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Exhibit 49B-Telegram from E. Fougera & Co., Inc., to X-ray suppliers Page re Orabilex recall, February 17, 1964.. 714

Exhibit 50-Letter from E. Fougera & Co., Inc., to doctors re Orabilex recall-Second notice, February 1964..

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Exhibit 51-Withdrawal of approval in the matter of Orabilex capsules..
Exhibit 52-Letter from E. Fougera & Co., Inc., to doctors re second
Orabilex recall, April 1964..

Exhibit 53-Memorandum from E. C. Hagan, Division of Pharmacology,
Food and Drug Administration, to Dr. J. H. Epstein, Bureau of Medi-
cine, re animal tests on Orabilex, August 4, 1958..

Exhibit 54-Letter from Clarke Davison, Ph. D., associate professor of pharmacology, George Washington University, to Hon. L. H. Fountain, March 21, 1964..

Exhibit 55 Intra-agency memorandum re Orabilex toxicity, November 16, 1962.

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Exhibit 56-Intra-agency memorandum re additional animal data on
Orabilex, October 7, 1958..

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Exhibit 57-Evaluation of animal studies with bunamiodyl sodium
(BUN) (Orabilex) by consultants to E. Fougera & Co.....
Exhibit 58-Letter and report from Leberco Laboratorics, Roselle Park,
N.J., to E. Fougera & Co., Inc., re animal studies with Orabilex, Janu-
ary 3, 1958.

Exhibit 59 Clinical evaluation reporting form for Orabilex..
Exhibit 60-Correspondence between E. Fougera & Co., Inc., and nine
clinical investigators whose work supported the Orabilex new drug
application...

Exhibit 61-Excerpts from supplemental new drug application for Ora-
bilex, requesting changes in labeling, October 14, 1960.
Exhibit 62-Letters from James J. Stovin, M.D., University Hospital,
University of Maryland, to Dr. Henry I. Hourovitz, E. Fougera & Co.,
November 4 and December 16, 1958.

Exhibit 63-Intra-agency memorandum from Margaret A. Milliken, M.D.,
to Division of New Drugs, January 10, 1962, transmitting two adverse
reaction reports attributed to Orabilex..
Exhibit 64-List of adverse reactions to Orabilex reported to FDA through
the adverse reaction reporting program as of August 1962...
Exhibit 65-Adverse reactions reported with use of oral cholecystographic
agents now being marketed.

Exhibit 66-Letter from W. B. Rankin, Assistant Commissioner, Food
and Drug Administration, to Dr. Delphis C. Goldberg, December 31,
1963, with enclosures re deaths in individuals who were given Orabilex...
Exhibit 67-Correspondence between E. Fougera & Co., Inc., and clinical
investigators re authorship of published articles dealing with Orabilex..

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DRUG SAFETY

(Part 2)

WEDNESDAY, APRIL 22, 1964

HOUSE OF REPRESENTATIVES,
INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE

OF THE COMMITTEE ON GOVERNMENT OPERATIONS,
Washington, D.C.

The subcommittee met at 10 a.m., pursuant to notice, in room B300, Rayburn Office Building, Hon. L. H. Fountain (chairman of the subcommittee) presiding.

Present: Representatives L. H. Fountain, J. Edward Roush, Florence P. Dwyer, and Bill Stinson.

Professional staff present: Dr. D. C. Goldberg and W. Donald Gray. Mr. FOUNTAIN. The subcommittee will come to order. Let the record show a quorum is present.

We will continue this morning with our hearings on the subject of drug safety. In previous sessions the subcommittee has heard from officials of the Food and Drug Administration-the agency which has the legal responsibility for deciding when a drug is safe for marketing-and from representatives of the manufacturers of drugs and the medical and pharmaceutical professions who also have an interest in assuring the safety of drugs. This morning the subcommittee will receive testimony on the activities of the Veterans' Administration which contribute to the safety of new drugs.

Due to its size and unified character, the Veterans' Administration hospital system is obviously in a very unique position to share useful information on new drugs with the Food and Drug Administration.

Representing the Veterans' Administration this morning is Dr. Joseph H. McNinch, Chief Medical Director of the Department of Medicine and Surgery.

We are very happy to have you with us, Doctor. We appreciate your coming. Before proceeding with your statement, you might introduce your colleagues, identify them for the record, and then tell the subcommittee a little about your own background.

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STATEMENT OF DR. JOSEPH H. McNINCH, CHIEF MEDICAL DIRECTOR, DEPARTMENT OF MEDICINE AND SURGERY, VETERANS' ADMINISTRATION; ACCOMPANIED BY DR. OREON K. TIMM, ASSISTANT CHIEF MEDICAL DIRECTOR FOR PROFESSIONAL SERVICES; DR. EDWARD DUNNER, DIRECTOR, RESEARCH SERVICE; AND VERNON TRYGSTAD, DIRECTOR OF PHARMACY SERVICES

Dr. McNINCH. Mr. Chairman and members of the committee: To my right is Dr. Edward Dunner, who is a member of my staff in Washington, and chief of our research activities. On my left is Dr. Oreon K. Timm, who is assistant chief medical director for professional services. To his left is Mr. Vernon Trygstad, a pharmacist who is a member of my staff in charge of pharmacy services.

I, myself, have been with the Veterans' Administration something less than 11 months. Prior to that I was director of research for the American Hospital Association for 1 year and, prior to that, I was a medical officer of the U.S. Army, for approximately 32 years, retiring from the Army May 1, 1962, and my last assignment in the Army was the chief or senior medical officer for the European Command.

Mr. FOUNTAIN. Thank you very much. You may proceed with your prepared statement and any other comments you may care to make.

Dr. MCNINCH. I appreciate the opportunity to provide the committee with information about the Veterans' Administration activity in the field of the testing and evaluation of new therapeutic modalities, including drugs. We feel, in the Veterans' Administration Medical Service, that we have a deep responsibility to constantly search for newer and better means of treatment of disease. At the same time we feel a very deep responsibility to insure the safety of the patients who are under our care.

The statement that I will give refers to the activities that are carried out in some 168 hospitals, 18 domiciliaries, and 214 outpatient clinics operated by the Veterans' Administration.

ADVERSE DRUG REACTION REPORTING

During the past year we have developed and initiated a procedure which provides us with a quarterly report from each hospital and clinic of any adverse reactions to drugs. Copies of these reports now are furnished Food and Drug Administration immediately upon receipt. They, in turn, now are providing each of our hospitals with their compiled report of reactions reported to them by all sources and also with their compilation of reports of drug reactions abstracted from the literature.

INTRAGOVERNMENTAL PROCUREMENT ADVISORY COUNCIL ON DRUGS

The Veterans' Administration is represented on the Intragovernmental Procurement Advisory Council on Drugs and on all of its committees. Two of these committees are concerned with the interchange of drug information and reports of adverse drug reactions.

DRUG SAFETY

INVESTIGATIONAL DRUGS

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In addition, we routinely contact the New Drug Branch, Food and Drug Administration, for information on the status of new-drug applications for new drugs not yet cleared for general use prior to approving their administration to patients on a clinical trial basis.

COOPERATIVE RESEARCH STUDIES

Since 1947 the VA has been actively engaged in research in the effectiveness and safety of drugs for the cure or mitigation of pathological conditions affecting veteran patients.

One very important and outstanding disease was that of tuberculosis. In 1947, beginning with streptomycin, the VA developed the VA armed services cooperative study in the chemotherapy of tuberculosis. Associated in this effort were a number of Army, Navy, State, and private tuberculosis hospitals. Representatives of the Food and Drug Administration and U.S. Public Health Service participated in deliberations held to design this early study and followed its results and results of other antituberculosis drug regimens through participation in annual meetings of the study group. The VA's early active role in research efforts designed to eliminate tuberculosis as a major public health problem is in a large measure responsible for the current successful control and treatment of tuberculosis. Annual publication of results of the early and subsequent regimens have been made available to all interested governmental and private organizations.

Mr. FOUNTAIN. If I may interrupt at that point, I think your statement there contains information of which very few people are aware. It is interesting to know the extent to which the VA has participated in the eradication of tuberculosis. I myself did not know of your activities in that direction.

Dr. McNINCH. This is evident, Mr. Chairman, I think in the number of tuberculosis hospitals which the VA has operated and now operates. At one time the number was 21. The successful treatment of tuberculosis has now reduced our need for tuberculosis hospitals to four.

Mr. FOUNTAIN. Go right ahead.

Dr. McNINCH. In the field of psychiatry, in 1956 the VA initiated its first large-scale cooperative study in chemotherapy in psychiatry. Through the mechanism of its cooperative studies the VA has played a pioneering role in the scientific evaluation of the use of drugs in the treatment of patients with mental disorders. The results have contributed significantly to the revolution which has occurred in the care of the mentally ill by virtue of the use of psychotherapeutic agents. Participation by a representative of the Psychopharmacology Service Center, National Institutes of Mental Health, has been of valuable assistance and has afforded an assured avenue of communication. A partial list of other cooperative research studies includes those in hypertension, atherosclerosis, arteriosclerosis, gastroenterology, cancer, parkinsonism, urology, and coronary artery disease. Drugs used in these studies include antihypertensive agents, anticolinergics, anticoagulants, folic acid antagonists and others.

Patient safeguards and scientfic reliability are built into each of these cooperative drug studies from the beginning. A meticulous

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planning and preparation period precedes by a year or more their actual initiation in patients. The problem to be investigated, either the true effectiveness of a drug already in use (for example, the VA cooperative study on cholesterol lowering agents as protection against heart attacks), or the study of as yet unmarketed drugs (for example, the VA cooperative study on oral drugs for the control of diabetes); these studies are usually proposed by a physician at one of the 168 VA hospitals. It is then reviewed by the central office research staff, and appropriate consultants, usually world leaders in the field, are called in for advice and assistance. A protocol detailing the study design and technique is then drawn up as a joint effort by the VA Research Statistics Section, the VA physicians at the hospital, VA central office research coordinator, and the consultants. The protocol or the design for the study invariably provides for detailed frequent reports on the progress of each patient, including specific statements on the presence or absence of medication side effects and their nature. An "escape clause" in each protocol allows the physician to remove the patient from the study if, in the physician's judgment, his health may be in any way jeopardized by the continuation of treatment.

Once drawn up, the protocol is circulated to a selected group of hospitals on whose staff are physicians qualified in the area of research involved, with an invitation to join the cooperative study. If he chooses to join, each physician must then present the protocol to his local hospital research and education committee, which again reviews in detail the design and safeguards of the study. Only after the local hospital committee has been satisfied that the study is sound and safe, and that it can be undertaken successfully at that particular hospital does the physician become a member of the cooperative study group. Individual studies involving drugs, as separate from cooperative studies, are conceived and designed in each hospital by the individual investigator, with the help, if needed, of basic scientists and biostatisticians, available locally or through one of the three VA research support centers. Once in final detailed form, the protocol is then presented for scrutiny to the local hospital research and education committee. This committee, with its own research talent plus that of any of the university or community consultants it may choose to call in, must be completely satisfied (a) that the problem to be investigated is a valid one, of scientific importance: (b) that the investigation is designed in such a fashion as to yield valid results, whether positive or negative; (c) that the investigator himself is competent to carry out the study in a scientific fashion: and (d) that the drug or preparation to be used has been proven safe in the dosage and route of administration to be used. Only if each of these points can be answered affirmatively is the investigator given permission to go ahead with the study.

Once underway, each study is reviewed regularly and any adverse reactions possibly due to the drug are reported immediately, both locally to the sponsor or manufacturer of the drug and to the central office, or my office, of the VA.

INDIVIDUAL RESEARCH PROJECTS

In addition to basic research and clinical evaluations in the cooperative studies touched upon, individual investigators, under direction and

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