Ethics in clinical trial regulation: ethically relevant issues from EMA inspection reports

Abstract

Background: Within the EU, regulators are obliged to take ethical issues into consideration during marketing authorization deliberation. The goal of this manuscript is to identify what kinds of ethical issues regulators encounter during marketing authorization application deliberations, and the incidence of these ethical issues.

Methods: This study used an EMA-provided Excel file that contains all the GCP non-compliance findings from all inspection reports from 2008–2012. There were 112 medicinal products and a total of 288 clinical trial sites. There were a total of 4014 GCP non-compliance findings. The findings that were ethically relevant were extracted using NVivo 10.0 and categories for the ethically relevant findings (ERFs) were created. Note was taken of the incidence of ERFs for each category and the inspectors’ gradings of these findings were extracted. This study also looked at the mean and the maximum number of ERFs per grading per medicinal product application, as well as the number of medicinal products with at least one ERF and those with at least major ERFs.

Results: With multiple coding, there were 1685 ERFs. ERFs were present in almost all of the medicinal products (97.3%). The majority of ERFs were graded as major. At least major ERFs were present in almost all medicinal products with ERFs. The categories with the highest number of ERFs were protocol issues, patient safety, and professionalism issues. In terms of the density of combined critical and major findings, monitoring and oversight, protocol issues, and respect for persons top the list. This study also showed that, on average, there were 7.54 major and 2.95 critical ERFs per medicinal product application, although ERFs can increase to 30 major and 12 critical.

Conclusion: Regulators regularly encounter ERFs that at least “might adversely affect the rights, safety or well-being of the subjects”. It remains to be explored how regulators respond to these ethical issues.

Keywords:

• GCP non-compliance findings
• Clinical trials
• Ethically relevant findings
• GCP inspection
• Marketing authorization application
• Research ethics

Note

Transparency

Declaration of financial/other relationships

RDLCB received funding from the Dutch Medicines Evaluation Board for this study. NSB and CCG are employed by the Dutch Medicines Evaluation Board. CMRO peer reviewers on this manuscript have no financial/other interests to disclose.

Acknowledgments

The opinions expressed in this article are the authors’ own and do not reflect the view of the Dutch Medicines Evaluation Board.

Notes

1 Admittedly, the distinction between a GCP issue that is not an ethical issue may be blurred by statements in ethics guidelines stipulating that a non-scientific study is not ethical as well. Although this may be true, this also blurs the distinction between a scientific issue that is an ethical issue as well as vs issues that are purely scientific. It is not within the scope of this article to resolve this dilemma. For the purposes of this article, a GCP issue is an ethical issue as well if we are able to match a GCP issue to the list of ethical imperatives in Table 1 of our publication, ‘What do international ethics guidelines say in terms of the scope of medical research ethics?’⁶. For purposes of illustration, the following are examples of GCP issues that we were not able to pair with any of the ethical imperatives: incomplete database reconciliation; investigational product labeling not in compliance with legal requirements; missing documentation on shipping conditions; incorrect shipping records of the investigational medicinal product; among others.

Additional information

Funding

This study was funded by the Dutch Medicines Evaluation Board.