Sluggish biomarker program offers FDA opportunity for reform

A paper recently published by the Friends of Cancer Research shows the FDA is moving slowly to qualify new biomarkers through a program formalized by the 21st Century Cures Act. The organization suggests more resources, possibly through user fees, could help.

Background on biomarkers

• Biomarkers are a vital tool for disease diagnosis, patient risk assessment and drug development. The FDA describes biomarkers as defined, measurable characteristics of the body that indicate biological and pathogenic processes, or the response to an intervention such as use of a medical product. While clinical assessments can capture how a patient feels, functions or survives, biomarkers provide researchers with a valuable window into the body’s inner workings. These tests can be molecular, histologic, radiographic or physiologic.
• Biomarkers have a variety of purposes. They can diagnose, such as how sweat chloride is used to confirm cystic fibrosis; determine risk, as BRCA gene mutations do for assessing the likelihood of breast cancer; or monitor disease status, as prostate-specific antigen levels can indicate tumor burden in people with prostate cancer. They’re also used to watch for treatment side effects and to measure patient response to a drug.
• Measuring drug response is a particularly important use case, allowing biomarkers to be used as clinical trial objectives, including as “surrogate endpoints,” which are meant to be predictive of clinical benefit. One example in oncology is objective response rate: Researchers assess whether a treatment shrinks the size of a target tumor under the assumption that reductions will correlate in some fashion with longer survival. Blood sugar levels are another well-known example, used in the testing of drugs for diabetes. The FDA maintains a list of surrogate endpoints that have supported traditional or accelerated drug approvals.
• The FDA validates biomarkers in two principal ways. They can be confirmed through the agency’s review and approval of a new drug or biological product, or through a qualification process the agency established in 2007. This process was formalized in 2016 through the 21^st Century Cures Act, which outlined a three-stage pathway for groups to submit prospective biomarkers for FDA verification.
• The Biomarker Qualification Program, or BQP, is meant to address a market failure of sorts. “One of the problems with biomarkers is there is really no one in charge of developing them,” explained JANET WOODCOCK, a former top FDA official, in an undated video on an FDA webpage about biomarker development. “What we are seeking at FDA is public adoption of new biomarkers by the scientific community, and that would mean that anyone who was doing a trial, say, and wanted to monitor kidney safety or do enrichment, they don’t have to go through evaluating the biomarker, seeing if it’s fit for purpose in their development program, doing preliminary work on it, and all that.”
• The development pathway outlined in the 21^st Century Cures Act was designed to be more structured and more transparent. As detailed in a 2020 final guidance, developers first submit a letter of intent, which the FDA reviews and decides whether to accept. If accepted, developers are tasked with assembling a qualification plan that the FDA has six months to review upon submission. An accepted qualification plan is then expanded into a full qualification package that the FDA must assess within 10 months after filing. Qualified biomarkers are available for general use in support of an investigational new drug or approval application.

Trouble-shooting a slow-moving program

• The FDA has only qualified eight biomarkers through the BQP, and most were qualified prior to the 21^st Century Cures Act’s December 2016 enactment, according to a database maintained by the agency. Four of those were qualified to assess safety, two are meant to be prognostic, and the remaining two are validated for diagnosis and monitoring, respectively. The most recent qualification was in 2018.
• A new analysis by the Friends of Cancer Research, published Oct. 28, 2025, in Therapeutic Innovation and Regulatory Science, characterizes the program as slow-moving, marked by review timelines that regularly exceed the FDA’s targets. Median times for FDA review of letters of intent and qualification plans are more than double the agency’s respective three- and six-month guidance. Sponsor development of qualification plans is also slow, taking a median of more than two-and-a-half years among the programs with analyzable timeline data.
• Worth noting: The 21^st Century Cures Act doesn’t set out any specific timeline the FDA must follow, so the target review times are merely the agency’s goal. “FDA aims to complete its comprehensive reviews of complete LOIs, QPs, and FQPs within 3, 6, and 10 months, respectively,” the agency’s guidance states. The organization analyzed median review times for programs submitted following the issuance of the guidance in November 2020, and agency turnaround times remained slower than stated in the guidance.
• Of the 61 programs accepted into the BQP through July 1, 2025, only five were biomarkers intended for use as surrogate endpoints, the authors noted. Sponsors took significantly longer to develop qualification plans for those biomarkers. Of the four programs with available data, the median development time was nearly four years, 16 months longer than the 31-month median for other programs.
• This is a significant issue, Friends researchers wrote, as surrogate endpoint biomarkers hold the most promise to speed review of new drugs. “These trends demonstrate the program may not be well-suited for advancing novel response biomarkers.” The researchers suggested the complexity of developing these biomarkers may be one limiting factor, noting that they typically require more supporting evidence.
• But the program could also benefit from greater resources and greater opportunities for FDA interaction, according to the authors. For instance, there are no dedicated funds tied to the BQP – a shortcoming that could be addressed by linking user fee act resources to FDA divisions that participate in qualification plan reviews. The addition of new resources could correspond with additional meetings and feedback between biomarker developers and the FDA. “Such an approach would help embed BQP review into the established workflow associated with traditional user-fee-supported application review,” they wrote.
• The BQP has been comparatively more effective at encouraging development of safety biomarkers, the analysis found. About one-third of the biomarker programs accepted into the BQP were designed to assess safety, as were four of the eight qualified biomarkers.

Research earlier this year found similar issues of timeliness

• Friends’ paper comes on the heels of other research into the BQP and, more broadly, the Drug Development Tools Qualification program, of which BPQ is a part. Two Harvard Medical School researchers published an analysis of BQP participants this past April in Clinical Pharmacology and Therapeutics, while an analysis of the Drug Development Tools process by researchers from Roche’s Genentech appeared in Therapeutic Innovation and Regulatory Science in May.
• Genentech’s paper is similarly critical of how well the Drug Development Tools initiative is working with regards to another type of measure, known as Clinical Outcome Assessment, or COA. In particular, the Genentech team highlights the “lengthy and unpredictable nature” of review timelines for these COAs, which describe how someone feels, functions or survives. COAs can be submitted to the FDA through the same three-phase process involving letters of intent, qualification plans and full qualification packages, with the same three-, six- and 10-month review timelines.
• The Genentech researchers found the FDA often misses these review targets, with about half of the analyzed programs assessed behind schedule. At the time of their analysis, only seven COAs had been qualified, and only three of those had been used by the agency to support benefit-risk assessments of new medicines. The authors suggest the FDA publish “actual qualification timelines” so developers can better plan their drug development and urged the agency to share best practices.

Analysis: An opportunity to deliver

• Taken together, the papers are suggestive of a regulatory pathway that’s falling short of its intended purpose. Drug Development Tools are meant, as the FDA wrote in its 2020 guidance, to “significantly facilitate” development of new drugs and better integrate “innovative technology and new science and approaches.” However, relatively few of these tools have been qualified through the process outlined in the 21^st Century Cures Act, at least in some part due to the lengthy timelines needed to prepare the required evidence as well as the FDA’s sluggish reviews.
• Alternative pathways may be more fruitful. For instance, NICOLE GORMLEY, director of the FDA’s Division of Hematologic Malignancies II, highlighted at a recent workshop how the FDA can also accept new biomarkers through “collaborative group interactions,” noting as an example minimal residual disease in multiple myeloma.
• One roadblock, as the paper indicates, is resources. With negotiations for the next PDUFA cycle beginning soon, industry and the FDA could explore ways to match the agency’s review of biomarkers via the qualification program with user fee resources. Those resources could be tied to new commitments by the agency on timelines and interactions.
• Investment in Drug Development Tools could align with Commissioner MARTIN MAKARY’s goal of accelerating drug reviews. Makary has returned frequently to this theme, in various contexts, throughout his tenure as agency head. Importantly, Drug Development Tools, by providing common, qualified measures upon which to assess drugs, could benefit many sponsors all at once.
• New commitments and priorities, however, could further tax an agency workforce that’s been greatly sapped by layoffs, and directed to take on new initiatives that will absorb significant staff time.

To contact the author of this item, please email Ned Pagliarulo (npagliarulo@agencyiq.com).
To contact the editor of this item, please email Karen Early (kearly@agencyiq.com).

Key documents:

• Hurry Up and Wait: Timelines and Takeaways from the Biomarker Qualification Program
• Participants in the FDA’s Biomarker Qualification Program
• Has FDA’s Drug Development Tools Qualification Program Improved Drug Development?