Joint HTAb-regulatory perspectives on understanding evidence challenges, managing uncertainties and exploring potential solutions (case study on YESCARTA)

The document outlines the outcomes of a series of workshops aimed at improving mutual understanding between Health Technology Assessment bodies (HTAbs) and regulators. The focus was on the challenges in evidence generation and managing uncertainties during decision-making.

Three case studies were used to illustrate these challenges:

1. Onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy.
2. Amivantamab (Rybrevant) for non-small cell lung cancer with EGFR Exon 20 insertion mutations.
3. Axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma and high-grade B-cell lymphoma.

Key Challenges Identified

1. Lack of Comparative Evidence: Insufficient planned comparative evidence against relevant comparators.
2. Uncertain Study Endpoints: Relevance of surrogate endpoints not always established.
3. Impact of Intercurrent Events: Affecting the validity of treatment effect estimates.
4. Data Maturity and Follow-up Duration: Particularly in claims of 'cure'.
5. Small Populations and Recruitment Challenges: Especially in rare diseases and paediatric indications.
6. Limited Knowledge of Certain Diseases: Affecting treatment pathways and prognostic factors.
7. Parallel Development of Multiple Products: Creating additional challenges.
8. Inadequate Additional Evidence: When new treatments become available.

Potential Solutions

1. Randomised Evidence: Strong preference for randomised trials, with novel designs suggested for challenging contexts.
2. Pragmatic and Registry-based Trials: Conducting trials in routine clinical practice settings to generate real-world evidence.
3. Estimand Framework: Aligning study design with regulatory and HTA objectives using the estimand framework.
4. Improved Outcome Collection: Enhancing the collection and reporting of non-primary outcomes.
5. Individual Participant Data (IPD): Access to IPD to enhance evidence synthesis and indirect comparisons.
6. Real-World Data (RWD): Complementing clinical trial data with RWD for better decision-making.
7. Frameworks for Decision Making Under Uncertainty: Developing structured frameworks to balance uncertainties.

Conclusion

The document emphasizes the importance of early and continuous collaboration between HTAbs and regulators throughout the product lifecycle.

It highlights the need for robust evidence generation strategies and methodologies to address uncertainties, ultimately aiming to improve decision-making processes for new medicinal products.

HTA agencies:

National Centre for Pharmacoeconomics (NCPE), Ireland Institute for Quality and Efficiency in Healthcare (IQWiG), Germany Norwegian Medical Products Agency (NoMA/DMP), Norway Belgian Health Care Knowledge Centre (KCE), Belgium National Institute for Health and Disability Insurance (RIZIV-INAMI), Belgium National Authority of Medicines and Health Products (INFARMED) Portugal, Spanish Agency of Medicines and Medical Products (AEMPS), Spain

Regulatory agencies:

European Medicines Agency (EMA), Netherlands Swedish Medical Products Agency (MPA), Sweden Medicines Evaluation Board (CEG/MEB), Netherlands Federal Agency for Medicines and Health Products (FAMHP), Belgium Federal Institute for Drugs and Medical Devices (BfArM), Germany French National Agency for the Safety of Medicines and Health Products (ANSM), France Austrian Medicines and Medical Devices Agency (AGES), Austria Health Products Regulatory Authority (HPRA), Ireland