Bioequivalence Studies in Drug Development: Methods and Applications

N. T. Longford, Bioequivalence Studies in Drug Development: Methods and Applications, Journal of the Royal Statistical Society Series A: Statistics in Society, Volume 171, Issue 4, October 2008, Page 1037, https://doi.org/10.1111/j.1467-985X.2008.00561_8.x

Bioequivalence is a term that is used for equal (therapeutic) effect of two or several medical interventions (treatments). Its importance in pharmaceutical research and development, and health care in general, stems from the need to provide evidence that two treatments (products) are indistinguishable in a well-defined sense. For instance, when a manufacturer wishes to produce an approved drug by a substantially different process, they must convince the regulatory agent that the new process indeed produces a drug that for the intended purpose is the ‘same’ as the old one. Fleshing out these definitions and devising procedures for studying them empirically is an exceedingly complex matter, drawing on expertise from biochemistry, health sciences, measurement, psychology, public relations and statistics (design of experiments, dealing with measurement error, estimation and hypothesis testing).

This monograph provides an overview of the statistical aspects of bioequivalence studies, with digressions to other aspects when they help to motivate and round off the material presented. One such aspect is the role of the regulatory agents, such as the Food and Drug Administration, which take part in the methodological discourse, and issue guidances about recommended approaches. The monograph has a strong practical orientation with many worked-out examples.

In practice, the ideal of bioequivalence is an unprovable concept, and therefore a whole string of compromises is required. First, some clinically unimportant differences are acceptable (the term ‘biosimilarity’ might be better suited for this); next, the effect in question is measured indirectly, by observing, on a small number of occasions, the concentration of the active compound in the subject’s bloodstream and summarizing these measurements; further, instead of assessing whether the effect is small for every subject, the analysis is often concerned only about the average effect (clinical trials for providing evidence of superiority have the same problem; Longford ( 1999)); and, finally, hypothesis testing is the agreed method for statistical analysis. See Lindley ( 1998) for an authoritative dissenting voice.

The monograph contains much valuable material, with a focus on the (agreed) regulatory process and its recent genesis. The first chapter gives the basic definitions. They are presented rather abruptly, without a commentary that would ease the reader into the topic. Chapter 2 discusses the outcome variables that are used in the analysis; they are surrogates for the effect of interest. The following chapters deal with the design of studies for bioequivalence and their analysis. A prominent role is played by the log-transformation because the multiplicative scale is often better suited for the outcomes. This message is scattered over the book, with a modicum of duplication. Later chapters address some specialized topics, such as interactions, alternative methods and individual bioequivalence, which I regard as the bioequivalence (Longford, 2000). Towards the end of the text (Chapters 9 and 10), equations, tables and computer code take over. These are useful for the analyst who has to execute particular instructions, but they fall short on motivation and explanation of the rationale. The graphics are informative and well designed throughout.

Each chapter is accompanied by many references. Of course, some key references, several by the authors of the book, appear in several chapters. The text is well edited, so that there are no typographical errors, but some passages have many long and convoluted sentences. I recommend the book as an extensive reference on bioequivalence and as informative reading for a student or professional who is already acquainted with the basics of clinical trials.