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Executive Summary

FDA is several months away from publishing a rule on the Competitiveness Council's proposal to permit institutional review boards (IRBs) to review requests for IND exemptions. When FDA and the council announced their reforms on Nov. 13, they said proposals, such as the one permitting IND sponsors to seek IRB approvals to initiate Phase I studies, would be effective "immediately" ("The Pink Sheet" Nov. 18, p. 9). However, many council reforms, including the IRB recommendation, will require notice-and-comment rulemaking, which at best can take many months. The agency has established a series of task forces to determine how the various proposals can be implemented. Associate Commissioner for Health Affairs Stuart Nightingale, MD, is heading a newly-established FDA group to oversee implementation of the IRB reform. The proposal to accelerate NDA reviews will become effective much more quickly. An internal FDA group began looking at the idea in January 1991 and a draft proposal, currently at the Office of Management & Budget, has been circulating in Washington since late summer. FDA's task force to implement this reform is headed by Associate Commissioner for Policy Coordination William Hubbard and also includes Center for Drug Evaluation & Research Deputy Director for Medical Affairs Bruce Burlington, MD; Center for Biologic Evaluation and Research Deputy Director Janet Woodcock, MD; Office of Drug Evaluation I Director Robert Temple, MD; and Office of Drug Evaluation II Director James Bilstad, MD. Another proposal that the council based on an ongoing FDA effort and that is likely, therefore, to be among the first proposals to become effective involves softening FDA's posture against the use of some drugs for unlabeled indications. Hubbard and Deputy Commissioner for Policy Michael Taylor will oversee implementation of this policy, which will not require rulemaking and could become effective within a few weeks. The task force's first priority is to make drugs more available for use in treating cancer. Taylor and Nightingale also will be responsible for putting into effect the council's proposal for international harmonization (see related brief). Deputy Commissioner for Operations Mary Jo Veverka is responsible for reforms involving general management of FDA operations and computerization of the agency. At a Dec. 13 briefing on Capitol Hill, Hubbard, Burlington and Office of Legislative Affairs Acting Director Kay Holcombe met with the staffs of Reps. Weiss (D-N.Y.) and Waxman (D-Calif.) and Sen. Kennedy (D-Mass.) to discuss how the council's proposals were developed and FDA's plans for implementing them. Waxman has been pursuing Lilly about that company's alleged influence on the White House and the Competitiveness Council ("The Pink Sheet" Dec. 9, p. 4). Lilly replied Nov. 22 that it discussed "two issues," with the council, "neither of which happened to involve proposed regulations under review." One issue involved reform of the drug approval process, and the other involved civil justice reform, Lilly explained. Lilly said that "each contact was in response to an invitation from the council to react to ideas being considered at the staff level." The company asserted that "it has every right and responsibility to bring its views on the potential impact of legislative and regulatory proposals to the attention of those in government." Lilly also has gotten involved in an early flap over an attempt to make use of the proposed changes. In a Dec. 11 letter, Rep. Weiss questioned FDA about the council's proposal to permit IRB review of INDs in light of an attempt by Lilly to exploit the proposal. The New York Democrat asked Commissioner Kessler whether the review of an IND exemption request by an institutional review board would jeopardize public health, and, "if so, why did FDA ever lend its support to this" council proposal "in the first place?" Days after the Nov. 13 FDA/council announcement of their joint proposals for speeding the drug review process, Lilly Government Relations Officer Irene Brandt called FDA's Hubbard to ask whether the firm could initiate a Phase I study of an experimental drug for Alzheimer's disease based on an IND approval from an IRB but not from FDA. The drug has not been identified publicly. Lilly has had two M-1 agonists in preclinicals under study for use in treating Alzheimer's disease, and the company is collaborating with Athena Neurosciences in an R&D effort focused on Alzheimer's disease. In his memorandum of the conversation, Hubbard said he told Brandt that FDA "in the coming weeks" would publish a "proposal seeking comment on whether some academic Phase I research should be permitted with only IRB approval." However, he also noted that previous proposals "had received negative responses from IRBs (who have said they don't have the capability to adequately review INDs for safety and don't want the responsibility for approving such testing)." Despite Hubbard's answer, Lilly Research Labs Group VP Leigh Thompson, MD/PhD, informed FDA Neuropharmacological Drug Products Division Director Paul Leber, MD, in a Nov. 21 letter that the company had filed an IND for the Alzheimer's drug with the Indiana University Institutional Review Committee. "If acceptable to the committee, we would anticipate initiating the proposed study at the Lilly Laboratory for Clinical Research sometime after the first of the year," Thompson wrote. He explained that the lead time would allow FDA "to establish procedures for implementation of" the Competitiveness Council proposal for IRB reviews of IND exemption requests. Leber told Thompson on Dec. 3 that FDA cannot permit IRB-only reviews of INDs without notice-and-comment rulemaking procedures. According to Leber's memo of the conversation, Thompson pointed out that when the council announced its proposals, it said the IRB reform would become effective "immediately." Leber said he responded that "the council had no authority to issue regulations," and Thompson "implied that he had understood all this and was merely 'tweaking' the system." Leber indicated that Thompson's letter appeared to be "a notice of an intent to violate existing law." A Lilly spokesperson said that although the firm had submitted an IND to Indiana, "no one has started on the studies" and the company is withdrawing the submission. Lilly acknowledged that Leber was correct in inferring that the company's intention was a "tweaking" of the system. "We tested the system, and the system responded," the Lilly spokesperson said. In a Dec. 11 statement, Weiss declared that the IRB proposal "is dangerous public health policy" because "IRBs were not established to conduct" scientific reviews of IND exemption requests. IRBs cannot "evaluate the risks of unapproved new drugs" and, therefore, the proposal "could expose innocent volunteers to hazardous drugs without the benefit of expert scientific review," Weiss maintained. Furthermore, the congressman said, because "most applications to conduct human drug trials are automatically approved if FDA fails to act within 30 days," the proposal is a "solution without a problem." Weiss decried "FDA's failure to aggressively respond to Lilly's action" because it "may open the floodgates to unregulated and potentially dangerous human drugs trials and will do nothing to speed the drug approval process." In his letter to Kessler, Weiss asked whether FDA has "formally" told Lilly its intended action was contrary to existing law. The congressman also asked whether FDA has "any other concerns it has not made public about the risk to public health, or the legality, of the other reforms" proposed by the Competitiveness Council. Weiss asked FDA to respond by Dec. 18.

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