Dr. RAUB. I'm optimistic, sir, and I believe most of my colleagues at NIH are. Yes. There can be a meeting of the minds on the principle issues here. We believe the notion of codifying these practices into a specific rule that all of us involved understand is an extremely important task. We believe the principles stated here are highly desirable. The NIH comments are being offered in the form of constructive commentary and suggestions in the hope of removing ambiguity or uncertainty wherever possible and also heading off what would be inappropriate and unrealistic public expectations, in our judgment, as to how things might flow through the system. But we are optimistic.

Dr. FRIEDEWALD. If I could comment along the same lines, to the extent that this proposal is an attempt to codify what is already going on, a process that has been quite good and flexible where there is real need, to the extent it does that, I would be all for it.

My concern is that it would go much beyond the current flexibility. I can't foretell with precision exactly how these will be used, especially because of the looseness of the various definitions and other elements here. My concern is that the new rules would lead to gross misuse.

Mr. LIGHTFOOT. If I'm not misinterpreting what you told me in your earlier testimony, the current system is good but codification would be the first step toward improving the overall system? Is that correct?

Dr. FRIEDEWALD. I'm not sure it would improve it. To the extent that we codify what is going on, I think there is a benefit. It would let people know what is available and what can be done under the system, and to the extent that is what comes forth, I think that is an advance. I'm arguing that I don't really see the need to radically change the current system, just to put down what exists in a way that people can better understand and respond to better. Mr. LIGHTFOOT. Thank you, Mr. Chairman.

Mr. WEISS. Thank you very much for your appearance here today. We are grateful for the work that you do and for the assistance you have provided us. Thank you so much.

Our next panel of witnesses consists of prominent medical researchers, clinicians, and educators in major medical institutions. I am going to ask the witnesses in a moment to come forward. Let me describe who they are. The first witness on the panel is Dr. Charles G. Moertel of the Mayo Clinic and North Central Cancer Treatment Group. Dr. Moertel is internationally recognized as a leader in the field of cancer treatment and research. In addition to his many other appointments, Dr. Moertel has served at FDA's request on the agency's Oncologic Drugs Advisory Committee since 1974.

Dr. Martin S. Hirsch, our second participant, is a virologist and infectious disease specialist with the Department of Medicine, Massachusetts General Hospital and Harvard Medical School. Dr. Hirsch has established a leading national reputation in antiviral drug research and is now recognized as one of the Nation's leading clinical researchers in AIDS drugs. In fact, Dr. Hirsch currently serves as the Chairman of the Steering Committee for the Government's AIDS Treatment Evaluation Program. Dr. Hirsch presented

testimony before this subcommittee last July on AIDS drug development.

Our final witness in this panel is Dr. Itzhak Brook, professor of pediatrics and of surgery, the Uniformed Services University of the Health Sciences. Dr. Brook has a subspecialty in infectious diseases. At FDA's request, Dr. Brook has served for the past year and a half as chairman of the agency's Anti-Infective Drugs Advisory Committee, which recently has played an important part in FDA's consideration of AIDS drugs.

Would you all stand, please? As you know, our practice is to swear in our witnesses. Do you affirm that the testimony you are about to give is the truth, the whole truth, and nothing but the truth? Let the record indicate that all the witnesses have responded in the affirmative.

You may now proceed with your testimony as you see most appropriate.

Dr. Moertel, why don't we begin with you?

STATEMENT OF DR. CHARLES G. MOERTEL, PURVIS AND ROBERTA TABOR PROFESSOR OF ONCOLOGY, MAYO CLINIC AND MAYO MEDICAL SCHOOL, AND CHAIRMAN, NORTH CENTRAL CANCER TREATMENT GROUP

Dr. MOERTEL. Thank you, Mr. Weiss.

As I hope my qualifications testify, I have achieved national and international recognition for responsible drug research. I have devoted my professional life to humane care of the cancer patient. I believe my abilities and accomplishments in dealing with drug issues on a national level are evidenced by the appointments I've held with every Federal agency concerned in this field.

It is my considered judgment that the▬

Mr. WEISS. Before you continue, the bells have rung for another vote. We will recess and try to get back here as quickly as possible. We will recess, I hope, for no more than 10 minutes.

[Recess taken.]

Mr. WEISS. The subcommittee is back in session. My apologies for the interruption. This will be happening throughout the day. Dr. Moertel, if you would proceed with your testimony. Dr. MOERTEL. Thank you, Mr. Weiss.

It is my considered judgment that the reproposed rule allowing nonresearch distribution and use of experimental drugs represents an irresponsible regulatory act which holds the potential of tragic consequence for the American public and which will have a seriously detrimental effect on drug research in this country. It is most assuredly not an act of compassion for the seriously ill.

In essence, this rule represents a repeal of the New Drug Act of 1962. My age allows me to clearly recall the deplorable conditions that led to the passage of this act. The thalidomide tragedy was only the tip of a very ugly iceberg. Dangerous new drugs were being disseminated in a nonresearch setting without any real care for established safety or established effectiveness. I would hope those who might be inclined to favor this reproposed rule will go back and read the shocking testimony that preceded passage of the New Drug Act of 1962.

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I feel it is naive to believe that the average practicing physician is any more sophisticated or any better trained in handling experimental drugs today than he was prior to 1962. It is completely unrealistic to believe that early favorable reports of a drug's safety and effectiveness based on incomplete studies or small patient populations necessarily reflect what definitive therapeutic evaluation will eventually prove or what extreme dangers may be revealed by more extensive study and more long-term followup.

The thalidomide disaster which produced multitudes of deformed children dramatically illustrates the devastating consequences that can result from premature drug release. There was full confidence based on early research results that this drug was not only effective but was completely safe. We must assume there is a far greater probability of a thalidomide type tragedy occurring today than there was in 1962.

Drugs today are vastly more potent and more complex in their activities. Today's recombinant DNA and synthesizing technologies have made possible the manufacture of drugs that could not have even been conceived a quarter of a century ago. Potential immediate and particularly long term side effects of these drugs cannot be reliably predicted by any technology available today.

Current laws restricting use of these drugs to small, well defined populations, are specifically designed to protect the American public from the catastrophic results if delayed fatal or disabling toxicity was only recognized after many thousands of people had already been exposed to the agent.

A very recent illustration of the potential extreme dangers that could be posed by premature release of a new drug is provided by the methyl CCNU experience. This cancer drug was allowed limited release for nonresearch treatment under the category C program, and this was a far more restricted release than that of this reproposed rule. It is now apparent that long term use of methyl CCNU produces a substantial incidence of fatal leukemia as well as a moderate incidence of irreversible kidney failure requiring renal dialysis.

I have recently been involved as a consultant in a legal action where a patient had surgical treatment for a cancer of the colon. Although the tumor had been completely removed, the patient's physician regarded the risk of recurrence as life-threatening and treated the patient with methyl CCNU. This patient later died of leukemia, not of the colon cancer, of which he may well have been surgically cured. His widow is seeking damages from his physicians so she can support her children.

It is entirely possible that methyl CCNU may play an important role in cancer treatment and that it can be used in a manner that avoids devastating late side effects, but we are only learning this now, after patient research.

In this reproposed rule, it is recommended that experimental drugs be made generally available for "immediately life-threatening" diseases and in "serious illness" for which no "satisfactory treatment" is available. Each of these terms, however, are very subjective and lend themselves to a wide range of interpretation. Old age can be regarded as life-threatening; severe acne in a teenager can be regarded as a serious disease; simple obesity can be

both life-threatening and serious under some circumstances or regarded as such and its treatment is far from satisfactory.

I can assure you that the Commissioner of Food and Drugs would be unable to formulate any clear-cut and unambiguous definitions of these terms. Furthermore, it would be prohibitively expensive to set up any type of monitoring system to ensure that practicing physicians nationwide would administer these new and unproven drugs to the most appropriate patients, under the most appropriate conditions, and by the most appropriate methods. Certainly no usable research data could be obtained from such uncontrolled experience.

Multiple sclerosis has been singled out in the reproposed rule as a signal example of serious disease for which no satisfactory treatment exists. Consultants in our Mayo Clinic Department of Neurology inform me that among those patients who come to us with a diagnosis of multiple sclerosis, approximately 25 percent have been misdiagnosed and do not actually have the disease. In many of these latter patients, their symptoms are purely related to psychologic factors. Although all MS patients fear serious disability, in fact only about one patient in five will eventually become nonfunctional. At the present time, approximately a quarter of a million Americans have MS.

If a new drug was touted in early studies as effective for MS and distributed with a Federal stamp of approval, literally every one of these MS patients as well as every patient misdiagnosed as MS, will be clamoring for the new drug.

Let us assume that this new drug was given pre-NDA release under this reproposed rule and that it was eventually found to produce a high incidence of fatal or disabling side effects after long-term use, for example, leukemia or irreversible kidney damage. Conceive, if you will, of the national tragedy that would

occur.

Beyond such obvious threats of death and disability from premature drug release, I am confident that this reproposed rule would seriously impair our ability to conduct the adequate and well controlled studies necessary to confirm the true safety and effectiveness of new drugs. Most new drug therapy for serious or life-threatening disease has not been and undoubtedly will not be 100-percent curative. We work within shades of gray. We have to establish relative effectiveness by conduct of controlled studies in which appropriate numbers of patients are assigned at random to either standard treatment or to the new treatment. Such studies are the only way of reliably establishing drug effectiveness; and, indeed, two such studies are required by law for NDA approval. If, however, any promising but unproven new therapy could be given in a nonresearch setting by the patient's family physician, there would be absolutely no motivation for a patient to enter a randomized study. Since the family physician would lose business and therefore income by referring his patient to a center conducting research studies, he would be positively motivated not to refer the patient. Even if a promising new drug should eventually prove safe and effective, we would still lose that valuable research time between promise and proof. Today this time is used to improve safety and effectiveness of the new agent, to develop the most ideal dosage

regimen, to explore combination treatment with the new agent and other agents, looking hopefully for added effectiveness, and to explore other promising drugs that may even be more effective. Such research could never be conducted if everyone with a disease already has routine practice access to unproven agents.

Under the reproposed rule, true progress in treatment of life threatening or serious disease would actually be delayed rather than hastened.

I work day by day in human cancer drug research. We have a very orderly, planned system for studying the most hopeful new cancer treatments that will establish their safety and their optimum use, that will establish their effectiveness, if they are effective, and above all, that ensures the most humane overall treatment of our patients. By conducting such studies, we not only offer hope to the cancer patient today but we are able to build a solid foundation for effective treatment of the even larger number of patients who will be afflicted with cancer in the years ahead.

The problem is not that the American cancer patient might be deprived of the benefit of some miracle drug that suddenly appears on the scene. I have been in this business for some 30 years and I have never seen such a miracle drug nor do I expect I will in the future. We have had some truly spectacular results with cancer drug treatment and I believe we will see these at an accelerating frequency in the future. All of these past accomplishments and I believe all such future accomplishments have resulted and will result from a careful building process using sound scientific research methodology.

From the humane standpoint, I firmly believe that the best possible cancer care is delivered to a patient who enters into a research program. The patient care will be delivered by an experienced cancer physician who takes an intense interest in the patient's problem and who is willing to make the extra effort required to contribute knowledge regarding treatment of the patient's disease. The conduct of these research programs is carefully monitored both within individual institutions and nationally to ensure responsible performance by the research physician and humane treatment of the patient. Even if the research treatment should prove to be ineffective, both patient and family have the satisfaction that they have made a contribution to cancer research that may prove of benefit to others. This system should not be disrupted.

A further point is that the reproposed rule could not be practically employed. As one who served on FDA advisory committees for many years, I can testify to the frequent extreme difficulty in deciding about safety and effectiveness of a new drug even when all studies are completed and a full NDA has been submitted. To expect the Commissioner or anyone in his agency to make such decisions based on incomplete data is grossly unrealistic. He could not look to non-Government scientists for such advice. I can assure you that we can't make appropriate decisions based on incomplete information any better than anyone else. Realistically, such decisions would be made on the basis of emotional fervor or special interests, not on the basis of scientific wisdom and judgment.

Some would tell you about Japan and some European countries allowing early release of promising new drugs, but these systems