ABSTRACT
When a brand-name drug is going off patent, the innovator drug company will usually develop a new formulation to extend its exclusivity in the marketplace. At the same time, generic drug companies may file an ANDA submission to the U.S. FDA for approval of generic copies of the brand-name drug. No generic copy of the brand-name drug can be made without regulatory approval confirming that they work as well as the brand-name drug based on bioequivalence testing. When a generic drug is claimed bioequivalent to the brand-name drug, it is assumed that they will reach the equivalent therapeutic effect, or that they are therapeutically equivalent. As indicated earlier, this statement is true only under the Fundamental Bioequivalence Assumption. Under the current FDA regulations, a patient may switch from the brand-name drug to its generic copies provided the generic copies have been shown to be bioequivalent to the brand-name drug. Although a generic drug is all right to substitute for any other generic or innovator drug product, the FDA, however, does not indicate that a patient may switch from a generic drug to another for all drug products, even though both of the generic drugs have been shown to be bioequivalent to the brand-name drug. Therefore, an interesting question for the physicians and the patients is whether the brand-name drug and its generic copies can be used interchangeably, especially when different generic copies of the same innovator drug product are available and competition among generic copies is fierce. Basically, drug interchangeability can be classified as a drug prescribability and
drug switchability (Chow and Liu, 1995a). Drug prescribability is usually referred to as the physician’s choice for prescribing an appropriate drug for his or her patients between the brand-name drug and its generic copies. The underlying assumption of drug prescribability is that the brand-name drug and its generic copies can be used interchangeably in terms of their efficacy and safety. To ensure drug prescribability, it is suggested that, in addition to average bioequivalence, population bioequivalence, which accounts for both average and variability of bioavailability, be established. On the other hand, drug switchability is referred to as the switch of a drug (e.g., a brand-name drug or its generic copies) to an alternative drug (e.g., a generic
has titrated to a steady, efficacious, and safe level. To ensure drug switchability, it is recommended that individual bioequivalence be considered. The concept of individual bioequivalence is to ensure bioequivalence within individual subjects according to some criteria. The issues of drug prescribability and switchability have been discussed in chapters 11 and 12. Recently, as more generic drugs become available, the quality, safety, and efficacy
of generic drugs have become a public concern because it is very likely that a patient may switch from one generic drug to another. This situation is particularly true in developing countries where only cheaper generic copies are available. There is a tremendous debate on the quality, safety, and efficacy of generic drugs because they are not identical in terms of inactive ingredients that are binded and bulked, coated and colored, and may vary from one version to another. The current FDA guidance and many regulatory agencies around the world require only that evidence of equivalence in average bioavailabilities between the brand-name drug and its generic copies be provided. Bioequivalence between generic copies of the brand-name drug is not required. Therefore, whether the brand-name drug and its generic copies can be used interchangeably has become a safety concern. To address this issue, Chow and Liu (1997) proposed the performance of a meta-analysis based on average bioequivalence for bioequivalence review. The idea of a meta-analysis is to provide an overview of bioequivalence among generic drugs based on data from independent bioequivalence trials (or submissions). The purpose is to assess not only bioequivalence among generic drugs of the same brand-name drug, but also to provide a tool to monitor the performance of the approved generic copies of the same brand-name drug. In Chow and Liu’s approach, a rather restricted, yet strong assumption of intersubject and intra-subject variances is made, which limits its practical use. To overcome this problem, Chow and Shao (1999) propose an alternative method for meta-analysis that relaxes the assumption. The proposed alternative meta-analysis increases statistical power when the inter-subject variability is not too large. In Section 16.2, the method of meta-analysis for bioequivalence trials proposed by
Chow and Liu (1997) is outlined. A numerical example is given to illustrate Chow and Liu’s method in Section 16.3. In Section 16.4, an alternative method for metaanalysis proposed by Chow and Shao (1999) is discussed. A brief discussion is given in Section 16.5.
