Equivalence trials study design

This chapter introduces basic concepts in statistical analysis that are of relevance to describing and analyzing the data that are collected in clinical trials, the hallmark of new drug development. (Statistical analysis in nonclinical studies was addressed earlier in Chapter 4.) This chapter therefore sets the scene for more detailed discussion of the determination of statistical significance via the process of hypothesis testing in Chapter 7, evaluation of clinical significance via the calculation of confidence intervals in Chapter 8, and discussions of adaptive designs and of noninferiority/equivalence trials in Chapter 11. 

Interchangeability Multisource (generic) bioequivalence study. Bioequivalence of all oral preparations except aqueous solutions. Orally or parenterally administered aqueous solutions chemical-pharmaceutical characteristics. Comparative clinical trial using clinical or pharmacodynamic end-points can be presented. End-points justified and validated for the compound and trial should be designed to show equivalence. Trial showing the absence of significant difference cannot be accepted Bioequivalence study report included ... 

Phase III studies can be tested against a placebo control with the intent of showing superiority over placebo. Another type of study design is to show equivalence or noninferiority to an approved therapy. An equivalence trial is intended to show that the response to two or more treatments differs by an amount which is clinically unimportant. A noninferiority trial demonstrates that the response to the investigational product is not clinically inferior to a comparative agent. 

Two products are bioequivalent in the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study [21 CFR 320.1(e)], An appropriately designed comparison could include (1) pharmacokinetic (PK) studies, (2) pharmacodynamic (PD) studies, (3) comparative clinical trials, and/or (4) in vitro studies. 

Clinical (PK, PD, Safety and Efficacy) Human clinical studies can range in complexity from standard-design PK studies to complicated, long-term efficacy trials evaluating one or more indications in multiple populations. Human PK studies are used as the benchmark for establishing bioequivalence of conventional dosage forms. For traditional pharmaceuticals for which reliance on systemic exposure may not be suitable, PD or clinical safety and efficacy may be performed to show equivalence. 

In view of these difficulties, it may be problematic to administer the same dose to all volunteers and to obtain pharmacologically equivalent results in clinical studies. This might also explain the occasionally great variation in study results (despite a carefully chosen trial design) and any potential inefficacy or undesired effect of the drug. (s. p. 56)... 

In a study of oral famciclovir versus oral aciclovir, designed to demonstrate equivalence of efficacy of the two drugs in the treatment of mucocutaneous Herpes simplex infection in HIV-infected individuals, there was no difference in the incidence or nature of adverse effects in the two groups (1). None of the withdrawals from the trial was considered by the investigator to be related to the study medication. 

The short answer is that it depends on the power (and therefore the sample size) of the study. To illustrate this, assume that the value of the design parameter a is dictated by regulatory concerns, which is reasonable especially in confirmatory trials. Further, before a new study is completed there is still some doubt as to whether the new treatment is efficacious, such that the value of x is conjectured to be 0.5. Resulting values of the error rates, a and p, are presented in Table 12.1 as a function of the power (or, equivalently, P) of the study. 

Other important issues are to do with the basic structure of trials. For example, what are the appropriate comparator treatments How many should be studied simultaneously Will the object of the trial be to find differences or to demonstrate equivalence Should a parallel group study or a cross-over trial be used How many centres should be used What should the block size be If a cross-over trial is employed will it be necessary to use incomplete blocks (These are designs in which each patient receives only a subset of the treatments being studied.) How long should the treatments be applied When should values be measured How should they be combined Should the results be analysed sequentially If the trial is to be blinded, how should this be achieved Is stratification desired What factors should be included in the analysis What is the general approach to be adopted What is the strategy for dealing with multiplicity of outcomes ... 

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