Surrogate endpoints/markers

Simplistically, approval to market a drug could be based on one positive, adequate, and well-controlled phase III study supported by a phase II study where the endpoint was a surrogate endpoint marker. For example, if it is accepted that chest x-ray findings may be indicative of pulmonary function deterioration and the claim for the drug will be preservation of pulmonary function, one adequate and well-controlled phase III study with a pulmonary function endpoint supported by one phase II chest x-ray positive finding adequately fulfills the requirements of the act. 

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. 

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. 

Picking the Right Thing to Measure in a Triai Surrogate Endpoints or Markers 121... 

Marker or a clinical endpoint for prognosis also referred to as surrogate endpoint. 

Wagner JA. Overview of biomarkers and surrogate endpoints in drug development. Dis Markers. 2002 18 41-46. 

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... 

Validation of Surrogate Endpoints or Type II Markers 17.3.3.1 General Criteria for Surrogacy... 

A marker validated as Type 0 or Type I may next be validated as a Type II marker or surrogate endpoint. The validation of surrogate endpoints is best done with data from Phase 2 or 3 studies, where dropout rates have been low, the treatment has continued unchanged over the duration of the study, the biomarker was measured early in treatment, patients have been followed for a sufficiently long time, and a difference between control and treatment (especially for placebo-controlled trials) was demonstrated. Note in the case of no difference placebo-controlled trials the biomarker then would be a Type 0 marker. It is desirable to have this type of data from several studies to establish the validity of the marker across studies, drugs, and various patient populations. 

Although CD4+ cell count is accepted as a valid surrogate endpoint for HIV disease, its appropriate use as a PD marker in pediatric studies in HIV-infected children is not clear. The CD4+ count is higher in infants compared to older children and does not stabilize until around 5 years of age. Therefore, while successful HIV therapy in adults will typically be associated with increases in CD4+ cells, immunologic success in infants may be manifested by a smaller drop in CD4+ cells or change in the CD4VCD8 cell ratio. 

A surrogate endpoint exists (e.g., a marker that shows activity but is not predictive of therapeutic activity) so that pharmacodynamic data can be generated. For example, a drug for asthma that exerted its effect by reducing inflammatory mediator release... 

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