Dr. FRIEDEWALD. My experience is in the National Heart, Lung, and Blood Institute and not the National Cancer Institute as stated here. I joined the Heart, Lung, and Blood Institute in 1967 and became affiliated with clinical trials in 1969. In 1974, I became Chief of the Clinical Trials Branch in the Heart, Lung, and Blood Institute. I then moved up in the hierarchy of the Heart, Lung, and Blood Institute and at all times, the Clinical Trials Branch was under me. Basically, since 1974, I have been involved with the Clinical Trials Branch and since 1969, with clinical trials. Mr. WEISS. NIH's April 16 draft response states that: [It is the clinical trials process that determines efficacy and hastens marketing, not ad hoc anecdotal experience by physicians not involved in organized research. [This excerpt is in app. 1, p. 187.] Mr. WEISS. Dr. Friedewald, what role do well defined clinical trials have, in your judgment, in meeting the need of rapidly getting effective and reasonably safe drugs to desperately ill patients? Dr. FRIEDEWALD. My position would be simply they are essential. They are the mechanism by which the information is gathered with regard to efficacy. I certainly agree with that statement, although I did not produce it. Mr. WEISS. On April 14, I believe you wrote a memorandum on FDA's proposed rules to the Director of NCI, which states: The long history of drug testing in this country would argue that the way to [rapidly get efficacious and reasonably safe drugs to the patients whose lives may depend on them] is to conduct well designed clinical trials to evaluate them. [The memorandum referred to is in app. 1, p. 196.] Mr. WEISS. That's your position. Is that correct? Dr. FRIEDEWALD. That's correct. Mr. WEISS. NIH's April 22 draft response states that the proposed regulation could interfere with scientific drug development, by among other things, reducing patients' incentives to enter and physicians' incentives to conduct clinical trials. [See app. 1, p. 175.] Mr. WEISS. Dr. Friedewald, do you share this concern? Dr. FRIEDEWALD. Yes; I do. Mr. WEISS. Didn't you refer to that concern again in your April 14 memorandum in which you stated: The rules will delay, and in many cases, prevent the obtaining of efficacy and safety information necessary to the intelligent use of drugs? [See app. 1, p. 197.] Dr. FRIEDEWALD. Yes, sir. Mr. WEISS. Dr. Myers, do you have the same concern? Dr. MYERS. Yes; I do. Mr. WEISS. Again, I think you have already indicated some of that in your prior testimony. In an April 8 memorandum at page 3, you stated: By removing the single additional safeguard of requiring some evidence of efficacy prior to widespread use, the ability to perform properly controlled clinical trials is bound to be compromised. [The memorandum referred to is in app. 1, p. 198.] Mr. WEISS. That is your position; is that right? Dr. Myers. That is clearly my position. Mr. WEISS. NIH's April 22 draft response states: Dissemination of investigational agents prematurely might pose an unacceptable risk to patient safety, in that it is possible for many drugs to be discontinued during or following Phase I studies because of unacceptable toxicities resulting from treatment with the agent. [This excerpt is in app. 1, p. 173.] Mr. WEISS. Would any of you disagree with that observation? Mr. WEISS. I assume that is correct, and that none of you disagrees with that. Isn't it, in fact, reasonable to assume that we might see increased toxicity from the uncontrolled use of drugs by physicians who do not know how to use them properly? Dr. Myers. Dr. MYERS. Yes. I think that's very true and in particular, the situation with azidothymidine is an interesting example because that drug, although it has efficacy, also has substantial toxicity associated with it. It also highlights an earlier point I made about the complexity of HIV infection and the progression of this disease. The fact that to be defined as an AIDS patient, you have to have an opportunistic infection or a tumor and there are some agents available to treat some of these additional infections. The complexity of trying to treat basically two or three infections at the same time with agents that are toxic and the risk of having cumulative toxicity or additional adverse effects in these patients is a very serious concern and one which we struggle with as we design the clinical trials that we are performing right now. Mr. WEISS. I'm sorry. You mentioned a drug and I didn't catch it. Was it AZT that you mentioned? Dr. MYERS. Yes. I mentioned AZT. Mr. WEISS. Dr. Myers, I gather from your earlier testimony that the proposed regulations, by permitting experimental drugs to be used very early in their clinical development, has no efficacy requirement. Am I correct? Dr. MYERS. My understanding of the way the proposed regulations are written is that that is true. There would be no requirement for efficacy in instances where a life-threatening disease is being discussed. My feeling is that the definition of "life-threatening disease" is so loose and our understanding of the natural history of HIV infection is still so undefined, that one could argue that almost anyone that is infected could have a life-threatening dis ease. Mr. WEISS. A major concern expressed in NIH's April 22 draft re sponse was ... lack of a clear requirement for some evidence of efficacy. ... By the very nature of drug development, many agents entering clinical trials-even in Phase II clinical trials-prove eventually not to be useful in therapy. For this reason, the likelihood is present that desperate patients may be exposed, under provisions of the new regulations, to agents for which harm is a more likely outcome than benefit. [This excerpt appears at app. 1, pp. 171-172.] Mr. WEISS. Dr. Friedewald, do you agree with that statement? Mr. WEISS. I trust, then, that you agree with the statement in NIH's April 22 draft response that the failure to require a demonstration of efficacy "could result in an unacceptably high risk.../benefit . . . ratio for desperately ill patients"? [This excerpt appears at app. 1, pp. 177-178.] Dr. FRIEDEWALD. Without question. Mr. WEISS. Dr. McCarthy, your office has commented that the impossibly high standard imposed by the reproposal for denying a treatment IND request "evidences a disregard for the rights of subjects especially those in desperate straits." [This comment appears at app. 1, p. 201.] Mr. WEISS. Would you please elaborate on that statement? Dr. MCCARTHY. Yes, sir. I think for some of the reasons you have already brought out in testimony that because either there would be little evidence if any on which to base a judgment of risks as well as benefits or because the risks could conceivably be unacceptably high, that subjects, receiving drugs under treatment IND's, could be exposed to highly toxic substances without the appropriate protections. The situation is further complicated, I think, by the fact that in both the preamble and the regulation, the proposed or the reproposed rule suggests that IRB review could be waived. The IRB's are those committees at the local level whose responsibility it is to determine both equitable distribution of drugs and that the risks are reasonable in relation to expected benefits. If waiver occurred, IRB's would not be able to make that kind of judgment on behalf of research subjects. Even if IRB review was not waived for so-called treatment IND's IRB's would have no evidence on which to make a judgment. It seems, therefore, that subjects could be placed at inappropriate risks in these circumstances. That's why we wrote that statement. Mr. WEISS. Dr. Raub, doesn't the National Cancer Institute currently have a mechansim worked out with FDA for treatment IND's called the Group C Program? Dr. RAUB. Correct, sir. Mr. WEISS. I understand that that program requires some evidence of efficacy as a condition for approving a treatment IND for an anticancer drug. Please describe for us what the program requires. Dr. RAUB. In general, sir, the idea is that when a potential cancer chemotherapeutic agent has moved well along in clinical trials-typically well into the phase II or even into the phase III area-when there is, in the judgment of the National Cancer Institute staff and advisors the indication that this agent is efficacious, is reasonably safe, and stands to benefit contemporary patients while the remaining steps in drug development and approval are underway then there is the means for the National Cancer Institute to present its proposal and supporting rationale to the appropriate staff in the Food and Drug Administration. Mr. WEISS. The program requires, I understand, reproducible evidence of substantial benefit to the patient population for which it is intended, a defined dose and schedule administration and definition of toxicity; is that correct? Dr. RAUB. Yes, sir. Mr. WEISS. NIH's April 22 draft response recommends that FDA "restrict distribution of agents [under treatment IND's] to those with some evidence of efficacy, in order to give desperately ill patients at least the potential of a response." The document also recommends conditioning such IND's on the ability of these drugs to "be administered safely and promptly.' [These excerpts appear at app. 1, pp. 178-179.] Mr. WEISS. Do any of you disagree with these recommendations? Dr. FRIEDEWALD. No, sir. Dr. MCCARTHY. No, sir. Dr. MYERS. I would just like to say that the word "some" gives me a little bit of concern. It leaves one with a very undefined sense of what "some evidence" means. Mr. WEISS. The statement itself only requires at least some evidence of efficacy. You personally think that is too limited? Dr. MYERS. I say that only because, depending on who you are talking to and what you are talking about, I have heard claims of more than some evidence of efficacy for a large number of agents or compounds which do in fact not have efficacy. In addressing the issue of when a drug should be available under a treatment IND to large numbers of patients, and considering the impact that would have on the ability to properly evaluate that agent in clinical trials, one must be very careful about the timing of when that treatment IND is awarded. Mr. WEISS. Since the proposed regulations do not require that efficacy be demonstrated as a condition for approving a treatment IND, NIH's April 16 draft response to those regulations concludes that "fraudulent" or "fringe" therapies, including "rather dubious substances" such as "laetrile, could be distributed by their proponents, who may also be able to bill patients for them." [This excerpt appears at app. 1, p. 188.] Mr. WEISS. Dr. McCarthy, do you believe that permitting the sale of drugs in this situation could result in the proliferation of fraudulent or fringe therapies? Dr. MCCARTHY. I have no experience to know whether that might be true or not. I would yield to my clinical colleagues on that point. My concern with the sale of drugs is a slightly different one. Namely that the institutional review boards, for which I have some responsibility, have to make a judgment that if a drug which is judged to be beneficial but still in an investigational stage is distributed, it must be distributed equitably. If the proposed changes in the regulations are made, then it appears that only a certain segment of the population would have access to those drugs. Thus the IRB's who are responsible for equitable distribution would not be able to fulfill the function that they are required to fulfill under HHS regulations. Therefore, we would have a dichotomy between what is required or permitted under FDA regulations and what is required under HHS regulations. That would give us two major concerns: a lack of congruence between FDA and HHS regulations and a lack of equity in the distribution of the risks and benefits of investigational drugs. Mr. WEISS. Dr. Raub, would you have a comment on the question I posed as to whether the proposed regulations would allow fraudulent or fringe therapies to be marketed? Dr. RAUB. If one reads the rule so as to deny the Commissioner adequate evidence on which to make a judgment and, therefore, no opportunity to exercise discretion, then I think it follows that in some instances there could be such inappropriate distributions of fraudulent materials or materials without any substantiation. Mr. WEISS. For "serious," in contrast to "immediately life-threatening" conditions, the reproposal states that approval of a treatment IND request requires some evidence of safety and efficacy. Dr. Myers, do you believe that the definition offered in the proposed regulations for the term "immediately life-threatening" is sufficiently precise? Dr. MYERS. No, I do not. I think the term "immediately life threatening"-given the fact that the document does not specify a time period in which the patient may die, again, specifically addressing HIV infection-is a term that is open to interpretation. You are basically saying if someone is antibody positive, they may have a serious disease. If they have AIDS with an opportunistic infection, they have a life-threatening disease. If they have AIDS KS, they may have a life-threatening disease. It all depends on what we understand of the progression of this disease. Mr. WEISS. Dr. Friedewald, would you care to respond to the same question regarding the definition of "immediately life-threatening"? Dr. FRIEDEWALD. Yes; I would. In my reading of the response of the FDA to the questions they received following the initial proposal, their interpretation of "immediately life-threatening" did not meet with my understanding of the meaning of these words. The sense of "immediately" was not in the interpretation of the words. It did not mean it had to be within a short period of time. I had a great deal of trouble in terms of the interpretation of what "immediately life-threatening" meant. Mr. WEISS. At this point, we will break and return in about 10 minutes. The subcommittee stands in recess. [Recess taken.] Mr. WEISS. The subcommittee is now back in session. Dr. McCarthy, I know that, by prearrangement, you had told us you have a very tight schedule today, and we are grateful for your fitting us into it. I have one remaining question of you. The preamble to the proposed regulations states that FDA will continue to prohibit "commercialization of investigational new drugs, as required by law." Yet, NIH's April 22 draft response states that the proposed regulations permit companies to "sell products under a Treatment IND for profit.' [This statement appears at app. 1, p. 176.] Mr. WEISS. Dr. McCarthy, can you conceive of such profitmaking activity as anything other than "commercial" in nature? Dr. MCCARTHY. Well, I'm not sure of all the implications of that question, sir. But it is my impression that the best experience we have in this area lies with investigational devices where manufacturers are allowed to recover developmental costs and in my judgment that creates a disincentive for them ever to move the device to marketability. I presume the same kind of forces would be at work here in drugs, if manufacturers are allowed to charge and recover the cost 75-752-87 - 2 |