Article
Changing evidence requirements for France’s Early Access Program (EAP): What could we see in the coming year?
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Henri Leleu, MD, PhD
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Martin Blachier, MD, MPH
France’s Early Access Program has been a lifeline for patients with severe or rare conditions, but mounting financial pressures and questions about being able to confirm preliminary clinical data in real life are driving changes. How will these reforms reshape access to innovative therapies, and what does it mean for the future of pharmaceutical innovation?
France’s Early Access Program: Facing challenges to sustain innovation and access
In the first part of this series, we explored how France’s Early Access Program (EAP) has been instrumental in providing patients with severe or rare conditions faster access to potentially life-saving treatments. Between 2021 and 2024, 122 positive rulings granted over 120,000 patients early access to innovative therapies. Yet, questions about the program’s long-term financial sustainability and shortcomings in being able to confirm preliminary clinical data in longer clinical trial follow-up, or in real life, have emerged. This has contributed to a declining probability of approval in the past year from 78% between 2021 and 2023 to 50% in the first half of 2024.
In this second part of our three-part series, we examine why the Haute Autorité de Santé (HAS) has embarked on a review of EAP’s methodological doctrine. We explore the drivers and implications of these changes, including stricter evidence requirements, the integration of real-world evidence (RWE), and the push for a more accountable framework to manage clinical and financial uncertainty.
In this second part of our three-part series, we examine why the Haute Autorité de Santé (HAS) has embarked on a review of EAP’s methodological doctrine. We explore the drivers and implications of these changes, including stricter evidence requirements, the integration of real-world evidence (RWE), and the push for a more accountable framework to manage clinical and financial uncertainty.
Why is HAS tightening evidence requirements?
1. Failure to confirm efficacy post-EAP
From 2021 to 2024, while 85 of the 122 early access approvals received favorable opinions (70%), only 47 (39%) of evaluated early-access drugs demonstrated sufficient efficacy to secure an ASMR rating of II or III. Alarmingly, 24 (20%) received an ASMR V indicating no substantial improvement over standard of care in the reimbursed indication despite initial EAP approval. This highlights gaps in predicting the long-term value of innovations. HAS has also drawn comparisons to the FDA’s accelerated approval pathway with concerns over delays in confirmatory trials and treatment guidelines:
- After drugs are approved in the FDA’s accelerated approval pathway, trials which confirm the drug’s clinical benefits are taking a median of 3.5 years to complete. Additionally, 25% of these trials take more than 5.8 years, which indicates significant delays in verifying the safety and efficacy of treatments.
- Drugs that ultimately yield negative results in post-approval confirmatory trials are still being mentioned or recommended in treatment guidelines that had incorporated them post-approval, raising concerns about patient safety and clinical decision-making.
Inspired by both internal reflections and international experiences, HAS seeks to create a clearer framework to ensure that therapies granted early access deliver on their initial promise. This is critical to protect patients and ensure public funds are not indefinitely allocated to treatments that ultimately fail to prove sufficient added value in clinical trials or in the real-world setting, especially in an era of mounting financial pressures.
2. Financial sustainability under strain
The 2021 EAP reform aimed to secure financial sustainability, but soaring costs have challenged this goal. Expenditure linked to EAP has risen from €472 million in 2022 to a projected €700 million in 2025, even after rebates applied during EAP. The Direction de la Sécurité Sociale (DSS) has expressed concerns about missed rebates and delays in price negotiations, creating fiscal risks as the government plans for the 2026 health insurance budget (PLFSS).
This financial strain is further underscored by the accelerating growth rate of hospital-distributed medicines, which include most EAP drugs. Between 2021 and 2023, hospital drug spending grew at an average rate of 13.5% annually, compared to 4.5% for the broader pharmaceutical market, adding nearly €800 million annually to public healthcare costs.
This financial strain is further underscored by the accelerating growth rate of hospital-distributed medicines, which include most EAP drugs. Between 2021 and 2023, hospital drug spending grew at an average rate of 13.5% annually, compared to 4.5% for the broader pharmaceutical market, adding nearly €800 million annually to public healthcare costs.
What to expect from the new doctrine
While the updated doctrine was initially expected in early 2025, delays suggest it will now be finalized later in the year. The revised framework will likely maintain HAS’s focus on ensuring robust, methodologically sound evidence at the time of assessment. This could result in reduced access for innovations relying on clinical development plans with single-arm studies, improper comparators, or unvalidated surrogate endpoints. However, HAS is expected to expand the role of indirect comparisons and real-world data to accommodate contexts where randomized controlled trials (RCTs) are unfeasible.
Structured development plans as a cornerstone
HAS is likely to place greater emphasis on the clinical development plan submitted during early access requests. This plan must outline a robust path to confirmatory data generation, with well-defined endpoints, comparators, and methodologies. HAS views this development plan as a core component of the “innovation presumption,” alongside unmet need and substantial patient benefit.
Defining acceptable evidence
Acknowledging the limitations of RCTs in certain contexts, HAS is exploring alternative evidence sources. These include:
- Indirect comparisons, such as network meta-analyses or matched adjusted indirect comparisons
- RWE from observational studies, provided they meet strict criteria for robustness and clinical relevance
Rules for these methodologies will also likely be published in 2025 as part of the HAS review. Key principles for external comparison methodologies are anticipated to align with HAS’s current standards, including the following. These principles aim to ensure that external comparisons are scientifically robust, minimizing uncertainties and supporting credible conclusions about treatment benefits and risks.
- Justification for the absence of randomization, with a clear rationale provided to support the chosen methodology.
- Proactive planning of indirect comparisons during clinical development, including a priori definitions of the clinical question, study population, intervention, comparator, and outcomes, all detailed in a comprehensive protocol and statistical analysis plan.
- Systematic reviews conducted to identify relevant prognostic variables, confounders, effect modifiers, and appropriate external data sources, ensuring robust evidence generation.
- Independent selection of comparators and external data sources, made without reference to the results of the uncontrolled trial. These must reflect the standard of care and align closely with the characteristics of the uncontrolled trial to mitigate biases, including selection, attrition, and measurement bias.
- Preference for methods using individual patient data, such as propensity scores, g-computation, or doubly robust estimation, to enhance the reliability of the analysis.
- Thorough exploration of underlying assumptions, including positivity, overlap, and balance, with residual confounding addressed through sensitivity analyses, such as the use of negative and positive controls, alternative external controls, or quantitative bias analysis. This ensures that any potential biases do not undermine the validity of conclusions regarding treatment effects.
- Comprehensive safety documentation, ensuring that safety outcomes are well-defined and comparable between the treatment and control groups.
Scrutiny of surrogate Endpoints
HAS is placing stricter requirements on surrogate endpoints, particularly in non-oncology settings, where the use of unvalidated measures has grown. Only endpoints with a proven correlation to long-term outcomes could be acceptable. Safety and quality-of-life data, aligned with patient-centered goals, could also gain prominence.
Evolution of the data collection process during EAP
One area where significant evolution is anticipated is the data collection process during EAP, which has been a long-standing point of contention within the industry. Industry representatives, including LEEM, have raised concerns about the high costs and limited utility of the current data collection framework, largely due to incomplete data. Data completion is currently around 65%, while HAS expects over 90% to consider the data robust. LEEM has specifically called for a reform of the PUT-RD — a protocol for temporary use and data collection; this is a topic that will be explored in greater detail in the third part of this series.
In response, HAS has been working to streamline and simplify data collection, exploring the use of existing registries, such as BaMaRa for rare diseases, and leveraging the National Health Insurance Claims Database. The Haut Conseil pour l’Avenir de l’Assurance Maladie has reinforced the importance of systematic RWE collection to balance early market access for innovative therapies. Such data would validate clinical trial results over longer periods and across broader patient populations, potentially uncovering long-term effects or providing comparative insights across treatments. The Haut Conseil has also highlighted the need for a national registry to monitor real-world outcomes of therapeutic innovations, particularly in critical areas such as oncology.
By addressing these challenges, HAS aims to enhance the value of data collected during EAP, ensuring better supported decision-making while reducing the financial and administrative burdens on stakeholders.
In response, HAS has been working to streamline and simplify data collection, exploring the use of existing registries, such as BaMaRa for rare diseases, and leveraging the National Health Insurance Claims Database. The Haut Conseil pour l’Avenir de l’Assurance Maladie has reinforced the importance of systematic RWE collection to balance early market access for innovative therapies. Such data would validate clinical trial results over longer periods and across broader patient populations, potentially uncovering long-term effects or providing comparative insights across treatments. The Haut Conseil has also highlighted the need for a national registry to monitor real-world outcomes of therapeutic innovations, particularly in critical areas such as oncology.
By addressing these challenges, HAS aims to enhance the value of data collected during EAP, ensuring better supported decision-making while reducing the financial and administrative burdens on stakeholders.
Opportunities and challenges of the new doctrine
The revised doctrine presents both challenges and opportunities for stakeholders. Stricter evidence requirements and financial pressures may make early access harder to secure. Already, half of EAP requests are being rejected due to insufficient presumed innovativeness which includes evidence-planning criteria. This underscores the need for early strategic planning during clinical development, including validating surrogate endpoints and anticipating indirect comparisons with access to registry data.
On the other hand, a clearer doctrine will bring greater predictability for industry, aligning EAP with international best practices. By expanding the use of real-world data and indirect comparisons, HAS may create new pathways for evaluation in complex contexts, while streamlined data collection processes could reduce costs and administrative burdens.
France’s EAP is at a crossroads, balancing its commitment to innovation with financial responsibility and the imperative to treat today’s patients while proving tomorrow’s outcomes. By refining its evidence framework, HAS aims to ensure that EAP continues to deliver on its promise.
Stay tuned for the final part of this series, where we will discuss the evolving data collection process, including the potential use of registries and health insurance databases to strengthen RWE collection.
On the other hand, a clearer doctrine will bring greater predictability for industry, aligning EAP with international best practices. By expanding the use of real-world data and indirect comparisons, HAS may create new pathways for evaluation in complex contexts, while streamlined data collection processes could reduce costs and administrative burdens.
France’s EAP is at a crossroads, balancing its commitment to innovation with financial responsibility and the imperative to treat today’s patients while proving tomorrow’s outcomes. By refining its evidence framework, HAS aims to ensure that EAP continues to deliver on its promise.
Stay tuned for the final part of this series, where we will discuss the evolving data collection process, including the potential use of registries and health insurance databases to strengthen RWE collection.
This article summarises Cencora’s understanding of the topic based on publicly available information at the time of writing (see listed sources) and the authors’ expertise in this area. Any recommendations provided in the article may not be applicable to all situations and do not constitute legal advice; readers should not rely on the article in making decisions related to the topics discussed.
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Sources
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- Haut Conseil pour l’Avenir de l’Assurance Maladie, Haut Conseil de la Famille, de l’Enfance et de l’âge, Haut Conseil du Financement de la protection Sociale. Pour un redressement durable de la sécurité sociale. Juin 2025. Available at: https://www.strategie-plan.gouv.fr/files/2025-07/Rapport%20Hauts%20Conseils%20-%20Redressement%20durable%20s%C3%A9cu%2020250701ter.pdf
- JORF. LOI n° 2023-1250 du 26 Décembre 2023 de financement de la sécurité sociale pour 2024. Article 76. 2023. Available at: https://www.legifrance.gouv.fr/jorf/article_jo/JORFARTI000048668773
- Sénat. Comptes rendus de la mission d’évaluation et de contrôle de la sécurité sociale. 20 mai 2025. Availalble at: https://www.senat.fr/compte-rendu-commissions/20250519/mecss.html#toc3
- Vanier A, Fernandez J, Kelley S, et al. Rapid access to innovative medicinal products while ensuring relevant health technology assessment. Position of the French National Authority for Health. BMJ Evidence-Based Medicine. 2024;29:1-5.
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