Introduction

The term bioavailability is a contraction for biological availability (Metzler and Huang, 1983). The definition of bioavailability has evolved over time with different meanings by different individuals and organizations. For example, differences are evident in the definitions by Academy of Pharmaceutical Sciences, the Office of Technology Assessment (OTA, 1974) of the Congress of the United States (1974), Wagner (1975), and the 1984 Drug Price Competition and Patent Restoration amendments to the Food, Drug, and Cosmetic Act. Throughout this book, however, the definitions and some related terms regarding bioavailability provided in the Act, which are adopted by the United States Food and Drug Administration (FDA), will be used (21 CFR, Part 320.1, 1983). The bioavailability of a drug is defined as the rate and extent to which the active

drug ingredient or active moiety from a drug product is absorbed and becomes available at the site of drug action. For drug products that are not intended to be absorbed into bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety is absorbed and becomes available at the site of action. A comparative bioavailability study refers to the comparison of bioavailabilities of different formulations of the same drug or different drug products. When two formulations of the same drug or two drug products are claimed bioequivalent, it is assumed that they will provide the same therapeutic effect or that they are therapeutically equivalent and they can be used interchangeably. Two drug products are considered pharmaceutical equivalents if they contain identical amounts of the same active ingredient. Two drugs are identified as pharmaceutical alternatives to each other if both contain an identical therapeutic moiety, but not necessarily in the same amount or dosage form or as the same salt or ester. Two drug products are said to be bioequivalent if they are pharmaceutical equivalents (i.e., similar dosage forms made, perhaps, by different manufacturers) or pharmaceutical alternatives (i.e., different dosage forms) and if their rates and extents of absorption do not show a significant difference to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of action when administered at the same

For discussion regarding the definition of bioavailability, see Balant (1991) and Chen et al. (2001a,b). The study of absorption of an exogenously administered compound (sodium

iodide) can be traced back to 1912 (Wagner, 1971). The concept of bioavailability, however, was not introduced until some 30 years later. Oser et al. (1945) studied the relative absorption of vitamins from pharmaceutical products and referred to such relative absorption as physiological bioavailability. In recent years, generic drug products, which are those manufactured by generic drug companies or the innovator companies themselves, have become very popular. Bioavailability=bioequivalence studies are of particular interest to the innovator and the generic drug companies in the following ways. First, for the approval of a generic drug product, the FDA usually does not require a regular new drug application (NDA) submission, which demonstrates the efficacy, safety, and benefit-risk of the drug product, if the generic drug companies can provide the evidence of bioequivalence between the generic drug products and the innovator drug product through bioavailability and bioequivalence studies in a so-called abbreviated new drug application (ANDA). Second, when a new formulation of a drug product is developed, the FDA requires that a bioavailability study be conducted to assess its bioequivalence to the standard (or reference) marketed formulation of the drug product. Thus, bioavailability studies are important because an NDA submission includes the results from phases 1-3 clinical trials, which are very time consuming and costly to obtain. Finally, under the Food and Drug Administration Modernization Act (FDAMA) passed by the U.S. Congress in 1997, after the approval, depending on the magnitudes of changes in components and composition or method of manufacture, the FDA may require the evidence of bioequivalence between the pre-and postchange products under NDA or postchange generic product with the reference list product under ANDA. For details, see the FDA guidance on scale-up and postapproval changes (FDA, 1995a; FDA, 1997a). The concept of bioavailability and bioequivalence became a public issue in the

late 1960s because of the concern that a generic drug product might not be as bioavailable as that manufactured by the innovator. These concerns rose from clinical observations in humans together with the ability to quantify minute quantities of drug in biological fluids. This initiated not only a period of four decades of extremely active scientific research and development in bioavailability and bioequivalence, but also started the process and formulation of the current regulatory requirements for approval of generic drug products. Spanning from the early 1970s to date, the research and development of bioavailability and bioequivalence can be roughly divided into four phases. The first phase is from early 1970s to 1984 when the U.S. Congress passed the Drug Price Competition and Patent Term Restoration Act that authorized the to approve generic drug products through bioavailability and bioequivalence studies. The second phase begins from 1984 to 1992 after the issue of the U.S. FDA guidance entitled Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design in 1992, which provides the sponsors a guidance as to how the data

review. The concept of population and individual bioequivalence for addressing drug interchangeability in terms of drug prescribability and drug switchability and their corresponding statistical methods has been discussed in the third phase since 1992. The fourth phase starts at the dawn of the twenty-first century when based on the fruit of research conducted in the last 30 years of the twentieth century, the FDA issued and implemented the new guidance on general considerations and statistical approaches to bioavailability and bioequivalence studies. In 1970, the FDA began to ask for evidence of biological availability in

applications submitted for approval of certain new drugs. In 1971, a drug bioequivalence study panel was formed by the OTA to examine the relationship between the chemical and therapeutic equivalence of drug products. On the basis of the recommendations in the OTA report, the FDA published a set of regulations for the submission of bioavailability data in certain new drug applications. These regulations became effective on July 1, 1977 and are currently codified in 21 CFR, Part 320. In 1971, by the time the FDA began to require evidence of bioavailability for NDA of some drug products, the Biopharmaceutical Subsection of the American Statistical Association simultaneously formed a Bioavailability Committee to investigate the statistical components for the assessment of bioequivalence. Metzler (1974) summarized the efforts by the Committee and addressed several concerns about some statistical issues in bioavailability studies. During the decade of the early 1980s, the search for statistical methods for the assessment of bioequivalence received tremendous attention. Several methods that met the FDA requirements for statistical evidence of bioequivalence were proposed. These methods included an a posteriori power approach, reformation of bioequivalence hypotheses (Schuirmann, 1981; Anderson and Hauck, 1983), a confidence interval approach (Westlake, 1972, 1976, 1979; Metzler, 1974), and a Bayesian approach (Rodda and Davis, 1980; Mandallaz and Mau, 1981). A detailed discussion of these statistical developments during this period can be found in Metzler and Huang (1983). In 1984, the FDA was authorized to approve generic drug products under the Drug

Price Competition and Patent Term Restoration Act. However, as more generic products become available, the following concerns were raised:

1. Whether generic drug products are comparable in quality to the innovator drug product.