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Regulatory Considerations

The importance of qualified biomarkers to provide valuable information that can help reduce uncertainty in regulatory decisions is well-recognized. Accordingly, regulatory agencies have established strict guidelines for the qualification process of biomarkers. In the US, the 21st Century Cures Act describes the process to develop a biomarker for regulatory use. To help sponsors with the development of biomarkers, the US FDA also has several resources, including the Biomarker Qualification Program, through which developers may request regulatory qualification of a biomarker for use in drug development (FDA 2018a).

When a new biomarker is proposed for use as a surrogate endpoint, the US FDA uses the type C meeting process to engage sponsors in discussions around the feasibility and limitations of the surrogate as a primary efficacy endpoint. Incidentally, the FDA is required by law to make public a list of “surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product” (FDA 2018a). The information, which is updated periodically, is expected to facilitate discussions between sponsors and the FDA on the use of potential surrogate endpoints. It should be underscored that a surrogate endpoint that is validated for a specific pharmacologic class of treatment regimens is not necessarily valid as a surrogate endpoint for other classes of drugs. Indeed, the acceptability of a surrogate marker is context-dependent, relying on several factors, including the disease, patient population, therapeutic mechanism of action, and availability of current treatments (FDA 2018a).

The US FDA relies on the accelerated-approval regulatory process to enhance the accessibility of medicines to patients with unmet needs, especially for conditions leading to death or serious illness. The process involves granting approvals to market interventions that demonstrate strong effects with respect to reasonably likely surrogate endpoints, i.e., reasonably likely to predict a clinical benefit. This implies that the evidentiary strength of the effect of treatment on the surrogate must be strong. The approval is granted with a requirement that the sponsors also conduct postapproval clinical trials to show that these markers can be relied upon to predict, or correlate with, clinical benefit. However, as argued in Fleming (2005), the use of such surrogate markers in accelerated approvals requires addressing important operational challenges, including timely completion of the postapproval commitment trials, to protect the best interest of public health.

The European Medicines Agency (EMA) also provides several guidelines relating to the qualification of biomarkers, highlighting important points to consider that have been identified as common and major challenges and limitations (EMA 2017a). A successful qualification process presupposes adequate demonstration of diagnostic and prognostic performance, predictive value for clinical outcome, as well as sensitivity to detect change reflecting the clinical status of patients. In addition, the guidelines stress that the study design and statistical methodology to be used must be prespecified, and that the clinical utility and the appropriateness of the analytical platform should be justified.

Concluding Remarks

The development of reliable and valid biomarkers is a critical component of drug development and regulatory review. In this section, we highlighted several statistical and regulatory issues associated with the development and qualification of biomarkers. When used as a surrogate endpoint, a biomarker serves as a substitute for a clinical endpoint, which directly quantifies clinical benefit or harm. Therefore, the development of a biomarker as a surrogate endpoint should also undergo a process consisting of analytical validation based on extensive documentation, and subsequent qualification by a regulatory body.

While the main emphasis in this section is on biomarkers that can be used as surrogate endpoints, there is also a growing interest in the use of biomarkers to enrich clinical trials, with a view to enhancing the efficiency of drug development and advancing the field of precision medicine. Such strategies may restrict inclusion of patients with a specified biomarker (to reduce variability), patients in high risk categories (prognostic enrichment), or patients who are more likely to respond to the study drug (predictive enrichment) (FDA 2019).

Finally, under certain circumstances, especially in the absence of evidence on relevant clinical endpoint that directly measures clinical benefit, surrogate endpoints can be acceptable for relative effectiveness assessment (REA) in pricing and reimbursement negotiations. As outlined in a recently issued guideline, acceptability of surrogate endpoints for REA requires equally rigorous scientific and clinical knowledge for the qualification of biomarkers as surrogate endpoints (EUnetHTA 2013). This includes demonstration of the relationships between the surrogate and the clinical endpoint based on biological plausibility and empirical evidence. In addition, the guideline recommends that the level of evidence, the associated uncertainties, and any limitations of their use should be explicitly explained. Further, it is noted that if a surrogate endpoint has already been adequately validated, it is not essential to carry out additional validation just for REA purposes.

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