other hand, it is a feasible job.
Mr. Goldhammer. On the other hand, many of these products
have been on the market 30 to 40 years and longer. I am certain the
Food and Drug Administration was aware of the more important ones,
knew the labeling, had considered the labeling, and made certain
decisions about whether or not action was indicated.
Let's take the antacid panel; that is the only one where you have
a final order. Will you identify one antacid product which was danger-
ous to health in a real sense prior to the issuance of the monograph?
Mr. Hutt. I doubt I could give you one which was dangerous to
health, although there was one combination which was concluded to
be a possible health hazard. I forget what the combination was.
Mr. Goldhammer. Was that a product which was put on the market
after either 1938 or 1962?
Mr. Hutt. I would have to go back to the record. I must confess
I have not looked at that monograph in some time.
The point is that the OTC review is not directed just toward out-
right health hazards but toward applying the most modern medical
and scientific knowledge to upgrade all over-the-counter drugs, in
terms of safety, effectiveness, and labeling.
I think it is very successful. The antacid monograph certainly
affected every antacid product. Every single one has had to be reform-
ulated or relabeled.
Mr. Goldhammer. We have to put it in perspective. These 200,000
products are on the market and 3^ou contend you cannot tackle them
on a case-by-case basis. Some of these products have been on the
market for one-half century. The Food and Drug Administration
apparently made up its mind that whatever was wrong with these
products was not bad enough to do anything about. I don't see that
you will change the situation any; you still will have to make up
your minds as to whether you want to proceed on a case-by-case
basis because of minor variations from the monograph.
Mr. Hutt. I do not agree with that. Once we have the monographs
we now have a court decision hi the National Nutritional Food As-
sociation case in the second circuit which states that our regulations
are substantive. If appropriate, we can utilize that decision and can
exercise summary judgment because we have engaged in substantive
rulemaking.
The difficulty with the case-by-case approach, not having engaged
in substantive rulemaking, is that you sometimes can get a court on
the basis of a lot of affidavits to issue a summary judgment order, but
many times you cannot. In any event, you have to get the affidavits.
Once you have a substantive rule you put the rule and the data
behind it on the desk of the judge and move for summary judgment
with nothing else. That is on a case-by-case
Mr. Goldhammer. That is on a case-by-case basis?
Mr. Hutt. No question. The difficulty is minuscule compared to
the other approach.
Mr. Goldhammer. If there are at that time 200,000 products out
on the market which deviated in some significant way you would
have to proceed against 200,000 products, would you not?
Mr. Hutt. The answer is yes, we would. However, what we are
finding with the antacid monograph is having clear rules in the
Federal Register, having done it so that there is no competitive
inequity, so that all competing products are affected in the same way
on the same day, then there is compliance or where there is not
compliance, it will be of such a relatively small nature we will be able
easily to pursue the enforcement procedure I just outlined.
Dr. Schmidt. That is the important point. We are establishing a
standard which will be followed in most instances clearly by the
industnr. The standard will give us a basis of taking an action.
Another important point is that as a physician I have been con-
cerned about several things. One is that self-medication is a very
important part of our health care system. The OTC review is directed
importantly against any unsafe products on the market. As you
pointed out, some of these products have been around a long time. 1
would think any substantial safety problem would surface.
Many of the products are fairly recent, such as aerosolized anti-
perspirants, so your generalizations are, like most, not universall}' true.
I have been very concerned about the number of products on the
market which are essential^ totally ineffective. It seems to me again
that it is good and it is desirable that drug products on the market
be safe and effective for the purposes claimed, and that last bit is an
important part of the OTC review.
I would not hazard a guess as to the number of products which are
totally worthless which are on the market, but I think one of the
effects of the OTC review will be that products which are out there
will be not only safe but effective for the purposes claimed and will
be fully and informatively labeled and that people will for once know
what they are doing and will stop wasting their mone}^ often on
worthless products.
Mr. Hutt. 1 did find the one example that I had recalled. It was a
combination of an antacid with an anticholinergic. The conclusion
was that the amount of an anticholinergic necessary to make it
effective would make it far too toxic. The panel was terribly concerned
about that.
Tliis is a good example, also, of the way industry has reacted even
before the report became available in the Federal Register. The
manufacturer came in and said he was removing the anticholinergic
immediately, before it had even gone through the entire administrative
process.
Mr. Goldhammer. Does that not occur often when you write a
letter to a firm saying its product appears to be in violation, or after
you have gotten a favorable court decision in a case? You then attack
the violation on an industrywide basis and the industry gets the
47
message from having lost a case. Don't they generally all fall in line
and you are not required to proceed against the whole class of products
•on an individual case-by-case basis?
Mr. Hutt. Our experience with the hangover remedies demonstrates
that is not true.
Mr. Goldhammer. Perhaps not always.
Mr. Hutt. We have brought case after case and have gotten
absolutely nowhere. Indeed, there is nothing to prevent the same
companies from putting out a totally different formulation as a new
hangover remedy after having lost the case on the last formulation.
I would again point out that Xerac Acne Gel case. They did not
await the court of appeal's decision before they put a new product on
the market.
Mr. Goldhammer. I will grant you there are times when it takes a
long time for a message to sink in and corrections may be delayed.
On the other hand, there are also perhaps an equal number of times
when the message does sink in that the court has expressed its legal
interpretation of a set of facts. You can notif}^ the entire industry
then that henceforth products bearing this kind of labeling will be
proceeded against. That approach has been successful in instances,
has it not?
Mr. Hutt. I am trying to think of one. Except in clear situations,
where we have used Federal Register notices, I am not aware of any
where that has been sufficient.
Mr. Goldhammer. How about phenacetin? Have you not gotten
out a regulation on that?
Mr. Hutt. Exactly.
Mr. Goldhammer. Without a monograph?
Mr. Hutt. Where we have done it on a case-by-case litigation
approach, we have had an enormous lack of success. One can look
at the wrinkle remover cases. Companies still are putting out wrinkle
removers. We can never catch up with all of those.
W r e had the hangover cases. We have a wide variety of other situa-
tions where we have brought individual cases, and the rest of the
industry said they will go right on with what the}^ are doing; FDA
will have to catch up.
That is why we have abandoned that approach as the major way
of law enforcement and gone to the rulemaking approach which is far
more effective.
Mr. Thompson. To try to summarize, your monograph system is
basically an attempt to broaden your authority and expedite the
FDA's proceeding against products they think are in violation of the
monographs. Is that correct?
Mr. Hutt. Yes.
Mr. Thompson. But the monographs do not preclude you from
proceeding in previous lines of litigation against products. Is that
correct?
Mr. Hutt. That is correct. In fact, we have two areas where we
continue to bring case-by-case litigation. Anything involving a health
hazard we will take up even though it is also going through the OTC
drug review and handle that on an immediate basis.
A good example of that is the high dosage of vitamin A and vitamin
D which we took out of the OTC review and handled in a separate
48
regulation in the Federal Register. That has now been appealed to
the courts. That matter also is pending before the OTC review.
There is also patent fraud. Where it is a cancer quack or something
of that kind, we will take action without awaiting the OTC drug
review.
We have taken hexachlorophene out of turn. There have been a
number of different products and ingredients we have taken where
we have been concerned about a health hazard.
Mr. Thompson. Is it an accurate characterization to say the mono-
graph system has broadened your capacity to deal with Dr. Schmidt's
concern about products on the market?
Mr. Hutt. We believe so.
Mr. Fountain. I appreciate your saying one court may do one
thing and another court may do something else. However, if I under-
stand the AMP decision, you do not have to produce any evidence to
establish the safety or effectiveness of a drug, but only that there is
no general recognition of safety or effectiveness. Is that not right?
Mr. Hutt. I agree, Mr. Fountain. The question is whether you can
do that by affidavits or testimony.
Mr. Fountain. You do not have to prove it is safe or effective?
Mr. Hutt. Yes.
Mr. Fountain. I think we may assume, with regard to the anti-
perspirant panel, that the members are qualified experts for safety
evaluation of antiperspirant products, inasmuch as your May 11, 1972,
notice relating to this states, "the individuals selected for panel
membership are leading experts in the therapeutic category that the
panel is reviewing."
Are they the type of qualified experts described in the statutory
definition of new drugs: that is, in section 201 (p) of the Federal
Food, Drug, and Cosmetic Act?
Mr. Hutt. They were chosen precisely for that purpose.
Mr. Fountain. You would accept their safety and efficacy state-
ments as scientifically and medically valid?
Dr. Schmidt. Yes. That is why I am awaiting their early recom-
mendation to me.
Mr. Fountain. Would you accept their findings and opinions as
representing the consensus of current and competent scientific and
medical thinking on the subject matters referred to them for evaluation?
Dr. Schmidt. Not necessarily and not as you stated it. I will not
accept very many people's unsupported conclusions. I have said
several times what I require from them, which is their conclusions,
and then both the evidence and the reasoning from that evidence
which led them to those conclusions, because I believe as Commis-
sioner of Food and Drugs I must make an independent assessment of
this. This is my job, and I will carry out my responsibilities.
Mr. Fountain. Mr. Goldhammer has reminded me that you might
not have appreciated the emphasis where I meant it to be. I asked
whether you would accept their findings and opinions as representing
the consensus of current and scientific medical thinking on the subject
matter.
Dr. Schmidt. I said no. However, I qualified the no. I said no to
the wording of your statement.
Mr. Fountain. And you object to the word "consensus"?
49
Dr. Schmidt. I think there is rarely a unanimous opinion among
experts, and the more expert a group is, the less apt there is to be a
unanimous opinion.
Mr. Fountain. Mr. Hutt.
Mr. Hutt. I would have to say that one could not accept, as I
have said before, and present to a court a bareboned recommendation
without being able to back it up with good, sound scientific reasoning.
Mr. Fountain. You keep responding by saying what you would
have to submit to a court. I am asking you what you would accept.
Dr. Schmidt. Mr. Fountain, I think what is relevant to me is not
what one judge as opposed to another judge may or may not accept
as evidence of a disagreement among experts. What is important as
far as this action goes, is what I will and will not accept.
Mr. Hutt has said that one judge might well have accepted one
affidavit from each of two people unsupported by any scientific
reasoning, and said "there is not general recognition of safety."
He also said that other judges will not accept one affidavit. The
judge said "I don't think it is safe." He requires the laying out of
scientific evidence for that person's not being willing to accept it as
safe.
If we are going to talk about one judge or another, I am siding with
judges who require evidence to be laid out.
Mr. Fountain. I think that is an appropriate waj r to reach a
conclusion. Sometimes you make administrative decisions before
you get to court.
Mr. Hutt. Mr. Chairman, let me emphasize one thing. If you are
asking whether, based upon a good sound scientific reasoning we
would accept these people as experts and their opinions as sufficient
to back up a decision to go to court on the ground that these products
are not generally recognized as safe and effective, the answer is a clear
yes. There is no question about that.
Mr. Fountain. Do your instructions to these panels include the
information that whatever their recommendations are, they must
take into account the fact that you may have to go to court and prove
it?
Mr. Hutt. Absolutely. Indeed I have become very unpopular
with all of the OTC drug panels for constantly pushing them veiy,
very hard for a clear statement of their scientific reasoning. I have
said over and over again I have no interest in which way they come
out on an}^ issue, but however they come out, they must state that
not only in good scientific terms but in terms that can be understood
by judges, because ultimately it is "the judges who will either enforce
or not enforce those monographs.
Mr. Fountain. You do not ask for legal opinions but scientific
opinions?
Mr. Hutt. I ask for scientific opinions.
Mr. Fountain. Regardless of the legal opinion?
Mr. Hutt. I ask for third grade English so they are understandable
to eve^one.
Dr. Schmidt. Including judges.
Mr. Fountain. We have so many things to attend to here we do
not purport to be qualified to pass judgment. As I said, we are con-
cerned with determining whether or not FDA has been acting expe-
50
ditiously and properly to resolve questions raised about the safety of
new drugs.
More than 9 months have elapsed since Prof. Joseph Page urged the
panel to consider reviewing zirconium aerosol antiperspirants on a
priority basis, and more than 8 months since the panel decided that
zirconyl aerosol in antiperspirants should be given priority attention.
Six months have elapsed since the panel voted unanimously that
zirconium aerosols are not generally recognized among experts as safe,
and almost 5 months since the panel gave the Commissioner of the
FDA a statement detailing the basis for its decision that the zirconium
aerosols should be placed in category II, the not recognized as safe
category.
Three months have passed since the panel reiterated its earlier
decision to place zirconium aerosols in category II.
Finally, 1 month has passed since the panel chairman informed the
FDA Commissioner, on March 25, that the panel had once again
voted to place zirconium aerosols in category II, this time recom-
mending that they be taken out of interstate commerce. Your answer
to that was that you wanted them to give you a full report with all of
the evidence to back it up.
What is the position of FDA on whether or not zirconium sprays
are generally recognized as safe among qualified experts?
Dr. Schmidt. During the past month since they gave me that hand-
written note, the panel has been laying out the evidence and rationale.
You heard that they are in session today or tomorrow.
Mr. Hutt. Tomorrow and Friday.
Dr. Schmidt. They will be finishing that report. Until I have that
report I do not have a recommendation other than a very brief one
from the panel.
They will state in that what they believe, and at that point, then,
we will evolve our position.
Mr. Fountain. As of now you do not have a position?
Dr. Schmidt. No, sir. I have no recommendation from them. I do
not have their evidence. I do not have their rationale.
Mr. Fountain. You have recommendations. What you are
saying
Dr. Schmidt. I have the sketchy one which stated that the chairman
agreed is inadequate.
Mr. Fountain. They did give a report, as I recall.
Dr. Schmidt. No, sir. What they did in November is to come out
with a report, the purpose of which was to gain comment. What I
would point out to you is that the panel has not considered the hazard
from zirconium sprays sufficiently immediate to recommend to me an
alteration of the process until March 25.
Mr. Fuqua. I am not a chemist, but zirconium is in various anti-
perspirants. Are they all the same formula?
Dr. Schmidt. They can vary.
Mr. Fuqua. When you say zirconium it is not one specific
formulation?
Dr. Schmidt. When I use the term zirconium, I include the element
plus the various complexes.
Mr. Fuqua. I understand you to say there are different
formulations?
Dr. Schmidt. Yes, sir.
51
Mr. Fuqua. Such as in soft drinks?
Dr. Schmidt. Talking about sodium, there is sodium chloride,
sodium cyanide.
Mr. Fuqua. They are entirely different?
Mr. Hutt. Hopefully.
Mr. Drinan. I followed the writing of Professor Page. In the New
Republic there is another article. During the past 9 months, how
have you handled representations from the industry about aerosols
and related things? Suppose they inundate you with letters and
briefs? Suppose they say they have changed the formula?
Do you people stay out and sa} T it all has to go through the advisory
committee?
Dr. Schmidt. Yes, sir. During the last 9 months our principal action
has been to tell the panel our criteria for successful action on their
part.
They have actually arranged for the presentations by industry
and world experts to them so the}^ can conduct their review. Any
letters I have received have been placed in the hearing clerk's office
and forwarded to the panel.
Mr. Hutt. There was one letter by one company which requested
a meeting that both the Commissioner and I attended. The sum and
substance of that meeting was that we told them we could tell them
nothing about it until we received the report from the panel.
Mr. Drinan. Have some companies tried to alter the chemical
formula so they would not be under the ban, if such comes out, from
the advisory committee?
Dr. Schmidt. Not to our knowledge. First of all, any complex
they have which they have developed would not be simply exchanged
with another zirconium or other complex. They are waiting for the
panel's report, evidence, and everything else.
Mr. Fountain. We will have to recess in a moment.
If FDA decides to classify zirconyl aerosols in category II, as the
panel recommended, how long would it take after you get additional
information before the industry will be required to submit NDA's
for those products if they want to continue marketing them?
Mr. Hutt. Again one must look at the process. If we were to do it
using the whole process, that would take perhaps 2 or 3 years. If we
are to expedite it, that could take a much shorter period of time. One
would have to give industry an opportunity to comment. We would
probably do it by rulemaking. This would mean publishing a notice
in the Federal Register, time for comment, and then a final order re-
quiring an NDA, if the recommendation comes forward and if we
pursue it.
Mr. Fountain. In the meantime, will they be permitted to ship in
interstate commerce?
Mr. Hutt. Yes, sir.
Mr. Fountain. Aside from public health considerations which are
the responsibility of FDA, I think it is apparent that your decision
would have substantial economic consequences for certain firms. There
is Procter & Gamble in their products, Sure and Secret. I am in-
formed Carter-Wallace, the producer of Arrid, is planning to spend
millions of dollars beginning in April to promote an Arrid zirconium-
containing aerosol antiperspirant. You are familiar with their plan, I
imagine.
52
Mr. Hutt. Yes.
Mr. Fountain. Do you know whether Carter-Wallace is going
through with that promotional plan at the moment?
Dr. Schmidt. We do not.
Mr. Fountain. Apparently Gillette Co. feels that it is now in a poor
competitive position because of the withdrawal of its zirconium aero-
sol product, and it, too, wants to get back into the market, if FDA
will allow Sure and Secret to be on the market for any length of time.
Therefore, I think time and speed of FDA action is important as we
look at this picture.
Dr. Schmidt. I would agree. We have told everyone who inquired
that we would very rapidly go through this process.
Mr. Fountain. Thank you again. We will have to suspend.
The subcommittee will adjourn until Friday mornins:, Mav 9, at
9:30.
Can you make it then?
Dr. Schmidt. Yes, sir.
Mr. Fountain. The subcommittee stands adjourned.
[Whereupon, at 12:08 p.m., the subcommittee adjourned, to re-
convene at 9 :30 a.m., Friday, May 9, 1975.]
USE OF ADVISORY COMMITTEES BY THE FOOD AND
DRUG ADMINISTRATION
(Part 2)
FRIDAY, MAY 9, 1975
House of Representatives,
Intergovernmental Relations
and Human Resources Subcommittee
of the Committee on Government Operations,
Washington, D.C.
The subcommittee met, pursuant to notice, at 9:45 a.m., in room
2247, Rayburn House Office Building, Hon. L. H. Fountain (chairman
of the subcommittee) presiding.
Present: Representatives L. H. Fountain, Don Fuqua, and Robert
F. Drinan.
Also present: Delphis C. Goldberg, professional staff member;
Gilbert S. Goldhammer, consultant; and Richard L. Thompson,
minority professional staff, Committee on Government Operations.
Mr. Fountain. The subcommittee will come to order.
Let the record show that a quorum is present.
Before our hearings were recessed on April 23, I observed that
whatever decision FDA makes on the zirconium aerosol antiperspirant,
it will have substantial economic consequences for certain firms,
particularly for Procter & Gamble, promoters for Sure and Secret
sprays already on the market, and for Carter-Wallace, currently test
marketing a similar aerosol product, and the Gillette Co., which now
wants to reenter the zirconium aerosol antiperspirant market.
I was about to discuss the Gillette Co.'s motivation for returning
to the marketplace when it became necessary for us to recess.
Earlier I had inquired as to whether or not Procter & Gamble had
filed an NDA for zirconium aerosols or whether it was true, as Professor
Page had alleged, that no NDA had been filed.
I do not know whether you, Dr. % Schmidt, or you, Dr. Crout, but
one of you had replied that an abbreviated new drug application had
been submitted b}^ Procter & Gamble for the aerosols in 1972.
Mr. Goldhammer informs me that on at least three or four occa-
sions in the last 6 weeks he specifically asked FDA to tell us whether
any applications had been filed or approved for any zirconium aero-
sols. The answer given each time was "No."
We now have what appear to be facts on that. We inquired of
Procter & Gamble and were informed that some 16 years ago they
filed a new drug application for zirconium-containing creams and
roll-ons with FDA.
Are you familiar with this filing? I know this was before your day,
Dr. Schmidt.
(53)
54
STATEMENT OE ALEXANDER M. SCHMIDT, M.D., COMMISSIONER OE
POOD AND DRUGS, EOOD AND DRUG ADMINISTRATION, DEPART-
MENT OE HEALTH, EDUCATION, AND WELFARE; ACCOMPANIED
BY J. RICHARD CROUT, M.D., DIRECTOR, BUREAU OF DRUGS;
PETER BARTON HUTT, CHIEF COUNSEL; ROBERT C. WETHERELL,
JR., DIRECTOR, OFFICE OF LEGISLATIVE SERVICES; ROBERT G.
PINCO, CHIEF, DIVISION OF OTC EVALUATION; MARK NOVITCH,
M.D., DEPUTY ASSOCIATE COMMISSIONER FOR MEDICAL AF-
FAIRS; AND DAVID M. LINK, ACTING DIRECTOR, BUREAU OF
MEDICAL DEVICES AND DIAGNOSTIC PRODUCTS
Mr. Hutt. Yes. That was for the nonaerosol product. We testified
at the last hearing that such an NDA had been filed and approved.
Mr. Fountain. The NDA was approved?
Mr. Hutt. Yes, sir.
Mr. Fountain. We were also informed that Procter & Gamble sub-
mitted to FDA an abbreviated new drug application covering the
aerosol zirconium sprays on January 10, 1972. This application, we
have been informed, specifically named the product Secret but the
application covered a formula range which also covered the Sure
product.
Is the information we received from Procter & Gamble accurate?
Mr. Hutt. Yes, indeed it is.
Mr. Fountain. I am placing into the record a copy of an FDA
letter dated June 20, 1972, provided to the subcommittee by Procter &
Gamble, which discloses the disposition FDA made of the P. & G.
abbreviated new drug application.
I shall read the letter in full:
Reference is made to your abbreviated new drug application dated January 10,
1972, submitted pursuant to section 505(b) of the Federal Food, Drug, and Cos-
metic Act for Secret (aluminum hydroxychloride, zirconyl hydroxychloride and
hexachlorophene) antiperspirant.
Pursuant to the policy of review of over-the-counter drugs as stated in the
Federal Register announcement of April 20, 1972, the material you have submitted
will not be reviewed at this time but will be handled by the appropriate OTC
panel at a later date.
The material you have submitted will be retained in our files.
This letter was signed by Dr. Paul A. Bryan, M.D., Director, Drug
Efficacy Study Implementation Project Office, Bureau of Drugs.
[The letter referred to follows :]
Department of Health, Education, and Welfare,
Iurlic Health Service,
Food and Drug Administration,
Rockvule, Md., June 20, 1972.
The Procter & Gamble Co.,
Cincinnati, Ohio
Gentlemen: Reference is made to your abbreviated new drug application dated
Januarv 10, 1972, submitted pursuant to Section 505(b) of the Federal Food,
Drug, and Cosmetic Act for Secret (Aluminum hydroxychloride, Zirconyl hydroxy-
chloride and Hexachlorophene) Anti-perspirant.
55
Pursuant to the policv of review of over-the-counter drugs as stated in the
Federal Register announcement of April 20, 1972, the material you have submitted
will not be reviewed at this time but will be handled by the appropriate OTC
panel at a later date.
The material you have submitted will be retained in our files.
Sincerely yours,
Paul A. Bryan, M.D.,
Director,
Drug Efficacy Study Implementation Project Office,
Bureau of Drugs.
Mr. Fountain. In its reply FDA expressed no guidance that I can
see to the company as to whether FDA would oppose the marketing:
of the drug in the absence of an approved abbreviated NDA, or
whether the drug is not a new drug within the meaning of the law.
What is your opinion one way "or the other as to whether this
should have been given P. & G.— that either it is a new drug requiring
an approved NDA, or it is not a new drug and does not require a new
drug application prior to marketing?
Mr. Hutt. At the time the letter was written, Mr. Chairman, that
was clearly our policy. That letter was entirely correct. We were not
opposing the marketing of that product as a new drug. It could go on
the market, and it would, along with all other OTC drugs, be reviewed
pursuant to the OTC drug review.
Mr. Fountain. Then the company was justified in marketing the
product on the basis of your June 20, 1972, letter?
Mr. Hutt. The company certainly was justified in marketing it.
Dr. Goldberg. For clarification, Mr. Hutt, would it be correct to
infer from your statement that FDA regarded this as a new drug
Mr. Hutt. I apparently misspoke. The Commissioner pointed out
to me I used an incorrect term. When I said new drug I meant newly
marketed drug and not new drug in the statutory sense. Therefore, I
misspoke.
If we had regarded it as a new drug at that time that letter would
not have been sent and we would have opposed marketing.
Dr. Goldberg. Then you would classify it as a drug that is gener-
ally recognized as safe and effective?
Mr. Hutt. Yes; at that time.
Dr. Goldberg. Without examining the data the company had
submitted in support of its application?
Mr. Hutt. That is right. What we were doing at that time was on
the basis of taking the general knowledge of zirconium that had been,
as we all know, marketed for some 16 years in deodorants and anti-
perspirants. We were not raising objections to the marketing of the
product while the whole class of zirconium-containing antiperspirants
was being reviewed by the OTC drug panel.
Dr. Goldberg. Had it been previously marketed in aerosol form?
Mr. Hutt. No; to my knowledge it had not.
Dr. Goldberg. Would that not have presented a new situation
with respect to the possible hazard of inhaling zirconium?
Mr. FIutt. It could have, yes. However, once again we were in the
process of an OTC drug review which was designed to ferret out those
issues, and it was simply concluded that that was the proper way to
go about it.
Mr. Fountain. Now, after the company has undoubtedly spent
millions of dollars in promotion, and after millions of dollars of zir-
56
coniura merchandise has been placed on the market, you are in the
position of having to make a decision which you apparently did not
make in 1972. If you decide that the product is a new drug requiring a
new drug application, then all the merchandise now on the market,
as indicated by your testimony of April 23, is illegal and subject to
confiscation. In other words, it is contraband. Is that correct?
Mr. Hutt. If we decide it is a new drug, once we go through the
entire administrative process, yes, sir. That would be correct.
Mr. Fountain. I believe that in the case of the drug efficacy review
covered by your so-called DESI orders, products which had been
evaluated by the NAS/NRC panels as ineffective or lacking evidence
of efficacy, had their NDA's revoked. Such drugs were then in the
status of being on the market without approved NDA's. I believe it
is FDA's policy to require the recall of such products. Am I correct?
Mr. Hutt. Not in all instances. It depends upon the type of drug
and a lot of other factors. In some instances we have required recalls
and in some we have not.
Mr. Fountain. In this connection we placed into our April 30,
1974, hearing record, an April 19, 1974, memorandum to you, Dr.
Crout, from L. M. Baukin, Director of FDA's Division of Regulator-
Operations in the Bureau of Drugs, and this letter now appears at
page 447 of the hearing record on the use of advisory committees
by the Food and Drug Administration. Mr. Baukin's letter states in
part :
Under established DESI compliance procedures, outstanding stocks of a drug
named in a final order withdrawing approval of an NDA are subject to removal
from trade channels by recall to the retail level.
Has Mr. Baukin expressed FDA policy correctly?
Mr. Hutt. I checked into that on several occasions in the course
of the last 2 years. I find that is not an absolutely rigid uniform policy,
Mr. Chairman. It expresses a very general policy probably in which
the majority of instances it is followed, but it is not a uniform and
absolute policy. I do not believe Mr. Baukin intended to express it as
such. He said it is subject to this policy, but that does not mean there
are not exceptions.
Mr. Fountain. At this point I will turn to where we left off on April
23, when I mentioned the Gillette Co's. interest in resuming the
marketing of an aerosol zirconium antiperspirant.
I am placing in the hearing record a Gillette Co. letter of March 24,
1975, to the chairman of the antiperspirant review panel referring
to the panel's November 1974, and January 1975, classifications of
the zirconyl aerosols in category II while at the same time advising
the Commissioner that marketing of such products may continue
during toxicological testing by the industry. The letter states in part,
and I quote:
After voluntarily recalling two antiperspirant products containing zirconium,
Gillette reformulated a new zirconium antiperspirant which was cleared for
national marketing in the spring of 1974. Marketing was delayed, however, when
the Panel expressed concern about the safety of ZCAA's and decided to consider
ZCAA's out of turn in the Panel proceedings. We have continued to delay market-
ing the zirconium product believing that the safety issues would be resolved by
the Panel and the FDA. However, the action taken by the Panel, instead of
clarifying the matter, has further confused it.
57
Gillette then asked six questions, most of which relate to the panel's
classification of zirconyl aerosols in category II and the effect of that
classification on the continued marketing of such products by members
of the industiy, including Gillette. Question 4 is pertinent to our
inquuy today, and it reads in part as follows:
We understand that we can expect the Panel to submit its proposed monograph
to the Commissioner about the end of 1975, and the publication of a final mono-
graph will be in 1977 after compliance with the other administrative steps.
Compliance with testing requirements could delay administrative action against
ZCAA's which have not demonstrated adequate safety until 1978 or 1979. Is our
understanding of the timing correct?
Page 3 of the letter states in part, and I quote :
As the Panel can appreciate, it would appear at present that no action will be
taken on ZCAA's until 1978 or 1979 . . .
It seems to us incongruous in the extreme that a product can be found not to
be GRAS and still be permitted on the market for many years before the questions
of safety are finally resolved, and yet this appears to be the context in which
Gillette must make its decision on zirconium.
I might add that GRAS means "generally recognized as safe."
[The letter referred to follows :]
The Gillette Co.,
Boston, Mass., March 24, 1975.
Dr. E. William Rosenberg,
Chairman, Antiperspirant OTC Drug Review Panel,
The Food and Drug Administration,
Rockville, Md.
[PRIVILEGED AND CONFIDENTIAL]
Dear Dr. Rosenberg and Panel Members:
The Antiperspirant OTC Drug Review Panel has spent considerable time
reviewing zirconium-containing aerosol antiperspirants (ZCAA). These products
were reviewed out of turn because the Panel was concerned about the potential
toxicity of ZCAA's.
In November, 1974, the Panel unanimously classified ZCAA's in Category
II, and although a recall of ZCAA's was not recommended, the Panel felt it was
inappropriate for these products to continue in interstate commerce during the
time that appropriate studies, to confirm or deny the safety of such products, were
being conducted. Early in 1975, however, the Panel, while not changing its classi-
fication of ZCAA's from Category II, stated that the continued marketing of
these products could be permitted contingent upon the vigorous pursuit of toxi-
cological testing by industry.
After voluntarily recalling two antiperspirant products containing zirconium,
Gillette reformulated a new zirconium antiperspirant which was cleared for
national marketing in the spring of 1974. Marketing was delayed, however, when
the Panel expressed concern about the safety of ZCAA's and decided to consider
ZCAA's out of turn in the Panel proceedings. We have continued to delay market-
ing the zirconium product believing that the safety issues would be resolved by
the Panel and the FDA. However, the action taken by the Panel, instead of clarify-
ing the matter, has further confused it. We are writing this letter to seek clari-
fication of the Panel's position on ZCAA's before we make a final decision with
respect to the marketing of a zirconium product. We would greatly appreciate
receiving the Panel's answers to the following questions :
1. Do we correctly understand that, as far as the Panel is concerned, Gillette
and any other company are free to market products containing zirconium and to
do so responsibly since any questions of health and safety are so remote there is no
health hazard involved?
2. Does the classification of ZCAA in Category II mean that the Panel has
found these products not generally recognized as safe (GRAS) ?
3. Was the Panel's statement that the major risks associated with these products
are primarily long-term based upon the continued marketing by only one
manufacturer or did the Panel take into consideration the national marketing of
ZCAA's by other industry members? Would marketing by Gillette and others
change the Panel's views?
58
4. Wo understand that we can expect the Panel to submit its proposed mono-
graph to the Commissioner about the end of 1975, and the publication of a final
monograph will be in 1977 after compliance with the other administrative steps.
Compliance with testing requirements could delay administrative action against
ZCAA's which have not demonstrated adequate safety until 1978 or 1979. Is our
understanding of the timing correct? Is the Panel aware of any developments
which would accelerate the timetable?
5. Does the panel plan to require any labeling for ZCAA's (cautions, safety
statements, etc.) different from other antiperspirants prior to issuance of the
monograph?
6. Is the Panel aware of any tests which can be quickly run to furnish prelimi-
nary safety information?
As the Panel can appreciate, it would appear at present that no action will be
taken on ZCAA's until 1978 or 1979. If Gillette's competitors utilize the delay
built into the monograph approach to go to market with other ZCAA's, Gillette
will have to review the decision it made to delay marketing and decide how it can
best meet its responsibilities to the consumer and still protect its market position.
It seems to us incongruous in the extreme that a product can be found not to
be GRAS and still be permitted on the market for many years before the questions
of safety are finally resolved, and yet this appears to be the context in which
Gillette must make its decision on zirconium.
In view of the importance of this issue and the time elapsed we would greatly
appreciate an immediate response to this letter from the Panel.
Very truly yours,
Robert W. Van Camp,
Group Vice President.
Mr. Fountain. This letter apparently was timed to coincide with
the panel's March 24 and 25, 1975, meeting, for it appears to have
been considered by the panel during its closed meeting on March 24,
1975. I am placing into the record pages 2-71 to 2-93 of the verbatim
transcript of the proceedings of that closed meeting. The names of
panel members who participated in the discussion have been deleted,
but FDA employees are identified.
[The material follows :]
The Food and Drug Administration, Closed Session — Antiperspirant
Panel
(March 24, 1975)
SPEAKERS
E. William Rosenberg, M.D., Chairman, Division of Dermatology, University of
Tennessee.
J. Wesley Clayton, Ph.D., Director, Toxicology Program, The University of
Arizona.
Charles A. Evans, M.D., Ph.D., Department of Microbiology, SC-15, University
of Washington.
Zenona Wanda Mally, M.D., 1835 Eye St., N.W., Washington, D.C.
Jane M. Rosenzweig, M.D., 1970 Jackson St., San Francisco, California.
Robert J. Scheupfein, Ph.D., Department of Dermatology, Massachusetts
General Hospital, Boston, Massachusetts.
Eli Shefter, Ph.D., Department of Pharmaceutics, State University of New York,
Buffalo, New York.
March Bruch, Food and Drug Administration, Executive Secretary, Rockville,
Maryland.
Marsha Gardner, Consumer Federation of America, Garrett Park, Maryland.
Robert Giovacchini, Ph.D., The Cosmetic, Toiletry and Fragrance Association,
Inc., Gillette Medical Evaluation Laboratories, Rockville, Maryland.
Lee Geismar, Food and Drug Administration, Panel Administrator, OTC Staff,
Rockville, Maryland.
Bob Pinco.
Peter Hutt, Lawyer.
George Thompson.
59
Dr. . The record will show Mr. Hutt,
Mr. Hutt. I have a small time problem. I can stand until five minutes to four
and then I will have to come back.
I have got to take care of a problem at exactly four o'clock with the
Commissioner.
I just read the Gillette letter. And understood that you wanted to discuss it.
And I think it raises a question that requires us to go back and say how did we
ever start along this road that we are going on the over-the-counter drug review.
Because this'issue arises for roughly 400,000 products. Not this product.
It rises. Ilvcry panel has the same issue with regard to one or more products.
Now, we just released two days ago the laxative report. And there are products
in the laxative report which flatly are found by the panel not to be generally recog-
nized as safe.
And so you can ask the question, each one of you and each one on that panel
can ask the question, "Well, why weren't those taken off the market five years
ago? Or two years ago. Or whenever?"
And the answer is to go back and see where we were in late 1971, when we set
up this exercise. To understand why we have to follow through in a routine,
orderlv, systematic way.
And in' addition as 1 pointed out to you every time we've met, why we have
specialized procedures where they are needed for real sort of danger to health
type problems, things that should be done immediately.
Now, let me go back and trace a little bit of that background and history.
What we, when I came in September of 1971, where we were was exactly as
follows.
We had eight law suits going in the courts, against either important or minor
over-the-counter drugs.
We had a case against Aspersleep; I don't know how many of you have ever
heard of that famous drug.
We had a case against Zerac acne gel ; another real big winner.
We had a case against Vice-Spice, which was a fake aphrodisiac.
We had a case against two hang-over remedies. Quick Over, and I forget the
names of them.
The only important one that anybody had ever heard of was Excedrin P.M.
A case against Excedrin P.M. And some equally crazy products.
Now, I figured that my staff of 18 lawyers could handle that type of litigation
on maybe 15 products a }^ear.
And the facts of the market place were such that there were roughly 100,000
to 500,000 products out there. And I did a little bit of rough calculation, and
divided 15 into somewhere between 100,000 and 500,000 — it didn't really make
much difference. Because the answer was that you never really got to the end
of it.
On top of that, we litigated one of those cases, Zerac Acne Gel. I have never
even heard of the product. Have you ever seen that?
Dr. . Yes.
Mr. Hutt. Have you really? Well, I don't know. We litigated that case all
the way up through the U.S. Court of Appeals.
We "had affidavits filed in the District Court. And they found that it was
not generally recognized as being safe or effective
We went to the Court of Appeals. And the Court of Appeals — well, when the
case was pending in the Court of Appeals, the attorney on the other side called
me up one day. And said, "I would justlike you to know that we changed our
formula."
Now. what that meant was, we started all over again. Because just because
we have the old formulation taken off the market, they could put a new formula-
tion out, and we would start all over.
So I said that's that. To hell with it. I am not going to go through any more
litigation.
I stopped all the litigation. All of it. Traded out all those cases. And we started
along the rule making approach.
Because until we got the solid administrative rule making base to cover all
OTC drug products, we were in the state of chaos, and could never, no matter
how many years went by, could never handle the products.
Now, right off the bat, we knew there had to be exceptions.
And it was a real easy thing that taught us that lesson. The thing that taught
us that lesson was hexachlorophine.
Because in January of 1972, well, we first unveiled the proposal in January,
right at that time we were up to our ears in the hexachlorophine problem.
55-495—75 5
60
And we had to take immediate action on hexachlorophine, even before we
gave it to the panel. We issued the notice of proposed rule making on hexachloro-
phine the day that we got the panel to even begin looking at the issue. It was
literally the same day.
The same day of the Federal Register. We couldn't wait.
From the beginning, I told the Bureau of Drugs that there were basically
two situations where we would take drugs out of turn.
One was where there was a danger to health. And the other was where there
was just rampant fraud. Just fake cancer quacks and all that kind of stuff.
And we have held to that. In either of those two situations, we will not wait for
the orderly administrative process. We realize that we've got to act immediately.
And that's always the way FDA has gone about it.
But you can't let the exceptions overtake your rule. Or you would be back
where I was in September 1971.
The fact that the laxative panel has come up with half of the products being
unsafe or ^ineffective doesn't remotely surprise me. I expect that will be true
as we go through everything over a period of time.
That doesn't mean "that today, I should go out with that proposed regulation
and take all those half of the products off the market.
To do that would put me right back where I can't afford to be.
Namely, putting all my resources into litigation rather than into covering all
hundred or five hundred thousand products at once.
This is what I would call attention, that will exist as long as we adopt the rule
making approach.
And it is the classic situation in cost benefit analysis, you give up something
in the short term in order to get something in the longer term.
And if you don't give it up in the short term, you will never get to the long
term results.
Now, let me go back to the exceptions because they are important.
Starting with hexachlorphine, which was the first exception, we said if there
is a sufficiently great hazard which I as a lawyer am not about to define. Whatever
that means. We will take that out of turn, and we will handle it even before it
goes to the panel.
Then we got into TBS and we said if there is not a sufficiently great hazard,
just take it away from the panel completely.
But the panel believes it is something we ought to take out of turn, once the
the panel's report has been made, as we did with TBS, then we will also do that.
That is sort of an intermediate step. And if it is a lack of safety, but does not
create a big enough health hazard to justify one of the other two approaches,
then we will handle it in the ordinary course of business.
Now, those are the three options that we've got.
I think that Gary and Bob and I have tried to spell those out to you over a
period of time. And maybe it is useful to go back and talk about those three
options.
Then again, I wanted to lay out the historical background so you understood
how we were coming at this.
And why certain things have happened. Let me continue for one moment,
and then come back to those three options.
The people out in the industry aren't stupid. They see what we have done.
And they see in some instances where they can take advantage of it.
There is a new toothpaste called AIM. You have seen television advertisements.
Until the OTC review, we had required an NDA for every fluoride toothpaste.
Having adopted the policy of not litigating except in health or fraud issues,
pending the OTC review, that particular company, and I don't remember which
one it is, decided this was a good time to put out their new toothpaste without
getting an NDA.
Their competitors came in complaining. And said, "Damn it. We had to get an
NDA. How come they don't have to get an NDA?"
And we said it is really a matter of priorities and resources in FDA.
If I were to start litigating against every AIM type product, then I would
have my 18 lawyers spread all over the courts of the country again on a piece meal
ad hoc case by case basis instead of handling it on a comprehensive basis in this
room.
And in the other panels like this. So it creates dislocations on a short term basis.
There is no question about that.
There have been probably 20 or 30 products of that type that I can think of
off the top of my head put on the market in the last year or two, taking advantage
of that situation. And there, it puts me in a tough spot because I was the one who
61
sort of made the principle decision two and a half or three years ago that this was
the intelligent way to go.
Because I would know that in five years from then, maybe two years from now,
we will have the full OTC business under control as opposed to 45 products under
control. .
And I was willing to give up what I had to give up m order to gam that.
Now, let's come back though to this issue of the Gillette letter.
The Gillette letter poses the issue to you that really we have been posing for
the last few months.
It is phrased a little differently, but it is the same damn issue.
The issue is whether either you have sort of a huge safety problem that justifies
the hexachlorophine approach.
Or an intermediate safety problem that justifies the TBS approach.
Or simply the usual safety issues, maybe a little bit greater. But roughly in the
same category as the antacid approach found.
Dr. . Tell me again about that TBS approach.
Mr. Hutt. OK. The TBS approach was to go through the report stage. And at
the end of the report to say instead of following and having a tentative order
and then a hearing on the tentative order, then a final order, which takes time.
And as of that time, you have a separate notice of proposed rule making. On
which there is time for comment and then a final order.
Which would be changed so you would shorten the time period involved roughly
in hah, I would say as a rough estimate. You would cut the time period in half.
And if anything came out ultimately in the whole procedure, then you could
always go back and modify the regulations dealing with TBS.
And that is still, that is an option that is still available. Any of these three
options are available here.
But what I wanted to do, and I still have some time. But I wanted to lay it out
in perspective to see the whole scene. Because you can't just take this one product
and make any sense out of anything.
You've got to put it into the entire spectrum of what the agency is trying to do
And if it deserves special treatment under either hexachlorophine or the TBS
approach, then you ought to make that recommendation.
And you ought to spell out the reasons which were spelled out at the time of
hexachlorophine and TBS.
Now, I think about you and Gary sitting there, and Mary, if you want to add—
if vou think that I have left anything out.
Ms. Bruch. Well, I think the one thing on TBS is one of the issues that the
panel debated was that the hazard was there and they saw no way that it was
going to go away.
The testing to prove that you could alter it was probably impossible and
unethical.
And that they felt that was one reason— that they asked TBS.
Mr. Htjtt. In both hexachlorophine and TBS, we had demonstrated human
harm.
Without any questions. With the hexachlorophine, we had dead babies in
France.
In TBS, we have extraordinarily well documented cases of sensitivity, photo
sensitivity, all over the country, and indeed, all over the world.
The only issue was whether it was being reduced because of getting an impurity
out or not. That is still an issue as far as I am concerned.
We haven't resolved anything. We haven't put out a final order.
That in my opinion is not an absolute requirement in the sense that if this
panel just felt very strongly that although there is no definitive proof of harm,
there is such a likelihood or probability or the harm is so severe that no reasonable
man should put up with it in the intervening period of time, then you can make
the same recommendation.
I am not saying that you have to wait for dead bodies. And clearly that has
never been the FDA's approach to things, and we would not approach it here.
But you have to have — the one thing is, you know, I have demanded of you,
and I demand of any scientist or of any lawyer, you have got to have reasons that
will convince people and you have got to spell them out in words of one syl-
lable and third grade English.
Because the lawyers who will look at it, and sometimes you need third grade
English for all of us to understand.
And it has to be articulated in a way that anybody would read it and say ;
"Yes. I see the problem. And that makes sense."
That's all 1 demand. Bob, you wanted to—?
62
Mr. Pinco. I think, I wasn't here at the very beginning. I think, what I under-
stand seems to be troubling the panel is that having categorized the thing into
these, the ingredients as it were, into category two. they would like to see the
thing happen immediately.
And I think we had discussed the limits. In fact, I mentioned it at the open
session and we were talking later, a few of us, about the limits that we have in
terms of where the agency is able to go and on what basis.
And it still places, again in this particular situation, 1 think that they are
troubled by the fact that everyone is going to run to the market place.
And you know, there will be five or six brands or so on in the market place.
After they have already in sense made their comparative decision, this is where
they want it to go.
Mr. Hutt. We have that problem again in all seventeen panels.
And we have to — the one thing that I also insist upon is absolute uniformity of
treatment.
If we are going to say that a given product can stay on the market, we cannot
then say that no one can come out and compete with them.
On the other hand, if we are going to — either everyone goes on or everybody
comes off.
It has got to be that way. Unless you as a panel can say there is a distinguishing
factor that this particular product has been proved safe.
In which case, you can say everybody ought to do the same test. And also
prove theirs safe.
And I am obviously not going to get into your specific zirconium problem,
because I don't know a damn thing about it.
I wouldn't know what should be done to prove safety. Or I wouldn't know a
safety test, I imagine, if I saw it.
So all I can do is to deal in generalities. , I wonder if it would be possi-
ble for you, either off the record, or you could perhaps choose not to, stop speaking
as an industry liaison and tell us a little bit about what went on at the Gil-
lette company, if you know about it.
Or would you rather not do that?
Dr. ■ — . I think he should not be put in a position of doing it if I can
speak for him.
I think — the agency has had a general rule that the industry liaison in dis-
cussing particular company things ought to do it in an open session.
Mr. Hutt. OK.
Dr. — . I don't think we should put — on the spot.
Dr. . I think he spelled it out rather clearly.
I think that I see a place for this to go in those three categories that you de-
scribed.
It is just a little dismaying to us to feel, as I feel, that as a result of our putting
it into a category 2, primarily because of our concern for its hazard, we have
actually encouraged its distribution in the market place.
Mr. 'Hutt. Well, I would not agree quite with your characterization because,
putting it in category 3 or 2 — I mean, putting it in 2 as opposed to 3, didn't
encourage it going into the market place.
Dr. . Well, the time delay between the implementation of the final
report and the final monograph
Mr. Hutt. Well, I understand that. Which is why we have the exceptions.
Without a question.
The difficulty is when you start down a process of this kind, and that the law
does have a concept that'all of you have heard of called due process of law.
The fact that this panel makes a recommendation doesn't mean it is auto-
matically accepted.
You know, there are rights to appeal up to the Commissioner. There are rights
to appeal to the Court.
And that is part of our legal process. So all that we could do would be to expedite
the process.
But they would still be entitled to their legal procedures.
And putting it in two I don't think has encouraged anyone to do anything.
I think it has encouraged them to test. And if indeed there is not enough testing
being undertaken, then I think that the Commissioner, and I know I can speak for
him on this without asking him, the Commissioner would be willing to do anything
that you recommend to make sure that that testing is undertaken. And that the
people get the message if they haven't gotten it.
I certainly would be willing to do that.
63
Dr. . Well, that confusion is certainly evident in that letter that
we received. , ., _ .
Mr. Hutt. Well, I think that the greater confusion in that letter if I can speak
with my friend Dr. present, is a lack of real understanding of the OTC
review. And , that is not meant personally.
In all seriousness, the delay that you talk about is inherent in the legal process.
And it is inherent in the way that we have gone about this particular project.
Which is why we built into the process the exceptions that I talked about.
But I think you can appreciate that it would be very difficult for me now, on
the laxative report released two days ago and rush out into the courts. And
start bringing law suits against all the products, where, first of all, they haven't
completed their legal process.
And second, overnight, I would have used up all the legal resources of the agency
bringing those lawsuits. ' ' ■
I would be jumping into a race without finishing the process. And where there
is justification, we will do that.
Where there isn't, we have just simply said that we won't.
So that part of the letter that says it is incongruous for something to be in
category 2 and still on the market, that's the way you answer that.
All of the things in the laxative report released two days ago that are in category
2 still have a right to submit comments.
At the end of the comment period, they have a right to request an oral hearing
And when the Commissioner rules against them, if he does, they have a right
to appeal that to the Court.
We do not have arbitrary authority, nor I might add, have I ever suggested
that we ought to have it.
That I don't think would be the answer either. I don't think any of you would
want it. , .
That's not the way the Government does business. Although we are accused of
it from time to time.
Mr. Pinco. , in the context of the information that was sent then to the
Commissioner, what your thoughts were, I think it maybe becomes clear to the
panel why there was no reaction.
I got that from Lee that you were sort of expecting action from the
Commissioner.
But based upon the way we set it up, unless we were going to go this serious
hazard route, which we all went around and determining getting that paper ready
and so on, the only mechanisms that we saw of this point, and as Peter discussed,
were the ones where your report comes out like the tribumsalane, in the regular
mechanism.
So we didn't see the need to respond. I hope you didn't think that we didn't
care. Because the Commissioner didn't
Mr. Hutt. The Commissioner is quite well aware of this problem. To say the
least.
Mr. Pinco. It is just that we didn't see another mechanism before.
Ms. Bruch. Our serious problem really is in hexachlorophine, it was fairly
easy because of an accident in the safety of the babies.
We probably have the actual cases in here where we were faced with the issues.
We so far do not have proven clinical cases.
Mr. Hutt. There is one thing that I think could certainly be done at a minimum.
And that is to make clear to everyone in the outside world what this panel and
FDA expect in terms of testing. Beginning right now as opposed to beginning in
four months, much less two years.
And if that has not successfully been done, that could be done. And I am sure
very effectivelv.
And I think, for example, the panel could easily say right now on an issue oi a
sort of interim conclusion to be directed to the industries, here is the kind of test-
ing that we would expect anyone would be doing today.
And if people are not starting that today, then when it comes time for your
report, you might well recommend the TBS approach of speeding up the process.
You 'don't have to reach that decision today, because, obviously, you don't
have your report in final draft form at this time.
Now, all I wanted to do right at this moment, the reason that I came down
immediately when I read this letter and heard that you were going to talk about it,
was to lav out some of those things.
I would be delighted to come back down either later tonight or tomorrow
morning or whatever. Or I could give you a time.
Dr. . Just before you go, you spelled out for us very nicely the legal
aspects. And of course, this is a country of laws. And we will abide by the law.
64
But you are a lawyer, and we are not. Let us now, the way you are prepared
to tell us you don't understand or you don't know the scientific aspects. But you
do know the law.
Let me speak for those of us who do not know the law. We seem to feel we
realize full well where we are.
Let me set that out in words that are very clear. We have a situation which
people who want to be dry under their arms can be as dry technically as possible,
even with these sprays. By using an aluminum roll on.
People who chose to use a spray because they perceive a pleasure of a spraying
rather than a rolling on, can be dry to the best one, come quite close to what these
achieve.
So in terms of the benefits, we see very little benefit from this particular class
of products. That is point one.
Very little additional benefit from these over either the roll ons, the zirconium
creams, the Secret cream, the roll on, the aluminum sprays. Very little benefit.
Secondly, we perceive here the potential hazards which if it occurred would be of
very large magnitude. Pulmonary fibrosis, which is a dreadful thing to happen to
people.
And it could be happening on a very large scale with a little bad hick.
Only a few people worked in fluorescent tube factories. But lots and lots of
people are breathing this thing.
If this thing causes trouble, it will cause a lot of trouble potentially.
And if it is a particularly nasty kind of trouble, where irreversible change occurs
in the lung, that is the second one.
Third, the nature of this kind of disease, it comes on insidiousty. It comes on
slowly. It is hard to test for.
The natural history of these diseases is that it is a long time before doctors
finally got on to them.
And people are very disappointed that it happened.
We find, as I indicated in my letter, no mechanism for coming to grips with
early disease. Within the FDA as far as I can determine.
Industry has flat out done all it can to get these files closed, one at a time. They
have not gone in there and followed through with a guy who says, "I have been
using sprays all my life. This one makes me cough. What did you put in it."
They have not gone and tried to test this guy with fiberoctic bronchostomy and
all kinds of things that could have been done.
They tried their best to quiet it down. In fact, statements of physicians deter-
mine nothing need to be done.
We can't go, "Which Position?" Their position or man's position.
It is very disturbing. This is another medical fact.
So if early disease be present, we are not in a position. We don't have the
technology for knowing.
We have the theoretical question. If you have a question, you just ask it. You
don't have the technology for knowing it.
Dr. . We have the technology, but it is not being applied.
Mr. Hutt. All right. Now, this gets right back, if I could just drop a footnote,
and come back to it, to what I said earlier.
Here things are not being done. That should be done.
That is something
Dr. . That is one of the things that
Mr. Hutt. We can deal very directly with that, and very quickly, and very
effectively.
Dr. — -. OK. That's one of the things that we can state. That we haven't
touched on that — we haven't.
The next thing is we have now one company selling, claiming a market advan-
tage. There time is up.
We are now going to have Carter- Wallace, we are now going to have Gillette.
We can expect that if we don't have anything in two years, this stuff is going to
sweep the market. And everybody is going to be using this stuff all the time. The
issue is going to be magnified.
Mr. Hutt. OK. Let me summarize by saying that the way this is set up, I
would be violating the FDA rules if I were to give you advice.
It is your job, so with Mary, so with Bob. If I were to say 3^ou are to do "X,"
or you "ought to do any of the alternatives, I would then probably get a law suit,
either by the consumer group that would be disappointed or by the industry
who would be disappointed. One or the other is going to be disappointed.
Now, I will steadfastly refuse to get FDA into that. And so with all the rest
of that.
65
Because that will foul up the whole system, and we will have to start out with
I can lay out the alternatives. You can lay out your concerns and what you can
prove and can't prove.
And what you've got to do is make a recommendation now to the *ood and
Drug Administration as to what you think the best approach is.
At that point, then FDA comes in and we can get into it and say, "Yes, we
agree." "No, we don't agree." Whatever.
Recognizing that I don't know what the outcome will be of your deliberation
or of our deliberations.
But for us to now tell j^ou what we want you to do is to recommend to us this,
that, or the other thing would be wrong.
That would just foul up the whole system. And I think you understand that.
I will be happy to come back if you like . . .
Mr. Fountain. These pages disclose that shortly before 4 p.m. on
March 24, 1975, Mr. Hutt appeared before the panel and said: "I just
read the Gillette letter and understand that you wanted to discuss it,"
Mr. Hutt, your discussion with the panel provides good insight into
the origins of the monograph, or drug class, approach in the regulation
of OTC drugs, the procedures adopted by FDA, and the problems
and possible deficiencies which have arisen.
In that discussion you indicated that you stopped all litigation
involving OTC drugs "because you felt it was futile to proceed on a
case-by-case basis. Can you fix the date when you stopped all litigation
involving OTC drugs?
Mr. Hutt. There was no particular date. It would have been m the
course of 1972 after we had decided to go ahead with the broad rule-
making approach. I had learned, as I related at the last hearing, Mr.
Chairman, that the litigation was proving to be even more futile than
I had originally thought. At least one company had totally reformu-
lated its product and I was faced with going back and starting the
litigation all over again, even on just that one product.
However, there would have been different dates for different pieces
of the litigation.
Mr. Fountain. During the course of the litigation about one
product, the company had reformulated the product?
Mr. Hutt. Indeed,\vhen that case reached the U.S. court of appeals.
That was the Xerac Acne Gel case.
Mr. Fountain. Was this about the time you published the proposed
1972 monograph regulation?
Mr. Hutt. It is my recollection it was after that time. Again, it
spanned at least 6 months.
Mr. Fountain. You told the panel that when you assumed your
present position as FDA General -Counsel in September 1971, the
agency had eight lawsuits in the courts against OTC drugs.
"Mr. Hutt. That was a rough number; yes.
Mr. Fountain. Approximately?
Mr. Hutt. Yes.
Mr. Fountain. One case was litigated. In that connection you said :
We litigated one of those cases, Xerac Acne Gel. I have never even heard of
the product. * * * We litigated that case all the way up through the U.S.
court of appeals. We had affidavits filed in the district court. And they found
that it was not generally recognized as being safe or effective.
I assume from that statement that you won that case in the U.S.
district court?
66
Mr. Hutt. We won that case in the district court. That is the one
that proved to be so futile because, when we got to the U.S. court of
appeals, the company informed me they had reformulated the product
which would have made the appeal in the U.S. court of appeals moot,
If I recall correctly, Mr. Chairman, and I would have to go back
to the record and check, in that case we concluded not to waste our
time with the appeal in the U.S. court of appeals. Instead we reached
an agreement with the company that they would abide by whatever
came out of the rulemaking; the final monograph for that class of
drugs. The litigation was therefore dropped. That is my recollection.
Mr. Fountain. We shall try to put this into context by putting
into the record the statements which you made at the time.
Mr. Hutt. Surely. My recollection is that it is virtually the same
thing I said, indeed, at the last hearing.
Mr. Fountain. The firm apparently appealed the decision to the
court of appeals since you state, and again I quote :
We went to the ccnirt of appeals. And the court of appeals — well, when the case
was pending in the court of appeals, the attorney on the other side called me up
one day and said "I would just like you to know that we changed our formula."
You then told the panel, and once again I quote:
Now, what that meant was, we started all over again. Because just because we
have the old formulation taken off the market, they could put a new formulation
out, and we would start all over. So I said that's that. To hell with it. I am not
going through any more litigation. I stopped all the litigation. All of it. Traded
out all those cases. And we started along the rulemaking approach.
How were those cases traded out?
Mr. Hutt. By exactly what I just described, as I recalled, in the
Xerac Acne Gel case. We got a stipulation from the company that
they would comply with the final monograph coming out of the OTC
drug review.
Mr. Fountain. Were you referring to the eight suits already m
process?
Mr. Hutt. Yes. I would have to go back on each of those eight.
There was one I disqualified myself and my staff handled that. I
think they got a change in the formulation on that drug.
My recollection is that Excedrin PM was never terminated. That is
still pending in the court because the attorneys on the other side
would not agree to a stipulation.
My recollection is that we did proceed through summary judgment
in one of the cases, Vice Spice, that famous aphrodisiac I mentioned
last time which is made of paprika, and that the remainder we suc-
ceeded in stipulating, and thus as I put it colloquially to the OTC drug-
panel, traded them out.
Mr. Fountain. How many of them involved charges that 01 C
drugs were new drugs not covered b} T approved NDA's?
Mr. Hutt. All of them. That was the whole purpose — to get rid of
all that useless litigation which had really not achieved anything
except waste the time of my staff and the Bureau of Drugs.
Mr. Fountain. Being an attorney I can understand some of your
feelings in a matter of this kind. However, am I justified in assuming
from the reading of your statement to the panel that you were simply
throwing in the sponge, so to speak, in a moment of frustration oyer
what had happened? I get the impression you decided at that point,
and I think perhaps you have said that, that it was futile to try to cor-
67
rect OTC drug violations as they were encountered because FDA
hadn't accomplished anything meaningful in bringing the actions it
had. Is that a justifiable inference?
Mr. Hutt. It was futile to adopt an outmoded means of enforce-
ment, that is, the case-by-case litigation approach.
I think, Mr. Chairman, at this time, if you would permit it, I would
like to read from some of the court decisions which have subsequently
been handed down reflecting the courts' conclusion that what I did
at that time made eminently good sense.
There are several court decisions in which the issue of the legality,
the propriety, and the good sense of the OTC drug review has been
raised.
I have a list of five of them here ranging from district court decisions
to the U.vS. Supreme Court.
Mr. Fountain. You can insert those in the record. You can sum-
marize them if 3^011 wish.
[The documents referred to appear in the appendix at pp. 318-331.]
Mr. Hutt. In Judge Bryant's decision of October 1972 in the
American Public Health Association case, he exempted all over-the-
counter drugs from his order for implementing the DESI review on
the ground that use of the over-the-counter drug review procedures
were eminently more sensible and reasonable.
Mr. Fountain. This was efficacy only, and not safety?
Mr. Hutt. Efficacy only, but since the OTC review procedures
involve safety, it involved safety as well.
Mr. Fountain. Each company had a new drug application on file
with FDA?
Mr. Hutt. No, not the "me too" drugs, none of them, of which
there are 13.
In a case that was litigated down in Georgia, the Colintrol 80 case,
the issue arose as to whether this was the kind of thing FDA should be
doing. The court quoted from earlier court of appeals decisions saying
that "agencies must exert the greatest resourceful, imaginative
ingenuity in devising procedures which in a day of ever-expanding
dockets will permit the regulatory process to function properly with
reasonable dispatch."
Then, after that quotation, they said this about the OTC review:
"It would appear to the court that in the instant case the FDA has
attempted to fashion procedures calculated to achieve precisely the
result applauded hy the fifth circuit court of appeals" in the quo-
tation I just read.
The precise issue of the legality of the over-the-counter drug review
arose in a case on the west coast. Here is what the district court judge
said in the Smart case:
It has been thought, possibly mistakenly, that over-the-counter drug remedies
are so safe and effective, and Congress is now, as I understand it, inquiring into
whether those expectations on OTC drugs have been appropriate. I take it to be
fully within FDA's jurisdiction to make that determination and to establish a
procedure for doing so as they have done here.
Then the court says :
Advisory committees are policy-determining groups whose deliberations are
entitled to protection.
It seems to me here we have a very sensible, a very valid, a highly appropriate
method of exploring a wide range of things that, if they were to be taken on an
item-by-item basis, would be impossible ever to handle, and it is only by the kind
68
of approach that has been worked out here that the Congressional purpose can
be achieved. It is obviously a proper purpose. It is in my view not only permitted
but a highly desirable method of seeking to achieve the purpose.
More recently, and I would conclude with this, the U.S. Supreme
Court, in the Bentex case, first lays out in detail the OTC drug review,
and then goes on to discuss not only the propriety but the need to
handle issues of this kind on a broad rulemaking basis that affects
everyone at once.
The Court said :
We think it is implicit in the statutory scheme, not spelled out in haec verba
that FDA has jurisdiction to decide with administrative finality, subject to the
types of judicial review provided, the "new drug" status of individual drugs or
classes of drugs. The deluge of litigation that would follow if "me too" drugs and
OTC drugs had to receive de novo hearings in the courts would inure to the interest
of manufacturers and merchants in drugs, but not to the interest of the public
that Congress was anxious to protect by the 1962 amendments, as well as OTC
drugs and drugs covered by the 1972 act.
The Court goes on to say:
A case-by-case approach is inherently unfair because it requires compliance
by one manufacturer while his competitors marketing similar drugs remain free
to violate the act.
They cite a good number of other cases in which the Supreme Court
has urged Government agencies not to use the case-by-case litigation
approach, which I discarded in 1972, but instead to go to a broad
rulemaking approach which the Supreme Court endorsed in 1973.
Mr. Goldhammer. I would like to attempt to put things into
perspective.
First, going back to the Bryant case, that concerned the DESI
review. Was not that DESI review a review of drugs for which new
drug applications had been submitted but which had been cleared
only on safety, and were now to be decided on the evidence of efficacy?
The Food and Drug Administration then contracted with the Na-
tional Acadenry of Science to review the data on efficacy for those
drugs, which, as I say, were covered by NDA's?
Mr. Htjtt. Yes, that is entirely true. That included, as you know,
Mr. Goldhammer, over-the-counter drugs as well as prescription
drugs.
Mr. Goldhammer. That is right. It did not cover those over-the-
counter drugs which were on the market prior to 1938 and were
believed to be exempt from the efficacy requirements as well as
safety requirements, the premarket clearance requirements. Is that
correct?
Mr. Hutt. That is not entirely correct. If a drug was on the market
prior to 1938 but another drug came on the market after 1938 with a
related, similar, or identical ingredient and was the subject of an NDA,
I would take the legal position that that NDA covered the earlier
drug and, therefore, the grandfather clause would not apply.
Mr. Goldhammer. I would agree that if a manufacturer came out
with a new product for the first time, even though it imitated some-
thing on the market which was grandfathered, FDA would be justified
in holding that to be a new drug.
Mr. Hutt. But, Mr. Goldhammer, what I am sa3ang is that the
fact that the NDA was issued after 1938 would be sufficient to break
the grandfather clause for the pre-1938 drug, in my opinion.
Dr. Goldberg. It has not been litigated on that point.
69
Mr. Hutt. No. But I believe you can read that into the U.S.V.
case the Supreme Court decided in June 1973, Dr. Goldberg. We have
taken that position, I might add, in the preamble to the final hearing
regulations which we published just roughly a year ago to implement
the Supreme Court decisions.
Mr. Fountain. Do an} r of the members have any questions?
Mr. Fuqua. I have no questions.
Mr. Fountain. Congress gave the Food and Drug Administration
some very potent enforcement tools to deter violations. Penalties
can be severe, as we all know.
I would like to ask you, Mr. Hutt, whether you do not feel that
the lawyer who notified you of the formulation change in the Zerac
Acne Gel case would have had some second thoughts about another
attempt to evade the new drug provisions of the law if you had told
him in no uncertain terms that if the change in formulation still
resulted in an illegal product, and they persisted in shipping it inter-
state, you would recommend that FDA apply the statutory sanctions
of seizure, injunction, and prosecution?
Mr. Hutt. He knew that, Mr. Chairman. He was a very well-
experienced attorney, an expert in food and drug law, and I would
simply have been telling him the obvious. Whether in fact I told him
that or not I cannot recall. I probably did.
Mr. Fountain. Did he know FDA would apply it?
Mr. Hutt. Certainly. That simply restates the law. Let me tell
you the difficulty again, Mr. Chairman. I did a little research on this
after our last discussion, to take a look at some of the cases on which
affidavits have not been sufficient to go to summary judgment, and
also the number of affidavits that have been required and the expertise
of the people required for useful affidavits.
There are a number of cases, even after the AMP case you cited the
last time, including one in the same judicial district, which have held
that it is not sufficient for FDA to put in affidavits and that there
must be a trial on the issue of new drug status.
The Exedrin PM case I cited the last time was in the same district,
namely, the Eastern District of New York, as the AMP case, which
was decided by the second circuit.
In that particular case we got affidavits from the following four
witnesses :
Walter Modell, professor of pharmacology at Cornell, one of the
world's experts on pharmacology; Dale Friend, associate clinical
professor of medicine at Harvard Medical School, certainly an expert
in the field; Raymond Houde, associate professor of medicine and
pharmacology at Cornell; and Frederick Wolff, professor of medicine
and head of pharmacology at George Washington School of Medicine.
The court held that was not sufficient to establish a lack of general
recognition of safety. It said that where there is a genuine difference of
medical opinion, some cases have said this very fact indicates a Lick
of general recognition. The court then stated that it would be unfair to
drug manufacturers to conclude as a rule of law, that summary
judgment would lie whenever the Government presents medical opinion
stating that a drug is not generally recognized as safe and effective.
The conflicting affidavit must be examined, for not every conflict in medical
opinion necesparily disproves general recognition.
70
The court ordered a trial. That is not the first case where that was
done.
There are cases where we have had up to seven affidavits from
prominent experts before we have been able to get summary
judgment.
Now, telling the attorney on the other side of the Xerac Acne Gel
case we could again seize, enjoin or bring criminal action would not
scare him because he knew that with 200,000 products on the market
we cannot bring, on a case-by-case basis, litigation against every one
of them. That is again not why we should not enforce the law but why
we had to find a new means of enforcing the law that would be effective
for the first time.
Mr. Fountain . Is it your feeling we need a completely new rewrite
of the law in this area?
Mr. Hutt. In my judgment; no. We have been able, with court
sanction in these cases, to do a little better than Congress did in
originally writing the law, to find a perfectly legitimate, lawful and
acceptable means of enforcing the law without requiring a change in
the statute.
Mr. Fountain. What proportion of FDA court actions would you
say terminate in the agency's favor without a trial or contest?
Mr. Hutt. I can state that with some degree of precision, Mr.
Chairman, because I have looked into that question; 99.7 of our
seizure actions result in no litigation. What that means is this: They
do not go to trial. They may well result in litigation to the extent that
there are initial interrogatories and legal sparring before a consent
order is negotiated, but only 0.3 percent of our cases actually go to
trial.
That is to some extent misleading, because those 0.3 percent are
the ones we are talking about here. They are the ones where there is
something important from an economic standpoint riding on the case.
Mr. Fountain. I can appreciate to some extent the reasons for
your actions when some of these situations arise. Yet, by not taking
action against those new drugs on the market without an approved
NDA, and letting the industry know that this is the policy or the way
you will handle it, are you not in a way sacrificing the deterrent effect
which normally flows 'from the desire of the manufacturer to avoid
statutory sanctions?
Mr. Hutt. We are sacrificing the short term for the long term. We
have two choices when you have a fixed amount of resources. ^ ou
can take those resources and go on a case-by-case basis, and in the
course of a year you might be able to affect 10 OTC drugs a year.
Over 5 or 10 year's, therefore, you would affect 50 or 100 drugs.
Or you can take those same resources and give up the short-term
10-a-year approach, and at the end of 10 years you will have affected
200,0*00. The decision we made was that the latter approach was far
more in the public interest and was a far better use of resources.
Mr. Drinan. What precisely is the short term you are giving up?
Ten drugs a year? What harm do they do to the public?
Mr. Hutt. The kinds of cases we were bringing were not those
which really involved harm to the public. They were more borderline
cases of misbranding.
For example, we brought a number of cases against wrinkle-remover
products on the ground they were new drugs, and not cosmetics.
There was never any suggestion
71
Mr. Drinan. What are you sacrificing in the short run? We have to
find out whether or not the consumer is being hurt. This, frankty, is a
false dilemma you are trying to elaborate, that it is either/or. I don't
think it is either/or.
Tell us more about the 10 a year. You say the}?- don't hurt the
public?
Mr. Hutt. In the Zerac Acne Gel case we were unable to show
danger to health.
In the wrinkle-remover cases we were unable to show danger to
health.
Mr. Drinan. Are they ineffective?
Mr. Hutt. Our contention in the wrinkle-remover cases was that
they did not remove wrinkles.
Mr. Drinan. You have to tell me what you are sacrificing in the
short term.
Mr. Hutt. What we are sacrificing in the short term is our ability,
on specific wrinkle removers and hangover remedies and acne cases,
to have them better labeled and better formulated.
Mr. Drinan. That brings up the question of the delay in following-
through on the advisory committees, however. There does seem to be a
very long delay. In the most recent case, weeks will go by before
definitive action will be taken. Do you think that such delay is con-
sistent with the statute?
Mr. Hutt. I am not sure, Father Drinan, what you mean by weeks
are going to go bj^. We received the report roughly 9 days ago. Within
a short period of time the Bureau of Drugs will have the recommenda-
tion to the Commissioner on that report.
It is a lengthy report and it does require some study!
I think Congress would be concerned if we were simply to implement
an advisory committee report without reading, understanding, and
analyzing it.
Mr. Drinan. You had three oral reports from that committee prior
to this?
Mr. Hutt. Yes. We said we could not just take an oral report. We
needed something in writing, that I would use to go to court if,
indeed, that is to happen.
Mr. Drinan. I yield back.
Mr. Fountain. For whatever it may be worth, you had the panel's
conclusions about 6 months ago.
Mr. Hutt. No ; we did not. We went through that at the last hearing.
We had interim recommendations that at that point were subject
to change, and, indeed, were changed.
Mr. Goldhammer. With each meeting there is a memorandum
sent to the Commissioner detailing in a page or two the most important
developments during that meeting. Is that correct, Dr. Schmidt?
Dr. Schmidt. Yes, that is correct.
Mr. Goldhammer. Do you see those reports?
Dr. Schmidt. Yes, sir, I read every one of them.
Mr. Goldhammer. There was a report issued, I believe, on Novem-
ber 24, detailing rather explicitly the concerns the panel had about
the zirconyl antiperspirant sprays.
As a consequence of that written statement the industry was given
an opportunity in December to answer the statement.
I believe the record of the hearing held on April 23 will corroborate
what I am saying.
72
In January the panel met again and decided that the information
provided by industry in the December meeting, which was in answer
to the November 24 written statement of the review panel, was not
persuasive to justify a change in the panel's decision that it is still
not generally recognized as safe, and it detailed at least seven reasons
why" they did not feel anything had been added by the December
presentations of industry.
I believe a memorandum of that January meeting was prepared and
I would recommend that it be placed into the record. The memoran-
dum to the Commissioner is dated January 31, I believe, and the
decisions of the review panel were again reiterated and the panel
detailed at least seven reasons they felt this was not generally recog-
nized as safe.
[The document referred to follows :]
MEMORANDUM
Department of Health, Education, and Welfare, Public Health Service,
Food and Drug Administration
TO: The Commissioner
FROM: Mary K. Bruch, Executive Secretary of Bureau of Drugs FDA OTC
Antiperspirant Panel .■,„«,,,, . m ™ » T
SUBJECT: Eighth Meeting of the OTC Antiperspirant Panel— INFORMATION
ALERT
The eighth meeting of the OTC Antiperspirant Panel was held at the Parklawn
Building on January 30 and 31, 1975. All members, except Charles Evans, M.D.,
Ph. D. attended the meeting.
OPEN session
There was no open session held. The announcement was made by the Chairman
that anyone wishing to make a statement to the Panel could do so.
Information Memorandum, OTC Antiperspirant Panel, Eighth Meeting,
Parklawn Building
panel members
E. William Rosenberg, M.D., Chairman; Zenona Mally, M.D.; Charles Evans,
M.D., Ph. D. (absent); Jane Rosenzweig, M.D.; Eli Shefter, Ph. D.; Robert
Scheu'plein, Ph. D. ; and J. Wesley Clayton, Ph. D.
liaison members
Consumer, Ms. Marsha Gardner; Industry, Robert Giovacchini, Ph. D.
FDA STAFF MEMBERS
Mary K. Bruch, Executive Secretarv, Division of Anti-Infective Drug Prod-
ucts; Lee Geismar, OTC Staff; Joe Hussion, OTC Staff; Gary Yingling, General
Counsel's Office; and Peter Hutt, General Counsel.
Closed Sessions
The Panel had been presented with a great deal of information at both the
November and December meeting. Procter and Gamble made a new submission
of data at the December meeting and also hand delivered additional information,
including an outline of proposed studies, to Panel members two or three days
prior to the meeting. Carter- Wallace had also made an additional submission.
All these data involved zirconium-containing antiperspirant formulations.
The first hours of the meeting were spent in reviewing the material presented
by Procter and Gamble on December 16, 1974. They discussed what has been
done in response to the Panel's initial concern and what is proposed.
There was much discussion about the consequence of placement of these aerosol
ingredients in Category II and III. The Panel concluded that it would be difficult
73
to say that there was general recognition of safety in light of all the experts
heard by the Panel who were unwilling to say they thought aerosol application
of these products was safe.
The Panel asked Mr. Gary Yingling to further clarify Category II and III
and to clearly state the time course and effects of placement in one or the other
of the categories. They were especially concerned about the problem of production
control and identity of the complex ZAG.
The Panel spent a great deal of time reviewing the studies which have been
done and especially what is known of the chemical structure of ZAG. The company
has provided the "outline of the production procedure but it is not clearly eluci-
dated. The analysis often depends on Al/Zr ratios and pH measurement. The
difficulty in control and analysis was stressed where the specific complex cannot
be tested for or identified.
The intricacies of projecting low-dose, long-term exposure in man to higher-
dose, short-term animal exposures was explored. The Panel is admittedly in a
difficult area which involves many products used by the consumer. The basic
risk is long-term effects from a repeated daily exposure as well as estimation of
the amount of particles reaching the lung and deposited there. The burden to
the body with possible exposure in the gastro-intestinal tract and the blood
stream was outlined by the Panel.
This difficult decision by the Panel required much weighing of the risk/benefit
rationales which have been spelled out in the Panel's Position Paper.
They asked Mr. Hutt to clarify for them his own view of Category II and what
placement there would mean.
Mr. Hutt reviewed the three categories and then particularly addressed the
problem of a novel compound which might have difficult analytical problems. His
point was that if there are five products, all with ingredient X, which has a history
of difficulties, but with closely controlled procedures, is shown to be safe in one
manufacturer's hands, then to be generally recognized as safe and effective, a
regulation would have to be written so that products which contain X would be as
safe and effective as the first manufacturers. If such conditions of manufacture
cannot be written, then an NDA would be required which would direct FDA to
look critically at each product to show that each is as safe and effective as the
original.
He also clarified the meaning of general recognition and told the Panel that
they were representative of a variety of scientific groups and were acting in their
place.
Mr. Hutt also re-emphasized the importance of risk/benefit by saying that if
the benefit is nil then the risk would also need to be nil or less, if that were possible.
After further discussion the Committee made their decision on Category II by
unanimous vote as follows: "All zirconium-containing aerosol antiperspirants/
deodorants be placed in Category II".
Our decision was made for the following reasons :
1. Unnecessary incidence of bronchial and respiratory distress.
2. Unnecessary burden of zirconium particles on respiratory and gastrointes-
tinal tract.
3. Likelihood of retention of zirconium particles in the lung.
4. Insufficient evidence that zirconium-containing particles in the body are not
altered into substances of probable antigenicity.
5. Insufficient evidence of safety of long-term exposure to zirconium-containing
aerosols.
6. Our assessment as to benefit-to-risk=rratio : Comparable degrees of perspira-
tion control are achievable with other preparations which are generally recognized
as having less potential for harm.
7. The chemical and physical complexities of zirconium-containing anti-
perspirant formulations preclude its being identified in a generic manner and
therefore each company's product should be evaluated separately. The Panel
believes the IND/NDA procedure would be required to achieve this.
The Panel believes that the major risks associated with the products, discussed
above, are primarily those of long-term use. We do not believe users of these
products are in imminent danger, since, at this time, we do not have documented
cases of serious clinical disease. We see no need to suggest a product recall.
The continued marketing of these products should be permitted contingent
upon the vigorous pursuit of safety testing by industry. The Panel plans to provide
guidelines for those tests it considers essential.
It is understood that the results of further studies (which should be pursued in
a timely way) are of such concern that they will follow the results until they have
made their report to the Commissioner and will recommend other actions if they
feel they are required.
74
One central issue in their decision was that one manufacturer was able to produce
effects in monkey lungs, in a 90-day study, with only slight alteration in the
preparation and formulation of a zirconium-containing aerosol. The Panel felt
that if this situation existed, the product should be considered not generally
recognized as safe and effective and be subjected to the IND/NDA procedure
so that the manufacturer would come under the New Drug inspection and controls
regulations.
COMMENT BY EXECUTIVE SECRETARY
The Panel spent a long period of discussion prior to making their decision.
They recognized the Commissioner's position as the recipient of many questions
on this subject. They also recognized, and questioned the consumer liaison member
about her view, that consumer advocates may believe a risk to the consumer still
exists and may also feel that the Panel was pressured into retracting their former
position in view of the course of their decisions on zirconium-containing aerosols.
The first aspect of this problem is decided but the question of aluminum
aerosols still needs to be settled. Also the Panel still has to discuss effectiveness
testing and labeling. Both subjects contain problem areas which really have not
been addressed by FDA previously.
Mary K. Bruch.
Mr. Hutt. Is that the one where they recommended that there was
no need to expedite it and take it out of the normal course?
Mr. Goldhammer. No. They did cay they were not recommending
that outstanding stocks of the product be removed from the market.
Mr. Hutt. My recollection is that they also recommended that
that should not be taken out of the normal procedure and that it
should proceed through the full OTC drug review procedure laid out
in the Code of Federal Regulations whereby it would be included in
their report and it would then be subject to all the normal procedures.
They recommended that no immediate action should be taken.
Mr. Goldhammer. Well, I understand
Mr. Hutt. Is my recollection incorrect?
Mr. Goldhammer. I do not have the memorandum.
Mr. Thompson. Are you talking about the January meeting?
Mr. Goldhammer. The January memorandum to the Commissioner.
Mr. Thompson. There was language that there was no imminent
danger to the public.
Dr. Schmidt. I have the quotes from the memorandum sent to me
by the panel on January 31. That does state that then decision at that
time was that all zirconium-containing antiperspirants be placed in
category II. They go on, however, to saj^, "We do not believe users of
these products are in imminent clanger, since, at this time, we do not
have documented cases of serious clinical disease. We see no need to
suggest a product recall." They go on to say, "Continued marketing
of these products should be permitted contingent on the pursuit of
safety testing by industry." And the panel planned to go on and pro-
vide guidelines for those tests that it considered essential.
Mr. Hutt. So at that time, Mr. Goldhammer, it is true they were
recommending against immediate action by the Food and Drug
Administration.
Mr. Goldhammer. Is the test for determining whether a product is
a new drug, and therefore not eligible for interstate shipment unless
it had an approved new drug application, the test of imminent danger
to health?
Mr. Hutt. Again we are plowing ground we went over for at least
an hour the last" time. The fact is that the issue is whether one com-
pletes due process of law, as we discussed at great length last time, and
you go through the entire administrative procedure, or whether you,
75
because of some health hazard, interrupt the normal procedure, take
everything out of order, and do something on quite an emergency
basis. The issue is not whether new drug status is contingent upon
imminent hazard to health. Of course it is not, and we both know that.
The issue here was whether we would follow a published procedure
that was laid out very carefully in the Code of Federal Regulations
that has been endorsed by at least four or five courts which have looked
at it now, including the U.S. Supreme Court, or whether we would
throw that to the winds and adopt willy-nilly a new procedure out of
thin air.
My judgment would be, absent some good solid health hazards,
which we may have here — and that is the issue before us now- — we
would be thrown out of the courts if we did not follow our published
procedure.
As you know, courts have held that a government agency must
follow its published procedure unless there is some reason to vary
from it, and it has to be a good reason.
Dr. Schmidt. I also point out that the health hazard that is being
raised is not an immediate or imminent hazard. It is the consideration
of whether or not this product over a long period of time with certain
exposures can sensitize pulmonaiy tissues and give rise to pulmonary
granulomas. The panel repeatedly said there is no evidence of imminent
or short-term hazard.
Again I will remind you that last time we discussed this process we
pointed out that on at least three occasions, when we thought there
might be a safety hazard, the process was speeded up; for example,
hexachlorophene was taken out of order and moved through the
process ahead of the panel's full report.
This panel at the January 31 meeting elected not to ask me to take
zirconium out of order. Until recently that was their decision and
their recommendation.
Nine days ago I received a written report from them asking the
contrary. 1
Mr. Hutt. Mr. Chairman, the transcript of the meeting to which
you made reference at the beginning of today's hearing will reflect that
I laid out veiy carefully for the panel the alternatives they had at
the March meeting.
Those alternatives — I have not seen that transcript but I remember
fairly well what I said — were to allow it to go through the adminis-
trative process ; to speed it up to the point of taking it out of order in
the way that we did TBS ; that is, at the time of their report to separate
it out from their report and expedite its handling at that time ; or to
speed it up and not wait for their report but to make an immediate
recommendation to the Commissioner.
They asked me at that time what I thought they should do, and I
said that was not my job to advise them. We were asking their advice
and their recommendation. It would be highly improper for me or
anyone from FDA to interfere in their decisional process until they
had made that decision.
» In this connection, the recommendation of the review panel as published at p. 24343 of the June 5, 1975,
Federal Register, vol. 40, No. 109, is "Because conclusive testing to establish the safety of zirconium-con-
taining aerosol antiperspirani s migln take years to accomplish, and because in that time millions of consum-
ers would be unnecessarily subjected to risk, the Commissioner should take immediate steps outside of the
normal OTC drug review' process to stop movement of these agents in interstate commerce until the safety
testing has been done adequately to secure the approval of an NDA."
The full Federal Register statement appears at pp. 262-294 of the appendix.
55-495 — 75 6
76
However, they had the options laid out for them very, very clearly
at that time.
Mr. Fountain. Getting back to my question about the possible
deterrent effect of doing certain things, let me cite an example of this
that I am familiar with. In December 1970 this subcommittee con-
ducted a very limited investigation to determine the extent to which
new drugs were being marketed without NDA's. As a consequence of
this very limited survey, the subcommittee referred to FDA two new
drugs on the market without NDA's. One was a new formulation of
Ayerst Laboratory's ophthalmic solution Epitrate, and the other was
Smith Kline & French's cold remedy Ornex.
FDA took prompt action, I am pleased to report, to obtain early
compliance. On January 11, 1971, FDA advised Ayerst Laboratories
of its opinion that Epitrate was a new drug subject to premarket
clearance. The firm acted promptly to discontinue distribution of the
new product and, on February 26, 1971, recalled all outstanding stocks.
I am placing a copy of Ayerst Laboratories' February 26, 1971, recall
letter into the record.
[The letter referred to follows :]
Ayerst Laboratories,
Division of American Home Products Corporation,
685 Third Avenue, New York, N.Y., February 26, 1971.
Important Drug Recall
Ayerst EPITRATE ® (epinephrine sulfate)
Gentlemen: Several months ago Ayerst Laboratories introduced a revised
formula of EPITRATE, a product with which you are undoubtedly familiar.
The revised formula contained the active ingredient, epinephrine, as the sulfate
salt in place of the bitartrate. The bitartrate form of EPITRATE had been used
successfully by ophthalmologists for approximately twenty years.
The Food and Drug Administration recently determined that the revised
formula of EPITRATE is technically a new drug, and as such requires an approved
new drug application, although controlled studies were conducted by a number of
oohthalmologists prior to its introduction.
1 At the request of the Food and Drug Administration, Ayerst Laboratories is
withdrawing the epinephrine sulfate form of EPITRATE, and replacing it with
the original product which contains epinephrine bitartrate.
In the meantime, please discontinue at once, all shipments of EPITRA1 h
(epinephrine sulfate). We would also appreciate your returning for credit your
existing inventory, at your earliest possible convenience, to:
Director of Production
Ayerst Laboratories, Inc.
Rouses Point, N.Y. 12979 ^^^^
Please note on the outside of the mailing container — EPITRATE RETURN b.
On March 4, 1971 we will send you, based upon your purchasing history, an
adequate supply of EPITRATE (epinephrine bitartrate 2%). This will be shipped
by the fastest possible means so that you can continue to supply your accounts.
You will be billed at the usual discount.
We sincerely regret any inconvenience to you and appreciate whatever assist-
ance you can offer in order to make this exchange expeditiously.
Yours truly,
H. K. Roberts,
Vice President, Marketing.
Mr. Fountain. So, in little over 2 months from the time the
subcommittee referred the violation to FDA, complete correction
had been effected, including recall of all outstanding stocks. You will
agree with me, I am sure, that that is efficient, effective, and economi-
cal enforcement.
Mr. Hutt. Do you have the facts on the Ornex case?
77
Mr. Fountain. I will get to that next.
Mr. Hutt. Good.
Mr. Fountain. The question I want to ask to follow up the prefaced
remark — don't you think that that type of enforcement consistently
used would pay off in greater compliance?
Mr. Hutt. I do not.
Mr. Fountain. You do not?
Mr. Hutt. I clearly do not. Our entire past history has shown that,
with rare exception, and that may be a single rare exception, it has
not paid off at all, and indeed resulted in the mess that we had to
straighten out with the OTC review.
It was reliance upon that kind of approach that resulted in the
fact that we have 200,000 OTC drug products on the market, but a
total of only about 450 or maybe 500 new drug applications, meaning
that there are virtually 200,000 unregulated products out there,
and nothing to protect the public. That is why the old approach, the
case-by-case litigation approach, was so totally ineffective.
Mr. Fountain. But Epitrate was a prescription drug.
Mr. Hutt. Yes.
Mr. Fountain. There were other prescription drugs being put on
the market without preclearance. Is that right?
Mr. Hutt. Prescription drugs are quite a different issue. I would
agree with you that there is greater effectiveness of the NDA system
in the prescription drug field of that.
I think I can give you an illustration of the figures. During the
period 1938 to 1962 we had roughly 8,000 new drug applications for
prescription drugs.
During that same period we had less than 500 new drug applications
for OTC drugs. Yet, as you know, there are many, many more OTC
drugs that were marketed during that time than prescription drugs.
Mr. Fountain. Any questions, gentlemen?
Mr. Thompson. Mr. Hutt, with the adoption of the OTC mono-
graph, are case-by-case actions precluded?
Mr. Hutt. No. We laid down a general rule that we would continue
the case-by-case litigation approach whenever there was a health
hazard .
Father Drinan, I should have mentioned that to you to alleviate
your concern.
If there is a health hazard we will do one of two things. We will,
as the Commissioner said, take an issue out of turn in the OTC drug
review and deal with it on an expedited basis, or we will bring a lawsuit.
Similarly, if there is patent fraud — I think I mentioned at the last
hearing a cancer quack which could, because of its effectiveness, also
be considered unsafe or just a gross fraud on the public — we will take
court enforcement action there.
Mr. Thompson. If you were to take a case-by-case method, your
research and data base for proceeding would have to be quite thorough,
would it not?
Mr. Hutt. Yes.
Mr. Thompson. Not unlike the type of information you would need
from an OTC panel if you were to promulgate a series of regulations.
Mr. Hutt. 1 would say it could be done more quickly, Mr. Thomp-
son, but it has to be good enough to win in court.
78
I have said many times that I do not believe just in litigating; I
believe in litigating to win.
Mr. Thompson. What would be the detriment and possible penal-
ties to FDA if a case-by-case method is taken and you erroneously
seized a product?
Mr. Hutt. We would lose the litigation. If we were not well prepared
we would get very bad precedent. That has happened on occasions in
the past, where there is one product out of a series of products which,
in effect, has immunity over a period of time because we have seized
it and lost.
Mr. Thompson. That could have a detrimental effect on subsequent
actions?
Mr. Hutt. Indeed it could. It would make it very difficult to bring
seizure actions against competing products as well.
Mr. Thompson. Particularly in a specified line or type of product?
Mr. Hutt. Yes. We brought a case against a product called Ayds.
a so-called reducing product, which we concluded was ineffective. We
lost that litigation, and since then we have been unable to adequately
control that type of product.
Mr. Drinan. I take it that the FDA was wrong, then. The product
was ruled effective and safe in the Ayds case?
Mr. Hutt. In our judgment, although we lost the litigation, we
believe to this day we were correct in that litigation.
As I am sure you understand, you win a few and you lose a few on a
case-by-case approach.
Mr. Drinan. You cannot really fault a case-by-case approach by
saying it is ineffective because in this case the judge presumably found
evidence that was contrary to what the FDA found. Did you appeal
the case?
Mr. Hutt. I cannot state with certainty whether we did or did not.
Mr. Goldhammer, do 3 T ou recall?
Mr. Goldhammer. That case was thrown out on grounds of res
judicata. The Federal Trade Commission brought a case with regard
to false advertising. They apparently put on a case which was by no
means a good one from the standpoint of the court. As a matter of
fact, the court ruled that there was not even a scintilla of evidence
put on by the Federal Trade Commission.
Then the FDA came along and filed a case, and, in effect, was thrown
out because this question alreadv had been decided — it was res
judicata involving another arm of Government.
The Food and Drug Administration might have been able to put
on a very persuasive case and may have won if it had not been for the
fact that another court had ruled in another case involving another
agency on the same issue.
Mr. Hutt. My recollection is that in one of those court decisions
involving a reducing product we lost it on the merits. I would have to
go back.
Mr. Goldhammer. Yes.
Mr. Hutt. I think you would agree with me that when you lose
one 3^011 are in a very difficult position when you start going against
the others. That, indeed, is part of the problem with the wrinkle-
remover decisions where we got some decisions out of the courts that
really did not help us at all, whereas if we had gone on a rulemaking
basis, established a clear administrative record, we could have achieved
79
uniform labeling for all wrinkle-remover products that I think could
be upheld in the courts. That is now, of course, what we are trying to
do.
Mr. Fountain. Are there products which remove wrinkles, or do
they just cover them up?
Dr. Schmidt. There are some products that tend to remove the
whole face. There are some products that burn and remove wrinkles
that way, and I consider them extremely hazardous.
Mr. Drinan. If I may follow up on a wrinkle in the thinking of Dr.
Schmidt. He is downgrading litigation. I know how litigation goes on
and on.
However, in the Bentex case, as I read it, the Supreme Court did
not really confirm and bless and ratify everything you people are
doing. It said group action, class action, is sometimes necessary, but
it did not, as I read it, say it is futile to proceed on a case-by-case
basis, at least at times.
I am wondering how this policy was formulated.
Dr. Schmidt, was it you who made this policy? Apparently you
have concluded no case by case is warranted because if you lose a
case, then it sets a bad precedent.
Did the whole Commission sit on that? Is there something written
down as to an apparent policy not to go that route?
Dr. Schmidt. I would like to go back and answer a question of the
chairman's that was never answered.
He said to our General Counsel, "Mr. Hutt, would it not be fair
to say that you, Mr. Hutt, in a moment of frustration, decided to
trade out these cases?" That question was not answered.
I shall answer it. It would not be fair to say that.
The necessity is to formulate some rational basis for handling just a
massive problem; that is the regulation of the content, labeling and
use of all OTC drugs which number into the hundreds of thousands.
As Commissioner of Food and Drugs I am responsible for the use
of our resources, which are limited.
The decision was made to go the route of developing regulatory
monographs which would control entire classes of OTC drugs, their
formulation, their labeling, and that their ingredients were both safe
and effective.
Mr. Hutt described the trading out of the cases involved. They are
agreeing to conform with the monograph. The industry has shown
willingness to abide by these regulatory monographs.
This is not in place of all case-by-case litigation by any manner of
means. I assure you that we have done so in the immediate past and
that we will continue to do so if there is evidence of a health hazard.
What Mr. Hutt was referring to was not "either/or" in the sense
of no litigation of anything on a case-by-case basis but an entire mono-
graph approach for everything.
The "either/or" is to try to get 400,000 OTC drugs into compliance.
On a case-by -case basis, that job is just simply impossible.
Mr. Drinan. I agree with that. Nonetheless, a monograph approach
involves severe delays.
Dr. Schmidt. I will not accept that definition.
Mr. Hutt. No.
Dr. Schmidt. We may define the word "severe" and the word
"delay" differentlv. However, vou see there never has been a search
80
of the literature, a gathering together of evidence, testimony from the
world's experts about the safety and efficacy of these ingredients. I
will not accept anything but a sound, scientific, logical, rational ap-
proach that will hold up in court, and neither will anybody else.
Two years to look at hundreds of years of experimentation and lit-
erature and thousands of products' and their ingredients is not a
severe delay. These products have been on the market for literally
scores and scores of years.
For the agency, in a relatively short period of time of 1, 2, or 3
years, to regulate in an effective way that entire mass of products, is a
surprisingly short period of time and I think a great achievement.
Mr. Hutt. And, Father Drinan, in contrast with the case-by-case
litigation approach, if we were again to try to attack the whole field
on a case-by-case litigation basis we would be talking not about delay
but we would be talking about never doing it.
You did ask one question, though, which I believe the Commissioner
did not address directly, and that is how was the policy adopted.
There was initially brought into the Food and Drug Administration
in the fall of 1971 a gr°iiP of medical and other experts to discuss how
we could go about regulating over-the-counter drugs. We presented
some of our ideas to them and they responded in the course of a day's
session.
Then in the Federal Register of January 5, 1972, we proposed the
procedure that we are talkins; about at this time. We received com-
ments on that, and in the Federal Register of May 11, 1972, we laid
out a final procedure, together with, if I recall correctly, an 11 -page
preamble with 98 numbered paragraphs which discussed in enormous
detail every comment which was made and how we reacted to that
comment, whether we agreed or disagreed, and how the procedure was
being changed. This, therefore, was not adopted in a closed room
without public participation. It was adopted in the open democratic
process which the law requires.
Mr. Drinan. Elaborate a bit more if you will on what was said
before; namely, that if there is any question on the safety of a drug
the FDA does*immediately proceed on a case-by-case basis.
How is the questionable safety evaluated or determined?
Mr. Hutt. I would like just to modify what you said in one small
respect. We could not say if there is any question of safety that we
would proceed on a case-by-case basis because there may well be
questions in the sense that a panel would say "We would like to see
someone run a further study," not that they are doubting safety but
simplv to confirm the safety.
In those instances, if we were to take everything out of order, once
again there would be chaos and we would be back to the case-by-case
litigation approach.
What we are talking about is where a panel says, "We think there
is a health hazard and it is of a kind that you should act promptly."
When those are isolated and brought to our attention we will take
action. .
Mr. Drinan. Tell me about the 99.7 percent of the seizures which
are always successful.
Mr. Hutt. Those are the ones where we found hairs m food, and
Mr. Drinan. By "we" you mean the Commission and not the
advisory panel?
81
Mr. Hutt. That is right.
Mr. Fountain. I think we all understand, but this is a good point
to emphasize.
As I understand it, the Food and Drug- Administration does not
have the burden of proving the safety of new drugs. That is the
burden of the manufacturer. Is that right?
Mr. Hutt. That is correct.
Mr. Fountain. In the case of Ornex
Dr. Schmidt. We do have the burden of proving in court, however,
that something should be removed from the market.
Mr. Hutt. We have the burden of proving it is not generally
recognized as safe and effective.
Mr. Fountain. We understand that.
In the case of Ornex, again referring to an example where FDA
acted expeditiously, you acted promptly and notified the firm, but in
that case the firm refused to recall the product.
Mr. Hutt. That is right.
Mr. Fountain. FDA promptly had the product seized.
Mr. Hutt. That is right,
Mr. Fountain. Again, there appears to have been no agonizing
about whether FDA had the manpower to bring the action. The
seizure resulted in the court contest.
The court never was given the opportunity to rule on the merits of
the Government's case because it was one of those where you, Mr.
Hutt, apparently compromised it. You "traded" it out.
Mr. Hutt. That is the colloquial way of saying we reached a
compromise.
I would like to mention one thing in that case so that the record is
clear. I personally had nothing to do with that case. I told my staff
if they wanted to litigate that case they could do whatever they
wanted. That was because, while I never had any connection with it
when I was at Covington & Burling, that firm had some connection
with that case and I, therefore, totally disqualified mj^self on that case.
I am frankly not certain how that case was resolved. Mr. Yingling
could correct me if I am wrong, but I recall hearing there was some
change in formulation along with a stipulation that they would follow
the monograph when the monograph came out,
I would have to have someone from the office provide something
for the record on that because I never did inquire into it at all.
I would point out, though, one thing. It is my recollection that
the court enjoined us from further seizures or from taking further
action, or stayed further action on our behalf, or my predecessor
agreed to it, in any event, through one form or another. So it was a
totally meaningless type of case to have brought. It achieved nothing
in terms of compliance.
Second, there were roughly at least a thousand, and some people
said up to 2 or 3,000, competing products, all of which stayed on the
market, were not changed in formulation, and have not been changed
in formulation to this day.
This again illustrates how bringing one isolated lawsuit is absolutely
meaningless in the real world.
Mr. Fountain. Let's see. Suppose you had let this case run its
course and the FDA had won.
Mr. Hutt. Yes.
82
Mr. Fountain. The message would not have been lost on the
drug manufacturer, and the industry as a whole. It might have had
an impact on these 2,000 cases.
Mr. Hutt. Our experience is directly to the contrary, Mr. Chairman.
We again, in the hangover cases, in the wrinkle-remover cases, in
the Xerac case, it had no impact, the fact that we won. It had no
impact whatever. Not one drug company changed its labeling, its
advertising, or its formulation as a result of that.
I testified to that last week, Mr. Chairman.
Dr. Schmidt. This points up the importance of the blanket regula-
tory monograph which by its very nature forces compliance of the
entire industry. I think it is naive to assume that people in this
very highly competitive market will do any more than say, "Boy!
I'm glad it was them involved in that case." For people to run and
get in line when they did not have to, to conform to some court-
case somewhere in the country staggers the mind.
I think your point that this one case did not use up our resources
is valid. We are not stopping case-by-case litigation. The point we
are trying to make is that it would be impossible for us to do this
same thing with very many cases. There are hundreds and hundreds
of these products which are mislabeled, or illogically formulated — not
dangerous.
A" lot of people think that when something is categorized as not
safe and effective that it means that there may be an imminent danger
to health, that there is a safet}^ question. However, it can be in this
category because of mislabeling. It can be in this category because
there is not substantial evidence of efficacy, with no safety question
at all.
Dr. Goldberg. With respect to Ornex, which was promoted by
the manufacturer as a new and superior drug at the time FDA ini-
tiatcd its action, I would submit that you will never know what the
consequences of a successful FDA action might have been because the
case was traded out.
I read the transcript of the court proceedings in Philadelphia in
which the company was granted a temporary injunction. The basis
for that was purely and simply, as 1 remember it, because the company
had advertised to the physician rather than to the general public,
and the court was persuaded that the manufacturer's reputation
might be hurt if it was not given an opportunity to present its case on
the merits with the product remaining on the market in the interim.
Mr. Hutt. That is right.
Dr. Goldberg. The judge said at the time he was not persuaded
there was any merit to the manufacturer's contentions.
Would you submit for the record who actually made the decision?
Mr. Hutt. Yes.
Dr. Goldberg. Traded out this case and the reason for it.
Mr. Hutt. I would be happy to do that.
[The information requested appears in the appendix at p. 309.]
Mr. Goldhammer. Mr. Chairman, I would like to have the op-
portunity of having the record reveal that I had been with the Food
and Drug Administration from the days even before the enactment of
the 1938 act. I think I am in a position to testify at this hearing on
how the Food and Drug Administration operated in those days.
Mr. Fountain. You are not saying it was necessarily better.
83
Mr. Goldhammer. I am saying that my experience is such that I
have good reason to believe that it was better.
In the first place, even when I retired from the Food and Drug
Administration at the end of 1964 we were a small organization. I do
not believe that our total appropriation exceeded $50 million.
Mr. Fountain. How many emplo^/ees were engaged in the operation
at the time?
Mr. Goldhammer. I cannot give 3^011 precise information on that.
It may have been somewhat in excess — I cannot give you information
on that. It was not a large organization, in any event.
In addition to that we had the responsibility for enforcing laws
which are no longer the responsibility of FDA. For instance, drug
abuse outside of narcotics was the responsibility of the Food and
Drug Administration. This took large enforcement effort.
The Food and Drug Administration also had the responsibility for
establishing tolerances for pesticides. This is no longer the responsi-
bility of the Food and Drug Administration. That was an important
and costly responsibility.
Whereas the Food and Drug Administration has added responsi-
bility today, many of these added responsibilities are compensated
for by the fact they have lost responsibility, important responsibility,
for instance, in hazardous substances, for which today there is a
wholly new agency.
The impression one would gather from the testimony of the wit-
nesses from the Food and Drug Administration is that the Food and
Drug Administration throughout its period of operation was in a
helpless position, not able to enforce the law effectively.
However, up until 1964 when I left, the Food and Drug Administra-
tion was enforcing the law effectively.
Many, many actions were being brought. I think, Mr. Chairman,
during the cyclamate hearing you introduced into the record the
evidence of a disastrous drop in the number of regulatory actions
which were being brought by the Food and Drug Administration. It
was a fantastic drop, beginning around 1970, as compared to what
it was in 1945 when the total appropriation of the Food and Drug
Administration was about $4 million.
I was Director of the Division of Regulatory Mangement for
many years, and an Assistant Director of the Division of Regulatory
Management for many years prior to that.
Prior to my assignment to the Division of Regulatory Management
it was called' the Division of Litigation, which is a clue as to the kind
of work this division did.
It was my responsibility to handle all court actions, once they were
brought, if there was any intimation whatever of a contest.
I can tell you we had scores of cases, and records in the files of the
Food and Drug Administration will bear me out, we had scores of
cases running simultaneously. Most of these cases when contested,
were won in court, We didn't run away from a contest. It was regarded
as our eve^day operational responsibility.
If it was necessary to bring a case we brought ;i case.
At any given time there were scores of cases which were active-, for
which we had to negotiate with attorneys, write interrogatories, take
depositions, and do all the things necessary to prepare for a court
trial.
84
Our ability to win cases greatly discouraged contests so that there
were very few.
I can tell you that in deciding the kinds of cases that were to be
brought, we considered not the individual drug but all of the drugs
involved in the particular class of the drug we were proceeding
against.
Mr. Thompson. Was there a case involving wrinkle remover?
Mr. Goldhammer. Yes, the wrinkle remover cases were brought
in at the tailend of my career. I had a hand in the consideration of
those cases.
Some we won, some we lost.
Mr. Thompson. There are still wrinkle removers on the market.
Mr. Goldhammer. Well, some we won, some we lost. It was a
question of enforcement.
Beginning with around 1969 or thereabouts one can note a
sharp drop in the initiation of cases. It is far more likely that failure
to enforce the law engenders disrespect for the law and widespread
violation of the law to the point where when you attempt to bring
about a correction you have gotten yourself into a position where 3^011
have a mountain of cases to tackle.
However, that was not the situation in the early days of FDA.
We kept current. As soon as the violation was encountered, if it
was worthy of correction, action was undertaken, even if it meant
going to trial.
Having won, then it was customary for the Food and Drug Admin-
istration to issue a notice to the entire industry. There were many
notices to the industry that such products would be regarded as new
drugs which required new drug applications. Implicit in that notice
was that failure to comply would bring action if the case were more
than just of a technical violation.
Mr. Chairman, I had to put that in lest we get the idea that the
Food and Drug Administration was always an agency which did
not act.
Of course, we always considered classes, We never considered an
action on a basis of an individual action. Always in our discussion
was, "What are we going to do about the others?" _
Mr. Fountain. The subcommittee will take into account this
period of time.
Mr. Hutt. I must respond to that very briefly.
Dr. Schmidt. The Defense Department looks different from how
it looked in 1930. Science is so vastly different. The efficacy require-
ments were not implemented in 1964.
Mr. Hutt. I would have to respond that I am in total disagreement
with Mr. Goldhammer. It was the lack of enforcement when he was
in the Food and Drug Administration that requires us today to now
correct the problem that we find in the marketplace.
I was in the private practice of law during the time that Mr.
Goldhammer was supposedly enforcing the law. I knew as an attorney,
and all of my fellow attorneys knew, that the Food and Drug Ad-
ministration would talk big and do very little back in those days.
That is why over-the-counter drug manufacturers marketed all these
products during the 1950's and 1960's — because what they did was
to look at the record of FDA. FDA was not bringing court enforcement
action. They were not enforcing the law. They were letting thousands,
85
hundreds of thousands, of over-the-counter drug products on the
market, every day, Mr. Fountain, without doing anything about it.
If you went and talked to FDA that is the story you got.
I would, like any attorney, look at the seizure actions every month,
and then I would look at the list of newly marketed OTC drugs.
For every thousand newly marketed OTC drugs you might find-
might, possibly find — one seizure, but it was usually not that high.
So the message FDA was giving is that "We are not enforcing the
law against OTC drugs." When I came to the Food and Drug Ad-
ministration I decided it was time to start enforcing the law.
That is why we brought about the OTC drug review, to stop the
lack of enforcement which had gone on for 20 years.
Dr. Goldberg. I have no vested interest in FDA before or after
you came to the agency. Lest the record appear black and white, or
white and black as the case may be, I would like to note that by just
flipping through medical journals I have found new prescription
drugs "pl acecl on tne mark et without approved NDA's, and FDA
seems to know nothing about them. They are regarded by FDA, as
in the case of one I inquired about only last week, as new drugs put
on the market without new drug applications. I am waiting to hear
what kind of regulatory action FDA will take in this most recent
instance.
I am not persuaded the agency has been turned around from
something it might have been at some other stage in its development.
Mr. Hutt. If we want to get into the question of prescription
drugs it raises different issues. It raises a new policy on abbreviated
drug applications, when they are required, and so on, which we might
want to get into in the future.
To get into it today would be trying to do too much at one time.
Mr. Fountain. I agree.
Dr. Goldberg. We certainly would like to review this situation.
Mr. Fountain. I agree.
Referring back to the Ornex situation, I am placing in the record a
copy of FDA's letter of August 8, 1972, to the subcommittee report-
ing the outcome of the Ornex litigation.
[The letter referred to follows :]
Department or Health, Education, and Welfare,
Public Health Service,
Food and Drug Administration,
Rockville, Md., August 8, 1972.
Delphis C. Goldberg, Ph. D.,
Professional Staff Member, Intergovernmental Relations Subcommittee, Committee on
Government Operations, House of Representatives, Washington, D.C.
Dear Dr. Goldberg: This is in response to your request for a status report on
litigation involving the drug Ornex. I apologize for this delay.
As you know, Smith Kline and French (SKF) introduced and began promotion
of its new product Ornex in January 1970. When the Food and Drug Administra-
tion (FDA) discovered that Ornex was marketed without an approved new drug
application, it asked Smith Kline and French for medical documentation which
might support a conclusion that the drug was generally recognized as safe and
effective for its labeled uses.
The data supplied bv SKF was evaluated as inadequate, and the company
was asked to recall its stocks of Ornex from the market. When it refused to vol-
untarily recall Ornex and cease distribution, FDA advised the company that it
would clear the market by a program of seizure actions. One seizure was ac-
complished on February 19, 1971. 1 On February 26, 1971, SKF obtained a pre-
liminary injunction restraining FDA from initiating further regulatory actions. 2
1 United States v. An Article of Drug . . . Ornex. Docket No. 223-71, D. N..T.
2 Smith Kline and French Laboratories v. Richardson, et al., Docket No. 71-3S7, E.D. Pa.
An appeal from the preliminary injunction was filed in the Third Circuit pur-
suant to 28 U.S.C. 1292(a) on the ground that the District Court lacked juris-
diction to enjoin FDA from conducting multiple seizures of an unapproved new
drug under the doctrine of Ewing v. Mytinger Casselberry, Inc., 339 U.S. 594
(1950), and on the further ground that the evidence before the District Court
established as a matter of law that Ornex was not generally recognized among
qualified experts as safe and effective for its labeled uses and was, therefore, a new
drug. 3
Thereafter, while awaiting the scheduling of oral argument on the appeal, FDA
on February 5, 1972, published its proposal to promulgate regulations classifying
over-the-counter drugs as generally recognized as safe and effective and not mis-
branded. (37 F.R. 85-89.) Because the proposal recognized that adequate con-
sumer protection and "equitable enforcement of the law requires that the agency
proceed against all manufacturers of similar preparations" rather than s selected
few, manufacturers of OTC drugs involved in litigation were offered an oppor-
tunity to settle the litigation by stipulating that they will abide by the OTC mono-
graphs applicable to their preparations. SKF, aware of this policy, requested
that it be accorded a disposition of its case consistent with that accorded to other
OTC manufacturers involved in litigation. Consequently, a stipulation disposing
of the three Ornex cases has been executed.
Pursuant to the terms of the stipulation, Smith Kline and French has reform-
ulated Ornex by deleting the salicylamide and caffeine components and has agreed
to make any other formulation and/or labeling changes necessary to comply with
applicable OTC monographs; upon joint motion of the parties, the suit for in-
junction and consequent appeal have been dismissed and the injunction against
FDA vacated; and, SFK having withdrawn its claim and answer in the New Jersey
seizure, the seized stocks have been condemned under a default decree.
A copy of the stipulation is enclosed. If we may be of further assistance, please
let us know.
Sincerely vours,
Gerald F. Meyer,
Office of Legislative Services.
Mr. Fountain. The mechanics of the trade out is suggested by this
])assage in FDA's letter:
Because the proposal recognized that adequate consumer protection and "equi-
table enforcement of the law requires that the agency proceed against all manu-
facturers of similar preparations" rather than a selected few, manufacturers of OTC
drugs involved in litigation were offered an opportunity to settle the litigation by
stipulating that they will abide by the OTC monographs applicable to their
preparations. SKF, aware of this policy, requested that it be accorded a disposition
of its case consistent with that accorded to other OTC manufacturers involved in
litigation. Consequently, a stipulation disposing of the three Ornex cases has
been executed.
Mr. Hutt. Who signed that letter, Mr. Fountain?
Mr. Fountain. Gerald F. Meyer.
Mr. Hutt. This was not
Mr. Fountain. August 8, 1972.
Mr. Hutt. This was not the letter to the company actually contain-
ing the stipulation?
Dr. Goldberg. This was an explanation to the subcommittee in
response to our request as to what the outcome had been.
Mr. Hutt. All right.
Mr. Fountain. Since 1971 this subcommittee has brought to the
attention of FDA a number of complaints from both industry and
consumers about misbranded drugs on the market, as well as new
drugs on the market without approved NDA's. For 3% years FDA
has told the subcommittee that no action would be taken, despite
the misbranding or new drug violations, until after the monographs
Smith Kline and French Laboratories V. Richardson, ct ah, No. 71-14S4.
87
had been published and had become effective. Presumably those
violative products are still on the market, and immune from FDA
action for an indefinite period — probably years. Is that right?
Mr. Hutt. I do not think for years. These undoubtedly were prod-
ucts which were not either patent frauds or health hazards, and there-
fore they fit into the general category of literally 200,000 products,
all of which must be reformulated and relabeled at some point in time.
The question again is, do you take some out of turn? Is there good
reason to do that or do you handle all on a scheduled systematic
basis?
Mr. Fountain. I can, of course, appreciate the tremendous problem
you have with respect to these over-the-counter drugs by the thou-
sands, many of which have been on the market for many, many years.
However, I find, at least from my point of view and based upon the
information I have, and that is the way we have to form our opinions,
I find it disturbing that FDA now appears to have extended its mora-
torium on enforcing the new drug provisions from OTC drugs to pre-
scription drugs. The subcommittee recently inquired about a number
of prescription drugs on the market without NDA's. We received a
reply with two enclosures dated March 28, 1975. I am placing in the
record the letter from FDA and one of the enclosures. The other enclo-
sure appears at pages 91-92.
[The documents referred to follow:!
Department of Health, Education, and Welfare,
Public Health Service,
Food and Drug Administration,
RockviUe, Mel., March 28, 1975.
Hon. L. H. Fountain,
Chairman, Subcommittee on Intergovernmental Relations and Human Resources,
Committee on Government Operations, House of Representatives, Washington,
B.C.
Dear Mr. Fountain: This is in response to the telephone request of February
20, 1975, by Mr. Goldhammer, Consultant to the Subcommittee, for information
on several drugs.
Enclosed is the data requested by Mr. Goldhammer on the following drugs:
Triafed Allerfin Action C
Allerphed Triprofed Actacin
Triacin Action Actacin C
Also enclosed are Federal Register publications referenced in the attachment
from the Bureau of Drugs as well as correspondence between the Agency and
Burroughs Wellcome and Company on this mailer.
If we can be of further assistance, please let us know.
Sincerely yours,
Robert C. Wetherell, Jr.,
^Director, Office of Legislative. Services.
Enclosures.
Drug Status
1. Are the identified drugs prescription or over-the-counter (OTC) drugs?
The listed drugs, Triafed, Allerphed, Triacin, Allerfrin, Triprofed, Action,
Action C. Actacin, and Actacin C are all prescription drugs.
2. Are these drugs subject to new drug applications (NDA's)?
While they are subject to the NDA requirements, we have permitted such pro-
ducts to remain on the market under the aegis of the prime NDA until such time
as final resolution is made. Consequently, we have not taken action against
products under this category pending completion of separate reviews by the OTC
Panel on Cold, Cough, Allergy, Bronchodilators and Antiasthmatic Drugs and
the FDA Advisory Committee on Drugs Used in Allergy, provided that they meet
the requirements" for continued marketing as described in the Federal Register
notice of December 14, 1973. Please see the Federal Register announcements of
May 15, 1973, December 14, 1973, and the incoming letter from Burroughs
Wellcome and our response to same, attached, which goes into more detail in
this matter.
3. Are these drugs listed under the Drug Listing Act.'
Of the drugs mentioned above, only Action marketing by Michigan Pharmacal,
and Actacin marketed bv Diacin Chemical Company, are regarded to be in
compliance with the provisions of the Drug Listing Act. A compliance program
specifically designed to assure compliance with the Drug Listing Act by all drug
firms marketing human drug products will issue shortly.
Department of Health, Education, and Welfare,
Public Health Service,
Food and Drug Administration,
Rockville, Md., March 4, 1975.
Mr. Clealand F. Baker,
Burroughs Wellcome & Co.,
3030 Cornwallis Road,
Research Triangle Park, N.C.
Dear Mr. Baker: This is in reply to your letter of January 31, 1975, expressing
your concern regarding the marketing of products similar to Actifed and Actifed
C preparations without clearing FDA's "regulatory procedures."
At the present time the ingredients found in your products (triprohdine HC1
and pseudoephedrine HC1) are being reviewed by the OTC Panel on Cold,
Cough, Allergy, Bronchodilator and Anti-Asthmatic Drugs and an FDA Advisory
Panel on drugs used in allergy. _ .
As you probably know there are a number of ingredients present in both
OTC and prescription cold, cough and allergy preparations currently being-
marketed. Appropriate formulation and labeling of OTC drugs for these uses as
well as the division between OTC/Rx is being considered in detail since the final
OTC monograph which emerges from this review will have a substantial bearing
on the formulation and labeling of Rx as well as OTC drugs used for these purposes.
FDA policy in this regard was published in the Federal Register of May 15,
1973, (copy enclosed) which specifies the interim guidelines for the formulation
and labeling of prescription drugs intended for cough and allergy purposes pending
the OTC drug monograph. On the basis of public hearings held on June 4, 1973,
the Commissioner concluded that it was premature to adopt guidelines on the
labeling of these prescription drugs. Since the issues involved in the OTC drug
review are so closely related, and sound medical practice requires consistent formu-
lation and labeling for these two types of products, it is essential that they both
be subjected to new requirements at the same time. The Commissioner submitted
the full record of the hearing for the prescription products to the OTC advisory
review panel for its consideration in preparing its report on this category of drugs.
In view of the above, the Commissioner concluded it was appropriate to add
currently marketed prescription cough and allergy preparations similar to or
containing ingredients also in OTC cold, cough or allergy products to the list of
drugs which may remain on the market beyond the applicable time limit for
implementation pending review of all relevant scientific data for the OTC drug
products. Please see the enclosed Federal Register notice of December 14, 1973.
Thus, at the present time, a firm may market a product falling under the scope
of this drug category as follows: _
1. In addition to the usual mandatory labeling requirements the current labeling
should bear the required disclosure of drug efficacy study evaluations in the
labeling and advertising as set forth in Regulation 21 CFR 3.81.
2 A firm which does not wish to disclose the drug efficacy study evaluation as
required by 21 CFR 3.81 may follow the proposed interim guidelines, per Federal
Register announcement of May 15, 1973. While this exemption does not apply
to certain ingredients as listed therein, the guidelines do provide for the interim
marketing of a product which contains an antihistamine and a nasal decongestant
limited for use for the treatment of seasonal and perennial allergic rhinitis and
vasomotor rhinitis, subject to review under the ongoing OTC study of such
We note that the proposed interim guideline of May 15, 1973 does not permit
the marketing of preparations offered for cough containing antihistamines and
oral decongestants such as found in Actifed-C.
89
3. Additionally, as with all drugs, we require that the products are manufac-
tured in conformity with current good manufacturing practice.
We also wish to point out that the Federal Register of July 27, 1972, and
February 9, 1973, makes no requirements for the submission of an NDA/ANDA
at the present time since only those DESI notices dealing with a fully effective
drug contains the conditions under which such drug(s) may be marketed.
We regret the delay concerning your submission with respect to the one-gallon
size container for Actifed Syrup. In explanation, the responsibility for the review
of this class of drugs was transferred from the Division of Cardio-Renal Drug
Products to the Division of Surgical-Dental Drug Products. Also, our information
is that the required stability data for the product was submitted only this month.
We have been advised that a review of this material is completed and that a
response to you will be issued soon. Should you wish to inquire further about the
status of this review, you may contact the Division of Surgical-Dental Drug
Products (HFD-160).
We recognize that there are situations where an NDA holder may, for a time,
bear an inequitable burden as a condition for marketing a particular drug while
related drugs are being marketed without such constraints. However, until a
final order is published in the Federal Register withdrawing approval of the prime
NDA, we are not in a position to institute a class action directed towards removing
related drugs from the market.
Sincerely yours,
J. Richard Crout, M.D.
Director, Bureau of Drugs.
Mr. Fountain. It is clear from these documents that the moratorium
now cuts across the entire drug market, including prescription drugs.
What is your comment on that?
Mr. Hutt. Mr. Fountain, I believe I mentioned earlier if we want
to get at all into detail on the abbreviated or full NDA, or old drug,
issue for prescription drugs, we should devote at least a couple hours
to it. We would be happy to do that.
There is a proposed Federal Register notice — in fact, a total of
five or six Federal Register notices that are in final draft form, which
will appear in the Federal Register, dealing with issues of bioavail-
ability, bioequivalence, and abbreviated drug applications, in the
relatively near future.
Mr. Fountain. I am talking about drugs on the market without
any NDA.
Mr. Hutt. They may be old drugs.
Mr. Fountain. New drugs.
Mr. Hutt. Who said they were new drugs?
Mr. Fountain. We will develop that as we go along. There are
new drugs on the market.
Mr. Hutt. Mr. Fountain, again would you like to get into all of
this?
Mr. Fountain. We will get into it.
Mr. Hutt. Right now?
Mr. Fountain. Stick around long enough.
Mr. Hutt. OK.
Mr. Drinan. I wonder whether Mr. Hutt would agree FDA ex-
tended its moratorium from OTC to the others. Would you quarrel
with that?
Mr. Hutt. Yes, indeed, Father Drinan, I would. I think what has
happened is that we have begun for the first time to try to look at
the issue of what, in the prescription drug area, is a new drug and a
no longer new drug — or old drug, as we call it. We are in between
switching from one system of regulatory control to another. We can
get into all the details of that if the subcommittee wishes.
90
Mr. Drinan. Concerning validity of the moratorium language,
nonetheless there is a delay, shall we say. In switching- from one way
of doing business to another, you have a lapse of time. I raise the ques-
tion as to whether or not the intent of the act is really being carried out.
The FDC Act says the public is supposed to be protected until the
safety and effectiveness have been shown.
Do you feel that in the switching from, as you characterize it, the
case by case to the advisory committee, do you think the act is really
being carried out, the basic intent of the act, which is to protect the
public until the safety is established?
Mr. Hutt. Yes; I do. As I pointed out, in the over-the-counter
drug area, if we can stay with that a moment, all of these products
are on the market. We do not have the ability tomorrow to go out
and take 200,000 products off the market.
We arc dealing with a situation we did not create, which was
created in the past.
Mr. Fountain. They are the ones Mr. Goldhammer let get on the
market?
Mr. Hutt. That is correct.
Mr. Drinan. Of these 200,000, how many of those were grandfathered
in? How many do you actually have jurisdiction over? How many
of those did, in fact, get an NDA?
Mr. Hutt. This is a good example of what we have tried to do to
repair damage which was done by the Congress to our enforcement
capability.
In both 1938 and in 1962, Congress exempted from the new drug
authority certain types of drugs, the so-called grandfather provisions.
We have established a rulemaking procedure which makes that
distinction irrelevant. We are not only defining what is a new drug
and an old drug, we are also defining what is misbranded. We are
not distinguishing between a pre-1938 drug and a post-1938 drug.
We can do that in a way, therefore, which makes the grandfather
clause irrelevant, and in effect takes public protection one step
further, and a major step further.
Mr. Drinan. You have jurisdiction over all of the 200,000?
Mr. Hutt. We do. The grandfather clause grandfathers only
from the new drug provisions of the law and not from the adulteration
and misbranding provisions.
Mr. Drinan. Would you respond to the other part of the question?
How many have in fact received
Mr. Hutt. No one knows. As to NDA's between 1938 and 1962,
there were 420 NDA's which went through the NAS/NRC review.
There was an additional number we have never counted which simply
dropped by the wayside because they had become obsolete. Therefore,
in 1966, when the National Academy of Sciences looked at this issue,
they looked at 420 drugs as contrasted with the hundreds of thousands
which were on the market.
How many were grandfathered we have no way of knowing. It
would be impossible to tell.
Dr. Goldberg. When you say no one knows, are you not authorized
to maintain a register of drugs under the Drug Listing Act?
Mr. Hutt. We are. The Drug Listing Act of 1972 requires this.
91
Dr. Goldberg. Why would you not know from your register what
drugs are out there if you are enforcing that act?
Mr. Hutt. The question put to me, Dr. Goldberg, was whether
I knew how many were grandfathered?
Dr. Goldberg. And how many were NDA'ed. That was another
question.
Mr. Hutt. We can go back. I said how many were NDA'ed, 420.
Dr. Goldberg. In your response to Father Drinan you made
mention of drugs which had been on the market and dropped out.
Mr. Hutt. We can count those.
Dr. Goldberg. I understood you to have said nobod}^ really knows
what is out there. I am asking why you do not know.
Mr. Hutt. I said we did not bother to go back and count the number
of once-effective NDA's between 1938 and 1962 for OTC drugs
which became obsolete and which we revoked.
Dr. Goldberg. That is irrelevant in terms of what is on the market
today. If products are no longer around why would you worry about
them?
Mr. Hutt. I was answering the question put to me. That is why
we did not count them.
Dr. Goldberg. Perhaps I misunderstood.
Mr. Drinan. I don't think so. Perhaps we can rephrase it. Of the
new OTC drug products coming on the market how many appear
without any preclearance at all from the FDA?
Mr. Hutt. I would not be able to give 3^011 an answer today, Father
Drinan. I would assume the vast, vast majority of them.
If someone puts out yet another aspirin product in a 5-milligram
tablet there is no new drug application for that. There is no question.
There are 8,000 antacid products on the market today in rough
terms. We had new drug applications for, between 1938 and 1962, and
I would say subsequently, roughly 10 out of those 8,000.
That will give you an idea of the dimension.
Mr. Drinan. With regard to the one advisory committee which
has finalized its work and is operational regarding antacids, tell us
about the effectiveness of its decrees.
Mr. Hutt. There has been total compliance, 100-percent compli-
ance, without one piece of litigation.
Mr. Drinan. Thank you.
Mr. Fountain. One of the two enclosures to which I referred earlier
is a copy of an FDA March 4, 1975, letter to Burroughs Wellcome Co.
The letter, on January 31, 1975, had expressed concern about the mar-
keting of new drugs by some manufacturers without FDA preclear-
ance, and to complete the picture I am placing in the record an April 8,
1975, reply to you, Dr. Crout.
[The letter referred to follows :]
Burroughs Wellcome Co.,
Research Triangle Park, N.C., April 8, 1975.
J. Richard Crout, M.D.
Director, Bureau of Drugs, Food and Drug Administration, 4600 Fishers Lane,
Rockville, Md. 20852
Dear Dr. Crout: Your letter of March 4, responding to our January 31 letter
expressing concern about the marketing of products similar to ACTIFED®
and ACTIFED-C® without clearance through FDA's regulatory procedures,
has been carefull}' reviewed. Your response was not unexpected. We are aware
55-495—75-
92
that, for some time, FDA has pursued a policy which permits introduction of new-
products, similar to recognized NDA products, without requiring adherence by
the new producers to clearance procedures mandated in the Food, Drug and
Cosmetic Act.
It may be administratively expedient for FDA to permit a bypass of any
regulation which it chooses not to enforce, but the Agency mandate to protect
the public against potentially dangerous products, or products which may not
meet quality standards, is certainly not carried out through this policy.
At the time of our January letter, addressed to Dr. John Jennings, Associate
Commissioner for Medical Affairs, our supplemental NDA for the clearance of a
one-gallon bottle size of ACTIFED Syrup had been held up for the better part
of a year. The particular concern communicated to us was the need for additional
storage and aging data to further document the stability of the product in a gallon
glass bottle identical in composition to the approved container for the commercially
available pint size. Eleven months stability data was required to be submitted
before approval was finally obtained, and we were required to use a 24-months
expiration dating.
Previously, our Quality Control Laboratories had rejected the use of plastic
containers because stability data was not satisfactory. However, some of the
products which are presently being marketed, apparently without FDA clearance,
are packaged in plastic containers without expiration dating. Do you have data
on file demonstrating the stability of these formulations in plastic containers
that we can compare with our own study results?
I would like to raise several questions about other specific points in your letter:
On page two in the first paragraph you state, "The Commissioner concluded it
was appropriate to add currently marketed prescription cough and allergy prepara-
tions similar to and containing ingredients also in OTC cold, cough, or allergy
products." The words "to add" seem to imply a deliberate action on the part of
FDA — that the addition of these products has been ca.rried out through the normal
FDA review and surveillance. It would follow that, although the need for an
NDA had not been enforced, FDA had, through its inspection procedures, assur-
ance that the manufacturer was observing good manufacturing practices before
the products were marketed.
Page two, numbered paragraph three, further stated, "Additionally, as with all
drugs, we require that the products are manufactured in conformity with the
current Good Manufacturing Practice." We would like to receive information
available under the Freedom of Information Act covering the reports of FDA
inspections which provided assurance to you that these products are, in fact,
manufactured under appropriate Good Manufacturing Practices, and the stability
data demonstrating that these products will maintain their potency in com-
mercial use as packaged.
Page two, paragraph two under number 2, of your letter states, "We note that
the proposed interim guideline of May 15, 1973, does not permit the marketing of
preparations offered for cough if they contain antihistamines and oral decongest-
ants such as found in ACTIFED-C®." However, the price lists of four of the
generic manufacturers named to you in our letter indicated they were offering
generic ACTIFED-C, despite the guideline.
If, in fact, the May 15 guideline is FDA's justification for adding certain
formulations which adhere to labeling specified therein, it should follow that
formulations or indications not included in the May 15 guideline, or covered
by NDA's, would not be acceptable prior to the clarification of the status of all
cough and cold products in the monograph to be published following the recom-
mendations of the OTC Cough and Cold Panel.
It is obviously true, as stated in the last paragraph of your letter, that NDA
holders bear an 'inequitable burden as a condition for continued marketing while
later market entries are permitted to be sold without such constraints. The
prime concern, however, in this situation is not the inequitable treatment of the
respective manufacturers, but whether the Food and Drug Administration is,
in fact, carrying out its mandate to insure appropriate formulation, manufacturing,
and packaging of prescription drug products. Public proclamations by responsible
FDA staff members give assurances to both professional and lay audiences that
the FDA surveillance procedures insure the quality of all prescription products,
particularly in the interchangeable group. The policy as enunciated is highly
inconsistent with the negation of need for surveillance as actually practiced
by FDA with respect to speculative generic market entries.
Sincerely,
Clealand F. Baker,
Vice President, Corporate Planning.
93
Mr. Fountain. I quote from the last paragraph of this letter:
It is obviously true, as stated in the last paragraph of your letter, that NDA
holders bear an inequitable burden as a condition for continued marketing while
later market entries are permitted to be sold without such constraints. The prime
concern, however, in this situation is not the inequitable treatment of the re-
spective manufacturers, but whether the Food and Drug Administration is,
in fact, carrying out its mandate to insure appropriate formulation, manufacturing,
and packaging of prescription drug products. Public proclamations by responsible
FDA staff members give assurances to both professional and lay audiences that
the FDA surveillance procedures insure the quality of all prescription products,
particularly in the interchangeable group. The policy as enunciated is highly
inconsistent with the negation of need for surveillance as actually practiced by
FDA with respect to speculative generic market entries.
I recognize that there are times when an agency cannot proceed
against all violations. However, I believe most of us in Congress
realize that an agency should establish priorities so that the public
will get the maximum protection within limits of funds.
As a general rule, it seems to me, it would appear prudent — and,
perhaps, this is your polic}'. As a matter of fact it was my policy in
the practice of law, whether plaintiff or defendant — to handle, first,
the most serious violations. In my opinion, the correction of viola-
tions which adversely affect public health, or which may adversely
affect public health should be given the highest priority.
Would you agree with that?
Mr. Hutt. We certainly do. That is what we have been doing.
Mr. Fountain. Enforcement action against those violations in-
volving the marketing of new drugs without NDA's establishing their
safety, it seems to me, should also merit very high priority. Is that
right?
Mr. Hutt. Only if, in fact, it is a high priority issue. If safety is
regarded as not a problem for the product then that would not be
a high priority issue.
Mr. Fountain. You have no way of knowing unless NDA's are
filed.
Mr. Hutt. That is not necessarily true. If it is what we sometimes
call a me-too product, and it is no different from 50 other products
on the market, then there is no safety issue involved unless we have
some reason to believe that there is a difficulty, in which case we would
take action.
Dr. Goldberg. Just looking at the zirconium aerosols as a case
in point, it seems to me that if FDA had actually accepted the appli-
cation for review, and had determined whether or not the Procter
& Gamble products were safe, they might not have been placed on
the market and FDA's dilemma with respect to making a determi-
nation as to how to treat these products in view of their potential health
hazard could have been avoided.
With further reference to the chairman's point, we must ask
whether premarket approval is required by the law and also whether
it is good policy when new types of products — and that certainly
was a new type of product in terms of its manner of delivery — are
being offered to the public that a determination be made, on the basis
of the scientific evidence, as to whether or not they are indeed safe
and effective.
Mr. Hutt. That particular NDA to which you refer was an abbre-
viated NDA. It was based upon the conclusion of the National
94
Academy that zirconium was safe. What P. & G. was simply doing
there was not the kind of thing you are suggesting, Dr. Goldberg,
of
Mr. Fountain. You mean safe for roll-on.
Mr. Hutt. They were submitting an abbreviated NDA for the
aerosol product based upon the conclusion of the National Academy
that zirconium in a roll-on and cream were safe.
Dr. Goldberg. They were not applying for roll-ons, but rather
for an aerosol form that could affect the products.
Mr. Hutt. That is right.
Dr. Goldberg. They went the proper route, in my judgment,
in making an application to FDA so you could determine whether
the product was safe and effective.
How could you conceivably know, without animal testing, whether
or not the zirconium, when put into aerosol form, had any potential
danger for the lungs or any other organ of the human body?
Mr. Hutt. You can say that about virtually every OTC drug
on the market these days or which came on the market 10, 20, 30,
or 40 years ago.
Dr. Goldberg. Precisely.
Mr. Hutt. What you are doing is using hindsight, which I have
used with Mr. Goldhammer a little while ago, my hindsight saying
he allowed all those products on the market.
I am sure he could use hindsight and say somebody 40 years before
he got there allowed all those products on the market.
Dr. Goldberg. Not at all. I couldn't disagree with you more,
Mr. Hutt. While I use the zirconium aerosol as a case in point, the
principle is one we have been talking about for the last 5 minutes —
whether or not a new type of product which has not previously been
screened for safety and effectiveness, and I submit that zirconium in
aerosol form is a new-type product, ought not to be precleared. In
fact, does not the law mandate that it be precleared, either by an
NDA or an AND A? Certainly scientific evidence has to be reviewed.
Mr. Hutt. We are not determining that, Dr. Goldberg. That is
the entire purpose of the OTC review. We are right back in the circle of
discussion to where we were the last time we appeared here.
Dr. Goldberg. The fact remains that j^ou avoided an opportunity
to review this particular product, the aerosol spray, when the manu-
facturer submitted an application.
Dr. Schmidt. That is not correct. What we said was that that review
would be done by the OTC panel. I would remind you
Dr. Goldberg. We are talking about a time frame, an action which
could have been taken, a product which might well have been kept off
the market several years ago. Moreover, your procedures for due proc-
ess might permit it to remain on the market several years more.
Air. Hutt. That is what we are determining now. We cannot pre-
judge that issue because it is an issue which is now before the Com-
missioner.
Dr. Goldberg. I am not asking you to prejudge it. I am differing
with your concepts of law enforcement and of your responsibilities
under the law in turning this over to a panel rather than acting on an
application which a company presumably in good faith put before you.
Mr. Hutt. As my late father used to say, "that's what makes horse
races."
95
Mr. Fountain. I have a prepared outline of questions, Dr. Schmidt.
If a panel has placed a drug in a given class of drugs into category II,
but the final monograph of that class has not yet been published, and
a firm wants to market that drug with the category II label for the
first time, is the firm free to market the product without filing an
NDA or will FDA require the filing of an NDA prior to marketing?
Mr. Hutt. If I understand you correctly, there is a report by the
panel that it is in class II, and that has been published as a proposal
in the Federal Register.
Mr. Fountain. That is right.
Mr. Hutt. It is before the final monograph. Why anybody would
ever do it is utterly beyond me, but the fact is — yes, they are free
to market that product for the couple of months they could market it
until they would have to take it off the market.
What we are finding is literally just the opposite, because people are
not irrational. What we are finding is that the minute that a report is
available in draft form the manufacturers are taking off the market
those which are in category II, and they are marketing products which
are in category I because they want to get on the market as fast as
they can something which is safe, effective, and properly labeled.
Your hypothetical question is simply totally unrealistic. It has not
happened, and I could not conceive of its happening.
Mr. Fountain. I am not so sure I agree with you. However, I shall
ask this. What about category
Dr. Schmidt. Is there an example? I would love to hear an example.
Mr. Fountain [continuing]. Category III drugs. I was asking the
hypothetical question based upon this background of information
which we have and which we have been exploring.
What about category III drugs? Would a manufacturer, who wants
to market a drug for the first time with claims which are placed in
category III by a review panel, and excluded from the monograph but
permitted to be used in labeling for, say, a 2-year period, be required
by FDA to file an NDA?
Mr. Hutt. No, sir, he can come on the market with the same
restriction as someone who was on there since 1890.
Mr. Fountain. During the 2-year period?
Mr. Hutt. Yes, during that 2-year period, as agreed by the U.S.
district court in the District of Columbia, he is subject to the same
restrictions, rights, and benefits as anyone else under the review
procedure.
Those are products for which there is no health hazard, Father
Drinan, again to go back to your earlier concern.
Mr. Drinan. Does the statute and the whole history of it justify
the distinction you continually make between safety and effectiveness?
Obviously effectiveness is evaluated as some sort of secondary cate-
gory. Is that justified by the whole history of the act?
Mr. Hutt. I think from the beginning, back to 1906, Congress has
understood that when an agency — and ours in particular — is faced, as
the chairman pointed out earlier, between issues which affect the
pocketbook as opposed to affecting life and health, one always puts
the latter first on a priority basis. That does not mean we can ignore
the former, and we do not ignore the former. However, it is taken into
account in form of priorities.
96
Mr. Drinan. Do I take it that if you had sufficient personnel and if
the Congress were persuaded they should give an appropriation for
this, effectiveness would be examined at the same level as safety?
Mr. Hutt. That is a fair statement, yes.
Mr. Drinan. Has the Commissioner suggested this lately to the
Congress? As an oversight committee we should say we would want
to elevate effectiveness to the level of safety so the public is not paying
out millions of dollar every year for drugs which are worthless.
Mr. Hutt. Father Drinan, if we had additional money at this time
there are still issues of safety which we have not reached. If 3011 are
talking about the need for resources in the Food and Drug Adminis-
tration we would be delighted if this committee would exercise over-
sight on that.
I can say that because I have only 1 week left with the Government
and the Office of Management and Budget has less control oyer me
than over others. Lack of resources is the major problem affecting the
Food and Drug Administration.
When the General Accounting Office issues reports on our agency it
issues reports asking us to do things which we do not have the resources
to do. It is time that Congress and the public understood that.
Mr. Fountain. Before you do leave
Mr. Hutt. I may leave a week earlier after that.
Mr. Fountain. I would appreciate it if you would submit for the
record, for whatever it is worth, your opinion as to what you feel are
the manpower needs of the agency and where the inadequacies may
be.
Mr. Hutt. I do not have the time, much less the competence, to
survey the entire agency even if I had 5 months as opposed to 5 days.
Mr. Fountain. In any given area, if you have any opinions. I do
not want to burden you. I realize you are in the process of going
elsewhere and do no t* want to take on extra burdens where you are.
You perhaps would like them lessened.
Mr. Hutt. If you wish to hold 5 days of hearings, let's say a day for
each bureau, to discover what it is that that bureau is not able to do
because of a lack of manpower and money, those probably can be the
5 most important days of hearings tins committee ever has held.
Mr. Fountain. One of these days I am hopeful we can do just that
and find out what it is not doing which it could do and what its inade-
quacies are, and any other information we may get with respect to
the way in which it'is administering its responsibilities.
But we have so many agencies to oversee, it is difficult to find the
time. However, I am hopeful we can do just that. I think you are
right.
Mr. Hutt. From my personal standpoint, every day 1 see decisions
made where we cannot do things because we do not have people to do
them because other things have higher priority.
The public and the Congress do not adequately appreciate that.
When you people sitting here ask us to do things you do not tell us
what we should stop doing so we can do the other things.
Dr. Goldberg. Can you tell us quickly how many additional
lawvers the General Counsel's Office requires?
Mr. Hutt. I can tell you how that has progressed, Dr. Goldberg.
When I arrived in September of 1971 we had 18 lawyers. At that time
we were grossly understaffed.
97
Today we have 30, and by the fall we will have 38.
We are asking Congress for an additional 10 positions, 7 of which
would be attorneys and 3 secretarial, to bring it to 45 attorneys.
A zero budget for my office prepared b}^ FDA would put an adequate
number at somewhere in the sixties or seventies.
Dr. Goldberg. That is your opinion of what the needs of the
office are?
Mr. Hutt. Yes. I have long believed, Mr. Goldhammer, there
should be an attorney in each of our regional offices to assist the
compliance personnel out there. We have one now in Los Angeles,
after a 3-year hiatus, who is performing very effectively in that
capacity. We had one there for 20 years and for 3 years we did not
have adequate personnel to put one there.
To give you historical perspective, in 1950 we had 20 lawyers. When
I came in 1971 we had 18.
Mr. Fountain. Placing an attorne}^ in the regional office makes
sense to me, at least for the moment.
I realize you plan to allow exceptions to your monograph procedures
and where a product is dangerous to health or constitutes rampant
fraud FDA intends to take separate action against that product.
As I understand it, hexachlorophene OTC products, have been
proceeded against, but I believe that that action occurred in January
of 1972 just about the time the monograph regulations were first
published as proposals. Is that true?
Mr. Hutt. That is correct. I believe it was the same day.
Mr. Fountain. Did you act in that case because of the reports that
hexachlorophene was responsible for the death of infants in France?
Mr. Hutt. That was part of it but there were other pieces of
information, also, Mr. Chairman. I believe all of the basis for that was
laid out in the preamble and placed on file in the hearing clerk's office
at that time.
Mr. Fountain. Mr. Goldhammer was reminding me that I made a
statement on the floor of the House expressing my concern about this
delay long before these deaths occurred. That is true.
After giving this information to the antiperspirant panel, as shown
at page 2-76 of the verbatim transcript now in the hearing record, you
said :
But you can't let the exceptions overtake your rule. Or you would be back
where 1 was in September 1971. The fact that the laxative panel has come up
with half of its products being unsafe or uneffective doesn't remotely surprise me.
I expect that will be true as we go through everything over a period of time.
Did I quote you correctly?
Mr. Hutt. Yes. I think 50 percent not making it into class III or
class I would be a rough estimate.
Mr. Fountain. That does not
Mr. Hutt. That does not mean they are unsafe.
Mr. Fountain. Continuing the quote:
That doesn't mean that today, I should go out with that proposed regulation
and take all those half of the products off the market.
To do that would put me right back where I can't afford to be.
Now
Mr. Hutt. That is correct.
Mr. Fountain. It appears you have spoken in general terms when
you stated that half of the OTC laxatives on the market were found
to be unsafe or ineffective. Are you able to give us information as to
now many were actually found to be unsafe? Do you have those?
Mr. Hutt. Unsafe? I was speaking in general terms in an informal
session and used the figure half.
We would have to supply that information for the record. I am not
entirely certain what those figures are.
Mr. Fountain. In your talk to the panel you used the word "un-
safe" as applied to the laxatives.
Mr. Hutt. Unsafe in the sense that what I was referring to is that
they were category II or III products and not category I.
Mr. Fountain. I imagine that means they are harmful and con-
stitute a danger.
Mr. Hutt. That is exactly what it does not mean. It does not mean
either of those. What it means is that there is not sufficient evidence.
On a benefit-risk ratio the panel says there is no reason for them to
be on the market. They go off the market pending future testing. That
does not mean that one person ever has been harmed.
Dr. Schmidt. There is a way of tliinking about this which helps a
little bit because in many of our conversations with people I have
noticed they have had a hard time with category II and saying,
"Things are put in categorjr II, and if so they must be unsafe."
What we are looking for is scientific and substantial evidence of
safety and efficacy.
If that does not exist then things may be in category III or in
category II, but it does not mean necessarily that there is positive
evidence of ineffectiveness or some hazard.
We are looking for evidence of safety, evidence of efficacy. In the
absence of that, things cannot be category I. They must be III or II.
Then a judgment is rendered as to whether or not experimentation
could be done within a reasonable period of time; that such studies
could prove the thesis that they are safe and effective and that proof
can in fact be gathered. It is easier to understand category II and
category III when approached that way than from the other way.
Mr. Fountain. I assume that whether something is safe or unsafe
depends upon the context in which it is used. With all the things going
on in the world today when we use the word "unsafe" I would think
it is harmful.
Mr. Hutt. Mr. Chairman, again I was speaking at a closed session
and using shorthand terminology which we use with the panels, people
who have been working in this area for, say, a year, and who use the
same shorthand I do.
Mr. Fountain. They knew what you meant?
Mr. Hutt. In my judgment, yes, because we had discussed this
before.
Mr. Fountain. You had no particular reason for using the word
"unsafe" — it was just part of the conversation?
Mr. Hutt. If I were to make a public presentation about it I would
refer in a good deal more detail to the correct definition of those terms.
Mr. Fountain. Did the laxative panel find, in fact, that many of the
laxatives on the market were unsafe?
Mr. Hutt. Actually harmful?
Mr. Fountain. Yes.
Dr. Schmidt. It might be helpful to have in the record the state-
ments that we made at the time of the publication of the proposed
99
monograph, the report to me. We did speak to that issue. We were
talking again about ingredients.
Mr. Fountain. That is right.
Dr. Schmidt. Some ingredients certainly were not well documented
in the literature with regard to their safety and efficacy.
As I said then, and would say again, and we have said it many times
this morning — were there evidence of a health hazard we would pro-
ceed immediately against that product.
Mr. Hutt. Mr. Pinco has reminded me that there were two which
the panel found unsafe but not to the extent of being an imminent
hazard to health.
The panel did raise some safet}^ questions, as was true with the
antacid report. Those products were reformulated even before the
report reached the Federal Register. That is how quickly we are
obtaining compliance, particularly where there is any real significant
safety issue involved.
Mr. Fountain. Of course, any ingredient in a drug can make it
unsafe. If jou found two of these laxatives which were unsafe what is
the justification for leaving them on the market?
Mr. Hutt. They were not.
Dr. Schmidt. Thej^ were not.
Mr. Hutt. They are off. What we are finding is that manufacturers
have no future in putting out unsafe products any more than we as
consumers have a future in consuming them.
When they find that the panels are concerned not just in a sense
with a lack of evidence but with affirmative evidence of possible or
potential harm, they are reformulating even before we can move the
mechanism to require it.
[Note. — One of the laxative ingredients found by the advisory panel
to be unsafe is podophyllum (podophyllin) . In reply to a letter from
the subcommittee chairman, FDA stated that as of July 3, 1975 podo-
phyllin has not been removed from the marketed laxative. For further
discussion of podophyllin and the exchange of correspondence, see
pp.1 13-1 18 of this hearing record.]
Mr. Fountain. There would be no justification for leaving such
products on the market under those circumstances?
Mr. Hutt. Well
Dr. Schmidt. If there is evidence of an imminent health hazard then
we will move immediately.
Mr. Fountain. Imminent?
Mr. Hutt. And also if there is evidence less than that, where the
panel recommends that there is a sufficient potential health hazard
that action should be taken immediately. We did it with TBS and
with hexachlorophene, and we are now in the process of determining
whether the same justification exists in the present circumstances for
zirconium, which, as we all know, we cannot discuss today because it
is a pending issue.
Dr. Goldberg. What is jour position where the product has been
found by the panel not to be generally recognized as safe? What do
you do in that case in terms of permitting continued marketing?
Mr. Hutt. Dr. Goldberg, I find it difficult to know at what stage of
the proceeding you are talking about and in which category.
Dr. Goldbeeg. Let's say the product has not voluntarily been taken
off the market by the manufacturer prior to the publication of the final
100
monograph. If there is a question as to its safety, if this has not been
established, what is your policy regarding leaving the product on the
market?
Mr. Hutt. It is in category II or III?
Dr. Goldberg. Category II.
Air. Hutt. In category II on the effective date of the monograph it
goes off the market. That is spelled out in the procedure, and we spell
out that, if at that point they do not comply, there is no question we
will litigate across the board on that. However, it will be a different
form of litigation from the old case-by-case approach. Here we have
the rulemaking proceeding in place. We can ask for summarjr judgment
in every instance, in my judgment.
Mr. Drinan. Related to this, how does the procedure you outline
affect Gillette's intention, as announced on March 24, 1975, to market
a new zirconium aerosol on the basis that the monograph mil not be
completely finalized until next jear or the year after? Will an NDA
be required or will they be able to move forward?
Mr. Hutt. That issue is pending before the Commissioner, Father
Drinan, right now.
The panel has recommended, as of 9 days ago, that we expedite
action on zirconium and that all present zirconium-containing aerosol
antiperspirants, the ZCAA's, should be acted upon immediately.
The Bureau of Drugs has that 100-plus page report which was made
public the day after we received it. If you do not have a copy we would
be happy to give it to you.
It is a very lengthy report. The Bureau of Drugs has that report.
It will make its recommendations to the Commissioner within a
matter of days. He will then act upon it.
Mr. Drinan. In the interim can Gillette market its product?
Mr. Hutt. We are talking about only a week. Could they? We have
no legal authority to prevent anyone from marketing any product.
If you are asking whether we will take legal action to prevent them, I
think we would first, since it is only a week or two, wait to rule on this
report.
Mr. Drinan. Dr. Schmidt asked for an example of where FDA's
monograph procedure has actually led to a new product being mar-
keted. Perhaps this is such a case where Gillette has come forward
and said: "We are, despite or because of the delay of the monograph
procedure, we are moving forward to market a new zirconium
aerosol."
Dr. Schmidt. The letter they wrote was prior to the panel's recom-
mending that it be taken out of order. Gillette, in part by means of
that letter, got resolution of a question they had. This was: "Are you
going to take zirconium out of order or are you going to take it in
2 years?"
As you well know, if Gillette goes on the market with something,
their investment in marketing and advertising could be in the tens of
millions of dollars. I would judge they probably would not come on
the market with anything once they learn that the panel was recom-
mending that it be considered out of order. They would surely
await my decision.
Mr. Drinan. What is the fact of the matter? They announced their
intention on March 24, 1975, 2 months ago. Have they in fact
101
Dr. Schmidt. They have not.
Mr. Drinan. All right.
Mr. Fountain. I get the impression that your current policy of
deferring action against violative OTC products would encourage
industry to take advantage of the moratorium. Apparently you do,
too, Mr. Hutt. You told the antiperspirant panel:
The people out in the industry aren't stupid. They see what we have done.
And they see in some instances where they can take advantage of it.
There is a new toothpaste called AIM. You have seen television advertisements.
Until the OTC review, we had required an NDA for every fluoride toothpaste.
Having adopted the policy of not litigating except in health or fraud issues,
pending the OTC review, that particular company, and I don't remember which one
it is, decided this was a good time to put out their new toothpaste without getting
an NDA.
Their competitors came in complaining. And said, "Damn it. We had to get an
NDA. How come they don't have to get an NDA?"
And we said it is really a matter of priorities and resources in FDA.
If I were to start litigating against every AIM type product, then I would have
ni}- 18 lawyers spread all over the courts of the country again on a piecemeal
ad hoc case by case basis instead of handling it on a comprehensive basis in this
room.
Then you said :
There have been probably 20 or 30 products of that type I can think of off the
top of my head put on the market in the last year or two, taking advantage of that
situation. And there, it puts me in a tough spot because I was the one who sort of
made the principal decision 2}/o or 3 years ago that this was the intelligent way to
go.
Mr. Hutt. That is correct.
Mr. Fountain. In what appears to be your stated intent, to ignore
the interstate marketing of new drugs without NDA's in conformance
with the purpose — — ■
Mr. Hutt. Mr. Chairman, I would point out one thing. When
complaints were made about that particular toothpaste we went to
the Bureau of Drugs, Mr. Yingling and I, and asked the Bureau
whether there was an}^ reason, from a health and safety standpoint or
any other standpoint that they could determine, why this drug should
be proceeded against for failure to have an NDA. The best judgment
of the Bureau was that there was no possible serious or potentially
serious issue which should be litigated.
Dr. Goldberg. Did the Bureau examine the formulation of the
drug?
Mr. Hutt. They examined information, Dr. Goldberg. I could not
tell you all that they did or did not examine.
Dr. Goldberg. I think there is a very salient question as to whether
they had information on that particular product, as differentiated
from other fluoride toothpastes; or whether they gave you an off-the-
top-of-their-head opinion that it is like other flouride toothpastes and,
therefore, they saw no particular safety issue.
Mr. Hutt. My best judgment is that they did have information
about it and they concluded there would be no difficulty today in
anyone making a safe and effective flouride toothpaste.
Dr. Goldberg. Do you know for a fact they had information on
this product?
Mr. Hutt. I know they had information. You asked me which
information they had. I do not know.
102
Mr. Fountain. Do you know whether or not they had information
as to whether or not the company had adequate controls?
Mr. Hutt. Adequate controls?
Mr. Fountain. Yes; manufacturing controls.
Mr. Hutt. Our best judgment today is that the way to review
adequate manufacturing is to go to the plant and not to require an
NDA. If the only issue is whether a manufacturer has adequate
manufacturing procedures then we should determine that by sending
an inspector to the plant to review the manufacturing procedures,
not by requiring a new drug application which deals with basic safety
and effectiveness.
Dr. Goldberg. You always did that. That is nothing new.
Mr. Hutt. That is true. That is exactly true.
Dr. Goldberg. That is part of the NDA approval process,
Mr. Hutt. That is part of it but that is not the reason for the NDA.
The reason for the NDA is to establish safety and effectiveness,
and unless there is some kind of special manufacturing problem,
which crops up every once in a while with a drug where a manufacturing
procedure is critical in terms of safety or effectiveness, the NDA
should not be used properly as a means of surveillance over manu-
facturing.
Dr. Goldberg. Might we request the witness to make a submission
for the record identifying the kind of clinical, animal and other data
that were available to the Bureau of Drugs with respect to "Aim"
at the time the}^ gave you that opinion?
Mr. Hutt. Surely.
[The information referred to may be found in the appendix at
p. 317.]
Mr. Drinan. Is it fair to say that 3 or 4 3 T ears ago, when zirconium
and all these products applied for an NDA, or should have applied,
is it fair to say in light of the recommendation by the advisory com-
mittee that the FDA should have denied access to the market at that
time? I quote the bottom line —
Because conclusive testing to establish the safety of zirconium-containing
aerosol antiperspirant might take years to accomplish, and because in that time
millions of consumers would be unnecessarily subjected to risk we recommend that
this be withheld from interstate commerce.
Is it fair to say now in retrospect that the FDA should have at the
initial stage denied access to the market?
Dr. Schmidt. This is the conclusion that comes after months of
study, testimony by world experts in a brand new, relative^ speak-
ing, field of medicine. Just in the past few years the relationships to
immunity to pulmonary granulomas have been studied extensively,
so that kind of conclusion can be drawn only after a process like this
panel went through. Therefore my answer would be no. It would have
been arbitrary in 1972.
Mr. Drinan. You mean the information just was not there.
Nobody really had a clue that this particular danger might be in this
particular drug called zirconium?
Dr. Schmidt. I think probably the key data that raised this
question were supplied by Gillette which reported lesions in monkeys
from inhalation of their product. This was subsequent to 1972.
103
Mr. Hutt. As contrasted, Father Drinan, with the Procter & Gamble
studies which showed no problem.
Mr. Fountain. Was this done before the drug was marketed?
Mr. Hutt. The Procter & Gamble studies were done and showed no
problem.
Dr. Goldberg. You know that only in retrospect. You do not
know, Mr. Hutt, whether your Bureau of Drugs people would have
accepted those studies as adequate at the time.
Mr. Hutt. In hindsight one does not know whether they would
have accepted them or not.
Dr. Goldberg. That is what the new drug approval process is all
about. We don't know.
Dr. Schmidt. Because of some evidence that has come up we are
talking about one thing and one type of spritzer can. There are many,
many kinds of spritzer cans with many, many kinds of products in
them. We are concerned about all of them and we are reviewing all
of them.
Dr. Goldberg. That is fine and I have no objection to that. How-
ever, we are discussing not only whether it is good policj^, but also
whether the law requires that new drugs be examined for these con-
siderations before they go on the market, rather than in hindsight.
Dr. Schmidt. Perhaps I was not explicit in relating the OTC drug
review process to what we did in 1972 with regard to zirconium-
containing antiperspirants.
Mr. Drinan. What about the person who wants to merchandise a
product? He obviously has the burden of proof. If he wants to be on
the GRAS list he has the burden. Was an original NDA
application
Mr. Hutt. That is not true, unfortunately, under the law.
Mr. Drinan. The burden?
Mr. Hutt. The burden is on us to prove a product is a new drug.
Mr. Drinan. It was decided this was not,. I take it?
Mr. Hutt. That is correct. It was decided it was a newly marketed
old drug.
Mr. Drinan. Was that an error?
Mr. Hutt. In my judgment, no, not at that time. Today it would
be; yes.
Mr. Drinan. You didn't even get to the question of the safety. You
just said this does not really need an NDA because it is an old drug.
Mr. Hutt. It was decided that the marketing at that time should
not be objected to by the Food and Drug Administration. We had no
reason to believe there was a problem with it. We therefore did not
object to the marketing and said that the product, like hundreds of
other OTC drugs coming on the market every day, would be reviewed
by the OTC drug review.
Mr. Drinan. You say there was no reason to question the safety.
Is that really true, that in all of the literature and all the science
available none of the information that has now come out was available?
Mr. Hutt. That is not true.
Mr. Drinan. You are contradicting yourself.
Mr. Hutt. I am sorry, sir.
Mr. Drinan. You said there was no reason to question the safety.
104
Mr. Hutt. In retrospect today, just as one could do it with every
OTC drug on the market today, one can raise questions, but in terms
of making a decision as to whether there was any greater reason to doubt
the safet}^ of that than 200 or 400 or 200,000 other products on the mar-
ket, there was at that time nothing that we were aware of or we would
not have made that decision.
One can say
Mr. Drinan. Should you have been aware of it?
Mr. Hutt. One can ask that question as we go through individual
drug by drug, every drug on the market today. Questions will be
raised about safety, about effectiveness, about proper labeling.
We testified when we were last here that every single OTC drug on
the market today, all 200,000, will be required to be either reformu-
lated or relabeled or both.
Now, one can say, therefore, that from 1906 to the present, FDA has
not been doing its job if one wants to look in hindsight and say with,
all of today's knowledge we know everyone was wrong in the past.
I point out to everybody that the same tiling will be said 20 years
from now. Products that this panel has reviewed and said are safe and
effective will in 20 years be questioned on the basis of new information
and a new insight into that information and someone will say the
earlier panel was wrong.
Mr. Drinan. I agree with that. What I am asking is whether the
information here is so new that at the time the FDA gave clearance
to these drugs some years ago they legally could not have foreseen
and are to be blamed for not foreseeing what we now know?
Mr. Hutt. My answer would be yes; but that is a matter of judg-
ment, solely a matter of judgment.
Mr. Fountain. Other than what you have said today, do you have
evidence, documented evidence, evidence in your records, that this
was not a new drug?
Mr. Hutt. Documented record evidence? I am not sure
Mr. Fountain. Was it found by FDA not to be a new drug?
Mr. Hutt. I am not sure what documented record evidence would
mean.
Mr. Fountain. Anything other than what you have said.
Mr. Hutt. A file memorandum where it says this?
Mr. Fountain. Yes.
Mr. Hutt. We do not have that. To the best of my knowledge we
do not have that for 99.99 percent of the OTC drugs on the market
today.
Mr. Fountain. Notwithstanding the request —
Mr. Hutt. I am talking about products which went out 20 or 30
years ago.
Mr. Fountain. I am talking about new applications.
Mr. Hutt. If I want to go out when I leave the Food and Drug
Administration and start a pharmaceutical company and market
aspirin, the Food and Drug Administration does not require me, nor
should it, nor legally could it, to obtain an opinion and document
that it is an old drug.
Dr. Goldberg. What if a manufacturer came forward and said,
"We are going to market aspirin in aerosol form." How would you
feel about that?
105
Mr. Hutt. Today?
Dr. Goldberg. Yes.
Mr. Hutt. I doubt we would approve it today.
Dr. Goldberg. Why do you assume you would have made that
decision with respect to the zirconium aerosol? There is no evidence
Air. Hutt. I am not sure I understand the relevance of the question.
You are asking about apples and oranges here.
A decision was made in 1972. You are now saying, on the basis of
hindsight, and I realize hindsight is much better, that if I knew in 1972
about zirconium what I know today obviously that decision would
not have been made.
That is true throughout all of history.
Going back, FDA over the years has given thousands of written
opinions, which we subsequently revoked in 1968, but literally thou-
sands of written opinions that various drugs, prescription and OTC,
were old drugs; that is, no longer new drugs, and thus not required to
have NDA's.
I think Mr. Goldhammer and I would agree in hindsight that was
a bad mistake back when that was done.
Dr. Goldberg. I like your macroscopic treatment of the drug world.
But getting back to the point I raised, and which you have not dealt
with, is the matter of whether you can say today what FDA would
have done in 1972 if, in fact, it had processed the abbreviated new
drug application submitted by Procter & Gamble.
You retained the data filed by the company, but there is no evidence
that it was reviewed bj r FDA. And there is no evidence, and there
couldn't be such evidence since it was not reviewed, as to whether or
not questions would have been raised about the kinds of studies done,
the adequacy of the preclinical and clinical data, and so forth, if the
application had been reviewed. It may simply have been deferred,
like many other drug applications are.
In connection with the status of the drug in 1972, as far as we are
aware, there is no documentation in the files of FDA that anyone in
the agency made the decision that this was not a new drug, and you
did not communicate that to the manufacturer.
Mr. Hutt. It was not necessary to and I do not believe they asked
for an opinion on that. They submitted an abbreviated NDA.
Dr. Goldberg. Your explanation to them
Mr. Hutt. Was that it would be deferred pending OTC drug
review.
Dr. Goldberg. You would not look at the evidence at the time it
was submitted.
Mr. Hutt. If we had concluded that it was a new drug, it would
have been illegal to put it on the market.
Mr. Fountain. Let me read the letter of June 20 from the Food
and Drug Administration signed by Dr. Bryan, Bureau of Drugs.
Mr. Drinan. When is that?
Mr. Fountain. June 20, 1972, addressed to Procter & Gamble, atten-
tion Mr. T. W. Mooney.
Gentlemen :
Reference is made to your abbreviated new drug application dated January
10, 1972, submitted pursuant to Section 505(b) of the Federal Food, Drug, and
Cosmetic Act for Secret (aluminum hydroxychloride, zirconyl hydroxychloride
and hexachlorophene) antiperspirant.
106
Pursuant to the policy of review of over-the-counter drugs as stated in the
Federal Register announcement of April 20, 1972, the material you have submitted
will not be reviewed at this time but will be handled by the appropriate OTC
panel at a later date.
The material you have submitted will be retained in our files.
Mr. Hutt. Yes.
Mr. Fountain. What does that letter mean?
Mr. Hutt. It means we have no reason not to permit it to be market-
ed at this time ; that is until the OTC drug review determines differ-
ent, it is not a new drug and does not require an NDA before it is
why being marketed.
Mr. Drinan. If Procter & Gamble thought it was not a new drug,
why did they submit it? They must have thought so.
Mr. Hutt. Undoubtedly. We concluded it was not necessary, which
I must say is a process that FDA has used going back to 1938.
Mr. Drinan. Maybe they have been making mistakes since 1938?
Mr. Hutt. That is possible.
Mr. Drinan. In this case, is there further evidence besides the letter
of June 20, 1972, as to who examined it, under what conditions, and
how can you justify this as coming within the intent of the law? You
categorically say itis not a new drug. You do not even get to the ques-
tion of safety.
Procter & Gamble, with their lawyers and chemists, thought it was
a new drug, and they applied. Therefore the burden is on the Com-
mission to say you have concluded, contrary to their evidence,
this is not a new drug.
Mr. Hutt. Again if we had any reason to suspect, whoever reviewed
it in the Bureau of Drugs, Dr. Paul Bryan, who wrote the letter and
who was at that time the Director of the drug efficacy study imple-
mentation project, would have made a different decision. It was sent
to him because there had been published in the Federal Register a
notice stating the conclusion of the National Academy of Sciences,
and FDA's concurrence, that zirconium in nonaerosol form was
effective, and they were submitting an abbreviated application for
the aerosol version of that product.
We concluded there was no purpose to be served by having an
abbreviated NDA at that time.
If we had pursued this without the OTC review, of course we would
then have processed it.
However, we had the OTC drug review in place precisely to handle
these issues and saw no reason to keep the product off the market,
any more than Aim toothpaste, pending the OTC drug review.
Mr. Drinan. What had the National Academy said precisely
against it?
Mr. Hutt. They had said zirconium in antiperspirants, which are
in cream and roll-on forms, is effective.
Mr. Drinan. Procter & Gamble was marketing an aerosol.
Mr. Hutt. That is correct.
Mr. Drinan. You had no scientific finding on that?
Mr. Hutt. But at that time we did not have knowledge of what we
now realize is a problem. We did not have an understanding, which
comes over a period of time as new information develops
Mr. Drinan. Dr. Bryan, apparently all on his own, said, "I don't
think the additive here or the new circumstance that this is in aerosol
107
form makes any difference," even though the National Academy of
Sciences said nothing about that precise question.
Mr. Hutt. That is a conclusion you have drawn, that he did it all
by himself.
Mr. Drinan. Tell us about the process.
Mr. Hutt. One of the problems today is that we did not realize
this was going to be an issue at this hearing. If the committee had
informed us they wanted us to look into who Dr. Bryan talked to, we
would have clone so. We can do that.
Dr. Crout. If there were no OTC drug review in place, quite
obviously that AND A would have been reviewed and a determination
would have been made, and the problem would have been handled
earlier than it is being handled now.
However, we would have ended up with no determination about the
products of other firms and we would have ended up with no class
determination about aerosols in general.
Once the OTC drug review was in place, we made a determination
to put all OTC drug products into that review unless somebody has
positive evidence there may be a safety hazard so we should take it
out of turn.
There is a new piece of information not available at that time that
I would like to emphasize, and that is that zirconium-containing
aerosol antiperspirants may be different from aluminum-containing
antiperspirants. That is a possibility.
I think it was quite reasonable at that time, for whoever reviewed
that, to consider the zirconium-containing aerosol as just another
aerosolized antiperspirant. They had been on the market a good num-
ber of years.
Therefore, the separation of zirconium-containing from aluminum-
containing antiperspirants as a possible health hazard occurred as a
result of the panel's work.
I don't think one can now go back and ask whether we would have
made a different decision in 1972 if we knew then what we know today.
The answer is obviously "Yes."
Mr. Drinan. No matter how you put it, it seems to reflect badly
on FDA. The FDA did determine in 1972 that zirconium aerosols
were not new drugs. You had to reach that conclusion.
Dr. Crout. We did not make that a positive determination.
Mr. Hutt. It was the inherent determination, no question.
Mr. Drinan. On what basis did FDA make that decision where
zirconium aerosols were on the GRAS list?
Dr. Crout. The decision was not made in those terms.
Mr. Drinan. The decision was made. Dr. Bryan's letter says
"go right ahead. You don't need an application."
Mr. Hutt. It may have been on the market before then, incidentally.
Dr. Crout. It was.
Mr. Drinan. I want to know. Zirconium aerosol was on the market?
Dr. Crout. Yes.
Mr. Drinan. How did it get there without FDA approval?
Dr. Crout. Because, as we pointed out, for years and years OTC
drug products have been appearing on the market without prior Food
and Drug Administration review.
Mr. Drinan. But that does not prove anything. It could have
been out there because of a bootlegger.
108
Dr. Ceout. We are not saying what it proves. But a general assump-
tion of the OTC drug review is that when we make a decision on
whether a drug is in the review or not, the general assumption is
that the drug is in unless it has a safety problem. That is an mherent
determination of old drug status.
Mr. Deinan. You are telling me zirconium aerosol was not a new
drug, and that is what you told Procter & Gamble on June 20, 1972.
I am asking as a simple country lawyer, tell us more about how
zirconium aerosol could have been an old drug everybody knew about.
Mr. Hutt. We seem to go around in circles on this. All we can
say is what has happened in the last 100 years on OTC drugs. Before
there was a 1906 act. between 1906 and 1938, between 1938 and 1962,
and up to the present, virtually all OTC drugs have been marketed
by the industry without coming in and getting Food and Drug
Administration approval. The law permits them to do that, The
statute does not require them to obtain an opinion from FDA even
if we say it is a new drug. The statute saj s we are then required to go
out and take regulatory action to get that product off the market,
There is absolutely nothing which requires them to ask our opinion.
Procter & Gamble first marketed its product in August 1971. That
was a year before they came in, or roughly a year before they came in,
with their abbreviated new drug application.
They went into national market in August 1971, so they probably
first marketed this in test marketing perhaps even as much as a year
earlier, without an abbreviated new drug application.
My colleagues have reminded me that probably the reason they
came in with the abbreviated new drug application was because of the
hexachlorophene in the product, not because of the zirconium.
You catch us a little off guard here in a sense. We are trying to
reconstruct off the tops of our heads events of 3 years ago which
involve people whom we did not bring with us.
Mr. Deinan. This is directly and essentially relevant to what we
are talking about in these hearings, the role of the advisory committee.
Mr. Hutt. I do not understand that.
Mr. Deinan. You told Procter & Gamble: "The advisory committee
will take this, Procter & Gamble, you have no worry. You don't
need an application."
In contradiction to your statutory responsibilities, you turned this
over to the advisory committee.
Mr. Hutt. I am sorry, I cannot agree with you. The company
marketed its product without any kind'of an NDA. If it were not for
this advisory committee this problem never would have been caught,
The reason thev submitted their abbreviated NDA, apparently now,
may not have been zirconium at all but hexachlorophene. Once they
got' rid of hexachlorophene they could have gone back and marketed
zirconium. There would have been no abbreviated new drug applica-
tion, no panel, no discussion of the issues in this 100-page report, and
the public would not be protected.
It is because of the OTC drug review that we are catching up with
this, product and doing it right.
Mr. Deinan. I agree, but I wonder why you did not say in the
beginning that until or unless the FDA gives clearance you are not
allowed to put it on the market.
109
Let me ask a simple question: Did Procter & Gamble, in its applica-
tion, seek to justify the safety aspects of their product at all?
Mr. Hutt. We' will have to go back and look at the new drug
application. We do not have it with us. We simply did not review it in
preparation for today. .
Mr. Fountain. I have to rely to a large extent on the information
I set from the staff, and the material we read, as well as the regulations
which have been read and which we have had an opportunity to
observe. .
However, as I understand it, I thought you were required to make
a review of any application which included hexachlorophene. Is that
not right? .
Mr. Hutt. Mr. Fountain, what I would think might be the best
way to handle tins is for us to go back, since we were not told this
whole abbreviated NDA would be the subject of detailed discussion,
and see exactly what was hi that NDA, what the status was, why it
was submitted, and make a full report to you.
Mr. Fountain. All right, and also include in that report an explana-
tion as to why, after Gillette submitted information indicating that
the inhalation of zirconium in the lungs of animals in October of 1973
was harmful
Mr. Hutt. It showed a harmful result for the Gillette product and
not for the Procter & Gamble product.
Mr. Fouxtaix. But Procter & Gamble had zirconium, did they not?
Mr. Hutt. Yes; but it showed an effect for one product and not an
effect for another product.
Mr. Fouxtaix. The point I make is not that they were identical,
but after you had this information back in October of 1973, and you
had had this abbreviated new drug application, where you sort of
said you mil not pay attention to it now — put it in the file — why you
did not go back and~ take a look at this situation.
Dr. Grout. We did. The slides from the Gillette study were re-
viewed by one of our toxicologists, as were the data in both studies. It
was his judgment that the data did not provide any evidence that the
Procter & Gamble product was unsafe, so that actually it turns out
Mr. Fouxtaix. Procter & Gamble, but what about Gillette?
Dr. Crout. Gillette's was not marketed.
Mr. Hutt. Their product was withdrawn from the market.
[The information requested may be found in the appendix at
pp. 331-333.] " . n
Dr. Crout. Let me make one final comment. Interestingly enough
the panel here is being more cautious, more severe, more stringent
than our own internal review. I merely want to point out that reason-
able men can differ, and in the long run the panels may come up with
positions which are quite as strong as any position we might take in-
ternally, sometimes even stronger.
Mr. Hutt. Also, Mr. Chairman, there is a difference between what
the panel is focusing on and what the internal review focused on.
The panel is, I think, not disagreeing with the analysis .of the Bureau
of Drugs, but it is looking at potential long-range possibilities which
the public should be protected against.
Dr. Crout. The purpose of our review, again, was to ask basically
whether there is a safety problem sufficient for us to take the Procter &
110
Gamble product out of the OTC drug review. A judgment was made
there was not reason to do that.
Dr. Goldberg. You were looking at that question in a very narrow
context which you describe?
Dr. Crout. That is correct.
Dr. Goldberg. However, am I not correct in saying that the NDA
process, as it has traditionally been viewed by FDA, is to take
the broad view; to examine not only whether there is evidence of
potential danger to individuals today, but also whether there are
questions of safety for the future. Isn't the panel, in effect, doing what
FDA should be doing in the new drug process?
Dr. Crout. Of course, but the panel is taking that broad approach,
and we know it.
Dr. Goldberg. Which is FDA's normal approach.
Dr. Crout. The panel works for FDA. Of course it is our approach.
That is right. We are careful in instructing those panels, and so on.
You bet that is their approach.
Dr. Goldberg. I want the record to show that the panel is not
dome; something over and above FDA's normal in-house responsi-
bility. It is not that they are applying more stringent standards; they
are doing the kind of thorough job that FDA has often done in the past
and should be doing regularly in examining these products.
Dr. Crout. Fair enough.
Mr. Fountain. If you come to the conclusion that certain decisions
should be made, even though you turn it over to a panel, you do not
have to wait for the panel to make a recommendation. Is that true?
Mr. Hutt. That is correct.
Mr. Fountain. I was reading some quotes from you in your con-
versation with the panel, Mr. Hutt. I was in the process of asking a
question when we got involved with these other questions, all of which
are important.
Is your stated intent, as I gather it from this colloquy here, to ignore
the interstate marketing of new drugs without NDA's, in conformance
with the purpose of the statute expressly prohibiting such marketing?
Mr. Hutt. First, that was not my stated intent. My stated intent
was that the marketing of products which present no known safety or
effectiveness issues, while the panel was in the process of reviewing
products which fall into that class, was not something that we should
put as a major enforcement priority, Mr. Fountain.
If those were determined by FDA clearly to be new drugs, then that
would have been a different issue.
Mr. Fountain. We had hoped we would be able to cover more
than we have today, and that we would be able to cover other areas,
but I doubt we will" be able to. We will have to pick a later time.
We shall adjourn until Monday morning.
Mr. Drinan. Thank you very much, gentlemen. You are very
good witnesses.
Mr. Fountain. We shall continue on Monday morning, at 9:30.
[Whereupon, at 12:30 p.m., the subcommittee adjourned, to re-
convene at 9:30 a.m., Monday, May 12, 1975.]
USE OF ADVISORY COMMITTEES BY THE FOOD AND
DRUG ADMINISTRATION
(Part 2)
MONDAY, MAY 12, 1975
House of Representatives,
Intergovernmental Relations
and Human Resources Subcommittee
of the Committee on Government Operations,
Washington, D.C.
The subcommittee met, pursuant to notice, at 9:43 a.m., in room
2247, Ray burn House Office Building, Hon. L. H. Fountain (chairman
of the subcommittee) presiding.
Present: Representatives L. H. Fountain, Don Fuqua, Edward
Mezvinsky, Barbara Jordan, Robert F. Drinan, Glenn English, John
W. Wvdler, and Robert W. Kasten, Jr.
Also present: Delphis C. Goldberg, professional staff member;
Gilbert S. Goldhammer, consultant; and Richard L. Thompson,
minority professional staff, Committee on Government Operations.
Mr. Fountain. The subcommittee will come to order.
The record will show that a quorum is present.
Mr. Hutt, I have one or two clarifying questions based upon a
telephone call received over the weekend.
We were informed by two sources, one of which was Mr. Goodrich,
that months before you became Associate General Counsel for FDA
in September 1971, Dr. Edwards and Mr. Goodrich decided to regulate
OTC drugs on a class basis by rulemaking and had already testified
to that effect before Senator Nelson's subcommittee.
In your testimony here on Friday, I am not sure what you intended,
but in your statement to the antiperspirant panel on March 24, 1975,
was it your intention to convey the idea that the rulemaking on a
drug-class basis originated with you?
STATEMENT OF ALEXANDER M. SCHMIDT, M.D., COMMISSIONER OF
FOOD AND DRUGS, FOOD AND DRUG ADMINISTRATION; J. RICH-
ARD CROUT, M.D., DIRECTOR, BUREAU OF DRUGS ; PETER BARTON
HUTT, CHIEF COUNSEL; ROBERT C. WETHERELL, JR., DIRECTOR,
OFFICE OF LEGISLATIVE SERVICES; ROBERT G. PINCO, CHIEF,
DIVISION OF OTC EVALUATION; MASK NOVITCH, M.D., DEPUTY
ASSOCIATE COMMISSIONER FOR MEDICAL AFFAIRS; AND GARY
L. YINGLING, ASSOCIATE CHIEF COUNSEL FOR ENFORCEMENT
Mr. Hutt. No, sir. I said I believe I was one of the people who had
to make the decisions, or something to that effect, I believe in that
OH)
112
statement I was referring specifically to the question of continuing
after the rulemaking had begun with the case-by-case litigation.
Mr. Fountain. I might add that Mr. Goodrich informed the staff
that FDA had never contemplated any deferral of enforcement of
the new drug provisions of the act during the pendenc}?- of the panel
review and the publishing of the final rules; that is when he was there.
Dr. Schmidt, the antiperspirant panel was composed primarily of
experts in the field of dermatolog}^. Is that right?
Dr. Schmidt. I would have to review the curriculum vitae of the
panel members before I can characterize them. I am not sure that is
correct.
Mr. Fountain. Were any of the panel members experts in lung
pathology?
Dr. Schmidt. There was one person.
I make two points. One person was generally familiar, at least, with
the field, but this panel consulted widely with some of the world's
experts in the question areas they were taking up. Panels all have
access to expertise all around the world.
This panel, in particular on the zirconium issue, consulted very
widely.
Dr. Clayton, a toxicologist, and a microbiologist were on the panel;
a pharmacologist, a pharmacist.
Dr. Rosenberg is a dermatologist who is listed. Another comes from
a department of dermatology.
I would also remind 3^ou that dermatologists today, particularly
academic dermatologists, have a wide variety of skills and get into
molecular biology and the sorts of things that academicians do in
many areas.
Mr. Fountain. As a matter of fact, a general practitioner of law
has a general knowledge but I would hate to rely on him altogether
when it comes to a specialty field.
Then I take it that no member of the panel was an expert in lung
pathology except as you have described, but the panel was in a position
to get information from all of the sources you mentioned.
Mr. Pinco. It depends on how you define the term "expert." I
think several members had a working knowledge of this area. They
also had enough knowledge to realize that there were areas they did
not have all the expertise they needed. That was one of the reasons
they went to various people from ail over the world, to try to bring
them together for that very purpose. That was the reason they had
that meeting and subsequent meetings, to build on that knowledge
which they had.
Mr. Fountain. Strike out the word "expert." Did you have a lung
pathologist?
Mr. Pinco. Not as such.
Mr. Hutt. I believe at the hearing two times ago that we agreed
to provide the curriculum vitae of the experts who were brought in
by the panel and on whom they relied in these areas that 3^011 are
now talking about, also.
Mr. Fountain. Then I take it from what 3^011 have said, Dr.
Schmidt, that you regarded the panel, or you regard the members of
the panel, as experts qualified by experience and training to evaluate
the safety of inhalation of zirconium aerosols?
113
Dr. Schmidt. Certainly they are competent to conduct the review
which they have conducted. "I would emphasize that many people
have volunteered to me information that this panel gathered together
the true experts in zirconium and zirconium toxicity, and so on, from
around the world. The panel had the best advice that science can
offer, and they certainly are qualified to evaluate the scientific infor-
mation that they receive.
Mr. Fountain. Then you say they were qualified to evaluate llic
safety of the inhalation of zirconium aerosols?
Dr. Schmidt. Yes. . ■■.
Mr. Fountain. During the hearing on May 9, I placed into the
record documents indicating that the Food and Drug Administration
established a policy of withholding regulatory action against OIL
and many prescription new drugs on the market without NDA s
pending review by OTC review panels.
At this time I shall place into the record additional Gocuments to
further illustrate FDA's policy of deferring action until after OTC
panel review. . „ \
The documents relate to "Podophyllum: A potentially dangerous
laxative * * *." , . ,
[The documents referred to follow, as does an exchange ol cor-
respondence between the subcommittee chairman and FDA. Com-
missioner Schmidt concerning podophyllum (podophyllin) . See pp.
309-317, 333-337 of this hearing record for documents relating to
advisory panel's finding that podophyllum is unsafe.]
Department of Health, Education, and Welfare
public health service
food and drug administration
Date: June 18, 1971.
Attn of: BD-2. .■ , . Mn
Subject: Podophyllum: A potentially dangerous laxative, by G. Kosenstein, M.D.
To: Henry E. Simmons, M.D., M.P.H. (BD-1).
Podophyllum is an irritant substance used internally as a laxative (8 to 15 mg.)
and topically for warts (20-2.V , Cone). The authors have documented that
podophyllum should no longer be used as a laxative. It is not dangerous to tne
patient in the doses in which it is present in proprietary laxatives, provided that
an overdose is not taken, but there is a report of phocomeha m the offspring ot a
patient who took "herbal slimming tablets" containing podophyllum during tne
5th to 9th week of pregnancy. Vv bet her this is or is not drug-related is not known
but phodophyllum does have an effect on mitosis, which renders it useful topically
for the treatment of warts. In the past, it-was used topically for various mahgnan-
Topical podophyllum preparations taken orally by accident or with suicidal or
abortifacient intent have caused death following doses of 300-600 mg., but some
patients recovered following good supportive therapy. One patient is reported
to have gone into coma 24 hours after application of podophyllum ointment m
the treatment of condylomata acuminata.
The following documentation is offered for removing podophyllum from tlio
list of accepted ingredients for OTC cathartics:
1 Following the report of phocomelia in the literature (Lancet) in 1952, the
British manufacturer of the tablets in question withdrew them from the market
and substituted another ingredient. „ TTT ^ „„„„ n , , x. n
2. The Ministry of Health of Italy informed WHO in 1963 that podophyllum
preparations should be labeled "Do not use in confirmed or sus] > - - ncy .
3. Windsor Cutting's "Handbook of Pharmacology", 3rd Edition, states, under
Vegetable Cathartics that podophyllum (and other examples) have no modern
use as cathartics.
114
4. Goodman and Gilman lists podophyllum under the Obsolete Cathartics.
They say that the obsolete cathartics "are described only because they represent
a potential source of drug abuse and intoxication. Their use cannot be too emphat-
ically condemned." With respect to the cathartic resins, in particular, including
podophyllum, they state that they act on the small intestine, are quite irritating,
and that several are still common ingredients in irrational cathartic mixtures.
"The cathartic resins should be abandoned".
5. In pregnant mice, a dose of 4 mg./kg. podophyllotoxin I.V. caused interrup-
tion of pregnancy in 100% of cases. (Didcock, K. A. et al.: The Action of Podo-
phyllotoxin on Pregnancy, J. Physiol. 117:65,1952.)
6. Repeated applications of 20% podophyllum to the mouse cervix revealed
that it is a weak carcinogen. (Garret, M.: Relationship of Podophyllum to Car-
cinogenesis, Cancer 19:947, 1966.)
7. The Medical Letter, Dec. 21, 1962, issued a warning against podophyllum
during preganey following the report on phocomelia. It mentioned that podo-
phyllum is present in Carter's Little Pills, and other cathartic mixtures.
R •commendations
1. The paper by Dr. Rosenstein, et al., makes a contribution and is recom-
mended for ultimate publication in revised form. Since it comes from FDA
personnel, however, it should not be published unless or until the Commissioner
move- to withdraw podophyllum from laxative preps, by a S.P.I.
2. There is ample evidence that podophyllum is obsolete as a cathartic and a
recommendation should go forward to the Commissioner along with a proposed
S.P.I.
3. An attempt should be made to identify the currently marketed OTC and
Rx podophyilum-containing products. A printout accompanying this paper
reveals a number of old products under NDAs. Some "Cold Tablets" contain
podophyllum in small quantities (1.5 nig. /tab.); a number of laxative combos,
containing podophyllum are also listed but how many of these are still on the
market and what else is on the market remains to be ascertained.
4. When ultimately published, the thrust of the paper should indicate why
oral podophyllum was removed from the market.
5. If you concur, I will arrange for S.P.I., and a briefing memo to Dr. Edwards,
including a list of orally administered podophyilum-containing drugs. Carter's
Little Pills are the best known, I suppose, but there is no reason why they cannot
reformulate.
Marion J. Finkel, M.D.,
Deputy Director,
Bureau of Drugs.
Memo Record, April 14, 1971; Office: OSE; Division: SHEDF
From : V. Berliner, pharmacology.
To: Dr. H. Ortiz through Dr. G. Rosenstein.
Subject: Podophyllum, re your request for Pharmacology opinion on hazards and
actions.
SUMMARY
Goodman and Gilman state on p. 1029 of the Fourth Edition, 1970 of their
"The Pharmacological Basis of Therapeutics: The cathartic resins should be
abandoned". Podophyllum is in this group. It is a cytoxic agent that acts as a
spindle poison thus interfering with mitotic processes. This property confers also an
embryotoxic and teratogenic potential. It has to be admitted that in spite of the
wide usage of this drug in several cathartic formulations the teratogenic property
became demonstrated in only few instances but it is possible that minor expressions
of this action went unnoticed and were not associated with podophyllum intake.
This insidious behavior may make it even more undesirable for routine use as a
cathartic.
There are no animal investigations that were conducted according to our present
guidelines for teratogenicity studies. It would be of academical interest to find out
how a drug with these properties would act in these studies and it might be a
worthwhile undertaking for OPRT. However, these studies are not suggested as a
basis for any action against Podophyllum. These could rest mainly on the already
available knowledge, that was compiled by Dr. G. Rosenstein.
These considerations pertain only to the use of podophyllum in cathartics.
It still may have merits for the treatment of conditions requiring cytotoxic
functions.
115
Department of Health, Education, and Welfare
Director, OTC Products Review Staff (BD-109).
Through: Acting Director, Bureau of Drugs (BD-1) ; Assistant to the Director for
Regulatory Affairs (BD-30).
PODOPHYLLUM CONTAINING DRUGS
We have been requested to draft a policy statement which bans cathartic
preparations containing podophyllum and restricts the drug to prescription
sale for other drug uses. The policy statement is based on two reports of terato-
genicity and one report of severe peripheral neuropathy with accompanying
intrauterine death. No conclusions were made on any of these reports as to the
relationship of the drug to the fetal incidents.
We have discussed the proposed policy statement with Dr. Philip Walters,
of OSE, and he had advised that the status of the drug as a safe and effective
cathartic should be considered by the OTC Panel reviewing this class of drugs
before we take any official action on our own. Mr. John McElroy of your office
informs us that the panel is actively reviewing at least one product containing
podophyllum (Carter's Little Pills) and a review of the data submitted by the
firm reveals that the enclosed articles which are the basis for the proposed SPI
are not among those submitted by the firm. We are also enclosing the background
material prepared by Dr. Gladys Rosenstcui.
Since the background support for the SPI is not awesome, we recommend that
the OTC panel thoroughly review the matter, including the two enclosed articles,
and that the Bureau's final action be taken based on that review. The matter of
safety and efficacy of the topical use of podophyllum and its derivates will be
considered at that time.
Podophyllum, we are advised does not raise a safety issue that warrants its
separation from the normal OTC Drug Review process.
Mary A. McEniry.
Intergovernmental Relations and
Human Resources Subcommittee,
Washington, D.C., May 16, 1975.
Dr. Alexander M. Schmidt,
Commissioner, Food and Drug Administration,
Parklawn Building,
Rockville, Md.
Dear Dr. Schmidt: During the testimony on May 9, 1975, you and Mr. Hutt
indicated that two laxative ingredients were found to be unsafe and that the firms
marketing the drugs reformulated the products even before the publication in the
Federal Register of the proposed laxative monograph.
It is my understanding from the proposed laxative monograph published in the
March 21, 1975 Federal Register that podophyllin was one of the two laxative
ingredients which were found unsafe. I would appreciate knowing when Carter-
Wallace removed podophyllin from its formulation, whether it has ceased ship-
ping the podophyllin product, and whether any action has been taken to remove
from the market the existing stocks of podophyilin-containing pills.
Sincerely,
L. H. Fountain, Chairman.
Department of Health, Education, and Welfare,
Public Health Service,
Food and Drug Administration,
Rockville, Md., July 3, 1975.
Hon. L. H. Fountain,
Chairman, Subcommittee on Intergovernmental Relations and Human Resources,
Committee on Government Operations, House of Representatives, Washington, D.C.
Dear Mr. Fountain: This replies to your letter of May 16, 1975 concerning the
removal of podophyllin from the formulation of the drug, Carter's Little Pills.
Our belief that podophyllin was being removed from Carter's Little Pills was
based on the firm's written communication of November 8, 1974 to the Over-tiie-
Counter Laxative Panel to the effect that Carter was making plans to retain its
pill form but would change its present formula to provide for the removal of
podophyllin. That communication is attached.
1116
In our followup on this matter we have learned that podophyllin has not yet
been removed. The firm has told us that it is experiencing difficulty m manu-
facturing a combination of aloes and phenolphthalein that would be comparable in
size to the present aloes-pod'ophyllin combination. As a consequence, it has experi-
mented with an aloin-phenolphthalein combination but clinical data must be ob-
tained and the manufacturing process and specifications for a new formula have
not been worked out. .
Further, the firm is exploring other active ingredients which have been tenta-
tively placed in Category I, safe and effective, as possible alternatives to a re-
formulated product.
As I noted in the recent hearings before your Committee, Category 11 products,
whether so designated because of a lack of evidence of safety or of effectiveness,
will be removed from marketing when the monograph is final. The exceptions to
this will be cases in which an ingredient represents an imminent hazard to health,
which is not the case in this instance.
We hope this information is helpful.
Sincerely yours,
Alexander M. Schmidt, M.D.,
Commissioner of Food and Drugs.
Enclosure.
Carter Products,
Cr anbury, N.J. November 8, 191 %.
Mr. John McElroy,
OTC Drug Product Evaluation Staff,
U.S. Food and Drug Administration,
Bureau of Drugs,
Rockville, Md.
Dear Mr. McElroy: Enclosed please find eight (8) copies of a communication
addressed to the OTC Review Panel on Laxative, Anti-diarrheal, Emetic and
Anti-emetic Drugs regarding CARTER'S LITTLE PILLS. A ninth copy has
been sent to Dr. Hugh A Miller, the Industry Liaison Officer for The Proprietary
Association.
I will appreciate it if you will deliver these copies on or before the Panel's next
ad hoc meeting, planned for November 11, 1974. We will be pleased to make an
oral presentation at the convenience of the Panel, if desired. Thank you.
Sincerely yours,
David A. Schlichting, Ph. D.,
Director, Proprietary Drug Research.
To: OTC review panel on laxative, antidiarrheal, emetic and antiemetic drugs.
From: Carter Products Division, Carter- Wallace, Inc., Cranbury, N.J.
Subject: Carter's Little Pills.
We were surprised to learn from Dr. Hugh A. Miller that the Panel now plans
to review and categorize laxative combination products. Since the second ad hoc
meeting is expected to be concerned with this subject, we want to bring some new
information to your attention. We will briefly summarize it here so that you may
review the subject quickly, but if you desire detailed information, we will be pleased
to prepare a supplement to our original submission.
Carter's Little Pills presently contain aloes (16 mg) and podophyllin (4 mg).
The panel has recommended that podophyllin be placed in Category II. In light
of that decision we are making plans to retain our pill form but to change our
present formula to aloin (8 mg) and phenolphthalein (16 mg). We have had a
product of that formula on the market in Canada, England. Switzerland and
New Zealand for a number of years., We also have animal and human safety and
efficacy data on the individual ingredients and the combination. We present
this information in summary below and respectfully request that you review and
categorize this combination.
The first consideration is the question of the activity and uniformity of aloin.
The laxative activity of both aloin and phenolphthalein in rats was demonstrated
in 1955 (1). We have improved on the model and have shown a dose-response
relationship for both aloin and phenolphthalein. The test involves the controlled
use of a corn meal diet that gives uniform G.I. tract contents and the use of a
carefully constructed scale for scoring the consistency of a uniform length of
exposed intestional contents. The scoring scale used is from 8 = watery to =
very hard and pelletized stools. The table below gives the results, indicating that
the individual ingredients are active but the combination is more active.
117
LAXATIVE ACTIVITY IN RATS
Dose range Significance
in mg/kg Score range versus placebo
Placebo - ... 4.0-4.5
Aloin 12.6-50 5.1-5.9 p<0.05
Phenofphthalein 50.0-200 5.2-5.7 p<.05
Aloin/phenolphthalein.. 10/20-50/100 5.1-7.6 0)
i This could not be compared statistically because it WbS done in a separate experiment, but by inspection is obviously
greater than either ingredient alone.
The uniformity of different lot- of aloin NF XI has been established in our
laboratories both chemically and biologically. Chemically, the product is assayed
by ultraviolet spectrophotometry and the assay has been within ±5% for the nine
lots of aloin received in the last three years. The product itself is acceptable only if
the product assay is within 10% of the labelled amount, i.e., 7.2-8.8 mg per pill.
Biologically, we have assayed two lots from different suppliers, as described above,
and obtained essentially the same slope and levels of activity for both.
The safety of the ingredients alone has been studied in rats. Reported attempts
to determine in LD 5 o have been unsuccessful. A maximum tolerated acute oral
dose has been reported in the literature for aloin as 7.5 g/kg and for phenolphthalein
as 7.0 g/kg (1). Our own attempts to obtain LD 50 values have also been unsuccess-
ful due to its low toxicity. We gave acute cral doses as high as 5.0 g/kg for aloin
and 5.0 g/kg fcr phenolphthalein in mice and were unable to obtain an LD 50 .
We obtained the same results with a 1 : 2 ratio of aloin/phenolphthalein at the same
doses. Oral doses of up to 3.0 g/kg of both materials in dogs have been reported
with no deaths or adverse reactions. These results indicate that the ingredients
alone and in combination as well within the acceptable levels of safety and, in
fact, approach the safety levels of foods.
Four clinical studies done by three different clinicians on 129 subjects are
reported here. The first study, by Chapman, D.D. and Pitelli, J. J., Curr. Therap.
Res., 16, 817-820 (1974) demonstrates the efficacy of the individual ingredients
and their contribution to the combination. They studied phenolphthalein (120
mg) versus aloin (60 mg) and versus phenolphthalein (60 mg) plus aloin (30 mg)
and a placebo. They measured the number of bowel movements, stool consistency
and transit times. The study was a double-blind Latin Square design done on. 28
normal males and females with regular bowel habits. It was demonstrated that the
combination produced a greater laxative effect and a shorter transit time than the
individual ingredients and the placebo. All three treatments gave softer stools than
the placebo.
The second study, by Burton Cahn, M.D. in 1963, was a double-blind crossover
study on 26 males in which 1, 2 or 3 doses, each containing aloin 8 mg plus phe-
nolphthalein 16 ma;, were given every third dav for three doses, followed by a rest
period. The test product was compared with CARTER'S LITTLE PILLS. The
two products were equally effective and the test product showed a trend in the
dose-response relationship as follows: 1 or 2 doses were effective in 50% of the
subjects' and 3 doses in 65% and 1 and 2 doses showed no side effects in 92% and
3 doses showed no side effects in 85% of the instances. There were no severe side
effects.
The third study, by F. H. Stern, M.D., was a double-blind study on two
similar aloin and phenolphthalein formulas (two slightly different ratios) on 50
subjects, comparing this product to CARTER'S LITTLE PILLS on another 50
subjects. There were four cells of 25 subjects each in the study. The results
indicated greater efficacy and fewer side effects with the test product as compared
to CARTER'S LITTLE PILLS. The test product showed efficacy in 76%) of
the subjects with respect to stool consistency and 70% with respect to time of
movement. Side effects were non-existent or minimal in 68% of the subjects.
The fourth study, by F. H. Stern, M.D., also compared the test product (8 mg
aloin plus 16 mg ' phenolphthalein) with CARTER'S LITTLE PILLS. There
were 25 subjects evaluated in each of two cells in a double-blind study. The test
product showed efficacy in 88% of the subjects regarding stool consistency and
70% regarding time of movement. There were no side effects in 52% of the
subjects, but data on the number with minimal side effects was not reported
separately.
118
These clinical studies indicate that a combination of aloin one part and phenol-
phthalein two parts is a more effective laxative than either ingredient alone. They
also indicate that pills containing 8 mg aloin plus 16 mg phenolphthalein, taken
in doses of 1 to 3 pills, are at least as effective as CARTER S LITTLE PILLS
in the same doses. Side effects are relatively low.
We have presented a brief summary of the safety and efficacy of aloin and
phenolphthalein. The animal data in mice, rats or dogs indicate that both ingre-
dients are well within acceptable safety levels, individually and in combination
of aloin one part plus phenolphthalein two parts. A dose-response curve or bio-
assay procedure has been developed indicating that both aloin and phenol-
phthalein alone are active and that the combination is more active. Different
lots of aloin from different sources have been shown to be similar in their chemical
and biological characteristics. Four clinical studies using 129 subjects have been
summarized. The results indicate that the individual ingredients are active but
the combination product is more active. There is a suggestion that a dose-response
effect exists between 1, 2 and 3 pills. Side effects are relatively few and of an
insignificant nature. . .
We recommend that the Panel approve the combination of aloin 8 mg plus
phenolphthalein 16 mg; that the dose range for aloin be set at 8 to at least 24
mg per day and that the minimum dose for phenolphthalein be reduced to 16
If this information should not be found sufficient for full approval by the
Panel, we would ask that you provide us with guidance concerning additional
information necessary for full approval.
Respectfully submitted,
Carter Products Division of Carter-Wallace, Inc.
Mr. Fountain. I am placing into the record, documents relating to
the status of certain OTC oraf antimotion sickness drugs, the safety
of which were questioned.
[The documents referred to follow :]
Department of Health, Education, and Welfare,
Office of the Secretary,
Office of the General Counsel,
July 8, 1973.
To: Jean Mansur (BD-68).
From: Peter Barton Hutt (GC-1).
Subject: Rx status of cyclizine and meclizine.
After reviewing the file on this matter, I have the following comments and
suggestions.
1. The laxative panel has already been formed, has held at least one meeting,
and has been provided all of the safety and effectiveness data relating to these
products. If we wish to do so, we could ask it to review this issue as its first
priority.
2. I' am unable to find in the file any indication that this is an urgent matter
that could not await review by the OTC panel on an expedited basis. The draft
of the memorandum is dated exactly five months ago. If it has had this low a
priority in the Bureau of Drugs, I would suggest that we could wait another two
or three months while the OTC review panel provides its recommendations.
3. As a general rule, we have concluded that we will handle OTC drug problems
outside the OTC drug review only in the rare situation where there is an immediate
health hazard or a patent fraud. If this represented an immediate health hazard,
we should have moved some time ago on it. In any event, it appears to me that
we should at the very minimum discuss the matter thoroughly with the OTC
drug review panel and give them an opportunity to consider the matter before
taking action. If the Bureau does believe that there is a critical health problem
involved, however, then the matter obviously should be rushed to the Federal
Register.
119
Department of Health, Education, and Welfare,
Public Health Service,
Food and Drug Administration,
July 18, 1973.
To: Gary L. Yingling, Director, OTC Staff (BD-109).
From: Office of the Assistant to the Director for Regulatory Affairs (BD-6S).
Subject: Status of oral preparations containing chlorcyclizine, cyclizine, or
meclizine.
Mr. Hutt has recommended that in the absence of an immediate health hazard,
the Bureau's proposal to restrict these drugs to Rx be deferred until such drugs
have been considered by the OTC panel on antiemetic drugs, which has already
been provided safety and effectiveness data. Although the call for data listed only
meclizine and dimenhydrinate, we recommend that the panel also review evidence
on cyclizine (Marezine) which was published as effective for motion sickness
(copy attached) in 1970.
We suggest that these drugs be given as high priority as possible in the scheme
of review. You may want the OTC panel to be aware of the action the Bureau
has contemplated, along with the reasons and background. Therefore, I am
enclosing a copy of the draft proposal.
Jean Mansur.
Mr. Fountain. Mr. Hutt, I want to return to the verbatim tran-
script of the antiperspirant panel's March 24, 1975, meeting, from
which I quoted during the hearing on Friday.
I think it is apparent that this panel had difficult}^ in understanding
the long delay in FDA's removing a categor}^ II drug from the market
after the panel had made the classification. For example, at page 2-83
of the transcript, Mr. Robert Pinco commented to you:
I think, what I understand seems to be troubling the panel is that having cate-
gorized the thing into these, the ingredients as it were, into category two, they would
like to see the thing happen immediately.
In response, Mr. Hutt, you said:
We have that problem in all 17 panels. The one thing that I also insist upon is
absolute uniformity of treatment.
At page 2-85 a panel member expressed the feeling that a delay in
action after classification would not only permit continued marketing
of products already on the market, but would also permit similar new
products to enter the market. This is reflected in the following exchange
at page 2-85, which I am quoting in part:
Dr. . It is just a little dismaying to us to feel, as I feel, that as a result
of our putting it into a category 2, primarily because of our concern for its hazard,
we have actually encouraged its distribution in the market place.
Mr. Hutt. Well, I would not agree quite with your characterization because
putting it in 2 as opposed to 3, didn't encourage it going into the market place.
Dr. . Well, the time delay between the implementation of the final report
and the final monograph —
Which I guess is an interruption — -
Mr. Hutt. Well, I understand that. Which is why we have the exceptions. With-
out a question. The difficulty is when you start down a process of this kind, and
that the law does have a concept that all of you have heard of called due process of
law. The fact that a panel makes a recommendation doesn't mean it is auto-
matically accepted.
Mr. Hutt, have other panels expressed concern about the delay in
removing category II drugs from the market?
120
Mr. Hutt. One other panel which comes to mind raised the same
type of issue as to whether implementation could or should be ex-
pedited. That was the antimicrobial 1 panel. I provided them with the
same advice I have provided all panels; namely, where there is a health
hazard that comes to the attention of the panel, matters can be taken
out of turn, out of normal procedure, and expedited. As we have re-
lated at both of the prior two hearings this has, in fact, been done and
was, in fact, done with TBS. That is the only other panel I am aware of
which has raised that issue, Mr. Fountain.
Mr. Fountain. At this point we want to move on to the work of the
antacid review panel. I hope we will be able, in the limited time avail-
able, to complete our questioning on that subject, with all members
participating to the extent they desire.
Are there any questions at this point which any member would
like to ask before I get into the antacid review panel?
Mr. Drinan. I would like to have the material they promised us
two sessions ago; namely, the curriculum vitae of the people on that
panel, that would be helpful.
Mr. Pinco. That was supplied the committee at the last meeting.
I can get you another copj^.
Mr. Hutt. I believe those CV's did not include the additional
experts who were brought in, Father Drinan. That will be provided
as soon as we can get that.
[Note. — This information was not provided by FDA.]
Mr. Fountain. Again I would like to emphasize that in our discus-
sion of specific antacids, this subcommittee has no opinion regarding
their safet}^ or whether they are misbranded. We are interested in
developing the facts bearing on the work of the advisory committees,
their decisions and recommendations, the instructions given to them,
and the use the Food and Drug Administration makes of the advice
received.
I believe, Dr. Schmidt, that the antacid panel was the first of the
review panels FDA established. Is that correct?
Dr. Schmidt. That is correct.
Mr. Fountain. It is also the first review panel to have completed
its work resulting in the adoption of the final order and monograph.
Is that right?
Dr. Schmidt. Yes, sir.
Mr. Fountain. I have been told that antacids as a class are probably
among the least toxic or questionable drugs when used as directed. Is
that information correct?
Dr. Schmidt. They would certainly be among those in that category,
yes.
Mr. Fountain. Then would you say they are among the category
which is the least toxic?
Dr. Schmidt. Yes.
Mr. Fountain. I am placing a copy of FDA's Januar}^ 5, 1972,
notice announcing a safety and effectiveness review of the OTC
antacid drug products, and requesting the submission of data and
information for the known antacid drug ingredients for review.
[The document referred to follows:]
121
Department of Health, Education, and Welfare — Food and Drug
Administration
Safety and Efficacy Review of Over-the-Gounier Antacid Drug Products
REQUEST FOR DATA AND INFORMATION
The FDA is undertaking a review of all over-the-counter (OTC) drug products
currently marketed in the United States, to determine that these OTC products
are safe and effective for their labeled indications. This review will utilize expert
panels working with FDA personnel.
A notice of proposed rule making outlining procedures and explaining the pur-
pose for this review is published elsewhere in this issue of the Federal Register.
To facilitate this review and a determination as to whether an OTC drug for
human use is generally recognized as safe and effective and not misbranded under
its recommended conditions of use, and to provide all interested persons an
opportunity to present for the consideration of the reviewing experts the best
data and information available to support the stated claims for these antacid
drug products we are inviting submission of data, published and unpublished, and
other information pertinent to all active ingredients utilized in antacid products.
FDA is aware that the following active ingredients are used in antacid products:
Sodium bicarbonate.
Calcium carbonate.
Aluminum hydroxide.
Magnesium oxide.
Magnesium hydroxide.
Magnesium trisilicate.
Dihydroxyaluminum aminoacetate.
Interested parties are also invited to submit data on any other active antacid
ingredients which they may wish to be considered.
To be considered, seven copies of the data and/or views must be submitted in
the following format:
OTC DRUG REVIEW INFORMATION
I. Label(s) and all labeling.
II. A statement of the complete quantitative composition of the drug.
III. Animal safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
IV. Human safety data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports (not testimonial reports) .
4. Pertinent marketing experiences that may influence a determination as to
the safety of each individual active component.
B. Combinations of the individual active components.
1 . Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports (not testimonial reports).
4. Pertinent marketing experiences that may influence a determination as to
the safety of combinations of the individual active components.
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports (not testimonial reports).
4. Pertinent marketing experiences that may influence a determination as to
the safety of the finished drug product.
122
V. Efficacy data.
A. Individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports (not testimonial reports).
B. Combinations of the individual active components.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
3. Documented case reports (not testimonial reports).
C. Finished drug product.
1. Controlled studies.
2. Partially controlled or uncontrolled studies.
.'!. Documented case reports (not testimonial report*).
VI. A summary of the data and views setting forth the medical rationale and
purpose (or lack thereof) for the drug and its ingredients and the scientific basis
(or lack thereof) for the conclusion that the drug and its ingredients have been
proven safe and effective for the intended use. If there is an absence of controlled
stucSies in the material submitted, an explanation as to why such studies are not
considered necessary must be included.
Data should be submitted to:
Food and Drug Administration, Bureau of Drugs, OTC Drug Products Evalua-
tion Staff (BD-106), 5600 Fishers Lane, Rockville, Maryland 20852.
These data shall be submitted within 30 davs from date of this publication.
(Federal Food, Drug, and Cosmetic Act, sec. 701; 21 U.S.C. 371)
Dated: December 30, 1971.
Charles C. Edwards,
Commissioner of
Food and Drugs.
[FR Doc. 72-14S Filed 1-4-72; 8:51 am]
Mr. Fountain. Was the antacid review panel established soon
after January 5, 1972.
Mr. Hutt. It was almost simultaneous, Mr. Chairman. I think it
was simultaneous. I believe the call for data appeared in the same
issue of the Federal Register.
Mr. Fountain. I am also placing in the record the minutes of the
antacid panel's second meeting which took place on May 8, 1972.
[The document referred to follows:]
Food and Drug Administration, Bureau of Drugs, OTC Panel on Antacids
Second Meeting, Parklawn Office Building, Rockville, Md.
may 8, 1972 — conference room c
Chairman, F. J. Ingelfinger, M.D. Panel members present: H. C. Ansel, Ph.D.;
S. C. Harvey, Ph.D.; E. W. Moore, M.D. ; H. M. Spiro, M.D.; executive secre-
tary, G. Rosenstein, M.D.; consultant, Philip M. Berman, M.D. for J.B. Kirsner,
M.D. (panelist); liaison representatives: industry, J. Pisani, M.D.; consumer, A.
Dickinson.
FDA Participants — Part time: Commissioner Edwards; P. B. Hutt, Esq.;
H. E. Simmons, M.D.; M. Novitch, M.D.; P. G. Walters, M.D.; G. L. Yingling,
Esq.
These summary minutes are for the May 8, 1972, Antacid Review Panel. They
were approved and adopted on March 1, 1973.
The various positions taken during the meeting are provisional in nature and
may be modified or otherwise revised during subsequent deliberations of the Panel.
Whenever there is a lack of unanimity on any given point, the vote will be given.
Regulations do not permit voting by the Executive Secretary, Consultants, or any
Industry or Consumer Liaison representative.
Franz J. Ingelfinger, M.D.
Chairman.
introduction
The meeting was opened by Commissioner Edwards, who emphasized the im-
portance of the OTC undertaking and that of the antacid panel as the first OTC
panel to meet. He explained the integral operations of the OTC Steering Com-
123
mittee headed by Dr. Jack Moxley. He emphasized that "the Panel exercises total
independence in the judgments they would make. In the final analysis, the deci-
sions are the panel's decisions". He charged the panel with "reviewing good hard
scientific data, if available, and if not available, using the panel's good scientific
judgment".
Mr. Hutt distributed to each participant "The Procedures for Classification of
OTC Drugs" signed earlier by Commissioner Edwards (published in FR 5/11/72).
He discussed the regulations in terms of safety, effectiveness, and combination
drugs.
SUMMARY NOTES OF THE ANTACID PANEL
The Panel concurred in the following statements after discussion of each issue:
1. From the viewpoint of safety, the quantitative composition of the active
ingredients in a drug product should be displayed on the label.
2. When sodium bicarbonate is used as an antacid, ten grams is the limit that
should be taken in twenty-four hours and the label should state: "Do not use if
you have heart disease, high blood pressure, kidney disease, liver disease or are
pregnant."
3. Sodium carbonate can be safely used in antacid products provided it is given
with acidic ingredients such as citric or tartaric acid which produces a fizz and
results in a pH less than 8 (pH of sodium bicarbonate).
4. Magnesium salt containing antacids need not be limited as to the amount
taken for fear of magnesium ion toxicity.
5. Magnesium Sulfate does not have antacid properties and there is no rationale
for combining this ingredient with antacids.
6. The Panel believes there is no rationale in adding a laxative to an antacid
unless the laxative is specifically relevant to the action of the antacid.
7. Although magnesium trisilicate is generally considered to be safe when taken
by mouth, a question of silicious nephrolith following chronic use of the drug
has arisen.
8. Antacid preparations should be labeled to express the following idea: "If
taking prescription medication, consult your pharmacist or physician, since this
product may interfere with the effectiveness of certain prescribed medications."
9. The Panel requested that experts in renal disorders, acid base balance, hyper-
tension and nutrition be contacted with regards to levels of salt and sodium bi-
carbonate that should be permitted over normal intake. Dr. Ingelfinger will
initiate such requests.
10. The Industry Liaison representative accepted the responsibility of obtaining
additional views as to the efficacy or advantages of effervescent products. The
initial response is to be in writing. Subsequently, an invitation may be extended
to meet with the Panel.
11. The Panel will consider making a determination about the advisability of
using lactose in antacids at future meetings.
12. The use of a bicarbonate for an antacid will be discussed at a future meeting.
13. Tartrates will be discussed at a future meeting.
Future meetings in Washington, D.C. were scheduled for: June 21-23, August
10-12, September 7-9.
Dr. Ingelfinger will make and distribute assignments regarding the submitted
data which he will distribute later.
Dr. Lamar, Bureau of Drugs, will be requested to meet with the Panel in June
regarding the relationship of magnesium trisilicate and renal calculi.
Mr. Fountain. I shall quote from the first paragraph of the
introduction :
The meeting was opened by Commissioner Edwards, who emphasized the im-
portance of the OTC undertaking and that of the antacid panel as the first OTC
panel to meet. * * * He emphasized that "the Panel exercises total independence
in the judgments they would make. In the final analysis, the decisions are the
panel's decisions." He charged the panel with "reviewing good hard scientific
data, if available, and if not available using the panel's good scientific judgment."
What interests me is Dr. Edwards' charge that the panel exercises
total independence in the judgments they would make.
Did any FDA personnel, including of course the staff of the General
Counsel's office, give any instructions or otherwise communicate with
124
the panel while its judgments were being formed, or after the} r had
been formed?
Mr. Hutt. Yes, Mr. Chairman.
Mr. Fountain. What was the purpose of that communication?
Mr. Hutt. There was constant communication. The entire concept
of having advisory committees for the Food and Drug Administration,
for the OTC drug review as contrasted with the use of outside com-
mittees for the NAS/NRC prescription drug review, was to have the
panel staffed by Food and Drug Administration employees so we
would not be subject to the same difficulties that arose in the NAS/
NRC review.
Mr. Fountain. Was there any communication with the panels while
their judgments were being formed?
Mr. Hutt. Yes.
Mr. Fountain. Designed to influence those judgments on any
matter?
Mr. Hutt. No, not designed to influence them but designed particu-
larly to make sure that judgments were reached on all of the issues,
to Degin with; second, that the reason for each one of those judgments
was fully laid out; third, that all questions that were raised by anyone
outside the panel, or that could occur to any of us, were fulty answered ;
and, fourth, that there was full and complete documentation of all
their judgments.
Therefore our job, not just for the antacid panel but all the panels,
is to meet with the panel constantly as they are forming their judg-
ment. As I always tell them, we have no interest in how the} T come
out on any issue but we do want to be sure they address the issues,
that thejr back up their decisions, that they articulate their reasons
in what I have often said should be third grade English. Without that,
I have pointed out to every panel — and literally up until this past week
I have been meeting with them on a regular basis — without that kind
of documentation and sharpening of their decision it would be much
more difficult to defend in the public, in Congress, in the courts and
every place else we must defend it. So there is total and constant and
complete interchange between my office, the office of the OTC review,
and the panels.
Mr. Fountain. To give you a further chance to elaborate, Commis-
sioner Edwards had charged the panel, as you note, in May of 1972
with "reviewing good hard scientific data, if available and if not
available using the panel's good scientific judgment."
On those occasions when FDA gave instructions or otherwise sought
to influence the panel's deliberations, or to inform them, as you say,
about all matters they should be concerned about, was it always to
bring additional scientific information on antacids to the panel's
attention?
Mr. Hutt. Mr. Chairman, as I stated, no. Quite frequently it was
to point out a sentence in a report which was ambiguous or that was
not immediately apparent to us as to its relevance or which was not
backed up by adequate scientific data or which raised additional
questions which were not fully answered by the panel.
We acted in very much the same way that the friendly prosecutor
would act. I would constantly — and I have done this many, many
times with every panel which has a draft report — I will take their
125
draft report and annotate in the margins questions which occur to me
in order to get the panel to answer those questions. Each time I have
done that I have pointed out that I have no interest, and no knowl-
edge, as to what the answer should be. However, it is terribly im-
portant that they answer the question one way or the other and ex-
plain the reasons for their answer.
I would saj T in all the times that I have met with panels, in none
of those times has it been for the purpose of reviewing scientific data.
Air. Fountain. Then I would assume that whenever questions
arose in their minds they would also call upon }^ou
Mr. Htjtt. For legal advice, 3 T es, sir, to explain some of the pro-
cedures or, as I did with the antiperspirant panel, to explain various
options open to them.
I think, if I may just harken back to the zirconium issue, the tran-
script will show that when I gave the options to the panel they then
asked me what they should do, and I said it was improper for me to
give them an answer; that, instead, is what we were asking them to
say, after which we would review their recommendations.
Mr. Fountain. As I understand it, it is generally known that serious
questions concerning the safety of Alka-Seltzer, for example, were
raised during the panel's deliberations.
According to our information, the panel had reservations about the
safety of aspirin-antacid combinations, like Alka-Seltzer (which con-
tain aspirin and the antacid ingredient, sodium bicarbonate), when
used in treating stomach distress, such as heartburn. Is that correct?
Dr. Schmidt. As a blanket statement, no, it is not correct.
Mr. Fountain. They didn't have reservations about their safety?
Dr. Schmidt. There were questions raised from outside the panel
about the whole subject of aspirin and aspirin causing gastrointestinal
bleeding. There were certainly discussions of Alka-Seltzer. There were
discussions of Bufferin aspirin and whether or not a product such as
an effervescent sodium acetylsalicylate was associated with serious
bleeding or not.
It was true that these questions were discussed.
Mr. Fountain. You are sajdng questions were discussed and they
got a lot of outside information but the panel itself had no serious
questions or reservations?
Dr. Schmidt. They had concern about the use of aspirin — acetyl-
salicylic acid — by patients with chronic gastrointestinal distress or
ulcers. I think everyone has that concern.
I do not believe they had significant concern about the use of Alka-
Seltzer by normal people properly and its relationship to any heavy
blood loss.
Mr. Fountain. Was their concern centered in any way on the fact
that acid is contraindicated when stomach ulcers exist, for example?
Dr. Schmidt. Certainly that was discussed and it was a concern,
particularly with regard to labeling.
Mr. Fountain. The first indication that the panel had considered
the safety of aspirin-antacid combinations appears in the minutes of
the panel's fifth meeting on September 7 to 9, 1972. I am placing those
minutes in the record.
[The minutes referred to follow:]
126
FOOD AND DRUG ADMINISTRATION
Bureau of Drugs, OTC Panel on Antacids — Fifth Meeting, Parklawn
Office Building, Rockville, Md.
september 7/9, 1972
Chairman, F. J. Ingelfinger, M.D.; members of the panel present: H. C. Ansel,
Ph. D.; S. C. Harvey, Ph. D.; E. W. Moore, M.D.; J. F. Morrissey, M.D.; H. M.
Spiro, M.D. (6/23); M. I. Grossman, M.D.; Acting executive secretary, A. M.
Welch.
Industry scientific representatives: R. C. Brogle, Ph. D.; W. H. Feinstone,
Sc. D.; K. K. Kimura, Ph. D., M.D.; J. C. Krantz, Ph. D. ; H. A. Miller, M.D.;
C. G. Pitkin, R. Ph.; G. Swenson, R. Ph., S.J. D.; liaison representatives: industry,
J. Pisani, M.D.; consumer, A. Dickinson. FDA participants: M. Novitch, M.D.;
G. Yingling, Esq.
These summary minutes for the September 7/9, 1972 meetings of the Antacid
OTC Review Panel were approved and adopted on March 1, 1973.
The various positions taken during the meeting are provisional in nature and
may be modified or otherwise revised during subsequent deliberations of the panel.
Whenever there is a lack of unanimity on any given point, the vote will be given.
Regulations do not permit voting by the Executive Secretary, Consultants, or any
Industry or Consumer Liaison representative.
Franz J. Ingelfinger, M.D.
Chairman.
The Panel reviewed the draft minutes for the third meeting (June 21/23) and
the fourth meeting (August 10/12). Both were adopted with a proviso that the
minutes for the August meeting included tentative statements for Phosphates and
Evaluation of Efficacy which are to be reviewed in detail during this the fifth
session.
Modifications or additions to previous statements as well as new statements
are attached.
industry scientific representatives
A group of Industry Scientific Representatives led by Dr. Brogle met with the
Panel and freely discussed with the Panel members the various statements and
points that were reported to them by the Industry Liaison Representative, Dr.
Pisani.
Following the meeting with the Industry Scientific Representatives, the panel-
ists made changes and additions based either upon the discussions with the Indus-
try Scientific Representatives, data submitted or other information available to
the panelists.
CHANGES MADE IN THE ADOPTED JUNE MINUTES
Page 3: Insert after 2d sentence.
Although the Panel will not consider the pharmaceutical necessities and excipi-
ents, it is the view of the Panel that it is important that the safety of these mate-
rials and the advisability of listing them on the label be reviewed by an appropriate
body. Since these materials are used in the formulation of many drugs other than
antacids, it is not appropriate that they be dealt with specifically and solely in
relation to antacids.
Page 3: Additional No. 4-
The Panel strongly recommends that the Food and Drug Administration grant
a variance from any labeling requirement defined by this Panel only when the
application for variance is accompanied by creditable scientific evidence that the
requirement does not correctly apply to the product in question and which proof
is also acceptable to a majority of a panel of no fewer than five disinterested
consultants.
Page 3: Additional item 5.
Some antacid products may cause a laxative effect and/or constipation. Those
products generally regarded as causing these effects should be so labeled. (Vote:
6 for, 1 abstained). A further statement will be drafted on the effects of individual
components, effects of doses, and the need for development of standards for
definition of laxation and constipation.
127
Page 3: Sodium, last paragraph.
This requirement does not apply to products containing less than 5 mg. (0.2
mEq.). The quoted statement is revised to read: "Do not use without the advice
of your physician if you are on a sodium restricted diet. (Vote: 6 for, 1 abstained).
Page 4 : Magnesium ii.
"May cause diarrhea" changed to "May have laxative effect." (Vote: 5 for,
2 abstained).
Page 4- Calcium.
To be added, "Some products, depending on their ingredients may cause
constipation and should be so labeled."
Page 5: Aluminum.
The first sentence would be modified to say: The Panel considers aluminum
compounds taken in OTC antacids to be safe in the amounts usually taken orally
in such products and does not feel it necessary to impose a limitation.
CHANGES MADE IN THE ADOPTED AUGUST MINUTES
The Panel voted not to make a statement concerning the number of antacid
ingredients in a product (Vote: 6 for, 1 opposed).
Page 5: Item 1 — 2d paragraph.
Delete entire parenthetical statement (Vote: 6 for deletion, 1 opposed).
Page 6: 1st line.
Add after formulation: "And/or mode of administration."
Page 6: Item 3 — 2d line.
Add after Antacid: "and acid neutralizing."
Page 6: Item 4 amended to read.
OTC products marketed as antacids or to relieve upper gastrointestinal
symptoms should show on the label the quantitative composition with respect to
all ingredients except those that are pharmaceutical necessities (see section ) .
This composition is to be given per tablet, per volume unit of liquid used in
expressing dose, per packet, or per packet combination. (Vote: 5 for, 2 opposed).
Page 6: Item 5.
Delete (Vote: 5 for, 2 opposed).
Page 6: Item 6 revised to read.
OTC products currently marketed as "antacids" are often used to treat
symptoms that are not known to be related to acidity of gastric contents. These
symptoms include "indigestion", "gas", "upper abdominal pressure", "full
feeling", "nausea", "excessive eructations" and the like. Some of these symptoms
are vague, most are poorly understood as to pathophysiological mechanism, and
none are known to be caused by or alleviated by changes in gastric acidity. The
Panel recommends that companies marketing products that make claims for
alleviation of these or other similar symptoms should within 2 years provide
evidence of efficacy of this product in relieving each symptom for which a claim
is made. The evidence should be based on statistically valid clinical trials con-
ducted by double blind methods including placebo controls. Claims for those
symptoms for which such evidence has not been provided should be withdrawn.
Page 6: Item 7 revised to read.
The Panel takes the position that it is unwarranted to make claims or to
print indications on the package label which link certain signs and symptoms, such
as "indigestion", "gas", "sour breath", "upper abdominal pressure", "full
feeling", "nausea", "stomach distress", "upset stomach", "excessive eructation",
with normal or hypernormal gastric acidity, since the relationship of such signs
and symptoms to gastric acidity is unknown or dubious. Furthermore, such claims
or indications encourage the user to draw conclusions as to the cause or inter-
mediation of such symptoms, a conclusion that even the medical profession is
incapable of drawing at this time. Therefore, the Panel recommends that these
claims and indications which link these symptoms to acidity not be permitted
until such time as a relationship is established (Vote: 6 for, 1 opposed).
128
Page 7: Item 1 under standards.
Delete.
Page 8: Last sentence amended.
The Panel believes that the presently available information on the effect of
calcium on the stimulation of gastric secretion does not merit further restriction
on the use of calcium-containing antacids. However, as more information becomes
available, such a recommendation may well become appropriate.
Pages 7 and 8: August 10/12, 1972 minutes revised to read.
Measurement of neutralizing capacity of antacids.
Materials.— Antacid, 0.1 N HC1, 1.0 N HC1, Standardizing buffer pH 4.0
(0.05 M potassium hydrogen phthalate), pH meter, magnetic stirrer, magnetic
stirring bars (25 mm long, 9 mm diameter), 100 ml beakers (45 mm inside diam-
eter), 50 ml buret, buret stand, 50 ml pipet calibrated to deliver.
Procedure:
1. Standardize pH meter at pH 4.0 with standardizing buffer and at pH 1.1
with 0.1 N HC1.
2. Pipet 50 ml 0.1 N HC1 into 100 ml beaker.
3. Place on stirrer, add stirring bar, stir at 240 rpm throughout.
4. Insert electrodes, verify that pH is 1.1.
5. Add 1 unit dose of antacid. If antacid is in tablet form, add whole tablets.
6. Stir for exactly 10 min.
7. Read and record pH.
8. If pH is 3.5 or greater, proceed; if pH is below 3.5, stop test.
9. If pH at Step 7 is 3.5 or greater, add 1.0 N HC1 from buret to bring pH to
3.5. Continue to add 1.0 N HC1 at the rate required to hold pH at 3.5.
10. Exactly 5 minutes after beginning addition of 1.0 N HC1 (15 min. after
adding antacid) read and record ml of 1.0 N HC1 used.
11. Calculation: 5 mEq (in 50 ml 0.1 N HC1 used in 1st 10 min.) 4- number of
ml 1.0 N HC1 added during period 10 to 15 min. = mEq acid neutralized in 15
min.
Criterion 1 : If pH is 3.5 or greater at end of initial 10 min. period, product may
be labeled antacid.
The Neutralizing Capacity of an antacid product should be expressed per unit
dose recommended on the label, or per minimum unit dose if more than one dose
is suggested.
Criterion 2: If antacid passes Criterion 1, neutralizing capacity as calculated
in Step 11 must be stated in package insert of ethically promoted products.
The neutralizing capacity of an antacid product is to be given in the package
insert of ethically promoted products but that this information should not be
given on the label of OTC products (Vote: 5 for, 1 opposed, 1 abstained).
August addendum to June minutes modified to read.
All OTC antacids should show on the label the sodium content. The sodium
content is to be expressed per tablet, per packet or packet combination, or for
suspension in volume unit used for expressing unit dose (see sodium, page 3).
This requirement does not apply to products containing less than 5 milligrams
(0.2 mEq) per unit dose.
Additional positions adopted or discussed.
Various types of burning distress felt in the upper abdomen retrosternally or
in the throat may be related to the regurgitation of acid gastric contents into the
esophagus, or to other and poorly understood mechanisms in which gastric acid
is involved. The Panel, therefore, believes that effective antacids (see section )
may be promoted to alleviate such symptoms as "heartburn", "sour stomach"
and "acid indigestion." The Panel, however, does not approve of the use of the
term "hyperacidity" unless such a condition has been substantiated.
All antacids are antipeptic in the sense that peptic activity is reduced as pH
increases and pepsin is irreversibly inactivated at pH's above 7. Some antacids
may have antipeptic action additional to that resulting from antacid action. No
claim for antipeptic activity should be allowed unless it is substantiated by
scientifically valid in vitro tests showing that the antipeptic action of the agent
in question is substantially greater than that of an agent with only antacid
action (such as sodium bicarbonate). There are conflicting reports on the effi-
cacy in treatment of peptic ulcer of agents that are antipeptic but not antacid
129
(example, sulfates dextran). The Panel is not aware of any studies showing
that addition of an antipeptic agent to an antacid increases its efficacy in treatment
of peptic ulcer or other conditions.
The Panel regards as unjustified by evidence currently available to it the
description of antacids as "floating, coating, or demulcent." The continued use of
such adjectives, or ones closely allied to them, will require additional studies to
confirm the claimed specific action. While the Panel recognizes that the addition
of anti-foaming agents to antacids may indeed endow such products with anti-
foaming characteristics, it does not now recognize any enhancement of antacid
action arising from this additional capability in an antacid product.
The Panel believes that there is no valid scientific evidence that the addition
to an OTC antacid of a drug which is not an antacid or a corrective for an antacid
side effect will result in a mixture which will have increased safety or effectiveness
for use in antacid therapy, but in fact, may reduce the safety or effectiveness of
the antacid product. The use of such mixtures should be limited to those individuals
who concurrently have symptoms which require for their relief the pharmacologic
action of both an antacid and the added drug. This limitation should be clearly
indicated on the product label. (Vote: 4 for, 1 against, 2 not present).
The Panel believes that it is irrational to add an anticholinergic drug to an
OTC antacid preparation for the following reasons: Optimal use of antacids and
anticholinergic drugs requires adjustment of the dosage of each drug independently.
Such combinations, regardless of their formulation, will result in products which
are either unsafe or ineffective. Similar considerations should apply to a combina-
tion of sedative-hypnotic substances. (Adopted without formal action of the 5
attending panelists). Similar considerations apply to combinations of other
analgesics with antacids. (No action).
Although the Panel is cognizant of the validity of combining an antacid with
aspirin for the purpose of buffering the aspirin, it takes the position that fixed
antacid-aspirin combinations should not be labeled or marketed for their antacid
effects. The Panel calls attention not only to the fact that OTC antacids are
sometimes zealously used, which may lead to aspirin toxicity with such combina-
tions, but also that aspirin has a potential for damaging the gastrointestinal
mucosa by mechanisms in addition to the topical action of the breaking of the
mucosal barrier.
The Panel considers the addition of proteolytic agents to antacid products to
be irrational. Although the role of pepsin in promoting peptic ulceration is not
clearly established, it is believed that the addition of pepsin to antacid products
may be potentially harmful. Similar considerations apply to the addition of bile
or bile salts to antacid products.
The Panel noted that some marketed products make therapeutic claim for the
carminative class of ingredients. The Panel found in reviewing the submissions
that no claims for therapeutic effectiveness were made for any such ingredients,
therefore, the Panel is not making a statement about these ingredients.
Mr. Fountain. Only one paragraph is devoted to the subject of the
safety of the aspirin-antacid combinations such as Alka-Seltzer. That
paragraph appears at page 10 and I am quoting it in full:
Although the Panel is cognizant of the validity of combining an antacid with
aspirin for the purpose of buffering the aspirin, it takes the position that fixed
antacid-aspirin combinations should not be labeled or marketed for their antacid
effects. The Panel calls attention not only to the fact that OTC antacids are some-
times zealously used, which may lead to aspirin toxicity with such combinations,
but also that aspirin has a potential for damaging the gastrointestinal mucosa by
mechanisms in addition to the topical action of the breaking of the mucosal
barrier.
I guess you would call this a rather short statement of the matter
which must have taken hours to discuss. We are given no information
as to whether any special instructions had been given to the panel by
FDA personnel.
We don't know from what the minutes show, whether the panel
might have been influenced by agency representatives, but had any
special instructions or guidance been presented by FDA during the
panel's consideration of Alka-Seltzer or any similar combination,
should the minutes have reflected such instructions?
130
Dr. Schmidt. You are posing a hypothetical question. The answer
to the hypothetical question — —
Mr. Fountain. There is nothing hypothetical about this, Doctor.
This is a factual situation.
Dr. Schmidt. I understand your question to say that if the FDA
had tried to influence the panel should that have been included in the
minutes
Mr. Fountain. Right.
Dr. Schmidt. That is a hypothetical question. The answer to the
hypothetical question is yes, certainly. I am unaware that FDA tried
to influence the panel in any way in making their judgments. What the
FDA has done repeatedly, as Mr. Hutt has said, is to set criteria for
their decisionmaking; that is, that their decisions must be well docu-
mented, and so on. I disagree heartily with your frequently-used term
that we spoke to them to influence their deliberations or such as that.
Mr. Fountain. I have not said you did that. I am simply asking
questions, doctor. If I have to be the devil's advocate to do it, I shall
continue to do so.
I note, for instance, that two FDA representatives, Dr. Novitch
and Mr. Yingling, addressed the panel. Since the minutes are part ol
the official record, was it proper to exclude froiii the record the fact
that Dr. Novitch discussed FDA's combination drug policy which
could have influenced the panel's independent scientific judgment?
Mr. Hutt. May I ask, Mr. Chairman, where it states that he
addressed the panel? I am not sure I understand the question.
Mr. Fountain. It does not sav that.
Mr. Hutt. Did he?
Mr. Fountain. He did, yes. Our information is that he did.
Mr. Hutt. If he did he would have stated and discussed what was
already in the Federal Register in terms of what the combination
policy'is, that is, a further explication of what is stated in the pre-
amble to the May 11, 1972, Federal Register final regulations as
well as the final regulations themselves.
Mr. Fountain^ I don't know how significant it is. I am simply
asking whether that fact should have been reflected in the minutes.
Mr. Hutt. If it should have been reflected it might have said,
"Mr. Novitch discussed the combination drug policy," but it is im-
possible, as you know, in minutes to reflect the substance of every-
thing that was said, and I doubt that that simple statement would
have been terribly helpful.
I think the summary minutes are intended more to reflect whether
there are true substantive points that are made rather than just
someone talking to the panel.
Mr. Fountain. The fact that someone from FDA addressed the
panel would seem to indicate to those who had knowledge of that
fact that they were individuals of whom questions could be asked. _
Mr. Hutt. Their presence as FDA participants is clearly noted in
the minutes.
Dr. Schmidt. These meetings can go on for 2 daj's, and minutes
certainly do not include eveiy exchange or every question and answer
because, gosh, the panel members can ask for clarification of the combi-
nation policy or any number of things.
131
Minutes are to include substantive discussions, particularly con-
clusions, recommendations, votes, and this sort of thing.
Mr. Hutt. This particular meeting; took 3 days.
Mr. Drinan. This is very relevant to the question of closing all of
the deliberative portions of the meetings or hearings of the advisory
committee. I have before me the Federal Register of June 4, 1974,
where the reasons the Commissioner closed these meetings are set
forth. In all candor this is not really satisfactory to me.
When the committee comes to the portion where they actually
deliberate and decide, the Commissioner, pursuant to law, says "I am
not going to release the transcript of what is transpiring here."
asons given, aside from the legal one, that this is within his
power, is that somehow the panel would be inhibited.
Was the panel ever polled as to whether they desire secrecy?
Mr. Hutt. Yes, Father Drinan. It was discussed fully within the
antacid panel. Indeed it was discussed fully with the chairman before
he agreed to serve.
A number of the scientists, both on that panel and on subsequent
panek, indicated that if it were to be held in open session constantly
that they would not be interested in participating because they believe
it would get bogged down with endless interruptions. In addition to
that, scientists who might be willing to criticize some of the work of
their brethren, and so forth, in private would not wish to get into
that kind of discussion in public.
Mr. Dkinan. That is not the reason given in the Federal Register.
It said this group would be inhibited. Were they asked whether they
would be inhibited?
Mr. Hutt. That is precisely the answer I just gave.
Mr. Drinan. Why would they be inhibited?
Mr. Hutt. Because they would not wish to discuss some of the
scientific work that has been done in an open public forum that they
might wish to give as a private opinion, in closed discussion.
On top of that I think it is fairly well known that any group which
discusses the subject as it becomes more cohesive and as the people
get to know each other are able to work together and exchange
views
Mr. Drinan. That is not a reason, as I understand it, to allow
secrec}^. The reason you gave is that the deliberations are based on
internal communications, and you cite the Freedom of Information Act.
That is a particular exemption, exemption 5.
Mr. Hutt. That is correct.
Mr. Drinan. Therefore, are you stating formally that everything
that was being discussed here in this advisory committee was based
upon internal communications and that they are privileged?
Mr. Hutt. Father Drinan, the two go together. The basis for the
internal communication privilege under the Freedom of Information
Act, as laid out in the legislative history of that act, is to afford free
and open discussion within the Government.
These people are Government employees. Thej^ are not private
citizens when they engage in this advisory committee work. They are
Government employees"; that is, special Government emplo^'ees.
132
The issue that you raise has been raised in the courts in a case
Smart v. Food and Drug Administration, decided by the U.S. district
court in California. The opinion of the judge states as follows:
Advisory committees are policy-determining groups whose deliberations are
entitled to protection. The Freedom of Information Act was never intended to
invade the privacy of discussions of this sort.
In connection with that lawsuit we presented affidavits to the court
showing that the members of advisory committees had been consulted
on this question of whether their discussion would be inhibited, and
they felt that it would be. They felt it would be contraiy to the public
interest and to their deliberations to open up all the discussion to
public scrutiny.
Mr. Drinan. Ma3^be they were wrong. You can follow the court
and get a reason and they sustain the exemption, but in your personal
judgment were these people on an advisory panel ill-advised? The
Commissioner went along with them and said secrecy would avoid
undue interference with this process.
What is the undue interference? Is it industry, consumers? What
is it?
Dr. vSchmidt. Undue interference would be the knowledge that
anything they said, however tentative, however exploratory, however
critical, however anything, could be spread in the public press with
far more harm resulting than good.
The idea of postulating, of trying things out to see what the other
panel members said, this would be inhibited.
The critical examination of scientific work by their colleagues, as
Mr. Hutt just said, would be inhibited.
This kind of discussion, it has been agreed over and over, is properly
held in confidence.
The important thing is that their conclusions and their recom-
mendations and the reasons for these be made public. That is what
is important.
That somebody came up with an idea to try out which might
prove to be an embarrassment all the way around is not significant.
That there be absolutely unimpeded discussion of all the issues is
terribly important.
Congress certainly has defended the right to debate policy, and so
on, in private sessions, and does to this day.
Mr. Drinan. The Freedom of Information Act permits this exemp-
tion. It may be that the Congress did not intend such a wide loophole.
It still appears to me that at the moment of truth we do not have
the transcript of the basic deliberations from which there emerged
these key recommendations.
I yield back to the chairman.
Mr. Fountain. Mr. Hutt, } 7 ou made reference to a court opinion.
Which one was that?
Mr. Hutt. Smart v. Food and Drug Administration.
Mr. Fountain. Was that a written opinion?
Mr. Hutt. No, it was an oral opinion delivered April 19, 1974, by
the Hon. Robert Schnacke, U.S. district court judge for the northern
district of California,
Mr. Fountain. Tell us in substance precisely what he said. You
say this was off the bench and not written out?
133
Mr. Hutt. Yes. In substance what he said was that lio dismissed
the suit brought by an individual who had asked that the advisory
committee transcripts be released, and who was also contending, in
effect, that the advisory committee proceeding should be conducted
in public, not in private; that is, not closed.
Mr. Drinan. He was a citizen in California who was a former — a
consumer grouper?
Mr. Hutt. No, a former emploj-ee of the Food and Drug Administra-
tion who had retired.
Mr. Drinan. What is his basic reason as to why he feels it should
have been public?
Mr. Hutt. He felt that the Freedom of Information Act and the
Federal Advisory Committee Act requires that. The court ruled they
did not.
Mr. Fuqua. Mr. Hutt, is there not a similar case relating to the
National Institute of Health relating to reviews of grants, and holding
that they were exempt under the Freedom of Information Act?
Mr. Hutt. Yes. The rationale of the Smart decision was upheld
basically by the U.S. Court of Appeals for the District of Columbia
Circuit just recently in the Washington Research Institute case,
which held that the so-called pink sheets, the internal review of
grant applications by outside advisory committees, are not available
for release under the Freedom of Information Act. It is the identical
principle involved.
Mr. Drinan. Mr. Hutt, was the Smart decision decided before the
amendments to the Freedom of Information Act became operative
over the veto of the President?
Mr. Hutt. It was decided before but those amendments, Father
Drinan, do not relate to this particular exemption, as you know. They
would be irrelevant.
Mr. Fountain. Mr. Hutt, I understand there has been another
case decided between the two cases you cite, Gates v. Schlesinger in
the U.S. district court.
Mr. Hutt. That was a Department of Defense case.
Mr. Fountain. I am advised that in that opinion they said advisory
committees are not part of the agency and, therefore, not subject
to the Freedom of Information Act. Is that right?
Mr. Hutt. In effect that case was overruled b}* the U.S. court of
appeals.
Mr. Goldhammer. In the Washington Research Institute case,
which was November of 1973, there, too, the circuit court held that the
review panel of the National Institutes of Health was not part of the
agency. I think you will find that very positive statement made.
Mr. Hutt. Mr. Goldhammer, my recollection is that the court held
that the work product of the review committees of the National
Institutes of Health was protected from public disclosure. Is that not
correct?
Mr. Goldhammer. Just the pink sheet.
Mr. Hutt. The pink sheet.
Mr. Goldhammer. Yes.
Mr. Hutt. Those pink sheets are the product of an advisory
committee to the NIH. That, I think, 3*011 will agree with me. That
advisory committee, in order to prepare those pink sheets, has to sit
and meet. Those meetings are closed to the public.
134
The court upheld that entire procedure.
Mr. Goldhammer. Yes, but they also made the statement, in so
many words, that the panels are not part of the agency.
I might say, Mr. Chairman, that there has been a more recent
decision which involved a travel agency case. Neither one of these
decisions was in the U.S. district court. The travel agency case was
not a reported case.
In that case the court held that title 5, section 552(b)(5); that is,
the exemption of the Freedom of Information Act requirement for
disclosure to the public, did not apply at all to advisory committees.
I understand the Justice Department intends to appeal.
Mr. Hutt. That issue was squarely decided by the court of appeals,
as you know, Mr. Goldhammer, in the Washington Research Institute
case. At least for the D.C. circuit that is no longer at issue.
Mr. Goldhammer. On the theory that the advisory committee is
not an agency of the Government, and, therefore, its deliberations are
not in the nature of interagenc}^ memorandums, which is encompassed
in section 552(b)(5) of title 5.
Mr. Hutt. Mr. Goldhammer, I am not entirely certain whether an
advisory committee is or is not an agency of the Government in this
context. The only court of appeals in the country which has looked
at the issue has said that an advisor}^ committee can meet in closed
session under the Federal Advisory Committee Act, and its work
product is not subject to release under the Freedom of Information
Act. It is protected under the fifth exemption from the Freedom of
Information Act.
Dr. Schmidt. The important principle here, at least to my view,
is that the product of those deliberations, the conclusions, and recom-
mendations — the things which would impact on the outside world — ■
and the reasons for them, must be public and explained publicly. It
is just how they get there, the trial and error, that is not being laid
out on the public record. I do not believe that this is any more signifi-
cant than are the deliberations of the Supreme Court before they
render a verdict be done in public. That is not done in public.
There are many, many types of deliberations which are not done in
public because of 'the chilling effect that that would have on the quality
of those deliberations. However, I believe the end product must be
public.
Mr. Fountain. I think it would depend upon the subject matter.
I am not sure what an opinion of the court making reference to advisory
commi: L n< cessarily mean, if it did not relateto the subject
matter in a particular case. It might be giving an opinion only about
advisory committees in that particular factual situation. I don't know
because I have not read these opinions.
Mr. Drinan. Going back to something which is very important, in
view of this discussion, in the Federal Register of April 5, 1973, it is
indicated that two nonvoting liaison representatives were appointed
to the advisory committee, one, Ms. Annette Dickinson, named by an
ad hoc group of consumer organizations, and Dr. Pisani, nominated by
the Proprietary Association, whatever that is.
Are these representatives employees of the Government, and who
decides they are nonvoting, and can they reveal, if they desire, what
went on in the deliberative sessions?
135
Mr. Hutt. They are members of the committee. They do sit
through all sessions of the committee except where a true trade secret
of a highly confidential nature is involved. Father Drinan, that has
been very, very rare.
For all intents and purposes they are, therefore, present during the
entire discussion. The}* are bound by the same rules as any other
member of the committee.
One of the difficulties, and I can understand
Mr. Drinan. Did they also agree that they wanted the session to
be secret?
Mr. Hutt. Some did and some did not. There has been a difference
of opinion within
Mr. Drinan. You told me unanimously all the members of the
committee.
Mr. Hutt. I said the scientific experts, the voting members of
the committee.
Mr. Drinan. Just the voting members; I see.
Mr. Hutt. I am sorry.
Mr. Drinan. The two nonvoting people — did they want it to :
be public?
Mr. Hutt. They did not vote on that issue.
Mr. Drinan. You didn't give them a chance to vote. The}* were
nonvoting members.
Mr. Hutt. That is right.
Mr. Drinan. They didn't vote on that. They didn't get a chance
to vote?
Mr. Hutt. That is correct. They had a chance to discuss it.
Mr. Drinan. I see.
Mr. Hutt. In some instances the consumer representatives urged
and were given an opportunity to urge that the committee hold their
sessions in public. The same was true in some instances where the
issue arose as to whether there should be a transcript of the closed
proceedings at all where some of the committee members wished to do
so and some did not. All members, whether voting or nonvoting, were
allowed to discuss the issue.
The only difference between an expert and a liaison member comes
down to the vote. I am unaware of any vote by any advisory com-
mittee thus far in the OTC drug review process where one vote, or
even two votes, would have totally changed what happened.
Mr. Drinan. Ts it fair to say Ms. Dickinson wanted all sessions to
be public, and she so stated?
Mr. Hutt. I would not be surprised. I do not know. I do not recall.
Mr. Drinan. Dr. Pisani was nominated by the Proprietary Associa-
tion. What is that?
Mr. Hutt. That is the over-the-counter drug trade association.
Mr. Drinan. Why did you call it the Proprietary Association?
Mr. Hutt. We did not name it.
Mr. Drinan. What was his position?
Mr. Hutt. I simply do not recall. He is vice president for medical
affairs.
Mr. Drinan. What was his position regarding secrecy? It was
only the consumer representative who said this exemption should not
apply?
136
Mr. Hutt. I do not know. Do you know that she did not want it
in closed session?
Mr. Drtnan. You said that.
Mr. Hutt. I said I did not know. You seem to know that. I do not.
Mr. Drinan. I asked a direct question. Ms. Dickinson wanted all
sessions to be public?
Mr. Hutt. I said I did not know.
Mr. Drinan. Who decided that she is a nonvoting member?
Mr. Hutt. The question of voting members and nonvoting members
arose in the following way:
When OTC drug review was first more than conceptualized;
that is, when we began to write clown procedures, the question arose
whether, because of conflict of interest, we could have any people
other than just recognized independent experts.
The decision was made that it was important to have two types of
input into the committee — people who would represent known
consumer interests, who would be advocates rather than independent
unbiased experts, and who could bring to bear the feelings of consumers
about these issues; and people who could act in the same liaison and
advocate capacity for the over-the-counter drug industry.
It was immediately recognized that they could not have a vote
because they would not be appearing there as independent, unbiased,
nonadvocate experts. They would be there in an advocate liaision
function.
Therefore, in order to avoid the conflict-of-interest issue for both
kinds of representatives they were included but without a vote.
Father Drinan, there is one problem, that is the lack of advisory
committee regulation; and we have recognized this and it is in the
process of being handled the way it should if we had been able to do
everything that should have been handled 2 years ago. We at this
moment have just, on Friday, sent to the Federal Register our pro-
cedural regulations which handle all of the questions that you have
raised with respect to advisory committees.
We had initially drafted advisory committee regulations sometime
ago. The Department of HEW asked us not to promulgate those be-
cause they were considering regulations and the Office of Management
and Budget was considering regulations.
We held off. The OMB decided not to issue detailed regulations.
The Department issued regulations which did not cover our regulatory
use of advisory committees. Just this Friday the Commissioner
signed, and this morning they were transmitted to the Office of Federal
Register, the regulations governing our advisory committees.
These cover all of the matters of meetings, public notice, when
meetings can be closed, when they may not be closed, and use of
nonvoting consumer and industry and other liaisons.
Mr. Drinan. What about the question of the ad hoc group of con-
sumer organizations?
Mr. Hutt. That was formed by the consumers themselves, not by
the Food and Drug Administration.
Mr. Drinan. Which consumers?
Mr. Hutt. The Consumer Federation of America took the lead in it
but it was joined also by Consumers Union, Mr. Jim Turner, Mr.
Robert Choate, and the Federation of Homemakers of America, Mrs.
Desmond.
137
Mr. Drinan. Who organized that group?
Mr. Hutt. As its name implies — you mean the whole group?
Mr. Drinan. How did you write to them and how did they settle
upon Ms. Annette Dickinson as their representative? I have a letter
from her, not entirely pertinent to this subject, but I want to know
what groups named Ms. Annette Dickinson to be their representative.
Mr. Hutt. When we first began the entire process we met with the
ad hoc group, which we had been meeting with on various occasions
over a period of time at their request to discuss a wide variety of issues
pending before the Food and Drug Administration in which these
consumer groups have an interest.
At one of the meetings we described the plans for the over-the-
counter drug review. We asked them if they would choose a consumer
representative for nonvoting liaison purposes as a member of each
Mr. Drinan. What is "liaison"? Liaison with whom?
Mr. Hutt. Consumer organizations and representatives, to provide
a consumer viewpoint to the panel. For example, a consumer liaison
would be obligated to go back to the consumer organizations with the
types of issues arising in each panel and to ask that organization and
those consumer advocates whether they wished to make their views
known, whether the}^ had any particular relevant information,
whether they knew of any particular serious problems that should be
raised, et cetera.
Mr. Drinan. Did Ms. Dickinson go back to her group when you
closed deliberations and make known to them this would be a secret
operation during the key proceedings? Did she make that known to
them and did they have a reaction?
Mr. Hutt. Yes, the consumer groups by and large asked us to open
those. Indeed they submitted comments on the proposal. The Com-
missioner concluded, for the reasons we have already discussed in some
detail, that that was inappropriate.
Mr. Drinan. Is that correspondence available?
Mr. Hutt. I am not sure it was in correspondence. I would have to
go back and look and see whether there was correspondence, Father
Drinan. I am sure there might have been some. If there is it is certainly
available.
Mr. Drinan. I yield back.
Mr. Hutt. I would like to make one thing quite clear.
The Food and Drug Administration felt quite strongly we should
not pick the consumer representative or the industry representative.
Obviousty we should pick the independent experts from people nomi-
nated and from people that we could find ourselves.
However, we went to the consortium of consumer groups and
asked them particularly that they pick the consumer representative
in any way that they wished, and they did that.
In the future we have a new mechanism for doing that which we
believe is a somewhat more democratic process. Beginning particularly
with the biologies review, where we have the same procedure, we put
a notice in the Federal Register and asked for nominations by any
consumer in the country, of any individual that they would like to
have considered as the consumer liaison on a panel.
Then, when we have those nominations, we send those nominations
with the CV's and all the information on the nominees to any group
which has previously signed up with the Food and Drug Administra-
138
tion to participate in the voting for the consumer representative, and
selection of the consumer liaison is done through a mail ballot. So it
is as democratic and as open and above board as we can possibly do
it now.
When the first few representatives were chosen we had not worked
out that process and we were, therefore, simply going to the consumer
groups for their nominees. We accepted them without question.
Mr. Fountain. Dr. Goldberg has a question. Before he asks his
question, I want to ask this:
I am curious as to what strength you give the voter groups. Is it
like the United Nations where 23,000 people have the same vote that
the United States has? How do you do it?
Mr. Hutt. Yes. The procedure will be that anyone who is interested
in participating in the voting must satisf}^ the person in the Food and
Drug Administration who is our principal liaison with consumer groups
that it is a genuine bona fide consumer group.
Then they are placed on the voting list and they will be asked to
vote every time this issue arises, Mr. Fountain.
We discussed many, many alternatives. Indeed at one of the recent
meetings with consumer groups we put on the agenda the exact
procedure which I have just laid out and asked them for their com-
ments to see whether it could be improved. They offered no objections
to it. They thought it was a reasonable approach.
Mr. Wydler. A question along the same line. Why don't you accept
somebody from Virginia Knauer's office or someone from the Execu-
tive Office who is appointed to represent consumer interests?
Mr. Hutt. We discussed this entire procedure with Mrs. Knauer's
office when it was first established. They were very much in favor
of this.
They believed that it should be someone from outside the Govern-
ment, just in the same wa}^ that the industry liaison representative
is someone from outside the Government.
They also believed very strongly in what we thought was the
critical point, namely, that the consumers select their own repre-
sentative just as the industry could, so that this would be their person
and there would be no suggestion that someone else was being, in a
sense, foisted upon them as their unwanted representative.
It was that principle of democratic selection which we thought was
critical to making it work.
Mr. Wydler. I often wonder by what right certain groups say the}^
represent the consumers. That could include everybod}", including me.
I wondered whether the Consumers Union represents my point of
view at all. It might be the opposite of my point of view on a particular
matter.
I am wondering bj what mysterious process a certain group becomes
the spokesman for consumers.
I can understand when a company is established and they are in
the business of manufacturing goods the}^ have some obviously valid
interest in that particular business, but I am trying to figure out how
a certain segment of the consumer population suddenly becomes the
consumer voice.
Dr. Schmidt. We have tried to determine all legitimate groups, as
Mr. Hutt said, and tr}ung to get around part of the problem you refer
139
to, by using a large number of groups. Clearly many of the consumer
groups are rather self-appointed representatives of consumers.
Seme of them, however, are very large, have large memberships,
and are well established as those tilings go.
Mr. Hutt. This would include, for example, the women's part of
the farm bureau and the junior league and many other widely
dispersed organizations which engage in consumer affairs.
Mr. Wydler. Neither is conservative or liberal in their orientation.
They are still quite a small segment of the
Mr. Hutt. I was not referring to conservative or liberal. They are
broadly based. What I intended to say is that they are not just the
people who sit in Washington and regard themselves as consumer
advocates. They are spread throughout the country, and as far as we
can determine, regardless of liberal or conservative tendencies, they
do to the best of our ability represent the country.
Mr. Fuqua. What do you consider consumer interests?
Mr. Hutt. The interests of ever3 T one who consumes the products
that are under discussion.
Mr. Fuqua. The price of it, availability, qualit}^? What is the
consumer interest?
Mr. Hutt. I may not understand your question. The issue before
this particular committee was the safety, effectiveness and proper
labeling of antacid products.
Mr. Fuqua. Price was not included?
Mr. Hutt. Absolutely not.
Mr. Fuqua. Nor quality or availability?
Mr. Hutt. No, sir.
Dr. Schmidt. One of the interests of the consumer is in the process,
how it is carried out — the procedure, and the integrity of the process.
To me one of the most important reasons for having the consumer
representative there is to give added legitimacy, acceptance and under-
standing to the final product of the panel. That is very important.
Mr. Fountain. Dr. Goldberg?
Dr. Goldberg. When a meeting has been closed and the record is
confidential, are the industry and consumer representatives free to go
back to their groups and discuss what transpires at that meeting?
Mr. Hutt. Here is the way it works. In the vast majority of
situations the minutes are prepared quickly and are disseminated
immediately, because the minutes do not show the individual views of
individual participants, and therefore the need for closing the meeting
is solved by the way the minutes are written. In short, release of the
minutes does not inhibit the discussion because of the way the}^ are
prepared.
For the same reason the experts and the consumer and industry
representatives are perfectly free to discuss the substance of what went
on in the same way the minutes reflect the substance of what went on.
There is agreement by all participants that there will be no attribu-
tion of individual views or discussion of anything that the committee
decides should not be discussed because it is premature.
There are many instances where the panel has concluded not to
release minutes and not to discuss issues in public because it is pre-
mature at that stage, and in those instances all people who have
participated agree to that procedure.
55-495—75- 10
140
Dr. Goldberg. Then, if I understand correctly, the industry and
consumer representatives are not prohibited from discussing subjects
over and above those reported in the minutes as long as they do not
go to the question of attribution of a particular statement or premature
release of policy positions which have been taken?
Mr. Hutt. Over and above those in the minutes?
Dr. Goldberg. Over and above the disclosures in the minutes.
Mr. Hutt. I am not sure what that would mean, Dr. Goldberg.
Dr. Goldberg. The chairman already has given you one instance
where a brief paragraph purportedly reflected several hours of dis-
cussion. It does not take much speculation to conclude there must have
been a lot of discussion that was not reflected in the minutes.
Mr. Hutt. I see. In other words, if, for example, there was concern
say about a particular scientific study and that particular concern was
not reflected in the minutes, yes, it could be discussed. That would
show in my judgment that the minutes should have reflected the con-
cern about the study. However, if that was the kind of situation which
arose, as long as there was no attribution of views and no violation of
an agreement not to discuss something which was premature, then
the experts themselves would be free to discuss that as well as the
consumer and industry representatives. The answer is yes.
Again, Dr. Goldberg, as I say, unfortunately this has not yet been
made public in the form of guidelines in regulations, but that will be
published in the Federal Register. This particular subject is discussed
in some detail in those regulations. They should be published b}-,
roughly, June 1.
Mr. Fountain. I want to get away from this and get back to the
making of the record regarding our principal purpose. I have one more
question inasmuch as there have been so many questions concerning
this subject.
Would it be proper for the consumer or industry to release drafts of
reports before they are finalized?
Mr. Hutt. This has been a subject which has again evolved as to
how it is done.
I would first say, Mr. Chairman, that the consumer and industry
liaison representatives are subject to the same rules, whatever they
may be, as the experts who are serving on the committee. When you
ask the question that way I would first have to answer that everyone
does'it one way or the other way but there is no split between them.
Mr. Fountain. I would think the} r all should be bound by the same
rules.
Mr. Hutt. Exactly. That is what the new regulations make clear.
Now, with regard to release of drafts, in the earty panels, as our en-
tire procedure was evolving, this was done informally. At the point
where the committee said, "We now have a draft of a document that
we would like to obtain consumer and industry feeling about on a broad
basis," then we would tell the industry and consumer representatives
that they were free to disseminate that in any way they wanted and to
bring back to the panel any comments that consumer groups or indus-
try groups or firms might wish to make on it, so that the panel would
understand what the concerns were about that document.
We have now formalized that as a result of a couple of years' experi-
ence.
141
First, we have asked the panel, and they have agreed, to release the
entire draft report only when it reaches a final draft stage. At that
point we publish a notice in the Federal Register of its availability to
any person who wishes to have it, and we put it in the hearing clerk's
office.
Prior to that stage the panel may release selected small portions on
which they might wish to get a particular type of comment in order to
get some insight which otherwise might not readily be available. There
have been some, as I said, small portions being released almost on a
continuous basis by particular panels, what you might call position
papers, even before they have been drafted in the form of a report.
Mr. Fountain. With respect to advisory committee meetings,
whether their recommendations or conclusions are accepted or re-
jected, and regardless of a person's opinion about them, I think we
will all agree they are important documents.
As you know, the Federal Advisory Committee Act requires the
preparation of detailed minutes. I guess we could have a debate about
what that means. What you do put in should be detailed, but it does
not necessarily mean you have to put everything in. I would think it
means detailed minutes of what transpires.
However, the minutes would seem to take on added importance
in the case of antacid regulations because they have been designated
under "General Comments," paragraph 3 of the FDA regulation,
published in the June 4, 1974, Federal Register, as part of the ad-
ministrative record.
I read from page 19863 of that issue of the Federal Register, and
quote in part from paragraph 3.
The record includes the panel reports and minutes but excludes the transcript
of the panel deliberations. The Commissioner is obligated to base his conclusion
with respect to a monograph on the entire administrative record. In the case of
the antacid monograph, the Commissioner has not read or referred to or relied
upon the words recorded in the transcript of the Antacid Panel meetings. Instead
he has relied solely upon the minutes of the Panel meetings, the data and infor-
mation submitted to and considered by the Panel, the Panel report, the
comments submitted on the tentative final order, the transcript of and material
submitted at the public hearing and the comments filed subsequent to the public
hearing.
Dr. Schmidt, I think it is obvious that a great deal of material
becomes part of the official record. However, the transcripts of the
closed meetings when the panel deliberates is not part of the ad-
ministrative record; you rely solely on the minutes for a recitation of
what occurred during the meeting.
It seems to me that this would, of necessity, make it appear that
the minutes do take on added importance. Would you agree to that?
Dr. Schmidt. Yes. The minutes to me, the minutes of the meet-
ing winch report the conclusions, the recommendations, and so on,
are the significant part of the official record.
What is most important, of course, is the final report with the
recommendations. The deliberations, the trial and error, the false
starts, the wrong pathways, and all of this I do not need nor use in
evaluating their work.
Mr. Fountain. Do you regard the 1-paragraph statement of the
panel's decision on combined aspirin-antacid drugs as an adequate
representation of the transcript when it omits reference to discussions
142
in which FDA personnel participated and might have had an impact,
directly or subtly, upon the ultimate decision of the panel?.
Mr. Hutt. The paragraph you read is their conclusion. It is an
adequate statement of their conclusion. One simply cannot put every-
thing that went before their conclusion into that type of a document.
Mr. Drinan. On this precise point, under the old rules or the new
rules, could Dr. Pisani be in touch with Miles Laboratories, really
liis employer, every hour on the hour and tell them how the secret
deliberations were going?
I would assume Dr. Pisani did that, and the consumer woman also
did that for her constituenc}^.
I am wondering whether from these secret deliberations the actual
wording emerged. I have the label here on this package. It is all very
ambiguous to me. I raise the basic question — whether or not the new
directions here, if they are new, reflect what the advisory committee
recommended.
As I read the evidence, the}^ said pretty categorically this is to be
taken only for people who have two ailments and that the analgesic
ingredient here is aspirin, and this is about the only major thing that
was touched by this particular deliberation.
I am wondering to what extent in those deliberations they said
that the minimum language that Alka Seltzer could have is thus and
so, and that Dr. Pisani got some consent from his people this would
be acceptable.
As you know, it is an open secret that some people think the
advisory committee members submitted to the pressure of Miles
Laboratories. I am not sa}dng that. I respect their integrit}^.
I want to know. Unless we have some indication from those minutes
we don't know what went on.
Dr. Schmidt. You know what went on because you have the minutes
and you have their recommendations. You also have the reasons for
their recommendations. I believe you have everything you need to
understand how they came out arid why they came out that way.
The report itself is reall}^ a good discussion of what they concluded.
Mr. Drinan. In the actual language adopted finally which was
acceptable to you, I find great ambiguity:
Especially recommended for those symptoms after too much to eat or drink,
take before bed and again upon arising.
It becomes incoherent here —
Pain relief alone, headache or body pains, fever and muscular aches that may
accompany a cold.
I don't see how any normal person, and I am a lawyer, "and I don't
understand that, could be expected to comprehend the meaning of
that.
Mr. Hutt. I would like to talk a moment about the procedure and
then come back to that. I think your first question did not indicate an
understanding of the procedure.
The procedure is that we first get the recommendation of the panel
through the final report, with a full scientific discussion of whatever
the reasons were for their conclusions. It does not end there.
That report is published in the Federal Register as a proposal.
People are entitled to come in and comment, and indeed that is
143
exactly what happened here on the very issue that is going to be the
subject of discussion today and that has been the subject of full
hearino-s in the Senate on two separate occasions.
Then there is, on the basis of the comment, a tentative final order in
which there is an absolutely clear requirement under the Administra-
tive Procedure Act that we lay out the comments and pur responses;
either we agree or disagree, and if we disagree why we disagree.
At that stage again the procedure does not end. There is an oppor-
tunity for an oral face-to-face hearing with the Commissioner at which
any interested person can confront us with specific targeted issues.
That was done here.
The health research group came in— Dr. Wolfe, Ms. Johnson, and a
physician who disagreed with the panel recommendations. They laid
out, for I believe 20 minutes, all of their disagreement.
The final stage, then, was when the Commissioner addressed each
point that they made in their oral comments in the preamble to the
final order.
After that final order, anyone, including the health research group,
was free to take that issue to court, They chose not to do so. I doubt
thev were persuaded that they were wrong but apparently they con-
cluded that we had justified what we had done to a point where a court
would not regard it as unreasonable.
Mr. Drinan. I know we will get into those issues later but I still
have a doubt in my mind that if I were Dr. Pisani I would have said
to the members of tiie advisory committee, "Would you feel this par-
ticular ambiguous language is not inconsistent with your recommenvhi-
tion?" If they said yes, they would not complain later on. We don't
know what went on.
I yield back to the chairman.
Mr. Fountain. I realize we can all have differences of opinion
about minutes and what they should contain. However, it appears to
me that the minutes of the discussion of the combination antacid
drug nowhere approaches the detail which would provide either you,
Dr. Schmidt, the public or the courts, if the case were taken to court,
with a really satisfactory indication of what actually transpired during
the closed meeting.
At the sixth meeting of the antacid review panel, held on Decem-
ber 8 and 9, 1972, the minutes show Alka-Seltzer was again discussed
in the context of its being the leading brand on the market composed
of an antacid in combination with an analgesic; namely aspirin. 1 am
placing pertinent pages of the minutes into the record.
[The material follows:]
Food and Drug Administration, Bureau op Drugs
OTC Review Panel for Antacids, Sixth Meeting, December 8 and 9, 1972,
Rockville, Md.
Chairman, F. J. Ingelfmger, M.D.
Acting Executive Secretary, A. M. Welch.
Members of the Pane! Present, H. C. Ansel, Ph. D., M. I. Grossman, M.D
S. C. Harvey, Ph. D., E. W. Moore, M.D., J. F. Morrissey, M.D., and 11. M.
Liaison Representatives: Consumer — A. Dickinson; Industry — J. Pisani, M.D.
Consultants, J. B. Kirsner, M.D. (12/8 only).
FDA Participants: P. B. Hutt, Esq. (part-time); M. ISlovitch, M.D.; U. L.
Yingling, Esq.
144
Industry Representatives (1218 only):
G. Beckloff, M.D., Marion Laboratories
B. Brennan, Esq., PMA
D. Carter, M.D., Miles Laboratories
A. Cooke, M.D., Miles Laboratories
T. Fand, Ph. D., Warner-Chilcott Labs.
A. Flanagan, M.D., Warner-Chilcott Labs.
B. Misek, Ph. D., Beecham Inc.
A. Ringuette, Esq., Miles Laboratories
G. Sunshine, Esq., Stuart Pharmaceuticals
These summary minutes for the December 8/9, 1972 meeting of the Antacid
OTC Review Panel were approved and adopted on March 1, 1973.
The various positions taken during the meeting are provisional in nature and
may be modified or otherwise revised during subsequent deliberations of the Panel.
Whenever there is a lack of unanimity on any given point the vote will be given.
Regulations do not permit voting by the Executive Secretary, Consultants, or
any Industry or Consumer Liaison Representative.
Franz J. Ingelfinger, M.D., Chairman.
* * * to make claims or to use indications on the package label that the
products may directly affect "nervous or emotional disturbances", "excessive
smoking", "food intolerance", consumption of "alcholic beverages", "acidosis",
"nervous tension headaches", "cold symptoms", and "morning sickness of
pregnancy" since the relationship of such phenomena to gastric acidity is both
unproven and unlikely."
21. Page 32-33, C. Drugs Combining Antacid and Other Active Ingredients. — First
sentence amended to read: "Although the Panel is cognizant of the validity of
combining an antacid with aspirin for the purpose of buffering the aspirin and for
concurrent symptoms, it concludes that fixed antacid-aspirin combinations are
irrational for antacid use alone and therefore should not be labeled or marketed
for such use." (Vote 6 for, 1 against).
22. Page 30. D. Drugs Combining Antacid and Other Active Ingredients, 1.
Amended to read: "The Panel concludes that there is no valid scientific evidence
that the addition to an OTC antacid of an active ingredient that is neither an
antacid nor a corrective for an antacid side effect, will contribute to the product's
safety and effectiveness for use in antacid therapy alone. The addition of non-
antacid or non-corrective ingredients may, in fact, reduce the safety or effective-
ness of the antacid product.
If antacid combinations are to be allowed, the use of the combination of an
antacid and an active ingredient that is neither an antacid nor a corrective for an
antacid side effect should be limited to those individuals who concurrently have
symptoms which require for their relief the pharmacologic action of both the
antacid and non-antacid ingredient. This dual indication should be clearly stated
on the product label.
1. The Panel concludes that it is rational to combine an antacid with an analgesic
if the individual who uses the product concurrently has symptoms which require
the relief of both of the active ingredients. The dual indication should clearly be
stated on the label and the label should include a prominently displayed warning
that such a combination shall not be used for the treatment of heartburn and/or
indigestion and/or sour stomach unless these symptoms are accompanied by
indications for an analgesic. Such a product is not appropriate for peptic ulcer and
related disorders. Any analgesic ingredient that is generally recognized as safe and
effective (See Analgesic Monograph) may be used as the analgesic ingredient.
2. The Panel concludes that it is rational to include a non-antacid laxative
ingredient in an antacid if the laxative is solely for the purpose of counteracting
the constipating action of one or more of the antacid ingredients. Any laxative
action ingredient that is generally recognized as safe and effective (See Laxative
Monograph) may be used as the laxative ingredient. No labeling claim for the
laxative effect would be truthful, because the amount of non-antacid laxative
ingredients present should not cause laxation, but only counteract the constipating
effect of the antacid.
Comment: Any other combination of antacid with non-antacid active ingredients
should be permitted by the Food and Drug Administration only after it "is shown
that the conditions for a combination drug set out in the regulations have been
met. The Panel is unaware of any other such combinations which meet these
conditions at the present time.
145
Mr. Fountain. The verbatim transcript shows dozens of pages —
and I am skipping over some items I want to cover but because of
limitations of time I will put them in the record — again, the verbatim
transcript shows dozens of pages of deliberations on the combination
antacid analgesic products like Alka-Seltzer.
The transcript shows the panel members went round and round in
their discussion, as we all do at times in some of our discussions.
It is clear they recognized a basic irrationality in using aspirin with
an antacid for an antacid effect.
The}^ also felt aspirin was contraindicated when combined with an
antacid for treating peptic ulcers. But when the Food and Drug per-
sonnel stressed FDA's combination drug policy, the panel sought to
modify their earlier position to bring their recommendation concerning
the analgestic-antacid combinations into harmony with FDA's com-
bination drug policy, and ultimately they came up with a statement
which, in effect, indicated that the panel did not believe the combina-
tion was irrational when used for treating concurrent headache and
acid indigestion.
However, the panel also said that the combination of antacid and
aspirin is irrational for use as an antacid alone.
Is that a fair summary of the panel's deliberations?
Dr. Schmidt. I think so, except that again some of your statements
impugn a cause and effect relationship. Between an explanation of our
combination policy by someone from the FDA on the one hand and
something the panel may have done on the other, the conclusions of the
panel that you read are accurate.
Mr. Fountain. Who makes policy at FDA?
Dr. Schmidt. Who makes policy at FDA?
Mr. Fountain. Yes.
Dr. Schmidt. Policy is made in a number of different levels by a
number of different people. Ultimately they
Mr. Fountain. You said some "explanation of our combination
policy" at FDA.
Dr. Schmidt. I said someone from FDA might have explained our
policy on combination drugs to the panel in order that they would
know what it is and so that their deliberations, and so on, would fit
within the policy of the agenc}^.
Mr. Fountain. Referring to the panel's fifth meeting held on Sep-
tember 7 to 9, 1972, minutes of which are already in the record, page 6
states :
The Panel takes the position that it is unwarranted to make claims or to print
indications on the package label which link certain signs and symptoms, such as
"indigestion," "gas," "sour breath," "upper abdominal pressure," "full feeling,"
"nausea," "stomach distress," "upset stomach," "excessive eructations," with
normal or hypernormal gastric acidity, since the relationship of such signs or symp-
toms to gastric acidity is unknown or dubious. Furthermore, such claims or indica-
tions encourage the user to draw conclusions as to the cause or intermediation of
such symptoms, a conclusion that even the medical profession is incapable of
drawing at this time. Therefore, the Panel recommends that these claims and indi-
cations which link these symptoms to acidity not be permitted until such time as a
relationship is established.
The vote on that was 6 to 1 , 6 for and 1 opposed .
I believe these claims which the panel felt should not be permitted
are being permitted to be used by the regulations, with a requirement
146
that evidence to support the claims be submitted within 2 years. Is
that not true?
Mr. Hutt. That is true. That was their final recommendation,
Mr. Chairman. That specifically was their recommendation, that
they be permitted for 2 years.
Mr. Fountain. Do you regard the September 7-9 position of the
panel, as I read it, a scientifically sound and reasonable one, Dr.
Schmidt?
Dr. Schmidt. The answer to the question is "Yes," with the quali-
fication that the science here is pretty soft science.
One of the problems that the panel had was that these words are
very vague and loose terms. They are not scientific terms. The
meaning to the public of these terms is questionable at best. There-
fore, the panel felt that if these claims were valid they should be
based on science and there should be an opportunity provided to
put science underneath these terms, so to speak.
The panel set out the claims that we call category I claims, that
there is some science to back the meaning of these, but that additional
studies would have to be done before they could be used permanently.
Mr. Fountain. I realize that you are the final arbiter, and as head
of the agency you make the final decision, and you reach that decision
by due process.
I assume, also, when you call upon panels you want their best
scientific advice.
The September 7-9 position of the panel with regard to the safety
of the aspirin-antacid combination such as Alka-Seltzer, and the
validity of the claims made, was, I assume, their best scientific
judgment.
Was that not what FDA was seeking from outside experts?
Dr. Schmidt. This was their judgment at the time; yes. That is
what we seek.
Mr. Fountain. The verbatim transcript shows that the panel was
confronted or subjected to what some might call "pressure" from
FDA personnel — I am not passing judgment on it but the implication
is there — to get the panel to back off from its position because of the
possibility that, if adopted, the panel's position might invite court
challenges or conflict with FDA's combination drug regulations.
To be more specific, during the December S, 1972, meeting there
was considerable discussion on medical claims being made for Alka-
Seltzer.
I am placing into the record pertinent pages of the verbatim
transcript of that meeting.
[The material follows:]
went of Health, Education, and Welfare, Public Health Service,
Food and Drug Administration — OTC Antacid Advisory Panel
The meeting convened at 9:04 o'clock a.m., Dr. Franz J. Ingelfinger, Chairman,
presiding.
(Except for FDA personnel, names of all participants have been deleted to
preserve confidentiality.)
PAGES 272 THROUGH 279
Dr. . Is it related to acid?
Dr. — — . This is the point. It concerns me that we do not.
, do you have any ideas?
147
Dr. . Would the FDA work be easier or harder if that phrase were in
there?
Mr. Yingling. I think if the word "upset stomach" does not appear that we
are going to have some problems.
Dr. . So you would advise with no offense to my log rolling friend here
your life will be easier with the phrase in than out?
Mr. Yingling. I think so.
Dr. . I don't think we should be guided by that. His whole operation
would be easier if it never started as far as the FDA is concerned.
Dr. — . By easier, do you mean less lawsuits or — — ■
Mr. Yingling. I disagree with that, but I mean less likely to go to the mat as
the term is used. Less likely to get into litigation if a term like that is allowed.
If there is no term like that, you are limiting their ability to seek to promote to
a consumer who overeats or overdrinks or makes some of these other abuses.
This is a very distinct market, I think, as far as industry is concerned. It is a
type of term that they have indicated can be used. You heard a very strong pitch
this morning for this type of term to be left.
Dr. . If we leave that in
Dr. . When I get on the plane, I have an upset stomach, and I have been
on a boat in which lots of people have had upset stomach. And they are at the
rail heaving.
Dr. ■ — . Thev are sick stomachs.
Dr. — . I can give antihistamines and prevent this. Do you want me to
go out and promote antihistamines for an upset stomach? It is the same sort of
nonsense.
Dr. . I agree.
Dr. . I do, too, 110 percent.
Dr. — . I think we are going to have to rewrite the whole section if we do
this because we have now the problem what we allow in five years by subtle control
tests.
Dr. . We are still requiring measurable antacid action. V« e are still re-
quiring some kind of sensible in vivo studies. All we are doing is allowing the
companies — we learned they apparently strongly want this kind of claim which
to me is a minor thing.
Dr. ■ — . You are arguing on the basis of public education.
Dr. . Public usage.
Dr. •. Not education, but public lack of education.
Dr. . Let me ask Gary if this statement which seems to be hedging a
little bit, "The Panel concludes' that antacids are truthfully and accurately pro-
moted to alleviate such symptoms as," and then if any other claim is — this im-
plies that any other claim is not truthful.
Mr. Yingling. It surely does from the way we arc reading it. In other words,
if this monograph goes forward as it is written and as set up and those would be
the only three claims that you would be allowed to put on an antacid product
so that Alka-Seltzer and all the rest of them you have seen before you, that would
be it, that would be the claim. And every product would be able to make those
three claims. They would, of course, try to change their advertising. And each one
would try to grab a part of the word and shuttle up their ad. But those would be
the only three terms in the market place which the Agency would allow.
Dr. . And once Alka-Seltzer, if this actually could be implemented,
changed the advertising, think of the public education that would result and to
everybody. This is a medical opinion. We are approving claims which we think
might be' on the basis of our knowledge related to acid. We have no idea that
upset stomach itself, knowing that, means anything. It would be using a criterion
of what the public is saying and what the Alka-Seltzer people have advertised.
The decision is related to acid.
It seems to me we have got to state what we think is medically correct and we
can defend and not just because the public uses something. If the FDA can't
put up with it, they can still change it. But I think we have got to stick to our
principles.
Dr. . I would like to eliminate "sour stomach" myself.
Dr. . Well, obviously, we are just discussing the issue you raised with us
about upset stomach. Do you want to tell why you think it is a useful phrase if
I can put you on the spot?
Mr. Yingling. Doctor, you are now on the spot, believe me.
Dr. Novitch. Yes, I think frankly it is the term that — I think it is the common
lay term. An upset stomach, most of which is probably related to hyperacidity,
148
and I think that is how it is interpreted by the layman without having had the
benefit of what has gone on before I walked in.
Dr. . Can you give any data?
Dr. Novitch. I can't give you any data on anything.
Dr. . Do vou think the majority is due to hyperacidity? I really question
that.
Dr. — — . I do, too. I am very, very skeptical.
Dr. . Particularly if you are on a boat with seasickness.
Dr. Novitch. I think that is one, seasickness.
Dr. . Most people recognize that as being something different.
Dr. . It is upset stomach. Add seasickness to the labeling.
Dr. . I don't want to prolong this all night.
Dr. . This extrapolates to the ridiculousness. You have to include indi-
gestion.
Dr. — — . It is enough of a point that we have to allow everybody to
Dr. Novitch. I will say that the industry people that we have heard from feel
that that is how their studies — I guess as Miles reflected this morning — that is
how their consumer studies show the buyers of their products interpret the symp-
toms as upset stomach. The whole host of them including those that are acid-
related. If some are not acid-related and antacid is given, it may be in some cases
inappropriate. But I think they lump all of those symptoms into the bag of upset
stomach.
Dr. . Can't you see what will happen? There will be some kind of litiga-
tion or something like that, and they will parade a thousand people up all of
whom say, "I have an upset stomach," showing doudenal ulcer patients, "I have
an upset stomach." It is the kind of battle, it seems to me, we shouldn't put these
folks into.
Dr. ■ — -. The same way people with appendicitis think of upset stomach.
Dr. . We parade 100 intestinal obstructions. Where does this stop? Is
this the only word you are going to promote?
Dr. . It is the only one I picked out.
Dr. . This is the other part that worries me.
Dr. . I think if we accept "upset stomach" there is nothing we wouldn't
accept.
Dr. . You have to accept everything.
Dr. . That is the point.
Mrs. . If the other categories were products, you wouldn't have this
problem.
Dr. . Explain that to me.
Mrs. . What you said just a few minutes ago, you felt very strongly this
would be a real public education effort to get people to realize what symptoms
were related to acidity and all this. That is what antacids are supposed to be is
relievers of acid. And if we hadn't ever come up with this whole separate category
of products that doesn't relieve acidity, but that relieves gastric symptoms,
then you wouldn't have that category of products which you could say was good
for upset stomach. And you could with a clear conscience ■
Dr. . That is irrelevant here.
Mrs. . Why not?
Dr. — — . Let's assume we didn't have the other category. All this is doing
is saying, "Now, if you have this symptom and upset stomach, you need something
th.il goes for acid." Hardly and strictly defined acid category here. But it may be
inappropriate.
Dr. — ■ — — . Let me ask Gary another question.
Gary, the way I see it now is that 4 people of the Panel would like to see this
staying the way it is without "upset stomach" included. Two would like to see
it included and one is undecided.
Dr. . I have now decided.
Dr. . Which side are you on?
Dr. . Stay as it is.
Dr. . O.K., five to two. This has to be faced.
Mr. Yingling. I think you still have to make up short minutes of this meeting
and indicate a five to two vote. And you have to put it to the Commis
