Surrogate endpoint

Sikora, K. (2002). Surrogate endpoints in cancer drug development. Drug Disc. Today 7 951-956. 

For drugs approved under accelerated approval regulations on the basis of a surrogate endpoint or an endpoint other than survival or irreversible morbidity, FDA may require a Phase IV study to confirm the drug s efficacy. Failure to show efficacy may result in withdrawal of approval. 

Relevance influences the usefulness of information, in that the more likely the user is to encounter the need for this particular information, the greater the relevance. For example, information about clinical conditions rarely encountered in an individual s practice has low overall relevance to the practitioner. Relevance also has another aspect that of closeness of fit of the information to the user s interest. Patients are primarily interested in outcomes that have personal meaning, such as morbidity, mortality, or quality of life. Information concerning these outcomes has high relevance. Information about the disease state or about surrogate endpoints has lower relevance for the patient. 

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. 

Endpoint. An indicator measured in a patient or biological sample to assess safety, efficacy, or another trial objective. Some endpoints are derived from primary endpoints (e.g., cardiac output is derived from stroke volume and heart rate). Synonyms include outcome, variable, parameter, marker, and measure. See surrogate endpoint in the text. Also defined as the final trial objective by some authors. 

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. ... 

Temple, R.J., A regulatory authority s opinion about surrogate endpoints, in Clinical Measurement in Drug Evaluation, Nimmo, W.S. and Tucker, G.T., Eds., WUey, Indianapolis, 1995. 

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 statins have been demonstrated to markedly lower plasma LDL levels (and triglyceride levels to a lesser extent). In fact, statins were approved by the US FDA on the basis of a surrogate endpoint reduction in plasma cholesterol levels. Since we know that increased plasma cholesterol levels are correlated with increased risk of coronary artery disease, it seems logical that reducing plasma cholesterol levels would lead to reduced risk. That turns out to be true in this case. However, see the case of hormone replacement therapy (HRT) for women for a more complex example, discussed below. 

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. 

Phase I. Clinical pharmacology in small numbers (tens) of healthy non-patient (or patient) volunteers to assess tolerability, preliminary safety, pharmacokinetics, and pharmacod)mam-ics where practicable [i.e. biological effect using surrogate endpoints (see Section 6.6.5.1) or, rarely, therapeutic effect]. 

There is a considerable literature on surrogate endpointsFrom a practical point of view, the physician working in the pharmaceutical industry needs to be precise in the use of the surrogate endpoint. 

The characteristics of an ideal surrogate endpoint for use in Phase I-IV trials would depend on whether the emphasis is on the efficacy or the safety evaluation of the potential medicine. 

Surrogate endpoint data can be used for a number of purposes. These include ... 

Whether a therapeutic or a surrogate endpoint is chosen as primary response measure. 

The efficacy endpoints defined in the protocol will be primary or secondary, and each of these maybe a therapeutic or a surrogate endpoint. For each of these there is a statistical and a clinical interpretation of the results. 

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. ... 

There are of course practical considerations in clinical research. We may find patient recruitment difficult in single centre studies and this is one of the major drivers to multicentre and multinational trials. Alternatively, we may need to relax the inclusion/exclusion criteria or lengthen the recruitment period. Unfortunately, while each of these may indeed increase the supply of patients they may also lead to increased variability that in turn will require more patients. A second issue is the size of the CRD which, if it is too small, will require a large number of patients. In such circumstances we may need to consider the use of surrogate endpoints (Section S.3.3.2). Finally, the standard deviation may be large and this can have a considerable impact on the sample size - for example, a doubling of the standard deviation leads to a four times increase in the... 

Fleming TR, DeMets DL. Surrogate endpoints in clinical trials are we being misled Ann Intern Med 1996 125 605-13. 

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