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Executive Summary

GENERIC DRUG REFORMULATIONS SHOULD BE COMPARED TO INNOVATOR product so that a "single-reference standard" is established, the Pharmaceutical Manufacturers Association said in Oct. 10 comments on FDA's proposed procedures for tracking NDA and ANDA reformulations of immediate-release products. Under the policy, announced in an April 12 Federal Register notice, the agency would compare the bioavailability of a new formulation to the bioavailability of the last formulation for which an in vivo bioequivalence study was done ("The Pink Sheet" April 17, T&G-15). "Just as approval of a new version of a drug product must be based on a comparison to the currently marketed product with an approved NDA, PMA believes that the originator's marketed product would best serve as a continually available reference standard," the association said. "Only with such a single-reference standard may prescribing physicians be assured that multisource products are not varying by greater than the plus or minus 20% variation allowed in comparison to the innovator's product." The association pointed out that comparisons of reformulated products to the last product that had a bioequivalence study "may not be feasible because that formulation may no longer be available, may be out of date, or may not be able to be prepared for reasons beyond the control of the manufacturer." Burroughs Wellcome and Sandoz also submitted comments suggesting that the innovator drug be used as the reference for determining the bioavailability of a reformulated product. PMA suggested that FDA's determination of whether a change in formulation is minor or major, and subsequently, whether a bioequivalence study is necessary, should be done on a case-by-case basis. "The definition of what constitutes a major or minor formulation change should be product-specific, with each company submitting an NDA or ANDA supplement providing the necessary justification for its classification." Kleinfeld, Kaplan and Becker, a Washington, D.C.-based law firm that frequently represents generic manufacturers, also submitted comments on FDA's reformulation policy. The law firm recommended that FDA clarify what it means by minor and major changes and what data is required. The firm suggested that FDA define "'major' changes as "those for which FDA will always require an in vivo bioequivalence study and identify all of these changes. An example of a major change might be a material change in one or more components of a drug." The same should be done for "minor" changes, "those for which FDA will never require an in vivo bioequivalence study," the firm said, citing the example of a change in the order of dry ingredients added during blending. The law firm suggested defining "moderate changes" as those that do not need a bioequivalence study "if other evidence is sufficient to establish that the change is not expected to affect the bioavailability of the drug." In support of moderate changes, Kleinfeld et al., added, FDA should require a summary of a bioequivalence study, a summary of all other supportive data, a description of the purpose of the change, and an analysis of the risk that the product's bioavailability will be altered by the change.

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