The authorisation of anti-cancer medicinal products: Clinical benefit, precision medicine and regulatory flexibility

In this dissertation, the difficulties and challenges related to the approval of anticancer medicinal products are discussed. In Chapter 1, a general introduction is provided, which focusses on the shift towards precision medicine, the European Union legal framework, authorised anticancer medicinal products and the relevance of evidence generation. In Chapter 2, an overview on European Commission (EC) designated orphan medicinal products (OMPs) for the treatment of pancreatic cancer is provided. We conclude that the success rate of OMPs for pancreatic cancer that reach the market is low. Increasing this rate is something to aspire. Developers are advised to make optimal use of orphan incentives. In addition, developers are strongly encouraged to provide yearly updates on advancements in development. Chapter 3 is dedicated to the question if investigational medicinal products that were granted Breakthrough Therapy designation (BTD) by the Food and Drug Administration (FDA) are truly breakthroughs. Based on our findings, we conclude that the success rate of the BTD program is lower than anticipated, given the few clinical trials that were assigned a high ESMO-MCBS score. Nonetheless, we believe that programs for fast drug approval do have a place in current regulatory practices. Chapter 4 provides detail on how clinical benefit of anticancer medicinal products tested in single-arm trials (SATs) was determined. Our research indicates that there is some room for improvement. This includes prespecifying and motivating a clinically relevant effect size and aligning the sample size to that effect. External controls may facilitate in the contextualisation process, but the limitations associated with such indirect comparisons must be addressed. We consider it of value to further discuss among stakeholders when approval on the basis of lower levels of evidence is justified. In Chapter 5, the possibilities to extend the therapeutic indication(s) of an already authorised medicinal product on the basis of results from investigator-initiated trials (IIT) are explored. We conclude that it is possible to support an extension of indication of an authorised medicinal product on the basis of results from IITs, but regulatory requirements still need to be met. Therefore, a collaborative approach and early dialogue between stakeholders is of importance for future decision-making. In Chapter 6, decision-making aspects of the first tissue-agnostic approvals are compared between the European Medicines Agency (EMA), FDA and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures related to the tissue-agnostic indication were of specific interest. Our results show that there are different approaches to further confirm the tissue-agnostic indication in the post-marketing setting, albeit these are not without inherent limitations. For future applications, a global strategy toward data generation post-marketing may be of interest. The final chapter (Chapter 7) provides a general discussion and perspectives for follow-up research. It is concluded that further research is needed to ensure that beneficial medicinal products are timely authorised, especially when they address an unmet medical need. Reflecting on prior decision-making and exploring regulatory possibilities, from a multi-stakeholder perspective, will be necessary to continue safeguarding public health.