Bioequivalence and bioequivalency testing

American Journal of Pharmaceutical Education, Summer 1999 by Balthasar, Joseph P

PROLOGUE

This lecture material is covered in one and one-half fiftyminute lecture periods. The primary objectives of the lecture are to: (i) review interpatient and intrapatient pharmacokinetic variability; (ii) introduce the concepts of therapeutic equivalence and bioequivalence; (iii) introduce the current FDA standards on bioequivalence; (iv) introduce the basic approach of bioequivalency testing; (v) provide an example of a clinical study assessing bioequivalence, showing calculations and conclusion regarding bioequivalency; and (vi) discuss the current FDA standards of bioequivalence as they relate to the approval of generic formulations of highly variable drugs and to the interchangeability of formulations of drugs with low therapeutic indices. The overall goal of the lecture is to introduce pharmacy students to bioequivalence and to bioequivalency testing, such that they may appropriately address the concerns of patients regarding generic substitution and appropriately advise physicians regarding the interchangeability of approved drug formulations.

INTRODUCTION

Generic drug formulations are often substituted for `brand name' (i.e., innovator) formulations by pharmacists in an effort to reduce the cost of prescription-drug therapy. In most states, generic substitution is allowed and encouraged, provided that the generic formulation is deemed to be therapeutically equivalent to the innovator formulation by the FDA. The FDA publishes a list of drug products and equivalents, which is entitled, Approved Drug Products with Therapeutic Equivalence Evaluations, and is commonly known as the Orange Book. The FDA's designation of `therapeutic equivalence' indicates that the generic formulation is (among other things) bioequivalent to the innovator formulation and signifies the FDA's expectation that the formulations are likely "to have equivalent clinical effect and no difference in their potential for adverse effects."(1)

The 1984 Amendments to the Drug Price Competition and Patent Term Restoration Act require that manufacturers seeking approval of generic formulations submit to the FDA data demonstrating bioequivalence to the innovator drug product (1). Currently, bioequivalence is determined by assessing the equivalence of the rate and extent of drug absorption. Typically, this investigation is made through a 12-36 subject, two-treatment crossover study, conducted with healthy normal adult subjects. Under current FDA standards, bioequivalence is concluded in cases where the innovator and test product differ in terms of their rate and extent of absorption by -20/ 25 percent or less. The FDA guidance, Statistical Procedures for Bioequivalence Studies Using a Standard Two-treatment Crossover Design, outlines a statistical method for assessing data and provides a decision rule for concluding bioequivalence(2).

In spite of the efforts of the FDA, controversy and disagreement exist regarding the therapeutic equivalence of drug products listed in the Orange Book. Additionally, there is a seemingly continual debate in the pharmaceutical literature over the appropriateness of the FDA's recommended approach of testing the rate and extent of drug absorption(3-6). Perhaps in part as a consequence of these debates, and perhaps in part due to the publicity of the recent generic drug scandals, pharmacists are often queried by patients, health care professionals, and HMO representatives regarding the therapeutic equivalence of drug products. This lecture is designed to strengthen the students' understanding of bioequivalence and bioequivalency testing, in an attempt to increase students' confidence in addressing these questions.

LECTURE FORMAT AND CONTENT

Interpatient and Intrapatient Pharmacokinetic Variability Interpatient variability in pharmacokinetics is recognized by pharmacists and other health care professionals as an important factor to consider in evaluating and planning drug therapy. In fact, much of the work in the field of clinical pharmacokinetics is devoted to attempts to understand and overcome this form of pharmacokinetic variability. Interpatient variability is often best demonstrated by examining the concentration vs. time profiles of a drug following the administration of a fixed dose to several patients. Between-patient differences in pharmacokinetics (i.e., the processes of drug absorption, distribution, metabolism and excretion) are expressed as differences in resultant concentration vs. time profiles (Figure 1)(7).

Intrapatient pharmacokinetic variability refers to variabilities in pharmacokinetics that occur within a patient from dose to dose during the course of drug therapy (Figure 2)(8). In contrast to the mindfulness of practitioners regarding interpatient variability, intrapatient variability is virtually ignored in discussions of pharmacokinetics, outside of those in the bioequivalence literature. The relative lack of attention paid to intrapatient pharmacokinetic variability may be partially explained by the argument that drugs exhibiting high intrapatient pharmacokinetic variability rarely are drugs with low therapeutic indices, as this combination would not be likely found in an approved drug(9). This argument, which likely has merit, implies that intrapatient pharmacokinetic variability is rarely a factor in maintaining the safety and efficacy of drug therapy. However, intrapatient variability appears as a key factor in designing and assessing bioequivalence studies.