Navitas Life Sciences welcomes the opportunity to provide comments on this Reflection Paper.

The current recommendations certainly take a significant step towards providing guidance on clinical trial management, with an emphasis on quality by design. This is particularly noticeable in the paper’s focused discussion on “Critical to Quality” factors. We believe that a revision to ICH E6 and E8 could go further, as proposed below.

Use of real world data

For the revised guidelines to stand the test of time, we should accept, and embrace, the fact that real world data sources such as electronic health records will become part of the standard data set for traditional trials of unapproved drugs. Therefore, we believe that to limit real world data to the annex on non-traditional trials is short-sighted. Instead, we would propose a reorganization of the annexes themselves; categorising them based on risk, rather than if they are traditional or not. This may mean that trials on unapproved drugs are still maintained, rightly, in a separate annex to those on approved drugs. However, it would remove the distinction primarily on data source. Software tools that can aggregate multiple sources of data for a variety of clinical studies that encompass very different risk levels already exist and are gaining prevalence in the industry. We should not limit our categorisation to the tools we have available today as they will no doubt continue to evolve rapidly.

E8 revision through working groups

In reviewing E8, working groups could also include members from outside the field of clinical trials. Quality by design has been an integral part of the manufacturing and automotive industry for decades and there may be opportunities for experts from these fields to help guide discussions. Pharma external SMEs would not only provide best practices and lessons learned but can offer a unique/outsider opinion on the current guidance.

Using a revised E8 as a platform to reference key documents is an essential step, and removes a significant pain point for users of this guidance.

Structure of ICH E6 revision and annexes

The revisions to ICH E6, and the associated annexes, focus on including and expanding “Critical to Quality” factors in the new guidelines. However, the CTTI list of Critical to Quality factors is extremely broad and there is a risk that ICH guidelines as a result, will simply duplicate considerable effort that has already been put into these and national clinical trial regulations. It may be more useful to provide context and metrics for these critical to quality factors. For example, it would be enormously valuable to provide insight into how risk based, or central monitoring can be effectively executed, globally. This can include circumstances where it is appropriate to use 100% central monitoring. Recall that the open letter explicitly details the absence of good information on central versus on site monitoring. Unfortunately this has received scant attention in this reflection paper.

Approach to revision

We are hopeful that the revisions to ICH E6 and E8 are not written in a similar style to this Reflection Paper as the readability of the reflection paper is extremely low. The Flesch Kincaid grade level score is 18 demonstrating that this document is “very difficult to read” and only understandable by postgraduate qualified readers. Although readers of ICH guidelines are likely to be highly qualified, this should not be a requirement to understanding the text. We sincerely hope that the final guidance is written in a more accessible fashion. Public consultation processes are an opportunity for all stakeholders to observe how ICH will conduct its own processes in the forthcoming revisions. If the internal processes result in unreadable documents, it does not provide stakeholders with confidence that the new guidelines will be different.

Communication with regulatory authorities

As outlined in the response letter to the EMA and ICH, communication and transparency are key issues with the current process. This results in groups feelings unheard, frustrated, and at odds with regulators. Furthermore, silence or lack of openness impacts execution of clinical trials and ultimately affects the development of new products and treatment of patients. The reflection paper does take steps to address this concern through stakeholder meetings and an open invitation for comments, however, it does not directly address how new guidance will allow for two way communication between regulators and companies. We recommend that a new approach is taken to encourage openness between both parties. An ideal solution would utilize current online resources to hold forum discussions, promote an open answering of questions, and allow the public to view responses/best practice guidance.

In summary, the reflection paper outlines several important areas for expansion and update however, we suggest that the revisions expand further. There should be more clarity around risk based monitoring and how critical to quality factors should be used. A different approach to the annexes should be employed, categorising trials by risk, rather than the extent to which they are traditional. New regulations should be clear and concise so that they are of practical use. Finally, ICH should strive to improve the level of two way communication to ensure understanding, promote ongoing guidance, and provide transparency.

Thank you once again for the opportunity to provide a response.

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