New guidance to advance use of surrogate endpoints in health technology assessments

An international collaboration led by the National Institute for Health and Care Excellence (NICE) in the UK has developed comprehensive recommendations to standardize the use of surrogate endpoints in cost-effectiveness analyses that address critical gaps in current health technology assessment (HTA) practices worldwide.

The recently published white paper, titled Surrogate Endpoints in Cost-Effectiveness Analysis for Use in Health Technology Assessment, aims to standardize the application of surrogate endpoints in economic models, offering vital recommendations for global HTA practices. The paper is the result of a collaboration between a working group of HTA bodies led by NICE and including Canada’s Drug Agency (CDA-AMC), the Institute for Clinical and Economic Review (ICER) in the US, and the National Health Care Institute (ZIN) in The Netherlands, the Australian Department of Health and Aged Care, the Institute for Technology Assessment in Health (IETS) in Colombia and Rubix Health in the US. The group worked to address significant gaps in current HTA guidance, focusing on the validation and integration of surrogate endpoints into economic modeling and cost-effectiveness analyses.

As highlighted in an associated press release from CDA-AMC,

“Until now, guidance on using surrogate endpoints in health technology assessment has been fragmented. The new guidance will provide clarity and support for pharmaceutical companies when using surrogate outcomes for analyzing the cost-effectiveness of the drugs they are developing.”

Surrogate endpoints (defined in the report as, “biomarkers or other intermediate outcomes that predict treatment effect on a final clinical outcome”) are increasingly being used in drug approval processes, particularly for expedited pathways like conditional or accelerated approvals. However, these endpoints often lack comprehensive validation, which creates challenges for HTA bodies tasked with evaluating the long-term effectiveness and cost implications of health technologies.

To align on the use of surrogate endpoints in health economic models, the working group addressed four main questions:

1. Regulatory standards: What are the regulatory standards for validating surrogate endpoints?
2. Statistical validation: What are the published statistical methods for validation of surrogate endpoints?
3. HTA guidance: What are the existing standards for validation of surrogate endpoints of HTA bodies?
4. Experience and lessons learned: How have surrogate endpoints been addressed in existing HTA evaluations by different HTA bodies and what lessons can be learnt from these assessments?

To address each question, the group undertook a comprehensive review of guidance documents, literature, and regulatory frameworks, supplemented by focus group discussions with HTA experts. The resulting 52-page report highlights the lack of consistent, detailed guidance across HTA and regulatory agencies for considering surrogate endpoints in decision-making. It also reveals minimal updates to methodological guidance among HTA bodies since 2018. The report provides a series of recommendations, including validation frameworks, methods to address uncertainty, principles for model design, and strategies for transparent reporting and stakeholder engagement. Additionally, it underscores the need to establish best practices in statistical approaches for validating surrogate endpoints.