The complex interplay between clinical trial methodologies and regulatory approval pathways is currently being shaped by a vigorous debate surrounding the role of biomarkers. Clinicians and researchers are increasingly advocating for specific biomarkers to transition from being mere informational tools within clinical trials to serving as validated surrogate endpoints. This shift, proponents argue, could significantly expedite the evaluation of treatment efficacy and streamline the approval process for novel drugs. However, regulatory bodies, notably the U.S. Food and Drug Administration (FDA), have historically maintained a cautious stance, often preferring definitive clinical outcomes over biomarker-driven data for drug authorization. This ongoing tension highlights a fundamental divergence in perceived risk and reward, with clinicians prioritizing faster access to potentially life-saving therapies and regulators emphasizing the absolute certainty of patient benefit.
The value and application of biomarkers within the FDA’s framework have been subject to considerable flux, partly attributed to a series of leadership changes within the agency. Dr. Vinay Prasad, a vocal critic of utilizing biomarkers as endpoints to support accelerated drug approvals, has experienced a notable tenure marked by repeated appointments and departures from leadership roles within the FDA’s Center for Biologics Evaluation and Research (CBER). His fluctuating involvement over the past year has, at times, introduced uncertainty into the regulatory landscape. A significant example of this regulatory deliberation occurred in February when Regenxbio received a Complete Response Letter (CRL) from the FDA for its RGX-121 therapy, intended for mucopolysaccharidosis type II (MPS II). The CRL cited, among other concerns, the FDA’s reservations regarding the use of cerebrospinal fluid (CSF) levels of heparan sulfate disaccharide (HS D2S6) as a surrogate endpoint to reliably predict clinical benefit in patients. This instance underscores the agency’s meticulous approach to validating biomarkers as proxies for true clinical benefit.
Ann Mongan, Director of Translational Research at Bristol Myers Squibb (BMS), offered insights into the potential of biomarkers to contribute to the development of surrogate clinical endpoints and the critical balance required between biomarker-derived measures and established clinical outcome assessments in drug development. Mongan is slated to present her expertise on refining biomarker selection to enhance oncology drug development at the upcoming Clinical Trials in Oncology West Coast conference. This significant industry gathering, scheduled for April 28-29, 2026, in San Diego, provides a crucial platform for discussing the evolving strategies in oncology research and development.
The Slow Pace of Biomarker Qualification: A Misconception?
Frankie Fattorini (FF) of Pharmaceutical Technology engaged Ann Mongan (AM) on the perceived slow pace of new biomarkers entering clinical use, particularly in light of the FDA’s Biomarker Qualification Programme, established in 2007. Despite its existence for nearly two decades, only six clinical biomarkers have been formally approved through this specific program, prompting questions about its efficacy in accelerating biomarker adoption.
"I think there is a little misunderstanding on whether biomarkers have to be approved to be useful," Mongan explained. "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." She elaborated on the fundamental role biomarkers play in the drug development process, stating, "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."
Mongan further clarified the typical trajectory of biomarker utilization. "In general, clinical studies in early development don’t publish a tonne of biomarker [data] unless there is any reason to," she noted. These reasons include biomarkers that are known to inform disease progression and could potentially be approved as surrogate endpoints, or predictive biomarkers used for patient enrollment that may eventually become companion diagnostics. "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." This distinction highlights that the value of a biomarker is not solely tied to its formal regulatory approval but also to its utility in guiding research and development.
Navigating the Discord: Researchers Versus Regulators on Surrogate Endpoints
FF then probed Mongan on whether a general discordance exists between researchers and regulators regarding the value of biomarkers as surrogate endpoints.
"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," Mongan stated. She cited the example of multiple myeloma, where there has been a strong advocacy for using minimal residual disease (MRD) negativity as a biomarker. MRD negativity signifies the undetectable presence of myeloma cells in a patient’s bone marrow or blood.
"The FDA’s Oncologic Drugs Advisory Committee (ODAC) approved it in a unanimous 12-to-zero decision," Mongan observed. "But if you think about it, a 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." This sentiment suggests that while unanimous approval indicates robust evidence, it might also reflect a prolonged period of deliberation that could have been shortened with earlier acceptance of well-supported biomarker data.
Mongan reiterated the regulators’ mandate: "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." This emphasizes the delicate balance regulators must strike between facilitating innovation and ensuring patient safety.
The Quest for Balance: Biomarker Data Versus Long-Term Survival
The discussion then shifted to the crucial question of achieving a balance between the imperative to collect biomarker data in clinical trials and the need for definitive long-term survival results.
"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," Mongan asserted. She acknowledged the inherent challenges, stating, "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." This perspective underscores the ethical and practical considerations in drug development for conditions with limited treatment options and protracted disease trajectories, where surrogate endpoints could offer a lifeline.
Predicting the FDA’s Stance Amidst Personnel Shifts
The impact of frequent leadership changes at the FDA on the agency’s stance regarding biomarker data was a key point of inquiry. FF asked about the predictability of the agency’s position on biomarkers given these personnel shifts.
Mongan expressed a degree of optimism, suggesting that scientific rigor ultimately prevails. "Regardless of the individual or the makeup of the FDA, I think science will triumph," she stated. "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." She conceded that "Approvals might slow down because of various other factors that we can’t control, but I don’t see this trend changing course."
Mongan concluded this point by highlighting the collective belief within the scientific and pharmaceutical community regarding the value of biomarkers. "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 benefit payers too. The payers understand the value of these biomarkers, which inform them whether the drug is benefiting the patient long term." This suggests a broader consensus on the utility of biomarkers that extends beyond clinical decision-making to encompass economic considerations for healthcare systems.
Enhancing Oncology Drug Development Through Biomarker Selection
Looking ahead, FF inquired about the specifics of Mongan’s presentation at the Clinical Trials in Oncology West Coast conference, focusing on fine-tuning biomarker selection for enhanced oncology drug development.
"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," Mongan explained. She emphasized that the focus would not solely be on identifying specific biomarkers but rather on a more strategic approach. "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." This suggests a holistic methodology for integrating biomarker strategy into the early stages of drug discovery and development, aiming to maximize the chances of success and streamline the path to regulatory approval.
The conference, hosted by Arena International Events Group, a B2B events company owned by GlobalData (the parent company of Clinical Trials Arena and Pharmaceutical Technology), promises to be a pivotal event for industry stakeholders seeking to navigate the complexities of modern drug development. The agenda includes discussions on critical issues such as the integration of real-world data, advancements in cell and gene therapies, and the evolving regulatory landscape for oncology drugs. The ongoing dialogue between clinicians, researchers, and regulators regarding biomarkers underscores the dynamic nature of drug development and the continuous effort to balance innovation with patient safety. As scientific understanding of disease mechanisms deepens and technological capabilities advance, the role and acceptance of biomarkers as surrogate endpoints are likely to remain a central theme in shaping the future of pharmaceutical innovation.
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