7

There is no doubt of the gap in biological knowledge and the deficiency in methodology of clinical investigation in more than ong field. We appreciated Dr. Simmons' candid statement at our meeting with FDA in June that much remains to be defined as to the meaning of "appropriate preclinical testing" and of "safety and efficacy" as applied to new drugs. So we can applaud the FDA-industry program to develop rational clinical guidelines.

But the need for flexibility must be emphasized as the guidelines program goes into effect. According to published reports, the Auerbach study suggested standardization of IND and NDA submissions and protocols in any future reorganization of the drug review process. "Standard clinical protocols could be developed for each drug class," said the Auerbach report. "Once these protocols had been developed, FDA could specify that they be used during the IND testing stage. No drug could be approved unless the standard protocols for its class had been used in the clinical testing." Is there a threat here to creativity in pharmaceutical research?

We recognize, with FDA and the scientific community, that our society has accepted the notion that laboratory test experience in animals may. well be transferrable to man, despite the fact that this is one of the biggest unanswered questions now facing science. We noted Dr. Simmons' expressed concern at your meeting in September that that may be an error, and we may in fact be depriving humans of drugs because of an animal experience that will never happen in man."

Our present system, reflecting society's mood, forces or results in the withdrawal from clinical test of any compound found to possess Bignifiant toxicity in laboratory animals. Have ye weighted the system do minh on the use of safety? Potential benefit of an untried drug or een only on tachodri by clinical uials in men. If these

22-265 - 74-68

trials can never take place because of an adverse effect in animals `. that might never occur in humans, tomorrow's safer, more effective drugs may be beyond our grasp. Can we ever solve the crucial riddle of benefits versus risks? We will not solve it if we do not try.

This scientific uncertainty is the genesis for our question to Chairman Rogers: "Is the public excessively concerned with drug safety?" In the initial letter to Representative Paul Rogers, we said: "The system too often stifles creativity and escalates costs of research...." What, did we mean? Dr. Simmons made the very point

at your last meeting. He said:

"...One thing that it is very important for the public and certainly the Congress to keep in mind is that we can keep adding more and more requirements which are justified scientifically, but we may reach the time when the goose just has no more golden eggs to lay to pay for what is required. Then society has to decide how are drugs going to be developed." In Dr. Richard Crout's thought-provoking presentation on the work of FDA's Office of Scientific Evaulations, we fearned that Office is handling a total pool of about 3,200 Investigational New Drug Applications and that an estimated 100 to 200 in the total pool may be potentially important new therapies. Why, then, we wonder, do only three to five medically important new drugs clear the NDA process in a given year?

Such drug product candidates, these potentially important new therapies, are the pharmaceutical industry's and medicine's most valuable assets. Though their fate should concern us most, we have

little data on this crucial matter.

Is the attrition rate of these compounds increasing during the IND process, decreasing, or unchanged? The future of U.S. leadership in chemotherapeutics may be wrapped up in the answers to the subtle and emalux question of why these are "drop-outs." We need to know how the crit ria for performing and interpreting animal and human

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studios is affecting the fruits of therapeutic research. Is the

risk-to-benefit equation set at a proper level to prevent the

premature discard of potentially valuable drugs? The present system is inherently designed to err on the safe side. We urge a complete and thorough study of individual case histories. This might help

us better judge whether valuable compounds are being lost to man.

We were all staggered by the mass of paperwork that floods

into FDA

six million four hundred thousand pages every year in

INDS, NDAS and antibiotic submissions alone.

For years now, I am told, FDA and industry have searched for a responsible way to dam this paper flood. A certified summary keeps coming up, with the millions of pages of raw data kept in sponsors' files until or unless asked for by the FDA.. Can a way be found to do this, not just talk about it?

Dr. Crout posed for all of us fundamental conceptual problems

principal among

of drug development, evaluation and regulation them that our society lacks a consensus on what drug regulation is, what FDA is and what society intends for FDA to do. Is it FDA's job to be policemen, to see each page of raw data adds up correctly in summary tables? Or should FDA take the data summaries and see whether they constitute scientifically appropriate studies? If the latter, by what standards? Who sets the standards? Is FDA judge and jury both?

These fundamental questions do indeed plague all of us, FDA included, and our August 4 letter to you, Dr. Edwards, asked the

question: ..Is the FDA judge, jury and the prosecutor under the

law or the regulations?"

These are some of the concerns of our Committee.

It's clear to me

that we share these same concerns with all of you. We believe that a

calm, objective study of these issues is badly needed. As my fellow committee member, Dr. Nathan Kline, wrote to Dr. Edwards recently:

"There is no complaint of malfeasance but a shared
despair at the size and complexity of the problem.
Our total effort is directed toward trying to get at
the underlying facts rather than offer a facile solution
or to pin blame on the FDA, or anyone else, and let it
go at that. A thorough investigation into the underlying
problems would include considerable more knowledge about
the drug industry, the investigators at the clinical level,
and a number of other factors including supported structure
of the Food and Drug Administration."

Dr. Kline also pointed out that we are interested in a much broader based understanding of the whole process of bringing drugs to market for the benefit of our fellow citizens. We hope the National Advisory Drug Committee and the FDA will agree.

Whatever the outcome, here and in Congress, perhaps, we in the academic world can make a broader contribution than in the past in the fields of health regulation, health science, health economics and public policy.

There is need to establish a non-government nor-industry center to serve as a focal point for the study of the development, use and regulation of pharmaceuticals. This could take the form of an academic center which would be available for advice to industry, government, and consumers on questions of public policy. In this way, we in academia might be able to help more effectively toward the solutions of some of the problems we have been discussing today.

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