Perspectives on Biomarker and Surrogate Endpoint Evaluation Discussion Forum Summary (2011) / Chapter Skim
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Appendix B: Summary from the Committee's Report *Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease*
Appendix B: Summary from the Committee's Report *Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease*
Pages 115-130
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From page 115... ...
During its deliberations, the committee identified a need for the FDA to evaluate biomarker use with the same degree of scientific rigor across the product categories regulated by the agency, including drugs, biologics, devices, foods, and supplements. The committee has also recommended strategies for implementing the evaluation framework, supporting the use of evidence-based regulation, and the protection and promotion of public health.
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From page 116... ...
Cholesterol and blood sugar levels are biomarkers, as are blood pressure, enzyme levels, measurements of tumor size from MRI or CT, and the biochemical and genetic variations observed in age-related macular degeneration. Emerging technologies have also enabled the use of simul
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From page 117... ...
These signatures can also be combinations of several of these types of measure ments; ideally, each component of a signature is identified. Biomarkers are used to describe risk, exposures, intermediate effects of treatment, and biologic mechanisms; as surrogate endpoints, biomarkers are used to predict health outcomes.
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From page 118... ...
Further, the committee notes that endpoints can be conceptualized in a spectrum. At one end are endpoints defined by biomarkers alone that have less relationship to patient or consumer experience; in the middle are clinical events that depend on biomarkers as part of the definition; further along the spectrum are endpoints that are more closely related to events that affect patients' and consumers' lives; and at the other end of the spectrum are the clearest clinical endpoints, such as death.
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From page 119... ...
Biomarker Evaluation Process The committee concluded that it was important to address several challenges revealed by previous biomarker evaluation efforts. First, preanalytical and analytical validation of biomarker tests has often been underemphasized in that it has not been considered an integral component of biomarker qualification.
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From page 120... ...
Recommendation 1: The biomarker evaluation process should consist of the following three steps: 1a. Analytical validation: analyses of available evidence on the ana lytical performance of an assay; 1b.
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From page 121... ...
In addition, the circle in the center signifies ongoing processes that should continually inform1, editable biomarker evaluation process. Figure each step in the and training are needed to conduct the evaluation reviews, focusing on the utilization step, because case-by-case analyses are the only way to ensure proper use of biomarkers given the state of the science.
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From page 122... ...
value cutoff concentration, and the total imprecision at the cutoff concentration. Depending on the use, biomarker tests need to be reliable, need to be reproducible across multiple laboratories and clinical settings, and possess adequate sensitiv ity and specificity for the biomarker being measured before data based on their use can be relevant in the subsequent biomarker evaluation steps.
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From page 123... ...
Although deterministic reasoning ultimately means that every contribut ing factor to the biomarker–intervention–clinical endpoint link is defined and understood, probabilistic reasoning emphasizes epidemiological and statistical relationships, acknowledging that all contributing factors are generally not fully understood and that some factors may be fundamen tally random. Related to the first component of qualification, prognostic value can be assessed by using concepts described by criteria proposed for estab lishing causation of noninfectious diseases (Advisory Committee to the Surgeon General, 1964; Hill, 1965)
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From page 124... ...
Strong evidence and a compelling context are needed for the utilization of a biomarker as a surrogate endpoint in situations with regulatory impact. In the case of chronic disease, where there are multiple pathogenetic pathways leading to development of clinical outcomes and multiple manifestations of disease, the probabilistic nature of predictions made using biomarker data means that no biomarker can give absolute certainty of an event's future occurrence nor absolute certainty of the timing of
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From page 125... ...
Clinical and surrogate endpoints have been defined in a way that may imply a clear distinction between the two, in that clinical endpoints typically reflect patient or consumer experience and surrogate endpoints do not. However, there is discussion surrounding this issue, which illustrates the scientific complexity of the distinc tion between clinical and surrogate endpoints.
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From page 126... ...
These potential harms emphasize the need to weigh a biomarker's potential context of use in the utilization step. The committee's biomarker evaluation framework is intended to accomplish the goal of consistent evaluation of biomarkers across different types of products and contexts of use.
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From page 127... ...
While review of proposed health claims takes into account the relationship of the specific substance that is the subject of the health claim to the health outcome of interest, it may not adequately consider the modifications of the substance's effect on the disease outcome by other bioactive components in that food or the diet. An individual substance or product composed of multiple substances may impact one or more biological pathways, each raising or lowering risk for a chronic disease or condition.
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From page 128... ...
In other words, a surrogate endpoint may not be on the causal pathway of the disease process and a substance or intervention may have mechanisms of action independent of the disease process. Dotted lines indicate possible pathways.
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From page 129... ...
2010. Evaluation of biomarkers and surrogate endpoints in chronic disease .
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