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Executive Summary

Legislation authorizing FDA to require postmarketing studies would facilitate quicker approvals of drugs for AIDS and other diseases, Commissioner Young testified at a July 13 hearing before Sen. Kennedy's (D-Mass.) Senate Labor & Human Resources Committee. "If we were able to require appropriate Phase IV studies, we might with much more confidence be able to do the type of evaluations you're talking about." FDA "cannot, under our current authority, require a Phase IV study," Young pointed out, but rather solicits voluntary agreements from NDA sponsors in exchange for expedited reviews. Young described the lack of authority as "a potential weakness in our current legislative capabilities." Some voluntary Phase IV agreements "have succeeded and others have failed." Young hit a responsive chord with his support for Phase IV; that was an important part of Kennedy's FDA legislative proposals in 1979. Kennedy assured Young that FDA could readily obtain such authority, if needed. "I would just welcome legislative changes in this area; I'm a strong believer in postmarketing surveillance," the senator said. It helps drug reviews proceed "much more rapidly, and if you need [legislation] in terms of this particular area, I just can't believe that it would take longer than an afternoon to get it through the Senate." Young said FDA, after "a great deal" of debate, "backed away" from mandatory Phase IV studies "because of the difficulty in getting" authority and instead, sought the Treatment IND regulations as an approach to faster distribution. Kennedy maintained that the pharmaceutical industry is confused as to the efficacy requirements for obtaining Treatment INDs. "There is confusion out there about the criteria that is going to be applied by the FDA in deciding whether to release a drug under a Treatment IND," the senator said. "Is the standard that a drug may be effective or must there actually be some kind of documented evidence that it is effective?" Young replied that a sponsor must submit "evidence [of] some degree of effectiveness, that it may be effective." He added that a Treatment IND can be approved before the drug enters Phase III trials. However, the FDA commissioner continued, "I can't tell any sponsor exactly how much" efficacy data is required for all drugs. "That will depend on the drug, the number of patients studied, and how good the study is." Efficacy data required for a Treatment IND does not require "anywhere near the amount of effectiveness data that is required" for proceeding to Phase III clinicals, Young said. "There must be some indication that it is going to be effective. That was the battle that was fought when the regulation went forward." In fact, he continued, the original proposal, "which was roundly criticized by the Congress and the scientific community, was that we have even a shred of effectiveness. The first proposal came out [requiring] no effectiveness at all." Kennedy said he wanted to "clear up the ambiguities" for AIDS patients who "were under the impression that the regs were considerably loosened up last year for getting these experimental drugs out to them." Because only one AIDS drug, trimetrexate, has been released under the Treatment IND process, Kennedy said AIDS victims have expressed "a lot of cynicism, skepticism, and frustration"; they feel "let down if not actually misled" by announcements of the Treatment IND procedure. The commissioner responded that over the past year, FDA has received only four Treatment IND applications for AIDS drugs. "One was for ribavirin, which was turned down [because] it did not have . . . the efficacy that would be required. One was trimetrexate, which was approved" for Treatment IND distribution," he explained. "Two were from the same investigator," who failed to supply "even a filing of an IND." The applications came in strictly as a Treatment IND, "with an idea but no animal studies done, no patients entered in, and no chemical analyses done of sufficient nature." FDA's problem, Young explained, is that "there is not a great deal in the pipeline," and the agency "cannot, regretfully, approve something that we do not have the applications for." However, he declared, "we're very early in this development of INDs," and "there are a potential of about five candidates for Treatment INDs in the next 18 months. We do not know [where they are] exactly in the time frame of their development because the trials are not open." Pharmaceutical Manufacturers Association VP-Science & Technology John Beary, MD, testified that the Treatment IND regulations "leave some uncertainty about the quality of evidence that must be presented to qualify for" approval. Beary further maintained in his written testimony that "it is time to re-examine the Treatment IND policy." For example, he said, because patients can obtain experimental drugs under a Treatment IND without the risk of receiving a control drug or placebo, "the program could well lead to decreased enrollment in clinical trials." Logistical problems "may also inhibit the success of the Treatment IND program, particularly when the disease affects large numbers of people," Beary continued. "As the number of people afflicted with AIDS increases, it appears that this system will not be able to cope with the increasing demand for new medicines." NDA approvals are accompanied by full-scale manufacturing, physician education, and wide distribution; however, Beary explained, "these activities do not take place under the Treatment IND program." The "cumbersome logistics" involved in physicians' filling out forms, consulting institutional review boards, and obtaining patients' formal informed consent could give the program "a hard time coping with the one million people affected with the AIDS virus." In addition, the distribution of experimental drugs under the program creates liability concerns for "both pharmaceutical firms and physicians," Beary contended. Companies are concerned about "providing drugs that are not yet approved," and primary care physicians "face major medico-legal threats in their practice environments," which may "chill a doctor's willingness to use an experimental drug in the office setting." PMA reports that 46 member firms have 50 AIDS-related drugs and vaccines under development. "These products include 16 antivirals, 21 immunomodulators, three anti-infectives, and 10 vaccines," Beary said. "In addition, 10 diagnostics have been approved and 23 others are under the development," he continued. "The number of products under development emphasizes that the pharmaceutical industry has made a major commitment to search for answers to this alarming disease." The fact that AIDS is a viral disease is one reason therapies have not been developed more rapidly, Beary maintained. For example, although the industry has developed "hundreds of antibacterial drugs over the past 50 years, only seven antiviral drugs have been developed during this time," he said. The difference is that whereas antibacterials "interfere with biochemical processes unique to bacteria and generally do not harm the human host," viruses "are intracellular parasites that use normal human processes for their own survival. Thus, medicines that destroy a virus often cause unacceptable toxicity to the human host because the medicine may destroy the patient's own cells as well." Another reason these AIDS drugs have not been produced faster is that the human immunodeficiency virus "implants its genes into the patient's own chromosomes at the time of infection, thus resulting in lifelong infection," Beary continued. "We do not presently have a technology for eliminating the cells that are diseased, nor does one appear to be on the immediate horizon."

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