Biomarker clinical endpoint

The robustness of the study results (i.e., how well established is the association between the pharmacogenetic enrichment biomarkers, drug exposure, and clinical endpoints )... 

Exposure-response data, using short-term biomarkers or surrogate endpoints, can sometimes make further exposure-response studies from clinical endpoints xmnecessary. For example, if it can be shown that the short-term effect does not increase beyond a particular dose or concentration, there may be no reason to explore higher doses or concentrations in the clinical trials. Similarly, short-term exposure-response studies with biomarkers might be used to evaluate early (i.e., first dose) responses seen in clinical trials. 

Surrogate endpoints, a subset of biomarkers, are laboratory measurements or physical signs used in therapeutic trials as a substitute for clinical endpoints expected to predict the effect of the therapy. A fully validated, surrogate endpoint predicts the clinically meaningful endpoint of a therapy consistently. ... 

Mechanism-based biomarker selection and correlation to clinical endpoints. 

An important qualification must be made. While a biomarker may be of proven value in establishing whether a drug has the desired effect in patients or healthy volunteers (see Section 4.6.3) and for evaluation of the dose-response relationship, a biomarker may not be a surrogate for the clinical endpoint. Thus, suppression of testosterone after an initial rise will give an almost immediate endpoint for the effect of GnRH analogues in prostate cancer but the relationship breaks down later in the disease. Measures of blood glucose control are vital... 

Of course, it is not always necessary to rely on biomarkers for rapid evaluation of dose-response relationships in ED. Thus, efficacy of new drugs is readily demonstrated in terms of the clinical endpoint for diseases, such as migraine, inflammatory pain, asthma, psoriasis, glaucoma and many others. 

Examples of some commonly used biomarkers and surrogate endpoints are listed along with clinical endpoints for several therapeutic classes in Table 17.1. 

Therapeutic class Biomarker/ surrogate Clinical endpoint... 

One frequent point of confusion is whether a clinical rating scale/ such as the Hamilton Depression scale/ is a biomarker or a clinical endpoint. As these scales attempt to capture the multifaceted dimensions of a complex clinical condition/ they are in fact clinical endpoints. However/ they are like intermediate endpoints because they do not encompass all dimensions of the disease being evaluated or the therapeutic response in all patients. 

The dependent variables in these PD models are either biomarkers, surrogate endpoints, or clinical endpoints. It is important to differentiate between these and to understand their relative importance and utility. 

Biomarkers play an important role in Phase 2 studies. These are covered in Chapter 20 in detail. Biomarkers are most important in early efficacy and toxicity studies when clinical endpoints take too long to become observable. After approval, biomarkers may prove useful in monitoring the course of pharmacotherapy in individual patients. 

A surrogate endpoint or Type II marker is a biomarker that is intended to substitute for a clinical endpoint (2,3). The US Food and Drug Administration has noted the... 

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