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Executive Summary

FDA will continue to require replication of key clinical findings in its new procedures for the accelerated approval of treatments for life-threatening or "severely debilitating" illness. While acknowledging there may be extraordinary circumstances where a confirmation of results may not be necessary, the procedure calls for a replication of Phase II results by a second study. Announced by FDA Commissioner Young at an Oct. 19 press conference, the procedure was published in the Oct. 21 Federal Register as an interim rule with a request for comments. The rule is effective immediately; FDA will accept comments until Dec. 20. Two recent approvals have not required replication of results: AZT in AIDS and timolol for reduction of post-infarction mortality. The agency said that it "would consider applying the same principle to other such cases in which the outcome of a multi-center study demonstrated as consistently dramatic an increase in survival among independently evaluable study sites and where repetition of the study would be unethical." However, "the agency cautions that persuasively dramatic results are rare and that two entirely independent studies will generally be required. Sponsors should therefore plan in advance a strategy for replication of key findings through a second well-controlled study," the rules says. The agency added that studies could be conducted concurrently to save time. In a Sept. 12 letter to HHS Secretary Bowen, PMA had suggested that the agency, in considering the risks and benefits of certain drugs, should relax "the rigid demands of the current regulations for more than one adequate and well-controlled study" ("The Pink Sheet" Sept. 19, T&G-5). The emphasis on the replication of key Phase II findings is one of only a few changes in the final plan from an earlier draft circulated in August ("The Pink Sheet" Aug. 15, p. 12). The procedure was formally requested in late July by the Presidential Task Force on Regulatory Relief, chaired by Vice President Bush. Basically, the plan continues to call for early consultation between FDA and the drug sponsor to design the preclinical and clinical studies necessary to gain marketing approval. The keystone to the rile is the call for an end-of-Phase I conference at which Phase II studies would be designed to provide sufficient data on which to base an approval. Postmarketing studies by the sponsor are also part of the plan. Under the procedure, FDA said it expects to reduce the time usually required for clinical testing by a third or a half. The interim final rule includes a lengthier definition than earlier drafts of the scope of products to which the new procedures would apply. The interim rule applies to new drugs, antibiotics and biological products for "life-threatening and severely debilitating illness." The two terms and the examples that FDA gives of the type of diseases meant by the terms is very similar to the Treatment IND reg issued in May 1987. A "life-threatening" disease for the new proposal is defined as one in which "the likelihood of death is high unless the course of the disease is interrupted (e.g. progression from asymptomatic HIV infection to symptomatic HIV infection, or further progression to a later stage of AIDS; metastatic cancer; amyotrophic lateral sclerosis)." The term life-threatening includes "any disease whose progression is likely to lead to death, especially in a short period of time (e.g., 6 months to 1 year)." The reg also applies to "any condition in which a study is to be carried out to determine whether the treatment has a beneficial effect on survival (e.g. increased survival after a stroke or heart attack)." The term "severely debilitating" is defined as a "disease or condition that leads to major irreversible morbidity (e.g. severe functional deficits in multiple sclerosis, Alzheimer's disease or progressive ankylosing spondylitis; prevention of blindness due to cytomegalovirus infection in AIDS patients)." The agency draws one distinction between appropriate situations for the new review process vis-a-vis a Treatment IND release. "Many other studies examine symptomatic relief (e.g. pain of ankylosing spondylitis) rather than irreversible morbidity," FDA points out. "While products being studied for symptomatic relief of a serious disease would likely qualify for Treatment IND consideration," the agency said, "they would not be covered by the procedures contained in this interim rule." FDA also sees Treatment INDs as being complementary to the expedited approval plan. The reg calls for FDA to encourage the sponsor to apply for a Treatment IND following early Phase II study if results are promising. The Treatment IND would "thereby serve as a bridge between the completion of Phase II clinical trials and the full analysis and evaluation of those trials," the rule states. At the Oct. 19 press conference, Young said that two companies have already expressed an interest in using the procedure, one for a cancer drug, the other for an AIDS treatment. Colorado-based Cell Technology announced in an Oct. 20 press release that its anti-cancer agent Imu Vert may be a candidate for approval under the system. The company announced the selection of several sites for advanced Phase II brain cancer clinical trials. If Imu Vert qualifies under the new rule, the company "could possibly file for approval of Imu Vert for brain cancer upon completion of Phase II testing in late 1989 and begin marketing the product commercially for this indication in 1990," Cell Technology said. The rule includes a substantial discussion of what the nature of FDA's early involvement in testing might be, and why such involvement would be important. PMA had recommended to Secretary Bowen that FDA should become involved in the pre-clinical studies only "at the election of the sponsor" to insure that the company's research processes are not impeded. However, the reg does not restrict FDA involvement in that way. An underlying irony to the proposal is its emphasis on early FDA involvement. One of the tenets of the IND/NDA reforms proposed earlier this decade was the removal of FDA from the early stages of drug discovery to keep FDA contact during the early development stages to a minimum.

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