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nance frequencies, (12th Ann. Meet. Biophys. Soc., Pittsburgh, Feb. 19-21) Biophys. J. 8: A117, 1968.

10. Apter, J. T., Marquez, E., and Janas, M.: Dynamic viscoelastic anisotropy of canine aorta correlated with aortic wall composition. (21st Ann. Conf. on Eng. in Med. and Biol., Houston, Texas, Nov. 18-21) Proc. Ann. Conf. on Eng. in Med, and Biol. 10: 44.5, 1968.

11. Apter, J. T. and Graessley, W.: Mathematical development of physical model of muscular contractile element. Abstracts 7th Ann. Symp. Biomath, and Computer Sci. in Life Sci., Houston, Texas, March 27-28, 1969, pp. 32–33. 12. Hardison, W. G. M. and Apter, J. T.: Phospholipid regulation of bile salt stimulated biliary cholesterol excretion. Clin. Res. 18 (2): 381, 1970.

13. Apter, J. T. Analog/Hybrid Computer in Teaching Medical Personnel, 9th Ann. Symp. Biomath. and Computer Sci. in Life Sci., 1971.

14. Grotberg, J., Hughes, R., and Apter, J. T.: Analog Computer Solution for Rebreathing Experiment on an Exercising Subject. Proc. Assoc. Adv. Med. Instr., 1972.

15. Grotberg, J., Hughes, R., Apter, J. T.: Analog computer solution of model for rebreathing experiment on an exercising subject. Proc. 25th Ann. Conf. on Engin. in Med. and Biol., 14: 379, 1972.

16. Apter, J. T., Mason, P., and Lang, G.: Urinary bladder wall dynamics, Urology Digest 12: 78, May 1973.

17. Apter, J. T.: Number of Women Pathologists. Amer. Med. Assoc.: Archives of Pathology 93: 371, October 1972.

18. Apter, J. T., and Berman, S.: Mechanical Properties of Muscle Fibers in Aqueous and Deuterium Oxide Solutions. The Physiologist 16: 3, August 1973.

Dr. APTER. I have a bachelor's degree in physics from the University of Pennsylvania. I have an M.D. from Johns Hopkins University School of Medicine and a masters degree in physiology from Northwestern University graduate school. I have a Ph. D. in mathematical biology from the University of Chicago. I am licensed to practice medicine and surgery in Maryland, Illinois, and Indiana.

I also have considerable experience in education in the analysis of clinical data, clinical experiments, and biological experiments.

In fact in my role as director of the section of mathematical biology at Presbyterian-St. Luke's Hospital, I was responsible for supervising and helping the clinicians in all departments in designing their experiments and analysing their data.

I am now listed as an outstanding speaker on the subject of medical data analysis for the Institute of Electrical and Electronics Engineers. I am certified as a practicing opthalmologist and my training has been primarily in mathematical analysis of experimental data.

Mr. FOUNTAIN. Thank you. Now proceed with your statement any way you care to.

Dr. APTER. I want to make it clear that, although I am a professor of surgery at Rush University, I'm speaking now for myself.

My written statement I presented at your request. I am speaking today because I have been subpenaed.

Congressman Fountain and members of the subcommittee, I am presenting, at your request, a set of procedures and criteria I consider essential in order for me to be able to judge the safety and efficacy of a chemical element or a compound to be used to treat human illness, in other words, of a drug.

I feel that animals are essential for establishing safety. Before a drug may be administered to a human, even on an experimental basis, its range of toxicity should be established for animals as similar to humans as possible. I would have to have access to the protocol that was used in the animal studies, to be convinced it was controlled, long

term, unbiased, and prospective rather than retrospective, that enough animals had been used to detect toxicity, if it exists, and that the age range of the animals was appropriate to the proposed clinical trial. The records of physical examination of the animals should be complete and detailed before, during, after, and long after the drug tests. Statistical evaluation of toxicity should be on the basis of the records themselves without participation of the personnel who prepared the records. Next, efficacy of the drug in the animals should be established if at all possible.

The ability of the drug to change an animal's illness at a dose established as safe should be demonstrated wherever an animal model can be prepared. Only when the disease is demonstrably impossible to reproduce in an animal, can the drug be tested for clinical effectiveness without animal trials.

Then, with respect to clinical trials, these must be "prospective" studies. In order to assume this we should have physicians that would perform these trials who are selected for their ability to write a protocol for a feasible double-blind controlled experiment that they would and could be bound by.

The protocol should include at least:

(1) Selection of the set of signs and symptoms that would define the patient population to be used in the study and that were of interest as far as the drug was concerned.

(2) Selection of the criteria for "change," "no change," "better," "worse," et cetera. The criteria, once established, should be adhered to. Forms should be printed to include all these details to minimize subjective evaluation of the patients by the participating scientists and clinicians.

(3) Written instructions to inform prospective patients of the toxicity, risks, purposes, and scope of the study.

(4) Random selection of the "treated" and the "control" patients from among the selected population.

(5) Selection of a "control" regimen as identical to the "test" regimen as possible.

All personnel involved should show that they are convinced that only such a prospective study will give the efficacy data needed for the drug. They will vow to keep accurate and complete records that are never changed. They will agree to accept their unsuitability for such a study if they fail to adhere to the protocol. The personnel will agree to have their data analyzed, without their interference, by a statistician.

Now, in the following consideration of the extent to which FDA has made it possible for me to judge drugs, I will not reveal discussions that took place at our committee meetings. In order for me to give advice on the conclusions to be drawn from clinical trials. I would want "raw data" or concrete evidence that each of these steps had been followed meticulously. Most of all. I would want to make certain that the physicians were willing to be held accountable for their records. At a luncheon attended by some employees of Abbott Laboratories, one of them started to question me about their drug Cvlert. Some of the patients had been recruited for the study via a television announcement made by the supervising psychologist. This was contrary to the protocol and, therefore, disqualified those patients from inclusion in

the study. But disqualifying some patients after the study was completed destroyed the random selection aspect of the protocol. The psychologist-in-charge objected to this conclusion of mine charging that I had not asked for "clarification" of his records. Good records based on a far-sighted protocol, will not need clarification and are a sine qua non for a prospective study. Post hoc "clarification" makes the study retrospective and, therefore, not acceptable for my purposes since I require a prospective study.

The FDA medical officers and statisticians who have sought my advice on Cylert and hexobendine have been exceedingly knowledgeable about their raw data and its analysis. They have made available to me all the data I needed to convince me of the reliability of the studies or the value of the drug. They have persuaded their administrators to support my efforts and to give me an opportunity to present my findings to appropriate advisory groups. On other occasions, some FDA officials have asked me to advise, however, without giving me adequate information for my purposes and/or without keeping complete records of my advice. For one example, I was asked to judge the efficacy of propranolol for angina pectoris on the basis of published studies and testimonials. When I asked for raw data it was not made available to me. For another example, I was asked to report on my findings on hexobendine at a meeting in California sans recorder, so that I was not protected by a careful record of my own. This was associated with rather unpleasant pressure from an FDA officer who accused me, in front of colleagues, of being a troublemaker because I asked that a formal and complete record of the proceedings be made. Please understand, I was accustomed to having a complete record made at all meetings in the past. He later decided not to have a meeting at all-at great inconvenience to me because I had traveled to San Francisco only to give my assigned report.

Third, I was asked to approve the "atropen" for a clinical trial even though the only safety information I had on this device was the manufacturer's testimonial that "millions have been sold in Europe."

Fourth, when I wrote to ask for a transcript of the portion of a meeting which I had attended, I could not get it. If an agency wants my best thoughts on a drug, I would expect them to accept my most considered advice, which might require a review of a meeting record.

My few experiences with the FDA medical officers convince me that their evaluations of drugs and of drug studies would be essential for me to help the FDA, as I have pledged to do. I would want that information before attending a committee meeting so that I could prepare a written evaluation beforehand. At the committee meeting I would have an opportunity to hear aspects of the data I could not see immediately, by listening to presentations of other members and of medical officers. Naturally, I would expect to be influenced only by facts obtained in prospective studies and would expect the FDA to require such limitations from me. Testimonials, even from committee members, should be discouraged. I would appreciate having access to the record of the proceedings of the meeting in preparing a final report of my evaluations. Since the "truth is not decided by majority vote." I would want any matter that is put to a vote by the committee members to be phrased so as to state whether or not the whole of medical experience obtained in a controlled manner led to a pro or con stance. Thank you.

[Dr. Apter's prepared statement follows:]

PREPARED STATEMENT OF JULIA T. APTER, M.D., PH. D.

Congressmen Fountain and Holifield, I am presenting, at your request, a set of procedures and criteria I consider essential in order for me to be able to judge the safety and efficacy of a chemical element or compound to be used to treat human illness, in other words, of a drug.

ANIMAL STUDIES

(a) Safety: Before a drug may be administered to a human, even on an experimental basis, its range of toxicity should be established for animals as similar to humans as possible. I would have to have access to the protocol used in the animal studies, to be convinced it was controlled, long term, unbiased, and prospective rather than retrospective, that enough animals had been used to detect toxicity, and that the age range of the animals was appropriate to the proposed clinical trial. The records of physical examination of the animals should be complete and detailed before, during, after, and long after the drug tests. Statistical evaluation of toxicity should be on the basis of the records themselves without participation of the personnel who prepared the records.

(b) Efficacy: The ability of the drug to change an animal's illness at a dose established as safe should be demonstrated wherever an animal model can be prepared. Only when the disease is demonstrably impossible to produce in an animal, can the drug be tested for clinical effectiveness.

CLINICAL TRIALS

These must be "prospective" studies. In order to assume this:

(a) Physicians performing these trials should be selected for their ability to write a protocol for a feasible double-blind controlled experiment that they would and could be bound by.

(b) The protocol should include at least

1. Selection of the set of signs and symptoms that would define the patient population to be used in the study.

2. Selection of the criteria for "change," "no change," "better." "worse," etc. Forms would be printed to include all these details to minimize subjective evaluation of the patients.

3. Written instructions to inform prospective patients of the toxicity, risks, purposes, and scope of the study.

4. Random selection of "treated" and "control" patients from among the selected population.

5. Selection of a "control" regimen as identical to the "test" regimen as possible.

(c) All personnel involved should show that they are convinced that only such a prospective study will give the efficacy data needed. They will vow to keep accurate and complete records that are never changed. They will agree to accept their unsuitability for such a study if they fail to adhere to the protocol. They will agree to have their data analyzed, without their interference, by a statistician.

In the following consideration of the extent to which FDA has made it possible for me to judge drugs, I will not reveal discussions that took place at our Committee meetings. In order for me to give advice on the conclusions to be drawn from clinical trials, I would want "raw data" or concrete evidence that each of these steps had been followed meticulously. Most of all, I would want to make certain that the physicians were willing to be held accountable for their records. At a luncheon attended by some employees of Abbott Laboratories, one of them started to question me about their drug Cylert. Some of the patients had been recruited for the study via a television announcement made by the supervising psychologist. This was contrary to the protocol and therefore disqualified those patients from inclusion in the study. But disqualifying some patients after the study was completed destroyed the random selection aspect of the protocol. The psychologist-in-charge objected to this conclusion of mine charging that I had not asked for "clarification" of his records. Good records based on a far-sighted protocol will not need clarification and are a sine quo non for a prospective study. Post hoc "clarification" makes the study retrospective and, therefore, not acceptable for my purposes since I require a prospective study.

The FDA medical officers and statisticians who have sought my advice on Cylert and hexobendine have been exceedingly knowledgeable about their raw

data and its analysis. They have made available to me all the data I needed to convince me of the reliability of the studies or the value of the drug. They have persuaded their administrators to support my efforts and to give me an opportunity to present my findings to appropriate advisory groups. On other occasions, some FDA officials have asked me to advise without giving me adequate information for my purposes and/or without keeping complete records of my advice. For one example, I was asked to judge the efficacy of propranolol for angina pectoris on the basis of published studies and testimonials. When I asked for raw data it was not made available to me. For another example, I was asked to report my findings on hexobendine at a meeting in California sans recorder, so that I was not protected by a careful record of my own. This was associated with rather unpleasant pressure from an FDA officer who accused me, in front of colleagues, of being a trouble-maker because I asked that a formal and complete record of the proceedings be made. He later decided not to have a meeting at all-at great inconvenience to me because I had traveled to San Francisco only to give my assigned report. Thirdly, I was asked to approve the "atropen" for a clinical trial even though the only safety information I had or this device was the manufacturer's testimonial that "millions have been sold in Europe". Fourthly when I wrote to ask for a transcript of the portion of a meeting which I had attended, I could not get it. If an Agency wants my best thoughts on a drug. I would expect them to accept my most considered advice, which might require a review of a meeting record.

My few experiences with the FDA medical officers convince me that their evaluations of drugs and of drug studies would be essential for me to help the FDA, as I have pledged to do. I would want that information before attending a Committee meeting so that I could prepare a written evaluation beforehand. At the Committee meeting I would have an opportunity to hear aspects of the data I could not see immediately, by listening to presentations of other members and of Medical Officers. Naturally, I would expect to be influenced only by facts obtained in prospective studies and would expect the FDA to require such limitations from me. Testimonials, even from Committee members, should be discouraged. I would appreciate having access to the record of the proceedings of the meeting in preparing a final report of my evaluation. Since the "truth is not decided by majority vote" I would want any matter that is put to a vote by the committee members to be phrased so as to state whether or not the whole of medical experience obtained in a controlled manner led to a pro or con stance. Mr. FOUNTAIN. Thank you very much, Doctor, for an extremely meaningful, and what turned out to be a revealing statement.

Doctor Apter, you spoke of your assistance to FDA advisory committees. I don't believe you have identified any particular committee. As I understand it, you are a member of the Cardiovascular and Renal Advisory Committee at the present time?

Dr. APTER. I am a member of that, but I have given advice to other committees.

Mr. FOUNTAIN. Can you tell us, if you know, how you were selected for this committee? Did someone, for example, from FDA approach you because of your special qualifications and ask you to serve or were there some other factors involved?

Dr. APTER. I don't remember who called me. Someone from the FDA called me in the summer of 1972 and I was given the impression that it was my ability to analyze medical data of all kinds that had led the FDA officer to consider me for that position.

Mr. FOUNTAIN. Now I believe, as I have already stated, you are both a biomathematician and a surgeon. I wonder if you would tell this subcommittee, based on your experience and your background, the ways in which you can be of assistance to the Cardiology Committee?

Dr. APTER. Well, I have had so much experience in working with clinicians in helping to analyze their experimental design that I felt that was my primary goal. I also study the effects of drugs on isolated heart muscle and could be of assistance as a pharmacology physiol

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