Population and Individual Bioequivalence

For physicians and patients, bioequivalent drug products can and should be used interchangeably to achieve a similar therapeutic effect. As mentioned in Chapter 1, therefore, bioequivalence studies, in fact, serve as surrogates for clinical trials in evaluation of therapeutic equivalence in efficacy and safety between the innovator product and its generic copies. However, when a physician has the possibility of administering a generic drug product, he or she needs to consider the anticipated therapeutic effect that may be obtained from the patient. If a new patient has just begun a drug regimen, the physician does not have any informations about the patient’s therapeutic response to any of the different formulation that he or she could prescribe. As a result, the only relevant information that the physician could have is the comparison of the marginal distributions for some pharmacokinetic responses or metric between the generic and innovator drug product from a population of subjects. If the marginal distributions follow an approximate normal distribution, the equivalence can be evaluated through inferences on population parameters, such as average and intra-subject variability. This concept, as indicated in Chapter 1, is referred to as the population bioequivalence (PBE). Given the information about population parameters, the physician can determine whether to prescribe an innovator drug product or its generic copies to a new patient who just begins to receive the drug regime. Prescribability, therefore, is the interchangeability for the new patient. On the other hand, suppose a patient with a chronic disease, such as hypertension

or diabetes, has been well controlled under long-term administration of an innovator drug product. In other words, the concentration of its active ingredients has been titrated to an efficacious and safety level within the patient’s individual therapeutic window. After the patent of the innovator drug product has expired and its generic copies become available, in the United States, many states have generic substitution laws requiring that pharmacists dispense the cheapest formulation unless the physician specifies that no substitution of the generic product is allowed (Hauck and Anderson, 1992). However, for the patients already receiving the long-term administration of a formulation, the physician now has the information about patient’s response to that formulation. To ensure the similar efficacy and safety by the generic

must still be within the patient’s same therapeutic window established by the innovator’s drug product. This concept is then referred to as switchability that requires bioequivalence within the same patient. Chow and Liu (1995) defined switchability as the switch to an alternative drug

product from a drug product within the same subject for whom the concentration has been titrated to a steady efficacious and safe level. On the other hand, Hauck (1996a) gave a definition of switchability such that a patient who is presently on one formulation can be switched to another formulation and retained essentially the same (or better) efficacy and safety profile. Switchability, therefore, is exchangeability within the same subject. To assure drug switchability, it is suggested that bioequivalence be assessed within the same individuals. This concept of bioequivalence is known as individual bioequivalence (IBE). From both definitions of switchability, individual bioequivalence not only assesses the closeness of the distributions of a patient’s pharmacokinetic responses under repeated administration between the generic and the innovator’s drug products, but also evaluates whether both distributions lie within the therapeutic window established by the innovator’s drug product. Statistical procedures for evaluation of average bioequivalence were introduced in

Chapters 4 and 9, respectively, for the standard two-sequence, two-period crossover, and higher-order crossover designs. On the other hand, Chapters 7 and 9, under the assumption of compound symmetry for the covariance matrix, described various methods for assessment of equivalence in intra-subject variability under either 2 2 or higher-order designs. Schuirmann’s two one-sided tests approach for average bioequivalence can be used jointly with the procedures for evaluation for equivalence in variability for assessment of PBE. Since this approach first evaluates ABE and bioequivalence in variability separately and then uses the intersection-union test (IUT) principle (Berger, 1982) to combine the individual results for assessment of PBE, it is called disaggregate criteria. However, the FDA statistical guidance on bioequivalence issued in 2001 uses a criterion that integrates average and variability into a single summary measure. It is then referred to as an aggregate criterion for PBE. On the basis of the same concept, aggregate criteria are suggested in the FDA statistical guidance for evaluation of IBE. A general two-stage model for pharmacokinetic metrics or responses is introduced

and limitations of average bioequivalence are illustrated through concepts of prescribability and switchability in Section 11.2. In Section 11.3 merits of IBE are provided and desirable features for bioequivalence criteria are given relative to improving the drawbacks suffered by ABE. Section 11.4 provides difference measures for describing the discrepancy of pharmacokinetic metrics between the test and reference formulations. Concepts of disaggregate and aggregate criteria are also introduced in this section. Different criteria for evaluation of population and individual bioequivalence, based on probability measures for discrepancy, are given in Section 11.5. Various moment-based aggregate criteria for population and individual bioequivalence are provided in Section 11.6. Interrelations among different criteria are explored in Section 11.7. Design issues for assessment of PBE and IBE are given in Section 11.8. Determination of population and individual bioequivalence limits are reviewed in Section 11.9. Final remarks and comments on selection of criteria and design for assessment of PBE and IBE are provided in Section 11.10.