Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘What types of equivalence trials are there?Clinical equivalenceEquivalence trials based on clinical outcomes such as death, stroke, heart attack,or hospitalization are termed clinical equivalence trials. However, some outcomes,such as death, are not always practical due to the timescale involved, andoutcomes such as improvement in depression are difficult to measure objectivelyand reproducibly.BioequivalenceAn alternative method is to use a pharmacokinetic (PK) approach, whichcompares the PK parameters derived from plasma or blood concentrations of thecompound. Here, the outcomes are more objective and measurable. Trials basedon PK parameters are called bioequivalence trials. The major advantages of a PKapproach are the clear definition of the outcomes (PK parameters) and the lowervariability of these outcomes.The basic assumption underlying the PK approach to bioequivalence studies isthat the same number of drug compound molecules occupying the same numberof receptors will have similar clinical effects. The bioequivalence problem is thenreduced to proving that equal numbers of drug compound molecules reach thereceptors. From administration of the drug to the molecules reaching thereceptors, factors of drug distribution, metabolism, and elimination now comeinto play. If the chemical nature of the compound in the two different (genericand original) formulations is identical, the distribution and elimination patternsare assumed to be the same once the drugs are absorbed. Any change in thenumber of drug molecules reaching the receptors is then due to differences inabsorption profiles. For that reason, the US Food and Drug Administrationbelieves that if the absorption properties of two drugs based on the samecompound are similar, then the two drugs will produce similar effects [3–6].Bioequivalence trials are discussed further in the following chapter.Design issues for equivalence trialsHow does design affect equivalence trials?Equivalence trials can be of parallel or crossover design. The two designs differmainly in the way they deal with intersubject variability. Between-subject variabilityis a measure of the differences between subjects, whereas within-subject variabilityis a measure of the differences within each subject. Subject validity has a largestatistical influence on the equivalence result, so the design chosen is important.Both types of variability are present in each trial, but in the crossover design –115