Single-arm trials supporting the approval of anticancer medicinal products in the European Union: contextualization of trial results and observed clinical benefit.

BACKGROUND: Single-arm trials (SATs) can sometimes be used to support marketing authorization of anticancer medicinal products in the European Union. The level and durability of antitumor activity of the product as well as context are important aspects to determine the relevance of trial results. The aim of this study is to provide details on the contextualization of trial results and to evaluate the magnitude of benefit of medicinal products approved based on SATs. MATERIALS AND METHODS: We focused on anticancer medicinal products for solid tumors approved on the basis of SAT results (2012-2021). Data were retrieved from European public assessment reports and/or published literature. The benefit of these medicinal products was evaluated via the European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). RESULTS: Eighteen medicinal products were approved based on 21 SATs-few medicinal products were supported by >1 SAT. For the majority of clinical trials, a clinically relevant treatment effect was (pre)specified (71.4%) and most often an accompanying sample size calculation was provided. For 10 studies, each testing a different medicinal product, a justification for the threshold for a clinically relevant treatment effect could be identified. At least 12 out of 18 applications included information to facilitate the contextualization of trial results, including six supportive studies. Of the pivotal SATs analyzed (n = 21), three were assigned an ESMO-MCBS score of 4, which corresponds to 'substantial' benefit. CONCLUSIONS: The clinical relevance of the treatment effects shown by medicinal products for solid tumors tested in SATs is dependent on the effect size and context. To better facilitate regulatory decision making, prespecifying and motivating a clinically relevant effect and aligning the sample size to that effect is important. External controls may facilitate in the contextualization process, but the associated limitations must be addressed.

Factors Contributing to the Efficacy-Effectiveness Gap in the Case of Orphan Drugs for Metabolic Diseases.

INTRODUCTION: Authorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it. METHODS: We included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016. Efficacy data were obtained from European Public Assessment Reports, relative effectiveness data from the Dutch National Healthcare Institute website, and real-world effectiveness data from literature and interviews with experts and patients. Efficacy and effectiveness were scored as 'no effect', 'unclear' or 'good' based upon a prespecified scoring system. RESULTS: We identified 31 authorized OMPs, of which 21 had post-marketing studies available, thus making it possible to score real-world effectiveness. Eight of 21 (38%) OMPs had a 'good' real-world effectiveness. The use of a clinical or validated surrogate primary endpoint and a representative study population seemed to be related to good effectiveness in the real world, as were type of marketing authorization, study population and disease prevalence. CONCLUSIONS: This study revealed that less than half of the authorized OMPs are effective in the real world. Since the type of primary endpoint used in the pivotal study seems to be associated with good real-world effectiveness, it is important to agree upon study endpoints through early dialogues among relevant stakeholders.