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Executive Summary

Searle is requesting FDA to amend its proposed ANDA reg to require pharmacodynamic data, in addition to the currently required pharmacokinetic tests, for certain generic drug products. In Oct. 9 comments to the agency, Searle asked that FDA revise the proposed reg "so that it requires the generation of pharmacodynamic data for a drug product intended to deliver the active moiety to the bloodstream for systemic distribution when it has been shown that one or more pharmacodynamic parameters correlate with the drug product's therapeutic effect." Searle is among the first wave of companies commenting on FDA's proposed rule to implement Title I of the Drug Price Competition and Patent Term Restoration Act of 1984. FDA has extended its original Oct. 10 deadline for comments to Jan. 9. The reg was published in the Federal Register on July 10 ("The Pink Sheet" July 10, p. 6 and July 17, p. 17). Noting that the "proposed regulations assume that pharmacodynamic testing can be used, if at all, only as a substitute for pharmacokinetic testing," Searle said that "the proposed rule fails to recognize that pharmacodynamic testing can be invaluable when used in addition to pharmacokinetic data -- for example, to determine the significance and likely therapeutic effect of differences in pharmacokinetic profiles between drugs." A "significant difference in pharmacodynamic effects would indicate that the patient is not receiving the same therapeutic benefit from the test product as he or she would from the reference product, despite the fact that the test product satisfied the pharmacokinetic standards established by FDA," Searle said. Pharmacodynamic data, Searle continued, "may also indicate direct or indirect safety concerns regarding the action of the drug in the body. Because pharmacodynamic effects cannot always be directly predicted from pharmacokinetic data, there is a very real risk that reliance solely on pharmacokinetic data will result in miscalculation as to the therapeutic effect of the drug." Additional generic drug testing requirements were also suggested by FDA reviewer Stuart Zimmerman. The reviewer, who works in the Cardio-Renal Drug Products Division, recommended a number of procedures for assessing potential hazards from impurities and excipients. Zimmerman similarly discussed the issue of testing for safety of excipients in 1985 comments on a guideline for NDA submissions. Regarding new product impurities, the FDAer pointed out that the safety profile of a generic drug may differ from the brandname product because of different impurities in the drug product. There is "a potential for some alternate impurity to be present which is suspect for adverse interactive effects in the ANDA product," Zimmerman said. As an illustration of the safety problems that can arise, the FDA reviewer cited the serious adverse reactions (Lyell Syndrome) to Warner-Lambert's NSAID isoxicam in 1985. The cases are thought to have resulted from trace elements of a manufacturing byproduct that were within the manufacturing quality control specifications. In view of the Warner-Lambert case, Zimmerman said, "it is not possible to always make the assumption that an equivalency of analytical methodology between a secondary ANDA drug manufacturer and the initially approved NDA manufacturer is the recommended choice. In certain instances, it may be necessary to develop more highly sensitive analytical testing methods that will permit a much closer monitoring for a potential impurity than was available for the originator's NDA quality control standards." Zimmerman suggested that the regs be amended to include requirements for the classification of potential impurities. "The sponsor/applicant should seek to determine, to what extent it is analytically feasible, which impurities are known and which are not known in terms of their chemical composition. Additionally, each impurity should be classified as soon as possible regarding its source in terms of either being derived from the synthesis or coming from the degradation of the active ingredient as a result of stability stressing." It would "also be beneficial," Zimmerman said, "to require that information be submitted that relates to the rate of degradation of certain potential impurities that are known to increase their levels with time. If this is stated, then this would serve to justify that tighter monitoring controls would be necessary for types of impurities known to continually increase. These are the ones [for which] FDA must assure that there exist good controls for monitoring." Zimmerman also recommended a number of requirements for detecting impurity differences that might not be seen if the ANDA sponsor uses different test methodologies or reporting standards than the innovator firm. For example, he suggested that ANDA applicants report exact levels of impurities, instead of stating that they are within specifications, so that changes in levels during stability testing can be better identified. Abbott Labs focused on the definition of products entitled to five years exclusivity under the law. The proposed reg would grant exclusivity to a new molecular entity, which is defined as "a drug that contains no active moiety that has been approved by FDA." Noting that the ANDA/patent restoration legislation used the term "active ingredient," Abbott urged that that term be used in the regs and that it be defined as the "active ingredient found in the finished dosage form prior to the administration of product to the patient, rather than any resultant form the drug may take following administration." FDA's proposed definition "is improper," Abbott maintained, "because it is wholly unsupported by the statutory text and legislative history, and because it completely alters the plain meaning of the provisions." The definition of a new drug has been a litigated issue for both exclusivity and patent extension provisions of the Waxman/Hatch law. Abbott is currently appealing a federal court's ruling that its anticonvulsant drug Depakote is not a new drug entitled to exclusivity because it is the salt of an already approved drug product. In a separate case, however, a federal court ruled that the active "ingredient" and not "moiety" should be used in determining patent extension. That ruling was made with regard to Glaxo's Ceftin ("The Pink Sheet" Feb. 27, p. 8) and is being appealed by the Patent and Trademark Office. Among other comments on the ANDA proposal, Lederle Labs objected to FDA's proposal that ANDA applicants must make certifications to FDA on any of the innovator's patents they are "aware of." The requirement "is in conflict with statutory language that requires certification only with respect to listed patents," Lederle said. In response to FDA's request for comment on whether ANDA suitability petitions should remain in the public domain, Hercon Labs said the petitions should be kept confidential until either formally approved or denied by the agency. The firm argued that public access to pending petitions allows innovator firms to beat generic companies to market by submitting NDA supplements.

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