Single-arm trials supporting the approval of anticancer medicinal products in the European Union: contextualization of trial results and observed clinical benefit
- Between 2012 and 2021, 18 anticancer medicinal products for solid tumors were approved in the EU based on 21 SATs (single-arm trials).
- Pivotal SAT-based applications often included additional information for contextualization, such as supportive studies and external evidence.
- Thresholds for success in SATs varied from 10% to 50% ORR (objective response rate), and justification for these thresholds was not always provided.
- External controls, such as historical data or matched analyses, are used for contextualization but have limitations, such as potential bias.
- Clinical relevance of ORRs depends on whether they translate into true benefits, such as improved survival or quality of life.
- Different stakeholders, including regulators and organizations like ESMO (European Society for Medical Oncology), may have varying definitions of clinical benefit.
- Tools like the ESMO-MCBS (Magnitude of Clinical Benefit Scale) and PASKWIL criteria are used to evaluate the benefit of anticancer medicinal products.
- All products in the study received a Conditional Marketing Authorization (CMA), and ongoing confirmatory trials are crucial for reassessing benefit-risk balance.
- There is a need for consistent definitions of clinical benefit among stakeholders to ensure equality in care.
- Transparency in regulatory decision-making and providing comprehensive information in the EPAR are essential for stakeholder understanding.
Randomized controlled trials (RCTs) are referred to as the ‘gold standard’ in testing medicinal products. These trials have several advantages over clinical trials with other designs due to their design features. For example, randomization facilitates subjects in the experimental and control groups being comparable at baseline. Randomization and blinding are useful techniques to determine whether there is a cause–effect relation between treatment and outcome. RCTs are the preferred trials to be included in applications for marketing authorization, as laid down in Directive 2001/83/EC. In this directive, it is stated that clinical trials relevant to the indication “shall be done as ‘controlled clinical trials’ if possible, randomised; any other design shall be justified”. Yet, it is not always possible to conduct an RCT, and, consequently, clinical trials with other designs need to be considered for registrational purposes. The latter includes the use of single-arm trials (SATs)...
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