The International Conference of Harmonization (ICH), which is made up of the regulatory bodies and pharmaceutical trade associations of key drug developing countries, recently released their revised “E8(R1) General Considerations for Clinical Studies” document. Last month, the Food and Drug Administration (FDA), one of the ICH's founding members, issued the ICH’s E8 document for comment by US stakeholders. On September 16, PRIM&R submitted comments approving of ICH’s work to modernize their guidelines and suggesting that the document could benefit from a better discussion of the broad ethical principles that underlie many of the human subject protections the document details. We also recommend that the ICH consider reorganizing some of its guidelines to make it easier for those designing and conducting research to learn more about these fundamental ethical principles and related best practices.
The ICH’s guidelines are frequently consulted by those running international trials, as the body was set up to expedite the development of new treatments and allow for the transference of clinical trial data between different countries by harmonizing regulatory requirements. For instance, the ICH guidelines contain language on how ethical review boards (IRBs and Independent Ethics Committees) ought to function. We therefore encourage you to consider submitting your own comments on the newly revised E8 document before the September 30 deadline; please see below for more on how to comment.
PRIM&R believes that the ICH’s plans to modernize E8 will result in a document that better reflects the contemporary clinical trial landscape, especially given the document’s new language on topical areas such as patient engagement and transparency. The document also appropriately acknowledges that the protection of the rights, safety, and well-being of human research subjects is a critical element of good study design.
However, PRIM&R flags for the ICH that much of the language on protecting human subjects and related ethical issues is cursory and that those reading the document will not be exposed to the core ethical principles for human subjects research, such as respect for persons or justice. If stakeholders do not understand the broad ethical principles that justify human subject protection requirements such as selecting appropriate subject populations and providing opportunities for informed consent, then they are more likely to see these requirements as merely operational tasks. However, as the PRIM&R community knows, these imperatives rest on a recognition that people who volunteer to contribute to research do so on the expectation that research will not put them at undue risk, that it will be of benefit to society, and that they have been given the relevant information about what their participation will entail.
Given that E8 is specifically designated as the starting point for thinking about the design and conduct of clinical trials, PRIM&R believes it should include an expanded discussion of the ethical principles governing research with human subjects. Specifically, we believe that the ICH should include additional discussion on issues such as respect for persons, fair distribution of burdens and benefits, special protections for the vulnerable, risk-benefit evaluation, and the like, and explain why they are important.
PRIM&R also suggests that the ICH rethink how its guidelines are organized and presented. Because the guidelines have been released piecemeal in response to emerging needs, ICH suggests that stakeholders consult them together in a holistic manner. For instance, in the draft E8 guideline, ICH directs readers to the other guidelines (e.g. ICH E6 Good Clinical Practice) for more details on the ethical considerations they briefly mention. Unfortunately, this means that stakeholders have to consult multiple ICH documents to appreciate the full complement of ethical considerations involved in designing and conducting clinical research.
To make it as easy as possible for interested parties to engage with these important issues, we suggest that the ICH put together an overarching “roadmap” to help investigators and sponsors navigate the guidelines and explain how and when they should be consulted and applied to research. The roadmap could direct readers to begin with the E8 guideline as it provides the “general considerations” for clinical trials, and then explain how other guidelines could be used in conjunction with E8.
The ICH has substantial influence when it comes to the conduct of research globally, and as such their documents deserve more attention from those in the human subject protection community. We encourage you to consider submitting your own comments, especially if you work on international research, and let the ICH and its members like the FDA know what you think. If you are based in the United States, you can submit your comments until September 30 through the FDA by going here. You are more than welcome to cite or quote PRIM&R’s comments. If you do, please leave us a comment below or send us an email at firstname.lastname@example.org to let us know!