Clinicians have often pushed for certain biomarkers to move from serving a purely informative role in clinical trials to becoming surrogate endpoints, which can provide a measure of a treatment’s efficacy and form the basis of new drug approvals.
Regulators, meanwhile, are often reluctant to accept biomarker data in lieu of more definitive clinical outcomes.
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The value placed on biomarkers by the FDA has been clouded amid a succession of changes in the agency’s top personnel. Dr. Vinay Prasad, who has criticised using biomarkers endpoints to support accelerated approvals, has assumed and dropped leadership over the FDA’s Center for Biologics Evaluation and Research twice in the past year. In February, gene therapy developer Regenxbio received a complete response letter (CRL) from the US Food and Drug Administration (FDA) for its RGX-121 therapy for mucopolysaccharidosis (II). The CRL, among other things, highlighted the FDA’s issue with the use of the CSF HS D2S6 as a surrogate endpoint to predict clinical benefit.
Ann Mongan, director of translational research at Bristol Myers Squibb (BMS), spoke with Pharmaceutical Technology about how biomarkers could be help build surrogate clinical endpoints, and the balance between using biomarker-derived and clinical outcome measures in trials.
Mongan will be speaking on fine-tuning biomarker selection to enhance oncology drug development at the Clinical Trials in Oncology West Coast conference, which is scheduled to take place in San Diego, 28–29 April 2026.
Frankie Fattorini (FF): The FDA has several avenues to approve new biomarkers, one of which is the Biomarker Qualification Programme established in 2007. Only six clinical biomarkers have been approved through this programme. Is the pace of new biomarkers entering clinical use slow?
Ann Mongan (AM): I think there is a little misunderstanding on whether biomarkers have to be approved to be useful. I would say more than 90%, if not more than 95% of biomarkers we use for clinical development do not necessarily have to be approved for clinical decision making.
Biomarkers inform the drug developer about the drug and its pharmacodynamic characteristics. If you don’t have biomarker, you essentially run a black box experiment. The drug either works or it doesn’t, and then you don’t really know anything about how to iterate.
In general, clinical studies in early development don’t publish a tonne of biomarker [data] unless there is any reason to. Here are a few reasons: When certain biomarkers are known to inform the course of the disease, those could be approved as surrogate endpoints; there are also predictive biomarkers that are used to enrol patients into the clinical study and may become companion diagnostics tied to the drugs.
Other than that, there wouldn’t necessarily be much reason for health regulators to approve a biomarker that only informs the drug developer about how the drug works, unless it impacts the patient.
FF: Is there a general discordance between researchers and regulators on the value of biomarkers as surrogate endpoints?
AM: In general, the health regulators are very conservative about approving surrogate endpoints because they are not definitive evidence yet that the drug is modifying the disease.
In the case of multiple myeloma, there has been a push to use minimal residual disease (MRD) negativity as a biomarker. MRD negativity indicates if you can detect the myeloma cells in the bone marrow or in the blood of the patient.
The FDA’s Oncologic Drugs Advisory Committee (ODAC) approved it in a unanimous 12-to-zero decision. But if you think about it, unanimous decision means that there is no controversy. By the time you amass so much data that nobody can have any objection to it, that means that they might have waited too long.
So, yes, I think in general the health regulators are very conservative because they don’t want to have to roll back a decision. They are doing their job; they’re there to protect patients. So I think it’s always a dialogue as to where the unmet needs lie and how severe they are.
FF: Is there a balance the needs of a trial to collect biomarker data and long-term survival results?
AM: Particularly in rare diseases or diseases that have a long course, such as neurodegenerative diseases like Alzheimer’s, if there is sufficient evidence that biomarkers are indicative of the progression of the disease, then being a little more aggressive in adopting those alternate clinical endpoints would be really helpful for patients.
This may feel unfair in some ways, because for such conditions, the patients and the payers don’t have the same certainty that a drug works compared to other diseases. But this is balanced with the magnitude of the unmet need for that condition.
FF: The FDA has seen several changes in personnel at top levels, with varying views of the value of biomarker data in making drug approval decisions. How predictable is the agency’s position on biomarkers?
AM: Regardless of the individual or the makeup of the FDA, I think science will triumph. Drug approval is not driven by a single health authority. There are health authorities across the world like the FDA and European Medicines Agency (EMA) and others around the world so when there is sufficient scientific evidence you can see a general trend. [Approvals] might slow down because of various other factors that we can’t control, but I don’t see this trend changing course.
As a community, I think we collectively believe that these biomarkers help us have a better understanding of the drug, the disease, and the long-term benefit for the patients. If you take patients and clinicians out of the equation, they can benefits payers too. The payers understand the value of these biomarkers, which inform them whether the drug is benefitting the patient long term.
FF: You’ll be speaking later this month at the Clinical Trials in Oncology West Coast conference on fine-tuning biomarker selection to enhance oncology drug development. What will this entail?
AM: I will outline a framework for translational research and translational development, specifically, how to learn about the new drug so that you can prepare for the next step. It’s not necessarily about which biomarker can be used, but about what kind of questions one needs to ask about the molecule given the target, biology, disease, and treatment landscape.
A detailed agenda for 13th Annual Clinical Trials in Oncology (CTO) West Coast conference can be accessed here. The conference is hosted by Arena International Events Group, a B2B events company owned by GlobalData, the parent company of Clinical Trials Arena and Pharmaceutical Technology.
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