The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011–2018

Abstract

BackgroundIn situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and findingsWe used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as ‘validated’. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being ‘reasonably likely’ (n = 30; 61%) or of having ‘biological plausibility’ (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.ConclusionsThe pivotal trial evidence su...

Views of European Drug Development Stakeholders on Treatment Optimization and Its Potential for Use in Decision-Making

“…In addition, the conditional approval procedure as it is applied today allows the industry to launch new medicines into the market based on incomplete datasets (e.g. data from phase II trials) (EMA, 2016b; EMA, 2017), thereby possibly contributing to the widening of the research gap (Gellad and Kesselheim, 2017;Gyawali et al, 2019;Schuster Bruce et al, 2019). Care should be taken that in our efforts to establish the treatment optimization concept, we do not inadvertently magnify the underlying problem.…”

“…Moreover, the accelerated and conditional marketing authorization mechanisms launched by FDA and EMA respectively have further solidified the use of surrogate endpoints in clinical trials (Fleming, 2005;Downing et al, 2014;Hoekman et al, 2015). While these schemes allow promising new therapies addressing unmet medical needs to enter the market faster, the antineoplastic drugs following such expedited approval pathways are rarely shown to increase patients' overall survival or quality of life in subsequent confirmatory trials (Gyawali et al, 2019;Schuster Bruce et al, 2019). These results suggest that the regulatory approval procedure does not sufficiently filter out medicines that are of limited value to patients and their healthcare providers (Prasad, 2017), which in turn contributes toward the issue of medical reversal, i.e.…”

The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs

“…Primary endpoints were categorized as surrogate or clinical efficacy endpoints, or safety endpoints based on the information provided by the European public assessment report and on previous literature describing the type of endpoints in pivotal studies for conditionally approved drugs. 18 Considering post-approval studies, all SOBs were extracted from EMA documents following previously published procedures. 17 The number of SOBs per drug and their original due dates and final submission dates (if applicable) were recorded.…”

Klinische Endpunkte in Studien

“…systematischen Reviews analysiert, insbesondere hinsichtlich der Konsequenzen, die aus der zunehmenden Verwendung von Surrogatendpunkten (z. B. Ansprechrate, PFS, DFS) in beschleunigten Zulassungsverfahren resultieren [ 2 – 6 ]. Diese Analysen ergaben übereinstimmend, dass die Verwendung von Surrogatendpunkten die Durchführung klinischer Studien zu Onkologika beschleunigen kann, nur selten jedoch während der Nachbeobachtung eine Verlängerung des OS oder zumindest eine Verbesserung der Lebensqualität als patientenrelevanter Nutzen überzeugend gezeigt werden kann und zudem weitere klinische Studien nach der Zulassung zum Nutzen der neuen Arzneimittel nur selten durchgeführt werden [ 3 – 6 ].…”

“…B. Ansprechrate, PFS, DFS) in beschleunigten Zulassungsverfahren resultieren [ 2 – 6 ]. Diese Analysen ergaben übereinstimmend, dass die Verwendung von Surrogatendpunkten die Durchführung klinischer Studien zu Onkologika beschleunigen kann, nur selten jedoch während der Nachbeobachtung eine Verlängerung des OS oder zumindest eine Verbesserung der Lebensqualität als patientenrelevanter Nutzen überzeugend gezeigt werden kann und zudem weitere klinische Studien nach der Zulassung zum Nutzen der neuen Arzneimittel nur selten durchgeführt werden [ 3 – 6 ]. Es ist deshalb auch nicht überraschend, dass in den insgesamt 193 Beschlüssen des Gemeinsamen Bundesausschusses (G-BA) zu den im Zeitraum zwischen Anfang 2011 und Mai 2020 abgeschlossenen Verfahren der frühen Nutzenbewertung zu Onkologika, darunter auch viele Orphan-Arzneimittel, der Zusatznutzen gegenüber der zweckmäßigen Vergleichstherapie in mehr als der Hälfte der Beschlüsse als nicht belegt, nicht quantifizierbar oder (sehr selten) als geringer bewertet wurde [ 8 ].…”