Abstract
BackgroundIn the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. To this date, we know very little about the manner that these regulators put this obligation into action. In this paper, we intend to look into the manner and the extent that ethical issues discovered during inspection have reached the deliberation processes.MethodsTo gather data, we used the Dutch Medicines Evaluation Board database and first searched for the inspections, and their accompanying site inspection reports and integrated inspection reports, related to central marketing authorization applications (henceforth, application/s) of drugs submitted to the European Medicines Agency (EMA) from 2011 to 2015. We then extracted inspection findings that were purely of ethical nature, i.e., those that did not affect the benefit/risk balance of the study (issues related to informed consent, research ethics committees, and respect for persons). Only findings graded at least major by the inspectorate were included. Lastly, to identify how many of the ethically relevant findings (ERFs) reach the application deliberation processes, we extracted the relevant joint response assessment reports and reviewed the sections that discussed inspection findings.ResultsFrom 2011 to 2015, there were 390 processed applications, of which 65 had inspection reports and integrated inspection reports accessible via the database of the Dutch Medicines Evaluation Board. Of the 65, we found ERFs in 37 (56.9%). The majority of the ERFs were graded as major and half of the time it was informed-consent related. A third of these findings were related to research ethics committee processes and requirements. Of the 37 inspections with ERFs, 30 were endorsed in the integrated inspection reports as generally GCP compliant. Day 150 joint response assessment reports and Day 180 list of outstanding issues were reviewed for all 37 inspections, and none of the ERFs were carried over in any of the assessment reports or list of outstanding issues.ConclusionNone of the ethically relevant findings, all of which were graded as major or critical in integrated inspection reports, were explicitly carried over to the joint assessment reports. This calls for more transparency in EMA application deliberations on how ERFs are considered, if at all, in the decision-making processes.
Highlights
In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes
Bernabe et al BMC Med Ethics (2020) 21:103 [1,2,3,4]. One of these is the document, Points to consider on Good Clinical Practice (GCP) inspection findings and the benefit-risk balance where the mandate of regulators in terms of the place of these ethical issues in the evaluation process is explained as follows: GCP inspection findings – even if not directly influencing the benefit-risk balance—will still be important if they raise serious questions about the rights, safety and well-being of trial subjects and the overall ethical conduct of the study. It is an obligation of clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use (CHMP) to assess the ethics of a clinical development programme, and major ethical flaws should have an impact on the final conclusions about approvability of an application
We discovered that based on 2008–2012 inspection reports comprising of 112 medicinal products and 288 clinical trial sites, inspectors frequently and regularly encounter ethically relevant findings (ERFs)
Summary
In the EU, clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use are obliged to assess the ethical aspects of a clinical development program and include major ethical flaws in the marketing authorization deliberation processes. Though it is fair to assume that at least some of the ERFs that “directly influence the benefit-risk balance” of an investigational medicinal product submitted for marketing authorization application would be carried over to the succeeding regulatory deliberation processes, we cannot make the same assumption about GCP inspection findings that do “not directly influence the benefit-risk balance.” The latter remains unknown and, as such, we know very little about the manner that “clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use (CHMP)” fulfill this obligation of “assessing the ethics of a clinical development programme.”. Though it is fair to assume that at least some of the ERFs that “directly influence the benefit-risk balance” of an investigational medicinal product submitted for marketing authorization application would be carried over to the succeeding regulatory deliberation processes, we cannot make the same assumption about GCP inspection findings that do “not directly influence the benefit-risk balance.” The latter remains unknown and, as such, we know very little about the manner that “clinical assessors, rapporteurs and the Committee for Medicinal Products for Human Use (CHMP)” fulfill this obligation of “assessing the ethics of a clinical development programme.” To respond to this need, it is the goal of this article to look into the manner and extent that ethical issues that do not affect benefit-risk balanced and were discovered during inspection have reached the deliberation processes, i.e., how “major ethical flaws”
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