Clinical Trials

❘❙❚■ Chapter 12 | Equivalence TrialsGlossarySuperiorityEquivalenceNoninferiorityClinical equivalenceBioequivalenceDemonstration of improved efficacy of a new treatment over placebo/standard treatmentmeeting statistical significanceDemonstration that the absolute reduction of events achieved by one treatment is similarto that achieved by another treatment, with the difference being within a predefined rangeDemonstration that the average efficacy of a new treatment, while being less thanthat of the standard treatment, is still within a predefined range and is not clinicallysignificantly lowerTherapeutic equivalence based on clinical outcomes such as reduced deaths or strokesTherapeutic equivalence based on pharmacokinetic parameters such as bloodconcentrations or receptor occupancy ratesIntroductionClinical trials, particularly Phase II (small patient groups) and Phase III (largepatient groups) studies, usually aim to demonstrate improved efficacy of a newtreatment over placebo/standard treatment. This type of trial is known as asuperiority trial. In other cases, such as when it is unethical to use a placebocontrol, it can be necessary to show that a new drug is comparable to an existingone. Such studies are known as equivalence trials. An example of this is theCANDLE (Candesartan versus Losartan Efficacy) study, in which twoangiotensin II receptor blockers for reducing hypertension were tested [1].Reasons for equivalence trialsImproved methods of drug delivery or manufacturing are also sometimesdeveloped, producing new forms of existing drugs. An equivalence trial can beused here to check that this change in formulation (eg, sustained release versusrapid release given more often) does not change the efficacy of the compound.Equivalence trials are also used when the efficacy of a drug needs to bedemonstrated across varying patient groups, as occurred in the Syst-Eur (SystolicHypertension-Europe) substudy. Here, the effect of nitrendipine – a calciumantagonist that lowers blood pressure – was compared in diabetic versusnon-diabetic patients [2].Another application of equivalence trials is assessing whether generic and originaldrugs have identical therapeutic effectiveness. It is important that patientsexperience the same efficacy from both formulations and ensure that they areinterchangeable without a change in side-effect profiles, given that generic drugswill be produced by companies whose manufacturing processes may not be ascomplex as those of the parent company.114