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Executive Summary

FDA's review of AIDS drugs for clinical endpoints other than survival would be made more difficult under the proposal to expedite the approval of life-threatening drugs initiated by Vice President Bush, attorney Nancy Buc (D.C. law firm Weil Gotshal and Manges), suggested at an Oct. 13 biotechnology conference in New York sponsored by the Shearson Lehman Hutton investment firm. "The whole idea of compressing Phase II and Phase III [trials] is much easier to talk about when the endpoints are defined than when they are not, and when you are talking about a larger Phase II trial instead of a Phase III trial, I'm not quite sure what you are really saying," Buc said. "I suggest that FDA is going to have to back off from this notion of messing [with the clinical trials] process because nobody is going to let them and they don't have the people to do it." Buc said that while the idea of compressing Phase II and III has had "a nice shot in the arm from the Vice President's hollering about it," the question of what will emerge from the political rhetoric remains to be seen. In the past, FDA has said that compressing late clinical trials would only be appropriate for "clearly promising" drugs. The former FDAer noted that if the endpoint for evaluation of AIDS drugs is not going to be mortality, then clinical trials will be difficult to design and expensive to conduct. "They are going to be hard trials to do and they are going to be hard trials to interpret, and all of that means that there is going to be a lot of judgment," she said. "FDA gets criticized the most . . . when it is being forced to exercise that kind of judgment about other people's clinical trials." In addition, Buc observed, the AIDS epidemic has created its own political groundswell -- recently manifested in the civil demonstration that took place at FDA's Rockville, Md. headquarters on Oct. 11. "Take a look at the question that AIDS patients are asking because nobody has ever really asked these questions quite this way before," Buc continued. "Why do I have to be the clinical trial guinea pig for some later generation of victims? Why can't I take what I want as long as somebody tells me what the risks and benefits are? Those two questions are very profound questions that go to the heart of what FDA is doing." Such questions, according to Buc, indicate that the political realities of the AIDS epidemic have brought a new participant -- the patient -- into the drug approval fray, which traditionally has involved only clinicians and the FDA. "With cancer, it is the clinicians who are arguing for the right to take power from FDA," Buc observed. "With AIDS, it's the patients." Buc pointed out that the nature of the physician-patient relationship has been altered by these AIDS questions "because it isn't a question of going to your friendly physician and getting him or her to prescribe something, it's getting the physician out of the way all together." However, she suggested that allowing patients to make their own risk/benefit evaluation for AIDS drugs sets a precedent for other patients doing the same for other drugs. "I don't think FDA is terribly well-equipped to deal with these types of questions," Buc concluded, adding that the agency has been most effective when its political skirmishes have been fought on medical and scientific grounds. "FDA is going to have to give some thought as to whether it is certain that it can make these medical and scientific battles, because if not, it is going to have to get some political help." Buc's remarks echoed complaints of similar potential problems at FDA with respect to the approval of new cancer agents, including the clinical endpoint issue and its regulatory and commercial ramifications. Until recently, the issue had been a long-standing bone of contention between FDA and the National Cancer Institute (NCI). "Cancer drugs . . . have traditionally been extremely cytotoxic, [and] I think it is largely a result o that that there has been a strong sense that these drugs really had to work . . . and the measure of that typically has been whether the patient lives any longer than would otherwise be the case," the attorney explained. "Until very recently, FDA was focusing intently on survival. Part of the reason for that was that in the mid-1970's their oncology advisory committee told them to do that . . . and because that seemed like the rational endpoint." Meanwhile, NCI has been a major player -- scientifically, economically and emotionally -- in the development of cancer drugs, according to Buc. Many of the currently available agents have come from NCI rather than the private sector, with industry participating only at the end of the development process. In recent years, the oncology community has tended to look at endpoints other than survival, such as tumor size, pain, progression or remission of disease and reduced toxicity. With FDA having agreed in principle to look at these "mid" endpoints, a number of new problems arise, Buc noted. "You probably need to have larger trials, and that means more expense," she commented. "Another is that if you don't exactly know which endpoint you are looking at in the beginning, you are going to have to do much more expensive trials just to measure all of these things as you go along. From a commercial standpoint . . . I'm not entirely sure whether the business community that is thinking about doing clinical trials with cancer drugs is really going to be any happier even if NCI is in some sense theoretically correct." Since there is currently a relatively small universe of effective cancer drugs, she noted, one typical protocol for testing a new agent compares a cocktail of between four and 10 known agents against the same mixture with the potential new drug added. "That means that unless your new [drug] is incredibly potent, you're not going to see much of a difference between four or five on the one hand or 10 and 11 on the other," Buc remarked. In addition, Buc identified an important implication of a less definitive clinical endpoint -- its effect on the promotion of a product. Using clinical endpoints other than survival "makes marketing the drugs very much more difficult, and it also means that a great deal more information has to be available about the drug to physicians and probably to patients" she suggested. "The trick to all of this is that under FDA [regs] you can only label a drug for what you have proven." Buc observed that once a drug has been shown active against a certain type of tumor on a specific organ, then oncologists will typically use the agent for other tumors at other organ sites either as a last resort or because of a strong clinical instinct. "You can't put out [promotional] materials if you are a manufacturer about unapproved uses, and that is one of the most common phenomena in cancer treatment," she said. "FDA has been absolutely rigid about not allowing the dissemination of information that goes beyond the labeling except in scientific meetings, which they limit as much as they can," the lawyer continued. "I would suggest that FDA may have to think real hard about whether that really serves the public interest, scientific interest and clinical interest, at least in the case of cancer drugs." According to Buc, the issue extend beyond the realm of just FDA and drugs and is applicable to surgical and radiation therapies for cancer as well. "The difference is that until very recently, nobody has looked at that," she noted, "and as HCFA starts to look harder and harder at how long the patient lives under Medicare, people are going to start looking at surgery the way they've been looking at drugs, and it isn't going to be fun for the surgeons."

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