Clinical Trials

❘❙❚■ Chapter 4 | Endpointsmeaningful. This is not always the case. Many trials, for example, considerrehospitalization or escalation of treatment usage to be outcome measures.However, it is possible for such outcomes to occur for reasons that are somewhatindependent of the disease process itself, such as initial poor compliance withtreatment requiring higher doses of therapy as a corrective measure. Theoccurrence of these measures may therefore not correlate strongly with thedisease process, but their absence might be a strong indicator of treatment effect.This is a fairly complex matter and requires further discussion and debate.For now, bodies such as the US Food and Drug Administration (FDA) preferclinically meaningful outcomes such as disease-specific death rates.An additional limitation of composite endpoints is that they can also giveinconsistent results, with certain outcomes improving and others worsening,making overall interpretation of the study difficult. Whether the outcomes chosenare clinical, biochemical, pharmacologic, pathologic, physiologic, or other, theirrelative importance should be determined prior to data collection, during thedesign of the trial.Surrogate endpointsAs we have discussed, it is not always practical or feasible to base endpoints on‘true’ clinical outcomes that, like death, might only occur after some time.Therefore, to be able to assess potential treatment effects, alternative measuresare needed. One solution that has recently been attracting interest is surrogateendpoints. Temple defines a surrogate endpoint in a clinical trial as a laboratorymeasurement or physical sign used as a substitute for a clinically meaningfulendpoint that measures directly how a patient feels, functions, or survives [1].Changes induced by a therapy on a surrogate endpoint are expected to reflectchanges in a clinically meaningful outcome measure [5].A potential surrogate endpoint should be chosen based on strong biologicalrationale. Commonly used surrogate endpoints include [6]:• pharmacokinetic measurements, such as concentration–time curvesfor a drug or its active metabolites in the bloodstream• in vitro measurements, such as the mean concentration of an antibioticagent required to inhibit growth of a bacterial culture• radiological appearance, such as increased shadowing seen on a chestX-ray film of a patient with smoking-related lung disease that is relatedto a patient’s breathing capacity42