A Friends of Cancer Research white paper proposes statutory changes allowing different levels of biomarker evidence across drug development stages, as well as near-term steps for the FDA to make the qualification process more transparent, predictable and useful.
Key Takeaways
- The FDA’s biomarker qualification program is a single, all-or-nothing determination out of step with evidence generation, a Friends of Cancer Research working group said in a white paper.
- Legislation is needed to implement a risk-based, tiered qualification framework better aligned with real-world drug development and biomarker evidence generation.
- The FDA can improve qualification transparency and review timelines, as well as the consistency in how review divisions apply determinations.
A Friends of Cancer Research working group wants an overhaul of the US Food and Drug Administration’s biomarker qualification program to better reflect evidence development over time, including statutory changes to establish a tiered, risk-based approach to validation.
In addition, the FDA should increase oversight of qualification program review timelines and performance, clarify the use of qualified biomarkers in clinical trials, and ensure consistent biomarker acceptance across review divisions, an FOCR working group said in a new white paper.
“Near-term improvements could be advanced through FDA guidance, internal policy, and structured engagement to better operationalize the intended role of qualification,” the white paper states. “These efforts should focus on making the pathway more transparent, predictable, and useful in practice, including clearer mechanisms for COU [context of use] expansion, more systematic use of prior evidence and regulatory experience, and improved engagement as evidence matures.”
“Longer-term reforms may require legislative action, particularly to support formal tiered recognition, dedicated resourcing mechanisms, and clearer accountability for program performance,” the working group said.
The biomarker qualification program established under the 2016 21st Century Cures Act is under-resourced and under-utilized, resulting in lengthy delays in new biomarkers qualifications and stalled packages.
The FDA’s drug development tools program, which includes biomarker qualification, is expected to get a boost under PDUFA VIII, which will begin in October 2027. Negotiations between the FDA and industry to renew the prescription drug user fee program have been completed, although commitment letter language has not yet been publicly released.
FOCR and other groups are pushing for statutory changes to the program. They also want FDA administrative changes to establish predictable processes and clear accountability mechanisms, as well as strengthen institutional and regulatory alignment.
Single, End-Stage Decision Is Problematic
During a June 9 briefing on the white paper, working group members said the qualification program’s structure is not aligned with real-world drug development and biomarker evidence generation.
The current qualification process involves step-wise submission of a letter of intent, qualification plan and full qualification package.
“Biomarker qualification largely functions as a single, all-or-nothing determination, requiring a complete evidentiary package before meaningful regulatory recognition,” the paper states.
However, evidence development often occurs in stages, and “we don’t have an ‘aha’ moment where we have the soup to nuts of it laid out,” said Rasika Kalamegham, head of US regulatory policy at Genentech.
“The pathway is almost disconnected from that reality of science and expects all of us to present the FDA with a bolus of data that answers all of these questions,” she said.
“What we have now in the qualification model is this single, end-stage decision,” said Lauren Oliva, US regulatory policy lead at Biogen. “It’s like all of your eggs are in that basket.”
The white paper proposes a tiered, “or more lifecycle-based, approach … reflecting more how biomarker evidence does get generated,” Oliva said. “What I’d really love to see is BQP to become less of that single determination and more durable and predictable in reflecting how those biomarkers are actually developed in practice.”
A tiered, risk-informed framework would recognize distinct stages of biomarker validation while aligning evidentiary expectations with the regulatory risks associated with the proposed use of the biomarker, the white paper states. For example, higher-risk applications, such as surrogate endpoints used to support product approval, would require more robust validation than biomarkers for exploratory analyses.
Tiers would reflect stages of evidence maturity and regulatory recognition. The level of evidence needed within each tier would depend on the biomarker’s novelty, prior evidence and intended regulatory role.
The proposed tiered mechanism “would allow you these degrees of freedom,” Kalamegham said. “So if you are just changing the technology that is being used in the tool to capture a measure, there is one level of evidence that would be needed. But if you are proposing a wholesale brand new biomarker that has never been seen before but is based on new biology, new evidence, that would require a different level of evidence generation.”
Michael Montalto, VP of precision medicine global development at Amgen, compared a tiered biomarker qualification approach to accelerated approval for new drugs.
“It’s really not hard to imagine having different thresholds of evidence depending on how we want to use” a biomarker, he said.
A tiered evidentiary framework also could make the qualification pathway more manageable.
“When the qualification program was conceived, the concept really hinged on a single entity seeing this process through, from submitting the letter of intent to getting it fully qualified, whether that is a sponsor or a consortium or whatever it might be,” Kalamegham said.
However, very little drug development tool work is carried out by a single entity, she said. Vendors who develop tools or diagnostics are different from clinical experts who can show the value in measuring a marker differently or developing a new tool.
“One possible advantage of having this tiered expectation is also that each entity is able to come in, contribute what they can, and then leave it for the next entity to pick up and start building on it,” Kalamegham said.
Some Statutory Changes Needed …
Formal implementation of a tiered framework would require statutory changes.
“The current statute defines qualification as a single determination based on a complete evidentiary package for a defined COU and establishes the sequential LOI, QP, and FQP process,” the white paper states.
“As a result, Congress should revise statutory authorities to support staged or incremental recognition of biomarker evidence, tiered evidentiary pathways aligned with the biomarker’s regulatory role and associated risk, and more flexible entry into qualification review based on the maturity and completeness of the available evidence,” the paper states.
If statutory changes are enacted, FDA guidance should further define evidentiary thresholds for each tier, expectations for progression across tiers, mechanisms for COU expansion, and show how tier assignments, evidentiary gaps and regulatory uses are communicated to requestors.
… But FDA Can Make Its Own Improvements
Aside from statutory changes, the FDA also can take steps to improve the qualification process, the white paper states.
Agency officials could improve transparency and feedback in qualification decisions by publishing submissions and determination letters with clearly defined and communicated timelines, expanding the publication of qualification submissions beyond executive summaries, standardizing feedback across BQP stages, and increasing review process transparency.
The FDA should establish more predictable engagement and review timelines, including providing regular status updates and clarifying expectations for when and how requestors should re-engage with the agency as they generate new evidence or when measurement tools or analytical approaches evolve during development.
The agency also should strengthen incentives and support consistent prioritization of BQP reviews, including clarifying coordination across product centers and ensuring BQP activities are prioritized alongside user fee programs.
The work group also recommended addressing the lack of predictability in how the FDA operationalizes qualification decisions.
The agency should establish clearer internal expectations for interpreting qualified biomarkers within their COU across divisions and strengthen cross-center and cross-division coordination during qualification and product reviews.
The FDA should allow regulatory lessons generated in product-specific programs to more consistently inform qualification. COU expansion based on incremental evidence that builds on prior knowledge and regulatory experience, rather than requiring redevelopment of the full evidentiary package, also would be beneficial.
The agency also should support prospective planning for anticipated modifications, similar to Predetermined Change Control Plans for medical devices, where requestors define anticipated COU expansions and identify the corresponding clinical evidence requirements early.
“This approach would enable predefined expansion of a qualified biomarker such that it can be deployed in multiple [clinical development plan] pathways and reduce duplicative review as evidence matures,” the white paper states.