ANDA REG PROVISION FOR ACTIVE METABOLITE BIOEQUIVALENCE TESTING IS "ARBITRARY" HURDLE FOR GENERICS, NAPM CONTENDS; INACTIVE TESTING OPPOSED

FDA's proposed requirement for bioequivalence testing of active metabolites as well as active ingredients is being attacked by the National Association of Pharmaceutical Manufacturers as an "arbitrary" and "unnecessary" roadblock to ANDA applications. In recently submitted comments on the proposed regs, NAPM suggested that in lieu of a broad active metabolite testing requirement, FDA "consider the question of metabolite bioequivalence only as to such metabolites as are clearly identifiable, definitively measurable, and which have a significant therapeutic effect." The association of generic firms based its request on an evaluation of the metabolite issue by University of Tennessee Associate Dean for Research and Research Training Marvin Meyer, PhD. Meyer concluded that "there may be occasions when the measurement of an 'active' metabolite is an appropriate requirement for a bioequivalence study, [but] this should be the exception rather than the rule." The Tennessee professor maintained that "unless there is substantial evidence to indicate the presence of nonlinear kinetics for the disposition of a drug,...the measurement of metabolites [does not] provide any data for the assessment of bioequivalence that cannot be determined by the measurement of only the parent drug." The policy for active metabolite testing "may make it difficult, if not impossible, for a generic product to be approved," Meyer contended. Metabolites "may not be readily available, or be difficult to synthesize," Meyer stated. "Further, assay methods may be more difficult to develop, particularly if the metabolite is rapidly eliminated; is present at low concentrations; or is relatively unstable." Meyer observed that the proposed policy could "lead to considerable controversy regarding guidances for individual drugs." It would "appear likely," he said, "that some innovator firms will present limited data to the agency, suggesting that one or more metabolites have some activity (perhaps from in vitro or animal studies), and then expect the proposed policy to be implemented by the agency based on such data." NAPM has similar practical concerns about FDA's proposed requirement for comparing inactive ingredients of a generic product to the innovator drug. Those comparisons are required to demonstrate that any differences do not affect a safety of the product. Noting the difficulty in obtaining formulation information on the innovator product, NAPM said it believes "FDA should not require this information." However, the association suggested that if FDA does require the information, then "the innovator's quantitative and qualitative formulas [should] be made available upon request so that the comparisons could be made." In other recent comments on the July 1989 proposed reg, both Parke-Davis and Mylan also opposed the inactive ingredient comparison. Parke-Davis concurred with the NAPM position that inactive ingredients used in an innovator product are often confidential and not available to generic companies. The firm also argued that additional information on differing inactive ingredients is not provided for under the ANDA/Patent Restoration (Waxman-Hatch) law, and "the statute specifically prohibits FDA from requiring submission of information beyond that listed in" the law. One of the most contentious provisions of the ANDA reg is FDA's proposal to kick off ANDA exclusivity at the date of a final court ruling. The brandname industry generally supports the provision, while some in the generic industry prefer starting exclusivity at the date of the initial court ruling. Under the law, the first ANDA applicant to challenge successfully the patent of an innovator product is entitled to 180 days of exclusivity, during which other ANDAs for the product may not be marketed. The exclusivity begins on the date of a court ruling or the initiation of marketing, whichever is earlier. FDA's proposal would define the court ruling as "the date of final decision of a court from which no appeal can or has been taken or the date of a settlement order or consent decree signed by a federal judge, which enters final judgment and includes a finding that the patent is invalid or not infringed." NAPM is concerned that using the date of a final court ruling would delay other generic versions from getting to the market and create a regulatory scheme vulnerable to collusion. The threat of collusion may be a particularly potent argument given the continuing revelations about corrupt practices in the generic review operations between sponsors and reviewers. "Such a position could easily lead to collusion between the victorious generic and the patent holder." Mylan also supported use of the lower court ruling in its comments, citing the potential for lengthy delays before any generics come to market while the appeals process continues. "NAPM does not believe that interpretation of the statute should be skewed in favor of one [applicant], who might wish to delay its market entry because of fear of having its district court decision reversed, against the public good and that of other generics awaiting market entry," the association said. NAPM's position on the 180-day exclusivity, however, is not embraced by the entire generic industry. The Generic Pharmaceutical Industry Association, in earlier comments on the regs, did not oppose FDA's interpretation. In comments submitted in January, GPIA requested that FDA clarify the reg to make clear that sponsors have the choice of putting off marketing (and the start of exclusivity) to wait final resolution of the litigation or beginning marketing after the lower court ruling. Among April comments form the brandname drug industry, the Pharmaceutical Manufacturers Association, ICI, and Sandoz all told FDA they were in favor of using the final court (i.e., appeal or higher court) ruling for the start of ANDA exclusivily. Use of the later court ruling date would have the obvious benefit of delaying the first as well as subsequent generic competitors. NAPM also objects to a number of provisions in the proposed reg that appear to limit generic companies' procedural rights in comparison to innovator companies. For example, the proposed reg would only give ANDA holders rights to a full evidentiary hearing if FDA proposed to withdraw their ANDA, as opposed to the innovator's NDA. That provision could affect generic companies in a situation such as the DESI hearing for dipyridamole. In that case, Boehringer Ingelheim decided not to defend its angina indication for Persantine after it obtained exclusivity for a new indication. NAPM's comments address a similar concern -- an innovator not defending its NDA because it "has another version of the drug waiting in the wings." NAPM "does not agree that an ANDA holder has no independent right to a hearing when the agency proposes to withdraw a listed drug," the association said. "FDA's position, that in an evidentiary hearino(nor the benefit of the holder of the listed drug, the ANDA holder is limited to submitting comments on the notice of opportunity for hearing and to participation as a 'nonparty,' is a denial of due process and ignores the substantial independent property right of the ANDA holder." Other notable areas of concern to the association include FDA's treatment of 505 (b)(2) applications (what used to be called "paper NDAs") and the agency's proposed requirement that ANDA applicants conduct a patent search beyond the patents listed with FDA. NAPM views the patent search requirement as "an untenable burden upon a generic applicant" that "goes beyond the law." One concern relating to 505 (b)(2) applications is FDA's proposal to treat the applications as ANDAs if they are for a listed drug. In the preamble to the proposed reg, FDA said that it is also considering either treating 505 (b)(2) applications for modified versions of listed drugs as ANDA suitability petitions or returning 505 (b)(2) applications to sponsors with a request for ANDA suitability petitions. The agency specifically requested comment on the proposal. NAPM pointed out that generic applicants might be disadvantaged if 505 (b)(2) were treated as ANDAs because the 180-day generic exclusivity only applies to ANDAs, and therefore the patent certification requirements are different for the two types of applications. The association objects to the ANDA suitability petition proposal "for the same reasons."