The public qualification pathway created in the 21st Century Cures Act has “not lived up to its billing,” but draft commitment letter language could help to address funding, expertise and incentive shortfalls.
Key Takeaways
- The FDA biomarker qualification program established in the 21st Century Cures law is under-utilized and under-resourced.
- The FDA and industry agreed on draft PDUFA VIII commitment letter language that could help address some of the program’s shortfalls.
- Former FDA official Janet Woodcock said the agency’s staffing problems will force nongovernmental entities to lead biomarker development for the next few years.
The US Food and Drug Administration’s biomarker qualification pathway could be boosted by the next prescription drug user fee reauthorization.
The FDA and industry have agreed on proposed draft commitment letter language for drug development tools (DDTs), including biomarker qualification, according to Jan. 8 Premarket Subgroup meeting minutes in the PDUFA VIII negotiations.
Although details about the agreement are not reflected in the minutes, the proposal could address some shortfalls highlighted by industry and former FDA officials at a recent Friends of Cancer Research meeting on modernizing oncology endpoints.
Experts said the under-used biomarker qualification program suffers from a lack of dedicated resources and multidisciplinary expertise and could benefit from a change in focus.
The FDA’s recent staffing upheavals also created challenges, and non-agency entities may need to play a bigger role in driving biomarker development, a former senior FDA official said.
Few Biomarkers Qualified
The 2016 21st Century Cures legislation established a public process for FDA qualification of DDTs, which include biomarkers, clinical outcome assessments and animal models.
The DDT program also is available for emerging and advanced tools, such as organ-on-a-chip models and artificial intelligence (AI)-enabled tools, under the Innovative Science and Technology Approaches for New Drugs program. ISTAND launched as a pilot in 2020, but recently transitioned to a permanent program.
The qualification process is based on three steps: submission and FDA acceptance of a letter of intent (LOI), submission and acceptance of a qualification plan, and submission and approval of a qualification package. The FDA aims to complete its reviews of complete LOIs, qualification plans and full qualification packages within three, six and 10 months, respectively, according to a November 2020 final guidance.
After a DDT is qualified for a particular context of use, it is broadly available for drug development programs.
As of Jan. 1, 151 DDT projects were in development, with 20 qualified, according to the FDA’s website.
Sixty-three biomarker projects are in development, with 11 qualified. Eight of the qualified biomarkers were reviewed under the legacy process that predated Cures, according to a recent FOCR study published in Therapeutic Innovation and Regulatory Science.
“For ongoing projects, reviews often exceed expected timelines, and about half have not progressed beyond initial LOI acceptance,” the article states.
Three biomarkers were qualified in the last two months of 2025:
- Serum glutamate dehydrogenase as a safety biomarker to assess drug-induced liver injury
- The AIM-NASH system, an AI-based histologic measurement of nonalcoholic steatohepatitis, also known as metabolic dysfunction associated steatohepatitis
- Bone mineral density as a surrogate endpoint for assessing fracture risk reduction with osteoporosis treatments, which was the first surrogate endpoint qualified through the DDT program, although the agency’s final decision came almost a year later than expected.
Looking For PDUFA Resources
The biomarker qualification program lacks a funding mechanism and has limited guidance on opportunities for iterative interaction with the FDA, FOCR said in its review.
“An optimized program could provide timely advice to help researchers identify and address potential challenges and, if they are unable to be overcome, facilitate more efficient withdrawals from the qualification program,” the article states.
“Targeted enhancements and dedicated funding for the BQP, potentially supported by allocating PDUFA resources to divisions participating in the review of a given qualification plan, could enable more timely, structured engagement with specific FDA therapeutic area experts,” the article states. “Additional resources to support the divisions overseeing biomarker qualification should be accompanied by expected timelines for interactions, such as meeting requests and conduct, feedback deadlines, and review periods.”
Rep. Diana DeGette, D-CO, a co-author of the Cures legislation, told the FOCR meeting the limited number of biomarker qualifications under the program suggests something “just isn’t clicking here.”
“Prescription drug user fee negotiations are happening now, as you know, so let’s lock in resources for biomarker qualification,” she said.
The current iteration of the PDUFA program expires in September 2027. Reauthorization negotiations began in late 2025.
At a Dec. 5 stakeholder meeting, FDA representatives said the biomarker qualification program faces delays when subject matter experts from various divisions are unavailable due to staff shortages. The program does not routinely use independent advisory committees, but will consult with individual independent experts on an ad hoc basis, the meeting minutes state.
“Multiple stakeholders expressed strong support for the program and stated the need to resource it with PDUFA resources,” the minutes state. “There was appreciation for the program’s collaborative approach in working with review divisions to ensure qualified biomarkers are effectively integrated into the broader regulatory framework.”
Public Process, Resources Pose Challenges
The Cures biomarker qualification program has not “lived up to its billing” due, in part to its public nature, said John Stone, principal of BGR Group, who helped lead the development and passage of the Cures legislation as a House Energy and Commerce Committee staffer.
Earlier iterations of the Cures legislation also included a separate, proprietary pathway that industry favored, but the FDA opposed due to resource issues, he said.
“Once the proprietary framework fell out, I think the excitement went away a little bit,” Stone said. “We ultimately landed on this public framework that … has not been utilized as wholeheartedly or efficiently as some would have hoped.”
Michael Montalto, VP of precision medicine-global development for Amgen, previously served as PathAI’s chief scientific officer and helped shepherd the company’s AIM-NASH system through the qualification process. He said biomarker development and qualification “is a little bit in this no-man’s land between drug development and the agency, as well as [the Center for Devices and Radiological Health] and all the regulatory qualifications that live there.”
The qualification process for AIM-NASH took five years. Since the biomarker program is not tied to user fees and lacks dedicated resources and staff, “that really materialized in long gaps in time between the various stages of the qualification program and not really understanding what the agency would accept for validation,” he said.
The multidisciplinary expertise needed to assess many submissions is often lacking, said Tala Fakhouri, former associate director for data science and AI at the FDA’s Center for Drug Evaluation and Research. Submissions containing AI components may go to CDRH, which eventually sends them back to CDER, said Fakhouri, who is now Parexel’s VP consulting for AI, digital policy and real-world research.
Lack Of Incentives
Incentives to participate in the public qualification process also are limited, industry experts said.
“Sponsors aren’t in the business of developing drug development tools,” Montalto said. “Diagnostic companies are, and emerging platform companies are.”
“They’re not really incented because the process takes so long, and they don’t really have assurances that there’s going to be a market even after five years” given the speed of technological change, he added.
In addition, academic organizations and small tech companies that are developing DDTs “don’t want to make information about their tool public because it is proprietary,” Fakhouri said.
Drug sponsors also may be reluctant to include emerging biomarkers as secondary endpoints in prospectively designed trials.
“A lot of clinical development teams will have concerns about that because the data could be used against them and this is a very kind of, at times, exploratory technology,” Montalto said. “Assurances, I think, that the sponsors can use the technology prospectively without having it kind of backfire on them is important.”
Incentives are not aligned to help the DDT qualification process grow in a meaningful way, Fakhouri said.
“At least from where I used to sit and see a lot of submissions coming in, it’s repetition again of the same errors or the same issues across sponsors that could be solved if there was a strong qualification program,” she said.
“Aligning incentives is important,” Montalto said. “Better guidance, I think, in terms of the actual adherence to the timeframe throughout the program, all those things are important.”
Fakhouri suggested the program would benefit from reframing its focus.
“We seem to always conflate analytic validation of tools with the clinical validation of tools, instead of getting qualification on the method itself so that then it can be used in different contexts,” she said. “I think that would open the door for a lot of sponsors to integrate these tools in their drug development programs.”
“You get analytic qualification for the construct, the measure that you’re trying to capture, and then that qualification applies for all sponsors,” Fakhouri proposed. “And then what you have to do for your clinical development program is show the clinical validation for your specific disease condition, which should be a much smaller step than doing everything from scratch every single time.”
Another Area For Non-FDA Stakeholders To Lead, Woodcock Says
Given the FDA’s large staffing losses in recent months, the nongovernmental sector, including patient and professional groups and industry, must lead on biomarker development for the next few years, said Janet Woodcock, former acting commissioner and long-time CDER director.
“The agency has been leading on this for the last 20 years. There’s no necessity it is FDA,” she said. “This science isn’t restricted to the agency, but FDA has led for so long people look to the agency saying you should develop the biomarkers, you should do this, but that’s not how it’s going to work.”
Woodcock also has told industry and other groups to take the lead on drug policy development in the wake of FDA staff cuts.