Biomarker surrogate endpoint

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. 

All the values allowing an accurate evaluation of the endpoints (toxicity and clinical response biomarkers, surrogate endpoints, or clinical endpoints). Treatment data, for example, dose and actual times of start and end of infusion. 

Association of American Universities (2000). Task Force on Research Accountability Report on University Protection of Human Beings Who are the Subjects of Research. Washington, D.C., June 28, 2000. www.aau.edu/HumSUbRpt06.28.00pdf Biomarkers Definitions Working Group (2001). Biomarkers and surrogate endpoints Preferred definitions and conceptual frameworks. Clin. Pharmacol. Ther. 69 89-95. 

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. ... 

Lesko, L.J. and Atkinson, A.J., Jr., Biomarkers and surrogate endpoints — Use in drug development and regulatory decision making criteria, validation, strategies, Ann. Rev. Pharmacol. Toxicol, 41, 347-366, 2001. 

The biomarker is not used because no synthetic analysis has been done. The data need to be pooled, synthesized, and analyzed. We have to xmderstand what the data are telling us about that biomarker and what the remaining gaps in understanding are. Studies have to be identified that will fill those gaps, and then somebody has to do that work, whatever it is and for a surrogate endpoint, of course, that work involves correlation with clinical outcomes. 

The purpose of a surrogate endpoint is use for regulatory approval in lieu of a clinical oufcome. Surrogate endpoints have the very same set of issues as biomarkers but at a higher level. Once surrogate endpoint data are analyzed, the gap in xmderstanding often... 

Source Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints preferred definitions and conceptual framework, Clinical Pharmacology and Therapeutics 69 89-95 (2001). 

The limitations of the use of biomarkers in healthy volunteers must be recognised. For example, although there have been attempts to simulate migraine headache in volunteers, to date none of these models can be considered adequate to serve as a surrogate endpoint. Patients with migraine are not difficult to recruit and are usually healthy apart from their migraine. In this case, it maybe more appropriate to establish tolerability and pharmacokinetics in healthy volunteers and then to select a maximum well-tolerated dose with which to perform a small proof of principle clinical trial in patients. This will need to be followed by larger trials to establish the dose-response relationship. 

The use of biomarkers and surrogate endpoints in patients is well established in virtually all therapeutic areas. After all, blood pressure has been used as a surrogate for cardiovascular risk for many decades. Some other examples are given in Table 4.5. 

There are many examples of biomarkers, which have been used as surrogates in prominent clinical trials that have been subsequently formd to be inadequate, illustrating the difficulty in identifying a surrogate endpoint. One notable scenario is that of a biomarker that responds to therapy and is highly predictive of survival, but does not predict the effect of treatment on survival. The use of CD4-I- counts in HIV trials is an example of such a biomarker. ... 

Much of the discussion about disease biomarkers is in the context of markers that measure some aspect of disease status, extent, or activity. Such biomarkers are often proposed for use in early detection of disease or as a surrogate endpoint for evaluating prevention or therapeutic interventions. The validation of such biomarkers is difficult for a variety of reasons, but particularly because the molecular pathogenesis of many diseases is incompletely understood, and hence it is not possible to establish the biological relevance of a measure of disease status. 

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... 

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