Date Published: September 10, 2019
Publisher: Public Library of Science
Author(s): Catherine Schuster Bruce, Petra Brhlikova, Joseph Heath, Patricia McGettigan, Aaron S. Kesselheim
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 We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame.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 supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.
Partial Text: The European Medicines Agency (EMA) is the central regulatory body providing recommendations on the authorisation (approval) of new medicinal products in the European Union (EU) . In situations of ‘unmet medical need’ and/or ‘in the interests of public health’ , conditional marketing authorisation (CMA) and accelerated assessment (AA) pathways provide expedited routes to EMA authorisation recommendations.
We used the EMA website search tool to identify products granted CMA between January 1, 2011, and December 31, 2018 . We obtained the names of products authorised via the AA pathway during January 1, 2011, and December 31, 2017, through a request (via Regulation [EC] No. 1049/2001) to EMA; for January 1, 2018–December 31, 2018, we obtained the names from the EMA annual report for 2018 . We excluded the following products: vaccines; reversal agents, e.g., idarucizimub (Praxbind, AA), for anticoagulant-associated bleeding; topical agents, e.g., cenegermin (Oxervate, AA), for ophthalmic keratitis; those without pivotal trials, e.g., ketoconazole (Ketoconazole HRA, AA), for Cushing’s disease; bleeding prophylaxis agents, e.g., human coagulation Factor X (Coagadex, AA), for Factor X deficiency-associated bleeding prevention; and those no longer authorised at time of data collection, e.g., boceprevir (Victrelis), for chronic hepatitis C infection, withdrawn during 2018 at the request of the marketing authorisation holder. We also excluded products authorised via a third expedited pathway, exceptional circumstances, products for which comprehensive data on efficacy and safety cannot be provided ‘because the condition to be treated is rare or because collection of full information is not possible or is unethical’ . These products are unlikely ever to have a full dataset as is expected for products granted CMA or AA.
Between January 2011 and December 2018, 26 products granted CMA and 25 granted AA met the inclusion criteria (Table 3). Among the CMA products, 18 were to treat malignancy, 3 were for genetic, and 2 were for infection indications, and one each was for neurological, gastrointestinal, and endocrine disorders (Table 4). Among the products granted AA, 8 were to treat malignancy, 8 were for infection, 5 were for genetic disorders, 2 were for respiratory conditions, and 1 each was for a gastrointestinal disorder and a lymphoproliferative disorder (Table 4). There were 33 pivotal trials for CMA and 58 for AA products. Among the 51 products, 5 had pivotal trials that reported clinical outcomes, and 49 had trials with surrogate endpoints. The pivotal trial endpoints are described in detail in Table 4. No studies were identified that confirmed the validity of the surrogate endpoints as predicting the intended clinical outcomes (F&P Level 2 or Ciani Level 1).
In this study, we found that most of the marketing authorisations issued between January 1, 2011, and December 31, 2018, for products assessed through 2 EMA expedited pathways, CMA and AA, were based on pivotal trials that reported nonvalidated surrogate endpoints. This information was not systematically or explicitly included in the product EPARs, including in the SpCs, the definitive, regulator-approved information for prescribers (SpC Annex 1) and patients (SpC Annex IIIB, Package Leaflet). Prescribers and patients may therefore not be aware that there is only limited evidence that the products concerned provide clinical benefit. Moreover, clinical benefit may never be established because in most cases, there was also no requirement for marketing authorisation holders to conduct confirmatory postauthorisation studies.
This is, to our knowledge, the first systematic study of the use of surrogate endpoints to support marketing authorisation of products assessed through both CMA and AA expedited regulatory pathways in the EU. The extensive use of nonvalidated surrogate endpoints is concerning because the likelihood that treatment will provide the intended clinical benefit is unknown. In the current study, it was not clear from the publicly available information about the products whether surrogate endpoints were validated or nonvalidated. Neither was it clear whether postauthorisation measures—when they were required—would confirm clinical benefits. Because products authorised through these pathways are intended to satisfy unmet need or are in the public interest, the marketing authorisation holders should ultimately be required to demonstrate that they fulfil these goals.