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Executive Summary

Advanced annual scheduling of FDA advisory committee meetings and agendas is recommended in a report released Dec. 8 by the Institute of Medicine's Committee To Study the Use of Advisory Committees by the FDA. Scheduling of advisory committee meetings "one or even two years in advance," the Institute of Medicine committee report states, would "[impose] greater discipline on the internal product evaluation process, and [make] it easier to schedule the time, and thus ensure the participation, of busy committee members." The report notes that "meetings scheduled in this way would require the following associated deadlines: agency (and presumably sponsor) agreement to review an application at a scheduled meeting; timely sponsor submission of all data to go to the advisory committee; timely completion by the agency of its review, and on-schedule distribution of material to the advisory committee members." The IoM committee maintains that current advisory committee meeting scheduling is affected by the availability of members, FDA review times, and a "deference to a sponsor's desire to submit data up to the last minute." The IoM committee recommended that FDA model its system of scheduling advisory committees on the National Institutes of Health's research grant proposal program: grant proposal submissions are required by a specified date to ensure review at a particular time. "Included in this scheme is a decision rule that late applications are not reviewed until the next cycle," the report states. Industry members "responded favorably" to the advanced scheduling proposal, the report notes, as long as committees are to meet at least three times per year. FDA, however, expressed concern that it would be "very difficult" to set a certain date six to 12 months in advance for the completion of an application review, the report states. Overall, the IoM committee found that the existing advisory committee system is "fundamentally sound, has served the agency well and does not need wholesale reorganization." However, the IoM committee said it is recommending a number of administrative and procedural changes designed "to improve the performance and usefulness of the advisory committee system, to strengthen its management, and to increase its accountability" (see chart, p. 22). The IoM committee was formed at the request of FDA Commissioner Kessler in 1991 to consider how FDA could make the best use of advisory committees to help speed up the drug approval process, a suggestion made in a report from the Lasagna Committee ("The Pink Sheet" March 4, 1991, p. 5). At the IoM committee's first meeting in December 1991, the commissioner added an emphasis on conflict-of-interest issues to the scope of the committee's mandate. That request grew out of several conflict-of-interest problems surrounding a series of high-profile advisory committee meetings that year. The committee was chaired by Laurence Earley, MD, University of Pennsylvania Hospital, and included: two current FDA advisory committee members; several former FDAers; former NIH director James Wyngaarden, MD, Duke University; and former Health Care Financing Administration chief Carolyne Davis, PhD, who is now with Ernst & Young. The committee also included two former high- ranking FDAers now with industry: Boehringer Mannheim Pharmaceuticals President Richard Crout and American Cyanamid Medical Research Division President Harry Meyer. The IoM committee received advice from, among others, an Industry Liaison Panel, chaired by Marion Finkel, MD, Sandoz' regulatory affairs VP and a former head of FDA's new drug evaluation office. The committee embraced a number of recommendations made by the industry group, including maintenance of a pool of qualified candidates for nomination, custom-tailoring (although sparingly) of committees and an emphasis on FDA neutrality during advisory committee meetings. The IoM group also was given extensive guidance by former FDA Deputy Commissioner and Hill & Knowlton exec John Norris, who emphasized advisory committee independence and greater involvement of committee chairs in scheduling, agenda setting and formulation of questions ("The Pink Sheet" June 15, p. 5). The IoM committee recommendations do not address the issue of greater use of advisory committees by FDA in the review process as has been suggested by other groups. Rather, the recommendations focus on standardizing advisory committee procedures and guidelines across centers, ensuring independence of the committees and establishing conflict-of-interest guidelines. Echoing calls by the Lasagna Committee, the Industry Liaison Panel and Norris for centralized high-level advisory committee control, the IoM committee recommended the appointment of an official at the commissioner-office level, possibly in the Office of the Deputy Commissioner for Operations. "A need exists for clear policy and management guidance to the FDA advisory committee system from the commissioner regarding the role, importance and general operations of advisory committees in the work of the agency," the report finds. With regard to conflict of interest, the committee said it concentrated on the legal and administrative aspects of the issue rather than broader concerns. The committee recommendations in this area urge the codification of criteria for granting waivers and streamlining the process for requesting waivers. The report details some inconsistencies in FDA policy regarding conflict of interest that have led to problems at advisory committee meetings over the last two years. The report refers to the Therakos' UVAR photopheresis treatment for scleroderma that failed to pass muster at the Arthritis Drugs Advisory Committee meeting in December 1990. Therakos charged that an FDA consultant at the meeting had an unrecognized conflict of interest in that he was conducting a study with a competing product, Merck's Cuprimine D-penicillamine. "The allegation precipitated an investigation by the [HHS] Office of Inspector General into possible violations of the law," the report notes. Complaints by the company led to a hearing before Rep. Dingell's (D-Mich.) House Energy & Commerce/Oversight Subcommittee in February ("The Pink Sheet" Feb. 10, p. 6). The report notes that there also have been a number of eleventh-hour exclusions or waivers obtained for committee members resulting from confusion or oversight by FDA staff. The report cites a Blood Products Advisory Committee member who protested "vigorously to the commissioner because of his last- minute exclusion from discussion of Baxter and Miles' recombinant Factor VIII products because he had served as a principal investigator of a Baxter study." The report also describes a frantic effort to obtain waivers for members of the Biological Response Modifiers Advisory Committee after the FDA staff's "late discovery of a business relationship between Cetus and Hoffmann-La Roche" just prior to its January 1992 meeting on Chiron/Cetus' interleukin-2 (Proleukin). Considerable attention is paid in the report to potential biases brought by FDA to the advisory committee meetings. The report emphasizes that the agency's reviews of sponsors applications "should reflect a critical but fair evaluation of the data" and FDA staff should "avoid the appearance of exerting undue influence over the committee." The IoM committee urges FDA to accept input from [advisory] committee members in the formulation of questions to the committee and allow the committee to make changes in the questions during the meeting. In another attempt to eliminate bias, the report recommends that "the division director should not sit next to the committee chair." Addressing compensation of advisory committee members, the IoM committee pointed out that FDA's $150 per day rate appears to be inadequate. The report recommends that HHS review this situation. Referring to the recently-passed user fee legislation, the report suggests that "it may be appropriate for the FDA to review the compensations of advisory committee members in relation to their contribution to product evaluation." IoM COMMITTEE RECOMMENDATIONS [Excerpted from the Institute of Medicine report on FDA advisory committees released Dec. 8.] "A high-level official in the Office of the Commissioner [should] be assigned primary responsibility for developing, disseminating, and enforcing administrative policy and management guidance to the advisory committees of the three centers." FDA should "develop uniform management guidelines for advisory committees across all three centers and...eliminate unnecessary differences in the management of committees." FDA should "adopt a policy of annual advance scheduling of advisory committee meetings and of meeting agendas, with review cycles having deadlines for sponsor submission of data, FDA completion of reviews and advance distribution of materials to committee members." FDA should "adopt and follow a strict schedule for advance distribution of review should be delivered to members at least three weeks in advance of a meeting...the specific questions for the meeting should be delivered no later than 10 days before a meeting." FDA should "provide sponsors of applications with the same materials that it sends to advisory committees. Questions should be sent to committees and sponsors on the same schedule." "In the formulation of meeting agendas and of questions, the advisory committee chair [should] be routinely consulted as a standard procedure...committee members [should] be routinely informed that they may modify FDA-prepared questions based on their review of the data and introduce questions of their own before or at an advisory committee meeting." "Questions asked of advisory committees [should] be fair and objective in tone and avoid language that might be considered biased or inflammatory." "[The IoM committee] commends CDER for [the clarification of the range of issues that it might bring to an advisory committee] and recommends that CBER and CDRH develop similar statements." "Each center [should] schedule an annual review by each advisory committee of the major NDAs and INDs (or their equivalents) in the pipeline of the respective reviewing division." FDA should "develop a standard format for sponsors to summarize their application briefly yet comprehensively, as well as a comparable format for a summary of the agency's review." "The three centers [should] consider the routine assignment of primary reviewers for each application." FDA should "adopt an agency-wide recruitment policy and develop a more systematic approach to seeking nominations on a continuing basis for potential advisory committee membership. ...Each center should develop and periodically update a pool of qualified candidates, rather than simply seek nominations to fill vacancies." FDA [should] seek technically qualified nominees from consumer organizations and other interested organizations to serve as voting members..." "FDA and [the Office of Special Counsel for Ethics should] begin immediately the process of codifying the criteria for granting 208 (b)(3) waivers, especially with respect to institutional conflicts, research grants and contracts, and competing products and technologies." FDA should "streamline its policies and procedures for requesting and processing waivers." FDA should "develop an orientation program for its advisory committee members and...this program [should] include explicit attention to conflict of interest." "Office of Government Ethics [should] develop and issue government-wide 208(b)(3) waiver rules as soon as possible." "Remove from OGE the responsibility for case-by-case review of advisory committee member waiver requests...such case-by-case review [should] be delegated to the departments." FDA should "develop criteria and procedures for identifying potential intellectual bias." "The commissioner, with the [HHS Secretary], [should] review the adequacy of compensation for Public Health Service advisory committee members...and take appropriate steps to maintain daily rates in relation to increases in the federal salary schedule."

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