A Model Structure for Describing Uncertainties in the Benefit Risk Assessment of Oncology Drug Applications

Nikolaos Zafiropoulos^1*Francesco Pignatti¹Andreas Kouroumalis¹Lorenzo Guizzaro¹Dominik Karres¹Pierre Demolis²Olli Tenhunen³Rosanne Janssens⁴Anne Taams⁵Lourens Bloem⁵Franz Koenig⁶Martin Posch⁶

• ¹European Medicines Agency, Amsterdam, Netherlands
• ²Agence Nationale de Sécurité du Médicament et Des Produits de Santé (ANSM), Paris, France
• ³Finnish Medicines Agency, Helsinki, Uusimaa, Finland
• ⁴KU Leuven, Leuven, Belgium
• ⁵Utrecht University, Utrecht, Netherlands, Netherlands
• ⁶Medical University of Vienna, Vienna, Vienna, Austria

Abstract Introduction The European Medicines Agency (EMA) uses structured reports to communicate the scientific review of drug applications. A European Public Assessment Report (EPAR) is published at the end of the review detailing the scientific assessment, which includes benefit-risk analysis and uncertainties in the favorable and unfavorable effects. Currently, there is no detailed guidance on how to communicate uncertainties in the EPAR. The aim of this study was to identify uncertainties described in the benefit-risk section a series of EPARs and derive a possible model structure for communicating them. Methods A series of approved oncology drug applications that had used the latest EPAR template by the time of analysis was selected. The model structure was adapted iteratively, aiming to identify a small number of key elements, with input from the study team. Finally, the model structure was discussed with two experienced clinical assessors to determine clarity and potential usefulness.. Results From 64 oncology EPARs published between 2011 and 2017 (26 related to products with orphan designation), 263 uncertainties in the benefit-risk assessment were identified. The final model structure included Cause (what caused the uncertainty), Aspect (what is the uncertainty about, further described as high-level domain and specific component), Type (what is the kind of the uncertainty, like not enough information or conflicting information); and Strategy (how is the uncertainty addressed). This four-element structure (Cause, Aspect, Type, Strategy; CATS) was discussed with expert assessors and found generally understandable and relevant. Discussion The CATS-model structure has been derived as a starting point for communicating uncertainties in benefit-risk assessment of drug applications. To increase relevance, it was derived based on issues raised during actual reviews and discussed with expert reviewers. Limitations include the narrow focus of the current series, and the need for validation. If useful, eventually this structure could be used to further enhance assessment report templates. Conclusion The proposed CATS-model structure may facilitate communicating uncertainties in the benefit-risk assessment of drug applications. Further refinements depending on the purpose and validation, aiming for broader applicability, are needed.