In randomized clinical trials, measuring significant differences in how patients feel, function, or survive is often impractical. Clinical outcomes can manifest too slowly or infrequently or become difficult to attribute if confounded by subsequent treatment. In these scenarios, surrogate endpoints, measurable predictors of clinical outcomes, offer a powerful alternative.

Among surrogate endpoints, predictive biomarkers that are objectively measurable and multipurpose are often preferred. A biomarker that can predict clinical outcomes may also guide diagnosis, patient selection and treatment modification.¹ In such cases, investment in a single biomarker can accelerate a trial and reduce costs by shortening time-to-events and facilitating enrolment of smaller, but more responsive, patient populations.

The value of biomarker-based surrogate endpoints also depends on regulator, payer and provider acceptance. For biomarkers without long-established validation, the accelerated approval pathway (AAP), which accepts emerging surrogate endpoints reasonably likely to predict clinical benefit, may be the only viable route to regulatory acceptance. In contrast, traditional approval pathways generally require direct clinical endpoints, unless a surrogate has been extensively validated.²

Originally designed for HIV, in which waiting for full clinical outcome data was ethically untenable, AAPs have predominantly been used for late-stage cancer, in which urgency and unmet need are high and progression-free survival is broadly accepted as a surrogate.³ As biomarker-based surrogate endpoints emerge for new therapeutic areas and widen the window for intervening before severe disease develops, the utility of an AAP is expanding, though regulatory and payer frameworks are still adapting. Understanding how to use the AAP, and what can go wrong, is essential for developers considering this approach.⁴

Risk and reward of an accelerated pathway

The AAP does not allow developers to skip the generation of clinical endpoints altogether. Instead, it permits market access before a clinical-endpoint-based confirmatory trial is completed.² For many developers, particularly smaller biotechs, AAP is primarily attractive because it can provide a critical early revenue stream to fund the confirmatory work ahead.

However, delaying the demonstration of clinical benefit is a calculated gamble.⁵ Regulatory agencies may revoke approval when confirmatory trials are not completed, fail or uncover safety concerns. Meanwhile, payers may refuse to cover a treatment based on surrogate-endpoint-based evidence if they are not confident in their population-level value compared to preexisting treatment options.³ These are not edge-case risks. Across oncology accelerated approvals with at least five years of follow-up, 57% failed to demonstrate clinical benefit in confirmatory studies on time and 22% were ultimately withdrawn.⁶

While developers cannot eliminate all risk, they can take steps to ensure their choice of surrogate is sound and their evidence aligns with regulatory and payer expectations. For AAP to be worthwhile, three missteps must be avoided:

1. Building on a flawed biomarker foundation
2. Implementing a self-competitive confirmatory trial
3. Assuming payer-regulator alignment

Flawed foundations cause collapse

Before committing to an AAP, the biomarker-based surrogate must be defensible. Selecting an invalid or misleading surrogate endpoint can be catastrophic, either delaying recognition that a drug is not viable, or obscuring results for an otherwise promising therapy.

Developers risk implementing an invalid surrogate if they assume it transfers cleanly across disease subtypes, drug classes, or patient populations. LDL cholesterol, for instance, is a valid surrogate endpoint for cardiovascular mortality for statins, but appears less predictive for other classes of lipid-lowering therapy such as fibrates.⁴ The challenge compounds further for multifactorial diseases with unclear biological mechanisms. Here, tracking multiple experimental biomarkers and clinical diagnostic signs in parallel can help build biological confidence before committing to a single surrogate.

Where possible, developers should lean on pre-validated surrogates and structured regulatory guidance. The FDA’s Adult Surrogate Endpoint Table lists over 200 accepted endpoints, and the FDA’s Biomarker Qualification Program and EMA reflection papers provide further validation support.^3,7,8 Engaging regulators and health technology assessment (HTA) agencies early, before significant trial investment is made, is essential to confirm that the chosen surrogate is acceptable from a regulatory and reimbursement perspective.

Confirmatory trials risk high attrition

Once a drug reaches market, patients may choose it over enrolling in a placebo-controlled confirmatory trial. The approved product directly competes with the confirmatory trial for the same patients, leading to high attrition in post-approval studies that jeopardises their success and timely completion.

This self-competition problem has a structural solution: Enrol the full confirmatory trial population at the start, before the drug reaches market. To secure accelerated approval, assess the biomarker surrogate endpoint in a subset of the full cohort at an early timepoint. The full trial can then continue uninterrupted, capturing the long-term clinical outcome data needed for full approval. This design is especially critical in rare disease and early intervention indications in which patient populations are small, or patients can easily infer they are receiving placebo.

Early initiation of a confirmatory trial involves a financial trade-off that requires advance planning. If the drug fails at the biomarker surrogate stage, the sponsor will have spent considerably more than a sequential design would have required. But the alternative, securing accelerated approval only to lose the confirmatory trial to attrition, is a far more expensive failure. As long as the biomarker foundation is sound and the financial commitment is made deliberately, a concurrent trial design can resolve a dangerous operational risk.

Navigating payer scepticism

Clinical developers cannot design their trial around regulatory requirements alone and assume commercial viability.  In industry forums, ICON experts have observed regulators and HTA bodies present side by side, articulating divergent evidentiary standards, without offering a clear path to reconcile those differences. Whereas regulators are primarily concerned with drug efficacy and safety, and often encourage use of surrogate endpoints, payers are primarily interested in population-level cost benefit of a therapy, and have a strong preference for long-term clinical outcomes.⁴ As a result, drugs that achieve accelerated regulatory approval can face restricted or denied reimbursement, undermining the early revenue stream the pathway was intended to unlock.

As science becomes more targeted and biomarkers increasingly define the patient population who will benefit, the case for a shared pathway that is accepting of validated surrogate endpoints may become stronger for HTAs. A drug with a validated biomarker can reach the right patients reliably – evidence that should aid in the justification of funding.

For many smaller biotechs that cannot afford to run a clinical outcomes trial, misalignment of evidentiary needs is cost-prohibitive. Strategic indication selection, however, can help resolve HTA scepticism and support premium pricing. Rather than pursuing a broad indication and relying on a subgroup analysis to demonstrate biomarker-defined benefit, targeting a narrower indication from the outset can strengthen the biomarker’s evidentiary case and the HTA value argument. While this can exclude patients who might otherwise benefit, a narrowly approved and reimbursed drug is more commercially viable than one with an expansive label that no public health funder will cover.

Matching pathway to evidence and expectations

Accelerated approval is a selectively valuable pathway that requires careful risk planning. Where validated surrogate endpoints exist, traditional approval pathways are generally lower-risk. Where disease biology is too poorly understood to identify a reliable surrogate, accelerated approval may not be appropriate. Success depends on meeting biomarker evidence standards, regulator expectations and payer scepticism as they currently stand, rather than where developers hope they will be.

Disclaimer: The above article is written by an external contributor. While Drug and Device World checks for accuracy, we are not responsible for views expressed/content or accuracy of any information posted in the article, and shall not be responsible for any decisions made based on such information.

Citations:

1. Ilic K. Biomarkers as Surrogate Endpoints in Drug Development: Finding Their Right Place. Clin Ther. 2025;47(10):944-949. doi:10.1016/j.clinthera.2025.07.026
2. FDA. Expedited Program for Serious Conditions–Accelerated Approval of Drugs and Biologics – Draft Guidance. 2024. https://www.fda.gov/media/158072/download
3. Sharma R, Gulati A, Chopra K. Era of surrogate endpoints and accelerated approvals: a comprehensive review on applicability, uncertainties, and challenges from regulatory, payer, and patient perspectives. Eur J Clin Pharmacol. 2025;81(5):605-623. doi:10.1007/s00228-025-03822-w
4. Taylor RS, Heerspink HJL, Buyse M, et al. Use of surrogate endpoints in health technology assessment and reimbursement of treatments for the management of chronic kidney disease. eClinicalMedicine. 2025;88. doi:10.1016/j.eclinm.2025.103465
5. Galloway F. Data-Driven Insights | 30+ Years of Accelerated Approval. Friends of Cancer Research. May 19, 2025. Accessed April 2, 2026. https://friendsofcancerresearch.org/blog/30-years-of-accelerated-approval-trends-timelines-and-impact/
6. Liu ITT, Kesselheim AS, Cliff ERS. Clinical Benefit and Regulatory Outcomes of Cancer Drugs Receiving Accelerated Approval. JAMA. 2024;331(17):1471-1479. doi:10.1001/jama.2024.2396
7. Federation of American Scientists. Validating Surrogate Endpoints to Support FDA Drug Approval. July 8, 2025. Accessed April 2, 2026. https://fas.org/publication/validating-surrogate-endpoints/
8. Center for Drug Evaluation and Research. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. FDA. Published online August 29, 2025. Accessed April 2, 2026. https://www.fda.gov/drugs/development-resources/table-surrogate-endpoints-were-basis-drug-approval-or-licensure