PhRMA Perspective on Population and Individual Bioequivalence

Abstract

The Food and Drug Administration (FDA) issued a second-draft guidance in August 1999 on the subject of in vivo bioequivalence, which is based on the concepts of individual and population bioequivalence (IBE and PBE, respectively). The intention of this guidance is to replace the 1992 guidance that requires that in vivo bioequivalence be demonstrated by average bioequivalence (ABE). Although the concepts of population and individual bioequivalence are intuitively reasonable, a detailed review of the literature has not uncovered clinical evidence to justify the additional burden to the innovator and generic companies as well as the consumer that the new guidelines would impose. The criteria for bioequivalence described in the draft guidance employ aggregate statistics that combine information about differences in bioavailability between formulation means and differences in bioavailability variation of formulations between and within subjects. The purely technical 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 achieve these goals. It is not clear whether the attainment of such goals is necessary in the evaluation of bioequivalence given the role this plays in drug development, and the lack of clinical evidence argues against a pressing need to change current practice. PhRMA is concerned that the trade-off offered by the aggregate criteria may ultimately represent more harm than good to the public interest. PhRMA recommends more rigorous evaluation of methods based on two-way crossover designs before moving to methods that require more complex designs. One such method is identified herein and contains procedures for estimating prescribability and switchability. The possibility of a phase-in or trial period to collect replicate crossover data to further evaluate IBE and PBE and possibly allow market access based on these criteria as they are being evaluated has been proposed. PhRMA believes this is unprecedented and will offer little additional information beyond that which can be obtained by simulation or has already been collected by the FDA. Simulation studies have the advantage of allowing evaluation of the sensitivity 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 appreciated and may be addressed by means other than a wholesale change in the current criteria.

Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination

“…It is then accepted that, when used as alternatives, the products ⁄ routes can be expected to provide sufficiently similar efficacy and safety to guarantee therapeutic equivalence. The differences between and procedures required to establish average, individual and population bioequivalences are not considered here (see reviews by Barrett et al, 2000 andGould, 2000), as all regulatory authorities require that data satisfy only the criteria for average bioequivalence. Also not reviewed are the arguments for and against the use of chiral ⁄ nonchiral methods for drug residue studies in food-producing species, except to note that residue depletion profiles depend on rate of depletion in the terminal elimination phase.…”

Population and Individual Bioequivalence: Lessons from Real Data and Simulation Studies

“…It has been noted that while there is little evidence to suggest that the ABE criterion has failed, consumers may find these specific questions above related to PBE and IBE more relevant. [8][9][10] There is some level of intuitive appeal for both PBE and IBE, although it is expected that the IBE criterion will be more relevant to consumers as they "switch" to generic formulations of chronically administered medications. The key motivation behind the proposed change lies in answering more appropriate questions regarding bioequivalence.…”

The use of asymmetric distributions in average bioequivalence

“…The use of bioequivalence trials is recommended to evaluate the interchangeability of two or more formulations. A brief summary of these trials (after 1970) is presented by Barrett et al [1].…”