PhRMA perspective on population and individual bioequivalence

The Food and Drug Administration (FDA) issued a second-draft guidance in Au gust 1999 on the subject of in vivo bioequivalence, which is based on the c oncepts of individual and population bioequivalence (IBE and PBE, respectiv ely). The intention of this guidance is to replace the 1992 guidance that r equires that in vivo bioequivalence be demonstrated by average bioequivalen ce (ABE). Although the concepts of population and individual bioequivalence are intuitively reason able, a detailed review of the literature has not u ncovered clinical evidence to justify the additional burden to the innovato r and generic companies as well as the consumer that the new guidelines wou ld impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in b ioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technica l aspects of the statistical approach are reasonably sound. However, PhRMA believes that important operational issues remain that need to be resolved before any changes to current practice are implemented, PhRMA believes that the ideals of prescribability and switchability are intuitively reasonable , but it is uncertain of the extent to which the proposed guidance can achi eve these goals. It is not clear whether the attainment of such goals is ne cessary evaluation in the of bioequivalence given the role this plays in dr ug in the development, and the lack of clinical evidence argues against a p ressing need to change current practice. PhRMA is concerned that the trade- off offered by the aggregate criteria may ultimately represent more harm th an good to the public interest. PhRMA recommends more rigorous evaluation o f methods based on two-way crossover designs before moving to methods that require more complex designs. One such method is identified herein and cont ains procedures for estimating prescribability and switchability. The possi bility of a phase-in or trial period to collect replicate crossover data to further evaluate IBE and PEE and possibly allow market access based on the se criteria as they are being evaluated has been proposed. PhRMA believes t his is unprecedented and will offer little additional information beyond th at which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the s ensitivity of various procedures to represent the data patterns as created within the simulation. Operating characteristics by which proposed criteria can be adequately judged have not yet been defined. The limitations of ABE for highly variable drugs and narrow therapeutic drugs are well appreciate d and maybe addressed by means other than a wholesale change in the current criteria.