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Executive Summary

Appointments of representatives from FDA, the National Cancer Institute and the National Institute of Allergy and Infectious Diseases representatives to the other agencies' advisory committees could raise conflict of interest problems, FDA contends. The agency's Center for Drug Evaluation and Research (CDER) expressed its concern about mixing the roles of the different advisory committees in a recent analysis of the Lasagna Committee recommendations on the regulatory review of drug therapies for cancer and AIDS. While FDA believes "strongly in fostering close relationships and mutual understanding "between the drug development and drug approval agencies, "it is paramount to distinguish between these different responsibilities," CDER said. FDA advisory committee members, CDER pointed out, "are not permitted to vote on matters in which they have had a direct or personal involvement." Similarly, it is "not appropriate for FDA to vote on issues affecting the development of drugs when these matters may come before us in the course of a regulatory review, setting the stage for allegations of conflict of interest." CDER's analysis of the Lasagna report was transmitted to Acting Commissioner Benson together with an Aug. 29 memo from Center Director Carl Peck, MD. The analysis elaborates on public comments made by agency officials when the National Committee to Review Current Procedures for Approval of New Drugs for Cancer and AIDS, chaired by Tufts University Dean Louis Lasagna, issued its final report ("The Pink Sheet" Aug. 20, p. 3 and p. 5). HHS Secretary Sullivan recently asked the Edwards Commission on the FDA to review the Lasagna report ("The Pink Sheet" Oct. 1, p. 10). Peck's memo states that CDER's analysis is an "equally important corollary" that should be considered by the Edwards group. In its discussion of the FDA/NIH advisory committee proposal, FDA also made the broader point that "FDA advisory committees deliberately avoid members who 'represent' organizations; rather, by design, membership is intended to be composed of independent experts who offer their individual professional judgments on matters before them." CDER added that it is "open to expanding the concept of non-voting liaison memberships such as the NIDA [National Institute of Drug Abuse] liaison representative to our Drug Abuse Advisory Committee." Regarding the Lasagna Committee's recommendation that product sponsors "should have the option of paying FDA for outside review of NDAs by qualified experts who have no conflict of interest," CDER responded that this approach "leaves agency staff who may be called upon by congressional committees to defend approvals or oversee post-marketing reactions relatively unaware of essential details about the drug." The Lasagna proposal might also conflict with FDA's statutory requirements, CDER observed. The CDER analysis discusses at length the Lasagna Committee's recommendations that the agency exercise its statutory and administrative "flexibility" to approve drugs at "the earliest possible point" and that FDA pay "particular attention to the statutory definition of 'substantial evidence' of effectiveness." CDER noted that the Lasagna report, "focusing on expert opinion, fails to mention that the [FD&C] statute itself requires that expert opinion be based on 'adequate and well-controlled investigations...on the basis of which it could fairly and responsibly be concluded by [qualified] experts' that the drug is effective," CDER asserted. "We do not believe the committee intended to suggest that expert opinion can lawfully substitute for adequate and well-controlled studies." FDA said, adding: "The notion that Congress intended expert opinion to substitute for adequate data has been rejected by many courts, including the Supreme Court." On the issue of "early availability of drugs," CDER pointed out, "there is no real disagreement here between the panel and the agency. We too, believe that drugs should be available at the earliest stage at which the statutory standard is met. The committee suggests that FDA somehow requires more than is required by statute, i.e., 'definitive evidence of effectiveness' rather than 'substantial evidence.' No FDA policy that we are aware of," the center advised, "requires more than 'substantial evidence,' i.e. two adequate and well-controlled studies." FDA noted how it has modified its two-study criteria in several circumstances to allow approval based on a single "well-designed" multi-center study. Three features of single studies have allowed "the conclusion that the statutory standard for approval is nonetheless met: (1) a multi-center study with independently evaluable sites can satisfy the goal of replication ordinarily served by a second study; (2) a highly statistically significant effect on survival provides a degree of reliability not ordinarily found in effectiveness studies...(3) where results are so compelling and reliable that it is unethical to repeat the study, it may be deemed impossible to satisfy the requirement of two studies. Impossibility sometimes provides authority to avoid an otherwise clear statutory standard." CDER argued against a blanket change in the approval criteria for any single class of drugs. "Surely, however, the authors of the [Lasagna] report would not have FDA approve a drug on the basis of a single study in less compelling circumstances." The agency remarked that "Congress has for many years known both about cancer and FDA requirements...and has not altered the statutory requirements for approval of drugs, permitting a lesser standard for any category of drug." The requirement for multiple trials and other criteria were recently addressed in a different forum by NCI Director Samuel Broder, MD. Speaking at a meeting of the Edwards Committee's Subcommittee of Human Drugs and Biologics, Broder expressed concern that new drugs are sometimes compared too stringently to existing therapies. A written summary of his presentation states that FDA's approval criteria "should stress safety and reproducible clinical activity. They should not necessarily include a requirement for multiple trials, for demonstration of improved survival in complex Phase III trials, or for trials of a new drug used in combination compared with a standard combination regimen." While such criteria may be appropriate for cancers with "very high cure rates," Broder said it "is our impression that the latter criteria are often applied by the FDA and by its Oncologic Drugs Advisory Committee, particuarly in their consideration of new drugs proposed for treatment of a malignancy in which there is a very small but finite cure rate, such as certain forms of ovarian cancer or acute myelocytic leukemia." The "net effect is to freeze the evolution of new and practical therapy for certain cancers." FDA just approved a new treatment for acute myelocytic leukemia, Adria Labs' Idamycin (idarubicin) on Sept. 27. The history of that approval is indicative of FDA's fast-track approach. The final approval came rapidly -- within three weeks of the final submission to the advisory committee and a little over a year after the filing of the NDA ("The Pink Sheet," Oct. 8, T&G-1). The cancer institute director also suggested that in some cases therapies "technically" defined as biologics might appropriately be reviewed as drugs. For example, he said Erwinia asparanase, monoclonal antibodies, and interleukin-2 might appropriately be reviewed as chemotherapy drugs. The Cetus recombinant IL-2 product Proleukin was recently dealt a set-back when FDA's Biological Response Modifiers Committee concluded there was not sufficient efficacy data to recommend approval. Cetus sought approval of the drug for treatment of metastatic renal cell carcinoma ("The Pink Sheet" Aug. 6, p. 6). Peck's memo indicates the agency's frustration in dealing with the outside groups set up to review FDA's procedures. Noting that FDA testified at three Lasagna Committee hearings and provided "extensive" background material. Peck remarked that the agency is "somewhat surprised and perplexed" by the recommendations and the content of the Lasagna report. "Although we can always do an even better job and we're constantly seeking ways to do that, in truth, our cancer and AIDS review sections stand out among our very best."

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