Evidence generation on benefits and risks of medicines and its impact on regulatory and downstream decision-making

Abstract

In the European Union (EU), the medicine regulatory system aims to protect and promote public health by assessment of quality, safety and efficacy data before a marketing authorisation can be obtained and a medicine can be marketed. This so-called benefit-risk assessment is always based on partially incomplete knowledge and thus subject to uncertainty. Also, the context of use of medicines in clinical practice is ever-changing. Therefore, regulatory pathways and instruments have been put into place to allow for continuous evidence generation and subsequent decision-making about the benefit-risk balance of a medicine after it is authorised. The objective of this thesis was to provide insights into evidence generation on benefits and risks throughout the medicine lifecycle, and how it affects decision-making by regulatory and downstream decision-makers in the EU.

This thesis first explores evidence generation for European regulatory decision-making based on three studies. Topics include the conditional marketing authorisation (CMA) pathway and its specific obligations for post-authorisation studies that are imposed to provide comprehensive evidence, as well as post-authorisation regulatory actions.

The thesis then delves into the impact of evidence for regulatory decision-making on downstream decision-makers, whose decisions also affect patient access to medicines, based on another three studies. Topics include impact on decision-making by health technology assessment (HTA) agencies, which provide recommendations or decisions on reimbursement of medicines, and decision-making in clinical practice. Two studies focused specifically on the CMA pathway and its typical specific obligations for post-authorisation studies.

Thereafter, the findings of the research presented in this thesis are placed in a broader perspective. This discussion revolves around the value of post-authorisation evidence generation for CMA medicines, the relative importance of studying both risk-related and benefit-related post-authorisation regulatory actions and associated learnings for regulatory decision-making, and the role of evidence generated for regulatory purposes in HTA and clinical practice. Additionally, the discussion puts forward aspects that enabled and strengthened the typical drug regulatory science studies that were performed for this thesis, as well as policy recommendations for regulatory, HTA and clinical practice decision-makers in line with the conclusions drawn throughout the thesis.

Last, the thesis describes three important developments in the regulatory system that will affect future evidence generation and may draw from the learnings in this thesis: significant innovations in medicine development such as advanced therapy medicinal products, developments in types of evidence such as ‘real-world’ evidence, and developments in the regulatory assessment of evidence such as real-time monitoring of effectiveness and safety.

The thesis’ overarching conclusion is that it is important to comprehensively consider multiple facets of evidence generation on benefits and risks of medicines: from the simultaneous generation of evidence concerning benefits and risks to the process of continued evidence generation throughout the medicine lifecycle, and how this affects decision-making by regulators, HTA agencies and physicians. It therewith provides a perspective on the evidence generation process, but also on drug regulatory science as a scientific field, including its role in evaluating the public health system and the methods that may be employed to perform this evaluation.