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Executive Summary

FDA's adverse drug reaction (ADR) regs should be modified to require reporting that facilitates picking up possibly important instances of therapeutic failures, FDA's Bioequivalence Task Force recommended in a report released Feb. 11. The report caps a 16-month review of bioequivalence issues raised at a public hearing held Sept. 29-Oct. 1, 1986. "The task force recommends that detailed plans for identifying signals or clusters of possible important instances of product failure from the ADR reporting system be developed," the report states. "The current ADR regulations [should] be modified to require that reports be submitted to the agency to aid in accomplishing these recommendations." The report suggests that the agency develop specific plans for how possibly important reports will be investigated, including the designation of responsibilities to individual agency departments. "These plans should indicate how and when these signals will be communicated to the appropriate agency components," the report states. "The task force recommends that a policy be developed to outline how, when, and by whom signals should be investigated, the role of laboratory testing, requiring repeat bioequivalence testing, field work to investigate individual cases, and the responsibilities of the several offices involved." The report was issued by the task force after considering the proceedings of FDA's bioequivalence hearing and the recommendations of two consultants asked to review issues raised at the hearing. The report notes that "a number of speakers at the hearing expressed doubt about whether the current adverse reaction reporting systems were likely to be effective in detecting therapeutic failures due to bioequivalence." Some speakers, for example, pointed out that FDA's ADR reporting form (1639) does not ask for identification of the manufacturer of a generic product. The report explains that a "single instance of therapeutic failure is . . . almost impossible to interpret unless there is a deliberate attempt to study it further with blood level data or an on-off-on-off procedure." In general, the report continues, "we believe that if a product fails, it will lead to more than one report, so we are not primarily concerned with one idiosyncratic report. However, in order to spot as early as possible any widespread problems such as problems with an entire lot, the agency will, in some cases, look at single, isolated, well documented cases. Additionally, the agency recognizes that important knowledge may be gained from the study of an isolated case." FDA has already begun to look at revising the ADR reporting system to detect therapeutic failures. Last November, FDA Office of Epidemiology and Biostatistics Director Gerald Faich, MD, told a conference that the agency was considering revising the ADR system to require 15-day reports for incidences of therapeutic failures ("The Pink Sheet" Nov. 9, p. 6). The agency also has established a committee to look into instances of therapeutic inequivalence. The committee, called the Therapeutic Inequivalence Action Coordinating Committee, was established in the Fall. The task force report emphasizes that "FDA should fully investigate possible inequivalence only when there is good evidence of a problem, and not on unsupported anecdotes." The agency notes that there have been "some efforts recently to stimulate reporting to FDA's voluntary ADR system of adverse reactions to generic products." Stimulating reports, FDA commented, will cause a "distortion of [the ADR] system. Thus, FDA has opposed and will continue to oppose, any attempts to solicit or otherwise stimulate adverse reaction reports for any product." The task force report recommends that the agency initiate 14 "action items". In general, the task force concluded that FDA's current system for evaluating drug bioequivalence is scientifically sound and does not require major adjustments. However, the report identifies a number of areas where FDA could initiate studies to evaluate scientific questions and where the agency should institute procedures to make bioequivalence information more widely available and better understood. Among recommendations for improving information on bioequivalence, for example, the task force suggests that FDA revise the Orange Book to differentiate those products approved on the basis of in vivo bioequivalence data from those products receiving approval based on in vitro data. Currently, all products deemed to be interchangeable carry an "AB" rating regardless of the type of bioequivalence study reviewed. The report recommends that only those products approved on the basis of in vivo data carry the AB rating. Products approved on the basis of in vitro data would still be listed as interchangeable but would be identified with a different rating code. The task force also recommends that the "Orange Book be more widely advertised to pharmacists" and that the agency explore "efforts to decrease the cost." Lowering the price, the report suggests, "could be accomplished by publishing an abbreviated version of the list alone, by selling the Orange Book without the monthly supplements, or by enlisting the assistance of a private organization to make the book available at a lower cost." At the hearing a number of participants commented that the Orange Book is expensive for pharmacists and that many pharmacists were not even aware that the guidance is available. In recent years FDA has expanded the amount of information in the Orange Book -- including information such as patent status, ANDA suitability petitions, and exclusivity data -- and lowered the annual subscription price of the book from $103 to $86. Also in the information area, the task force recommends that the agency "publish procedures under which drugs or classes of drugs would be added to or deleted from the list of drugs subject to either more strict or less strict criteria than the general rule." In addition, FDA should "publish full information about the bioequivalence evaluation procedures and decisional criteria, either in the form of a formal guideline, or as a supplement or companion piece to the Orange Book," the report states. Participants at the hearing requested that the agency allow outside recommendations, via the notice and comment rulemaking procedures, to be considered as FDA sets criteria for evaluating generic drugs. The task force, the report states, "believes the agency can make clearer the decisional criteria it employs to determine bioequivalence," but "does not agree . . . that notice and comment rulemaking is the appropriate mechanism for disseminating information about the decisional criteria." The report explains that notice and comment procedures are slow and would not allow for the judgment calls inherent in bioequivalence decisions. As an alternative, the "agency could publish a formal guideline specifying the decisional criteria used to evaluate bioequivalence studies," the report states. "This guideline would be subject to public comment and would commit the agency to follow the guideline." The task force recommends that three areas of study should be conducted by the Biometrics Division: product variability, the treatment of outliers, and alternative study designs to address variability within subjects. The report notes that several speakers at the hearing addressed the issue of whether product to product variability is comparable to lot to lot variability. "Based on limited data available to FDA," the report states, "the product to product variability in blood levels among bioequivalent drug products on average does not appear to be significantly greater than variability seen between different lots of the same product of a single manufacturer." While the "task force believes that current requirements are adequate to assure the quality and uniformity of all drug products, . . . the variability among drug products deserves further study," the report states. "The task force recommends that the Division of Biometrics gather data and develop statistical methodology to consider whether a problem exists regarding product variability. Appropriate action will be taken, should a problem be discovered." According to officials at FDA, the Biometrics division, which has a staff of approximately 60, will be aided in its review by agency staffers from other divisions. Over the next month, the agency plans to set up schedules and approaches, through an Action Plan-like milestone framework, for implementing the task force's 14 recommendations. FDA's bioequivalence report is available from the agency's Dockets Management Branch, Room 4-62, 5600 Fishers Lane, Rockville, Md. 20857.

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