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I Introductional Material

Introduction

Marc Buyse

IDDI, Belgium, CluePoints, USA, and Hasselt University, Belgium

Overview of Surrogate Endpoint Evaluation

In clinical research, interest typically focuses on the most clinically relevant endpoints such as survival (in cancer), myocardial infarction (in cardiovascular disease), loss of vision (in ophthalmic diseases), performance on some rating scale (in psychiatry), and so on. The objective of therapy is to improve clinical endpoints that are considered most relevant to patients. However, these endpoints may be difficult to use in prospective trials for a number of reasons:

1. clinical endpoints may require a very long follow-up time (e.g., survival in early stage cancers), such that the assessment of new therapies using these endpoints would be unduly delayed and potentially confounded by other therapies;

  • 2. clinical endpoints may require a large sample size if the event of interest has low incidence (e.g., cytotoxic drugs may have rare but serious side effects, such as leukemias induced by topoisomerase inhibitors);
  • 3. clinical endpoints may be difficult to measure (e.g., quality-of-life assessments involve multi-dimensional instruments that are hard to validate);
  • 4. clinical endpoints may be costly to measure (e.g., cachexia, a condition associated with malnutrition and involving loss of muscle and fat tissue, is assessed using expensive equipment that measures the levels of nitrogen, potassium and water in the patient's body).

A potential strategy in these cases is to look for surrogate endpoints or biomarkers that can be measured earlier, more frequently, more conveniently, or more cheaply than the true clinical endpoint of interest.

The Biomarker Definitions Working Group (Biomarkers Definition Working Group, 2001) proposed formal definitions that have since been widely adopted. A clinical endpoint is considered the most credible indicator of drug response and defined as a characteristic or variable that reflects how a patient feels, functions, or survives. In clinical trials aimed at establishing the worth of new therapies, clinically relevant endpoints should be used, unless a biomarker or other endpoint is available that has risen to the status of surrogate endpoint. A biomarker is defined as a characteristic that can be objectively measured as an indicator of healthy or pathological biological processes, or pharmacological responses to therapeutic intervention. A surrogate endpoint is a biomarker that is intended for substituting a clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these.

 
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