Is that correct?

[This statement appears at app. 1, p. 142.]

Dr. BROOK. Yes.

Mr. WEISS. So, in essence, he would be required to authorize or approve an application for a treatment IND?

Dr. BROOK. It seems that the Commissioner didn't leave himself much leeway of saying no at that stage, and it's more like a-in the absence of negative and derogatory information, he would have to allow it.

My concern is that at such an earlier stage, there won't be much negative or derogative information to prohibit him from doing that. Rather than stressing the positive, it is stressing the negative. The lack of information. Rather than saying if he has information he would then be allowed to prohibit it. So I think the Commissioner would be almost forced to allow a very early and premature release of agents before they have been adequately tested.

Mr. WEISS. Thank you very much.

Is there anything further that any of you want to add to the testimony that you have given?

If not, let me express the subcommittee's appreciation to you for taking time from your very, very busy schedules to share your expertise with us.

The subcommittee will now stand in recess until 1:30.

[Whereupon, at 12:55 p.m., the subcommittee recessed, to reconvene at 1:30 p.m., this same day.]

AFTERNOON SESSION

Mr. WEISS. The subcommittee is back in session. Dr. Young, if you and your associates will all stand and raise your right hand. 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 answered in the affirmative, and the reporter will take note of all of you who stood behind your nameplates.

Before we begin, the subcommittee is in receipt of a letter with a statement from Senator Orrin G. Hatch, the distinguished ranking minority member of the Senate Committee on Labor and Human Resources, who asks that his statement be entered into the record, and we will, of course, be pleased to do that, without objection. [The statement referred to is in app. 1, p. 207.]

Mr. WEISS. Dr. Young, let me at the outset express my appreciation to you, not only for the work that you have been doing, but for having been with us all day today.

As difficult as it may be for you to take time from your very hectic schedule, I think that your example should be followed by other Federal Government witnesses who are asked to testify here. You have demonstrated a genuine concern in the testimony that is being given on this very important issue, and all of us are grateful to you and to your associates for sitting through this hearing.

Before we proceed, let me for the record note that the Wall Street Journal today has an editorial that attributes to me a characterization of you which is totally untrue. The author never spoke with me. I never said such a thing to him or anyone else. You are,

indeed, I think, one of the finest people we have in the Federal Government, and I just want to have that stated on the record. And with that, I think we are ready to proceed.

We have your prepared statement. You may proceed as you think most appropriate.

STATEMENT OF DR. FRANK E. YOUNG, COMMISSIONER, FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY DR. PAUL D. PARKMAN, ACTING DIRECTOR, CENTER FOR DRUGS AND BIOLOGICS; DR. DONALD B. BURLINGTON, ACTING DIRECTOR, DIVISION OF BIOLOGICAL INVESTIGATIONAL NEW DRUGS, CENTER FOR DRUGS AND BIOLOGICS; THOMAS SCARLETT, GENERAL COUNSEL, FOOD AND DRUG DIVISION; JOSEPH A. LEVITT, EXECUTIVE ASSISTANT TO THE COMMISSIONER; AND JOHN A. NORRIS, DEPUTY COMMISSIONER

Dr. YOUNG. Thank you, Mr. Chairman. And before beginning, I want to thank you for that clarification. You and I have worked on a number of issues. I felt that the alleged quote of you in the Wall Street Journal editorial was very uncharacteristic, and I am pleased to hear your clarification. I know of your call to public service and you know mine.

I would like also to thank you for acknowledging that we have sat through this entire hearing. We learned a lot here today, and we feel that these are just the kind of hearings that help us to engage the issues.

I would like, Mr. Chairman, to focus on a few things that I heard this morning to try to clarify them. I am going to highlight my testimony. However, I may take a few moments longer because I will try to answer some of the questions I heard this morning.

Mr. WEISS. You're entitled.

Dr. YOUNG. Thank you.

I'm really pleased to be here because this gives us the opportunity to discuss ways in which we can bring hope to thousands of desperately ill patients and their families. The Food and Drug Administration plays a critical role in improving the quality of health care in this country. As those in the academic and governmental research communities are engaged in the initial discovery and clinical testing of new therapeutic agents, it is FDA's role and responsibility to harvest the fruits of research by facilitating the swift transfer of new discoveries from the laboratory to the marketplace, but with the appropriate safeguards of safety and effectiveness.

Only with this transfer can new important therapies serve their true purpose: that is, of healing the sick. As Commissioner of the Food and Drug Administration, and as a physician, I can assure you that FDA has no higher priority than facilitating the timely availability of important, safe, and effective new products to desperately ill people.

Therefore, I am particularly pleased to discuss this issue, a codification process, to make breakthrough drugs available to desperately ill individuals. Many of our citizens confront serious and lifethreatening diseases that despite all of the advances of medicine, still we do not have the answers. It's almost as if we were to look at a football field, and one speck of dirt on that field represents our

knowledge in the entire field, or ignorance. And thus the central issue is how to obtain more information and to bring that to and through the marketplace to patients.

I would also share, Mr. Chairman, your concern for people who are desperately ill with far-advanced AIDS and who fear the ultimate death sentence from a despicable disease that destroys the immune system. I know you have focused on this over the period of time that you have been representing the district-not only the district, but your seat on this chair of a very important committee. As Commissioner of the Food and Drug Administration, I am also cognizant of the many dramatic new pharmaceutical agents that are under development by our research-based, innovative pharmaceutical companies, and the newly developing creative biotechnology industries.

We must, I emphasize, harvest the fruits of investment of a quarter of century of fundamental research in molecular genetics. This year we celebrate 100 years of success in research at NIH. America has reason to be proud of the dedication of the pursuit of fundamental knowledge. And never before have we needed fundamental knowledge as we attack a wide variety of important diseases.

Though the rule is designed to deal with a wide variety of diseases, I am going to, for the purpose of discussion, focus primarily on AIDS. I want to emphasize that that is not the total scope of this rule.

We are faced with a national emergency due to the natural emergence of a new infectious agent that will tax our ingenuity as we attack this dastardly disease. But how will we do it? There are three keys that I would like to discuss for you: flexibility, focus, and responsiveness.

Flexibility: We must be flexible to recognize that we need new measures in desperate times. We simply cannot be content with business as usual when there is a need to treat desperately ill people. With this in mind, I developed a new initiative to work with AIDS just as one of the diseases that I would like to discuss with you.

But I emphasize again that we are committed to assist all individuals who are desperately ill and have grave problems.

First, I requested that we develop a new double A classification for AIDS drugs in which we promise the American people that we would evaluate these drugs in less than 180 days of review time within FDA.

Furthermore, we would work rapidly to discuss with sponsors the required content of the investigational new drug applications. These efforts led to the approval of AZT, or Retrovir, in 108 days, the fastest approval, to my knowledge, in the history of FDA. And we heard the applause given by many to that action this morning. The same approach led to the disapproval of the new drug application for Isoprinosine in less than 180 days as well.

We therefore pledge either the approval or the disapproval of new drug applications as rapidly as possible within this new double A classification.

Second, I have personally met with sponsors of drugs to ensure that companies have their scientific team introduced to our review team so that there is no needless administrative delay. But we will

still assure FDA's independence and thoroughness throughout this evaluation process.

And I must add, more recently I have also met with sponsors of vaccines as well, both in Government and outside the Government sector.

Third, I began approximately a year and a half ago to consider an additional flexible approach codifying the IND process, and that is dealt with in much more detail in my testimony.

Let me move to the next point, focus. We must focus our efforts. We must keep our eye on the ball. Therefore, in a time of diminishing Government resources, we must use our personnel efficiently and effectively, and above all, be mindful of our patients' needs.

Accordingly, under the leadership of Dr. Ed Taber, we developed a team approach to review AZT or Retrovir and granted a treatment IND that was widely acknowledged this morning by Dr. Hirsch and others, as a prudent thing to do. We did this in the fall of 1986, and eventually enrolled thousands of patients on this treatment IND.

This action was undertaken because there was sufficient scientific data that on balance led to the conclusion that the anticipated therapeutic benefit outweighed the risks, and this action is just what we are aiming for in this regulation.

When there is no adequate therapy available in immediately lifethreatening conditions, the reproposal requires that the Commissioner have adequate support for making the necessary determination, and it is expected that the Commissioner will be provided with sufficient data to make the specified determination.

The distinction between serious and immediately life-threatening is made because of consequences of denying treatment to a patient who may die soon. I emphasize in my prepared testimony that lifethreatening means there is a reasonable expectation that the person will die within 6 months. Under such circumstances the conditions are much graver than for a patient with a serious, but not immediately fatal condition.

Thus, the proposed rule attempts to balance the gravity of illness with informed consent of the potential risk by both the patient and the physician. I would like to illustrate this, if I could proceed to the charts?

This graph which depicts roughly all of the IND's that we would receive in FDA. We look as eligible for this particular condition about 3 to 4 percent of all of the IND's in which first there is no alternative therapy; and second, the disease is immediately lifethreatening-i.e., there is a reasonable expectation that that person might succumb to the disease in approximately 6 months. In the preamble language we attempted to provide the kinds of information that would be required. And I believe the witnesses this morning, particularly Mr. Cooper, with his thoughtful comments, pointed out that they agreed with the general purpose of the rule and felt that the rule had had some of that language in the preamble aspect. Mr. Cooper requested explicitly that that type of language be put in the rule itself. I believe that was his suggestion.

The next category, still less than 10 percent, are the diseases that are serious. And in that case we are looking at individuals

who would survive a longer period of time, but again for whom there may be no alternative therapy. That alternative therapy issue is a very important one.

If we then look at how this occurs in the clinical trials, we would see the following type graph. I think it clarifies some of the concerns which I have also heard in the meetings that I had during this comment period. I want to emphasize before going to the graph that in the abundance of caution, I have gone out and held over 13 meetings in less than 35 days-I believe less than 35 days— to try to be sure that I got all of the opinions. Dr. Brook mentioned this morning that I had an opportunity to discuss this with him. These are the exact graphs that I used for these meetings. I would like to have the meetings, their dates, the slides, the pictures of the slides, and the minutes of the meetings, put in the record, if I could, Mr. Chairman.

Mr. WEISS. Without objection.

[The information referred to is in app. 1, p. 215.]

Dr. YOUNG. This basically is what we are talking about. In the early portion of a drug's development, the product is discovered and brought to a point in the laboratory when it looks as if it's promising.

From there it goes into animal tests. And, as Mr. Cooper stated correctly, the animal test data is of value, in evaluating new drugs. This usually takes about 2 years or so. The blue portion illustrates the amount of time that FDA expends on review of data. We review the IND application in about 30 to 90 days. I hasten to add that the blue portions are the portions within FDA's time, and the yellow are the sponsor's time.

Phase I usually constitutes a study of approximately 20 to 40 patients, and focus on safety; some amount of efficacy, but primarily safety.

In phase II, one looks at approximately a couple of hundred individuals in controlled trials, usually placebo-controlled trials. In the main body of the regulation, we provide that there will be a conference between FDA and the sponsor at the end of phase II. That enables the sponsor to be better prepared to move into the definitive phase, phase III, which usually takes 2 to 3 years. In this phase, the definitive amount of work is done, i.e., the enrollment into large clinical trials and the study of those patients for safety and effectiveness in a detailed fashion. This leads to the submission of a document of approximately 100,000 pages plus exhibits. The volumes are a little bit taller than I am, by about one and a half times. They are submitted to FDA and it takes, on the average, 2 years for FDA to review them.

We then look at postmarketing surveillance in phase IV. So that if one looks at the entire process, one has about 1 to 2 years here, 1 to 2 years here, and another 2 to 3 years here, a total of 7 to 9 years after which then we have about 2 years of final review within FDA.

The red arrows indicate the earliest time that we would anticipate that we would start a treatment IND. And, in fact, if one looked at velocity, one would see that the majority of treatment IND's would be started somewheres here in phase III.