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Biomarkers are essential to the entire drug development life cycle, as they can improve the success rate of a drug development program, in addition to expediting time-to-market.

Biomarkers can be used for a wide range of purposes, including monitoring the safety of a drug or therapy and determining whether treatments are achieving desired outcomes. Moreover, biomarkers have the potential to reduce costs and save time during clinical trials by predicting which patients may respond more favorably to a drug from a safety or efficacy perspective.

Figure 1. The role of biomarkers throughout the drug development life cycle

Regulatory pathways for the integration of biomarkers in drug development

The US Food and Drug Administration (FDA) outlines three primary sources for biomarker evidence, which include scientific community consensus, drug-specific development and approval process, and the biomarker qualification program (Figure 2). Although each pathway has its own strengths and limitations, biomarkers should be carefully evaluated with respect to the pathways detailed below, as specific pathways will be more appropriate for some biomarkers.

Scientific community consensus

Published scientific literature provides the basis for the hypothesis regarding the use of a specific biomarker in the drug development process. Drug developers who pursue the regulatory pathway of scientific community consensus rely on available, published data that has informed scientific community consensus, which has been scrutinized and reviewed by multiple stakeholders. This extensive review and evaluation can lead to a greater understanding of biologic processes or diseases. Yet, drug developers looking to determine the clinical utility of a biomarker may face challenges when solely relying on scientific literature, due to the fact that the studies that inform scientific literature are often a product of varying objectives, which can result in complications and challenges when correlating and comparing information across multiple publications.

Drug-specific development and approval process

Drug developers are encouraged to utilize the drug-specific development and approval process when biomarkers are developed for a particular investigational new drug (IND) or biologic program. Although the drug-specific development and approval process regulatory pathway is expected to be utilized for to achieve regulatory acceptance of biomarkers that are intended to be used for a specific candidate drug, other drug developers or drug companies can make use of the information provided for any specific drug program if it can be demonstrated that the biomarker is suitable for more generalized applications.

Biomarker qualification program

Biomarkers can be qualified through the Center for Drug Evaluation and Research’s (CDER’s) Biomarker Qualification Program. CDER’s Biomarker Qualification Program is responsible for qualifying biomarkers for a specific context of use, and once qualified, these biomarkers become publicly available and can be applied to any drug development program where the context of use (COU) is appropriate. In these instances, there is no need to review the information again. The intent of the Biomarker Qualification Program is to establish the value of a biomarker to be used in drug development for a specific COU. The FDA defines context of use as a concise description of the biomarker’s specified use in drug development, comprised of two components, the BEST biomarker category, and the intended use of the biomarker in drug development. A single COU should be associated with each biomarker qualification effort.

Figure 2. Regulatory pathways for the inclusion of biomarkers in drug development

Determining the right regulatory pathway for your biomarker

Drug developers may have some difficulty determining which regulatory pathway is the best fit for a specific biomarker in the early stages of drug development. In these cases, drug developers are encouraged by the FDA to contemplate several factors, including the reasons and circumstances for using the biomarker in drug development, available resources, the type of biomarker, and opportunities to collaborate and partner with others. As biomarker development is a voluntary activity, regardless of whether the drug developer is a single company or a consortium, the selection of a regulatory pathway is always left to the discretion of the drug developer.

Considerations for biomarker qualification

The context of use (COU) for a biomarker needs to be clearly defined when biomarkers are submitted to CDER for qualification. For instance, targeted patient selection for clinical trials is enabled by enrichment biomarkers, allowing for the identification of a patient population in which the drug candidate will likely have the most significant effect. Another example of context of use would be a surrogate endpoint biomarker, used as an endpoint in a clinical trial, to determine whether the drug is effective, and patients are experiencing the expected therapeutic effect.

The required evidence for biomarker qualification is not uniform or standard for all biomarkers submitted to CDER; rather, evidentiary criteria are dependent upon the potential impact on patients. Evidentiary criteria differ for distinct types of biomarkers, and when the stakes of the biomarker being correct are extremely high and the consequences of a wrong predication are very serious, the evidentiary criteria bar is greater. However, some common criteria for qualification of biomarkers are in place regardless of context of use, including robust analytical validity (Figure 3).

Figure 3. Evidentiary framework for biomarker qualification

Partnering with a CRO/CDMO to support the use of biomarkers in drug development

Choosing the right contract research organization (CRO) or contract development manufacturing organization (CDMO) partner for bioanalytical support for your biomarker throughout the entire drug development life cycle is just as critical as selecting the right regulatory pathway. The right CRO/CDMO partner can help your organization ensure regulatory requirements are met to gain approval for the use of a specific biomarker throughout the drug development life cycle.

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