Surrogate Endpoints in HTA Decision-Making
The need to stay ahead of competitors and offset losses from patent cliffs drives the need for accelerated drug development timelines, even more so in disease areas with high unmet need. The use of surrogate endpoints, which act as intermediate measures for patient-relevant outcomes, is often essential to achieve earlier regulatory approval. Their appeal lies in efficiency: trials can often be conducted with smaller sample sizes, shorter durations, and reduced costs compared with studies based on final clinical endpoints 1. This is particularly relevant in disease areas where conducting long clinical studies is not feasible, such as chronic illnesses, rare diseases, and oncology.
A steady increase in manufacturers seeking accelerated approvals, especially in oncology and rare diseases, has placed surrogate endpoints at the centre of the HTA debate. Agencies like the EMA often rely on surrogate measures such as Progression-Free Survival (PFS) and biomarkers to expedite access, but this has triggered scrutiny over post-approval evidence obligations and difficulties in meeting stringent HTA evidence requirements. Regulators and HTA bodies are under increasing pressure to balance the benefits of faster access with the risks of basing pricing and reimbursement negotiations on measures that may not fully capture the value of the therapy, for example, predicting long-term health outcomes 1. Balancing the need for rapid access with the demand for robust evidence has become a central challenge in today’s health technology landscape.
Surrogate Endpoints: Recent Trends
Since 2010, six major agencies (PBAC, IQWiG, CADTH, NICE, INFARMED, and ZIN) have revised their stance to reflect increasing surrogate acceptance 2. As of 2023, all HTA agencies except Spain’s AEMPS allowed surrogates as part of HTA submissions under certain conditions, though requirements differ 2. The increasing acceptance of surrogates has, in turn, led to more transparent requirements for endpoint validation, robust modelling frameworks, and the use of post-launch real-world evidence (RWE) to confirm outcomes 3,5. Agency-level changes further illustrate this trend. Since 2010, six HTA agencies (ACE, HAS, AIFA, DMC, INFARMED, and ZIN) have revised or expanded their guidance on surrogates, signalling a demand for more rigour and consistency. These shifts highlight an international recalibration: acceptance is expanding but conditional on stronger methodological frameworks and clearer evidence standards 6.
| Agency | Stance on Surrogates | Recent Changes |
|---|---|---|
| NICE (UK) | Accepts surrogates only when robust evidence links them to OS. Often uses managed access if uncertainty remains 5. | Has tightened requirements; increasingly ties approval to ongoing evidence collection and managed entry agreements 5 |
| IQWiG (Germany) | Requires statistical validation (meta-analyses) showing that surrogate reliably predicts OS/clinically relevant outcome 7 . | Softened slightly to acknowledge that valid surrogates may be considered but remains among the strictest agencies globally 7. |
| HAS (France) | Acknowledges surrogates but may downgrade benefit rating if robust OS or QoL evidence is lacking 2. | Introduced more detailed guidance on surrogates, reflecting rising emphasis on methodological rigour and validation 2. |
Furthermore, the European HTA regulation, through mechanisms such as the Joint Clinical Assessments (JCA) and Joint Scientific Consultations (JSC), is also driving further standardisation of evaluation methodologies. Over time, these developments are likely to contribute to fewer inconsistencies, which until recently have fragmented the landscape across member states.
Despite Increasing Acceptance, Market Access Challenges Remain
From a payer’s perspective, surrogate endpoints raise significant challenges. When surrogates are utilised, the link to patient-relevant outcomes is often associated with higher levels of uncertainty. Studies using surrogate endpoints are almost twice as likely to report positive treatment effects as those based on final outcomes, and the estimated benefits are often 28–48% larger 8. This creates challenges for HTA bodies evaluating trade-offs and cost implications for new health technologies.
A statistical correlation with patient-relevant outcomes does not necessarily guarantee true surrogacy. The validity of surrogates can vary widely by patient group, disease area, and drug class, particularly in precision medicine, where tumour subtypes, gene expression, and treatment mechanisms alter these associations. In addition, methodological issues, including treatment switching and post-progression therapies, can weaken the credibility of surrogates in HTAs.
These complexities underscore the need for context-specific validation of surrogates, as insufficiently supported correlations risk undermining payer confidence, constraining reimbursement, and limiting patient access 4.
Olaparib and the Challenge of Surrogate Endpoints in HTA
The case of Olaparib (Lynparza), among others, illustrates how reliance on surrogate endpoints can limit market access, despite faster regulatory approval. Olaparib pivotal trials in breast and ovarian cancer were based on PFS and iDFS, which is sufficient for regulatory approval. However, HTA bodies were reluctant to grant broad access, emphasising the uncertainty of whether these gains would translate into overall survival (OS) or quality of life (QoL) improvements. Payers also emphasised the need for additional RWE to fully demonstrate how PFS translates into OS or QoL gains 4. In this case, reliance on PFS and iDFS as the primary value drivers constrained the level of added benefit recognised, and consequently the achievable price in France and Germany.
In practice, payers frequently require additional evidence to support reimbursement. For example, the HAS and the G-BA are more likely to recognise an “added benefit” when surrogate outcomes are supported by comparative data also demonstrating an improvement in safety, symptoms or QoL4. A purely surrogate-based value proposition is rarely sufficient for a positive benefit assessment.
Navigating Evidence Limitations to Demonstrate Clinical and Economic Value
To address the market access challenges associated with the use of surrogate endpoints, manufacturers need to design trials that strike the right balance between meeting minimum regulatory requirements for speedy marketing approval and generating sufficient evidence to satisfy payers’ requirements. Where possible, OS should be included as a co-primary or key secondary endpoint, and patient-relevant validated clinical endpoints such as QoL should also be prioritised 4.
Moreover, surrogate endpoints must be validated not only statistically but also in light of disease-specific biological mechanisms, biomarker prevalence, and the clinical context4. Whenever possible, manufacturers should consider whether their evidence strategy should extend beyond randomised controlled trials to include RWE, in order to reassure payers of their commitment to demonstrating long-term outcomes and reduce uncertainty.
Conclusion
Ultimately, HTA bodies rarely accept surrogates in isolation; they increasingly expect a package of evidence that combines surrogate data with patient-reported outcomes, safety data, and plans for confirmatory endpoints. Positioning surrogates within this broader evidentiary framework is key to reducing uncertainty, strengthening payer confidence, and supporting more favourable access and pricing negotiations. However, when not supported by strong methodological frameworks and complementary evidence, they risk undermining both value demonstration and pricing potential.
With the rollout of the JCA in 2025 set to harmonise European standards, the impact of incomplete evidence strategies will be felt more broadly across member states, since there will be less room for divergent national interpretations. For manufacturers, market access success depends on anticipating payer challenges and, if using surrogate endpoints, deploying surrogates within a holistic evidence package to be best placed to demonstrate value, achieve pricing potential, and deliver faster patient access.
References
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- Baldwin D, Carmichael J, Cook G, et al. UK Stakeholder Perspectives on Surrogate Endpoints in Cancer, and the Potential for UK Real-World Datasets to Validate Their Use in Decision-Making. Cancer Management and Research. 2024;Volume 16:791-810. doi:https://doi.org/10.2147/cmar.s441359
- Boukouvalas, S. et al., 2023. Challenges associated with surrogate endpoints for healthcare decision making in oncology. Poster presented at: ISPOR Europe 2023. Available at: co64-challenges-associated-with-surrogate-endpoints-for-healthcare-decision-making-in-oncology131519-pdf.pdf
- International collaboration provides new guidance on the use of surrogate endpoints in cost-effectiveness analysis. NICE website: The National Institute for Health and Care Excellence. Published January 17, 2025. Accessed October 2, 2025. https://www.nice.org.uk/news/articles/international-collaboration-provides-new-guidance-on-the-use-of-surrogate-endpoints-in-cost-effectiveness-analysis
- 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;88:103465. doi:https://doi.org/10.1016/j.eclinm.2025.103465
- IQWiG. General Methods A.; 2023. https://www.iqwig.de/methoden/general-methods_version-7-0.pdf
- Ciani O, Buyse M, Drummond M, Rasi G, Saad ED, Taylor RS. Time to Review the Role of Surrogate End Points in Health Policy: State of the Art and the Way Forward. Value in Health. 2017;20(3):487-495. doi: https://doi.org/10.1016/j.jval.2016.10.011