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FDA GENERICS OFFICE EXPLORING "POPULATION BIOEQUIVALENCE"

Executive Summary

FDA GENERICS OFFICE EXPLORING "POPULATION BIOEQUIVALENCE" and other bioequivalence statistical issues for discussion at a future meeting of the Generic Drugs Advisory Committee, FDA Office of Generic Drugs Director Roger Williams, MD, told a joint Parenteral Drug Association/FDA conference in Rockville, Md. on Sept. 21. Population bioequivalence compares the patient-to-patient variability of plasma concentrations of both the innovator formulation and the generic version of a drug, Williams said. The current standard is to compare just the average of the mean concentrations of both forms. A "driving force" behind the exploration of population bioequivalence is a desire "to develop an easier, more reliable way" of assessing bioequivalence "for drugs with high inter- patient variability," Williams said. The Office of Generic Drugs (OGD) is also looking at "individual bioequivalence," where the goal is to "evaluate how each person responds" to both the innovator and generic formulation. The evaluation of population bioequivalence methods is part of a more general statistical review similar to one that resulted in a July 1 guidance on statistical standards, Williams indicated. That guidance sprang from discussions of problems with the current standard that were brought before the Generic Drugs Advisory Committee in September 1991 ("The Pink Sheet" July 6, T&G-5). "The office has embarked again on another effort to look at statistical issues," Williams said. A "core committee" of Center for Drug Evaluation and Research personnel and outside consultants will meet in October to prepare an information package for an early 1993 advisory committee meeting, Williams said. The FDAer emphasized that OGD is still satisfied with the current statistical approach. Williams noted that the advisory committee meeting "will not necessarily lead to any changes" in testing requirements. Another area of concern for OGD involves in vitro dissolution testing, Williams said. He displayed a dissolution curve for a generic version of tolmetin compared to the reference drug (McNeil's Tolectin). While both products met the USP standard of at least 85% dissolution at 30 minutes, the two curves were dissimilar. At 10 minutes, for example, the brandname product was 88.2% dissolved while the generic was only 68.8% dissolved. "The reality is that the [generic] drug is not equivalent," Williams commented. However, he noted, the Office is grateful to receive such data from industry, because there is "a strong tendency for the Office not to receive a data set like this." Remarking that the concept that in vitro testing is a surrogate for in vivo bioequivalence "permeates the way we do business," Williams said at this point OGD is only examining the question. "We'll keep you posted." The generics office is examining several other scientific issues, Williams noted. The agency is continuing to seek methods for determining bioequivalence of nonsystemically absorbed drugs such as albuterol metered-dose inhalers, topical corticosteroids, cholestyramine, sucralfate and tretinoin. Ongoing chemistry/manufacturing issues include how to handle impurities and excipients as well as a continuing review of scale-up requirements.
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