Monday, May 20, 2013

Biomarkers versus Surrogate Endpoints

“Biomarkers” and “Surrogate endpoints” are closely related, although a biomarker can serve as a surrogate endpoint, the terms of biomarkers and surrogate endpoints are not synonymous.

FDA Guidance for Industry “Qualification Process for Drug Development Tools” provided the clear definitions for biomarker and surrogate endppoint.

A biological marker or biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or biological responses to a therapeutic intervention.4 A biomarker can define a physiologic, pathologic, or anatomic characteristic or measurement that is thought to relate to some aspect of normal or abnormal biologic function. Changes in biomarkers following treatment may predict or identify safety problems related to a drug candidate or reveal a pharmacological activity expected to predict an eventual benefit from treatment. Biomarkers may reduce uncertainty in drug development and evaluation by providing quantitative predictions about drug performance.

A surrogate endpoint is defined as a biomarker intended to substitute for a clinical efficacy  endpoint. Surrogate endpoints are expected to predict clinical benefit (or harm, or lack of benefit or harm). A clinical endpoint is defined as a characteristic or variable that reflects how a patient feels, functions, or survives.
In the subsequent FDA public workshop “ Measurement in Clinical Trials: Review and Qualification of Clinical Outcome Assessments”. a glossary included the slight different definition for biomarker and surrogate endpoint.

Biomarker — A patient characteristic that is measured as an indicator of biologic processes; normal, pathogenic, or response to a therapeutic intervention. Patient characteristics that are classified as biomarkers are those that are not significantly influenced by rater judgment or patient motivation and effort (e.g., not a measure of a patient’s volitional performance of some defined procedure). Measurements that can (and therefore, should) have a sufficiently well defined procedure for measurement so that minor aspects of rater or technician involvement have no impact on the measurement are included within the category of biomarkers. Biomarkers are not psychomodulated measures.

Surrogate endpoint — An indirect outcome measure that is used as a substitute for a direct measurement of how a patient feels or functions. All biomarkers used as a clinical trial outcome assessment are surrogate endpoints or proposed as surrogate endpoints. The acceptability of a surrogate endpoint is dependent upon a demonstration that it can be used to reliably infer treatment benefit. The term is also sometimes applied to indirect psychomodulated measures to emphasize that they are indirect, and a substitute (replacement) for a direct measure of how a patient feels or functions.
In a paper by Strimbu and Tavel “What are biomarkers?”, biomarker and surrogate endpoint were defined as following:

Biomarkers are by definition objective, quantifiable characteristics of biological processes. They may but do not necessarily correlate with a patient's experience and sense of wellbeing, and it is easy to imagine measurable biological characteristics that do not correspond to patients' clinical state, or whose variations are undetectable and without effect on health. It is also even easier to imagine measurable biological characteristics whose variance among populations is so great as to render them all but useless as reliable predictors of disease or its absence.

In contrast, clinical endpoints are variables that reflect or characterize how a subject in a study or clinical trial “feels, functions, or survives”. They are, in other words, variables that represent a study subject's health and wellbeing from the subject's perspective.

When used as outcomes in clinical trials, biomarkers are considered to be surrogate endpoints; that is, they act as surrogates or substitutes for clinically meaningful endpoints. But, not all biomarkers are surrogate endpoints, nor are they all intended to be. Surrogate endpoints are a small subset of well-characterized biomarkers with well-evaluated clinical relevance. To be considered a surrogate endpoint, there must be solid scientific evidence (e.g., epidemiological, therapeutic, and/or pathophysiological) that a biomarker consistently and accurately predicts a clinical outcome, either a benefit or harm. In this sense, a surrogate endpoint is a biomarker that can be trusted to serve as a stand-in for, but not as a replacement of, a clinical endpoint.
FDA Guidance for Industry “Qualification Process for Drug Development Tools” provided the detail descriptions for the biomarkers.
Biomarkers include measurements that suggest the etiology of, susceptibility to, activity levels of, or progress of a disease. Alterations in biomarker measurements indicate responses  (favorable or unfavorable) related to an intervention. The biomarker may reflect biological processes closely related to the mechanism of action or processes substantially downstream. Biomarkers may assess many different types of biological characteristics or parameters, including
    • genetic composition (e.g., BRCA, HER2)   
    • receptor expression patterns
    • radiographic or other imaging-based measurements (e.g., progressive free survival (PFS), CT lung densitometry, thrombolysis through arteriogram,...)
    • blood composition measurements (e.g., serum enzyme levels, prostate specific antigen) electrocardiographic parameters
    • organ function (e.g., creatinine clearance, pulmonary function tests, cardiac ejection fraction)

Biomarkers can be categorized into three categories:

Prognostic biomarker
a baseline patient or disease characteristic that categorizes patients by degree of risk for disease occurrence or progression. A prognostic biomarker informs about the natural history of the disorder in that particular patient in the absence of a therapeutic intervention.
Predictive biomarker
a baseline characteristic that categorizes patients by their likelihood for response to a particular treatment. A predictive biomarker is used to identify whether a given patient is likely to respond to a treatment intervention in a particular way. It may predict a favorable response or an unfavorable response (i.e., adverse event).
pharmacodynamic (or activity) biomarker
a dynamic assessment that shows that a biological response has occurred in a patient after having received a therapeutic intervention. A pharmacodynamic biomarker may be treatment-specific or more broadly informative of disease response. Examples include blood pressure, cholesterol, HbA1C, intraocular pressure, radiographic measures, and C-reactive protein.

  • Surrogate endpoints are a subset of pharmacodynamic biomarkers; it is likely that only a few biomarkers will be appropriate for use as surrogate endpoints. In other words, only pharmacodynamic biomarker may be qualified as surrogate endpoint.  
  • Prognostic biomarker can be very useful in sub-group analyses.
  • Predictive biomarker can be very useful in designing the enrichment designs.

In Summary,          
  • Surrogate endpoints are biomarkers
  • Not all biomarkers can serve as surrogate endpoints
  • Surrogate endpoints are a subset of pharmacodynamic biomarkers;
  • Surrogate endpoint should predict/be correlated with clinical endpoint, but correlation alone is insufficient

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