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

Rick A Vreman,Wim G Goettsch,Aukje K Mantel-Teeuwisse,Menno E Van Der Elst,Lourens T Bloem,Jarno Hoekman,Hubert Gm Leufkens,Stijn Van Oirschot,Olaf H Klungel

doi:10.34172/ijhpm.2020.198

Abstract

Background: The European Medicines Agency (EMA) aims to resolve uncertainties associated with conditionally approved drugs by imposing post-approval studies. Results from these studies may be relevant for health technology assessment (HTA) organizations. This study investigated the role of regulator-imposed post-approval studies within HTA. Methods: For all conditionally approved drugs up to December 2018, regulator-imposed post-approval studies were identified from EMA’s public assessment reports. The availability for and inclusion of study results in relative effectiveness (re)assessments were analyzed for 4 European HTA organizations: NICE (National Institute for Health and Care Excellence, England/Wales), HAS (Haute Autorité de Santé, France), ZIN (Zorginstituut Nederland, the Netherlands) and the European Network for Health Technology Assessment (EUnetHTA, Europe). When study results became available between an HTA organization’s initial assessment and reassessment, it was evaluated whether and how they affected the assessment and its outcome. Results: For 36 conditionally approved drugs, 98 post-approval studies were imposed. In total, 81 initial relative effectiveness assessments (REAs) and 13 reassessments were available, with numbers of drugs (re)assessed varying greatly between jurisdictions. Study results were available for 16 initial REAs (20%) and included in 14 (88%), and available for 10 reassessments (77%) and included in all (100%). Five reassessments had an outcome different from the initial REA, with 4 (2 positive and 2 negative changes) relating directly to the new study results. Reassessments often cited the inability of post-approval studies to resolve the concerns reported in the initial REA. Conclusion: Results from regulator-imposed post-approval studies for conditionally approved drugs were not often used in REAs by HTA organizations, because they were often not yet available at the time of initial assessment and because reassessments were scarce. When available, results from post-approval studies were almost always used within HTA, and they have led to changes in conclusions about drugs’ relative effectiveness. Post-approval studies can be relevant within HTA but the current lack of alignment between regulators and HTA organizations limits their potential.

Highlights

To enable timely access to innovative drugs, the European Medicines Agency (EMA) can conditionally approve drugs based on a less comprehensive evidence package when immediate availability of the drug outweighs the risks due to the less comprehensive evidence package.[1,2] Importantly, the benefit-risk balance still needs to be judged positive, but more uncertainty may be considered acceptable in light of the drug’s potential to address unmet medical needs.What constitutes a ‘less comprehensive evidence package’ is to some extent clarified by EMA guidelines and can be related to small sample sizes, surrogate primary endpoints, short follow-up times, and limited safety data, amongst others.[1]
Included health technology assessment (HTA) organizations were major European HTA jurisdictions that systematically publish full initial HTA reports and reassessment reports on their websites in a language understood by the investigators, being: England + Wales (National Institute for Health and Care Excellence, NICE), France (Haute Autorité de Santé, HAS), the Netherlands (Zorginstituut Nederland, ZIN) and the European Network for Health Technology Assessment (EUnetHTA)
Characteristics of Included Drugs, Pivotal Studies and Specific Obligations Forty drugs have been conditionally approved between January 2006 and December 2018

Summary

Introduction

To enable timely access to innovative drugs, the European Medicines Agency (EMA) can conditionally approve drugs based on a less comprehensive evidence package when immediate availability of the drug outweighs the risks due to the less comprehensive evidence package.[1,2] Importantly, the benefit-risk balance still needs to be judged positive, but more uncertainty may be considered acceptable in light of the drug’s potential to address unmet medical needs. What constitutes a ‘less comprehensive evidence package’ is to some extent clarified by EMA guidelines and can be related to small sample sizes, surrogate primary endpoints, short follow-up times, and limited safety data, amongst others.[1] research has shown that the evidence package available at approval for drugs with a conditional marketing authorization (CMA) is less comprehensive compared to drugs approved with a standard marketing authorization.

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