Why do sponsors receive requests for information (RFIs) during a clinical trial application (CTA)? What are the stumbling blocks and the most common queries? And what do these requests from the regulators mean for sponsors?
These are some of the questions that IDEA Regulatory set out to chart and understand when we conducted an analysis of common RFIs submitted to the EMA’s CTIS portal at the first-in-human (FIH) and early clinical trial phases.
What prompts an RFI?
If the regulatory reviewers identify an issue in the CTA, for example, missing information or errors in the application, they will submit an RFI. The RFI might seek to get justification from the sponsor or to steer the sponsor in another direction, or if information is misplaced just to ensure the applicant makes the necessary correction.
It is then up to the sponsor to provide additional information or make the corrections required.
Do RFIs differ depending on company size or product type?
Our recent review found that the core issues are broadly the same, irrespective of company size or product type, or therapeutic indication. However, we did see that smaller companies, particularly those that are still in early phase or FIH studies, more frequently have administrative issues or documentation gaps. These can include missing required documents, version control issues, incorrect or inconsistent dates, and mismatched information between documents.
While larger companies that are likely more familiar with the submission process are less likely to have administrative issues, they still frequently have document inconsistencies. These include issues with clarity of the documentation or unclear language in the submission when it comes to key information, or information in one document (e.g. protocol) differing from another in the dossier (e.g. PIS and ICF). In our experience, one of the reasons for these inconsistencies is the fact that there are often different teams contributing to the CTA, often working in silos on their particular document or section of the dossier, and there is no change control process in place for checking if changes made to one document affect others in the submission.
Highly innovative products tend to generate more RFIs due to data gaps and requests for better justification of claims, specifications and methodology. The more common issues for conventional products are compliance gaps with good laboratory practice (GLP) or data completeness issues.
What are the most common deficiencies with RFIs?
Our analysis of RFIs shows the most frequent causes of an RFI are protocol gaps. In our review, several categories stood out; These included missing required regulatory language (e.g. GCP or GDPR compliance statements), lack of clarity with the study design, insufficient detail in the safety monitoring plan and document inconsistencies or mismatched versions. For example, if there was a correction, it’s not clear when that update was made, in which version, why, and who was involved.
While requests for things such as clarification or suggestions for improvements to study design can require significant work from the Sponsor to address, these are less common and most of the questions raised appear to be minor quality control and administrative issues. However, they do need to be clarified, and they will be raised by the regulatory reviewers in a RFI. And for sponsors, what that means is easily avoidable delays in getting the CTA approved and the study started.
What will it take to avoid RFIs?
Our review uncovered the fundamental gaps with RFIs were related to quality, clarity and consistency. What this indicates is that most RFIs are preventable with more careful preparation, greater alignment across documents and thorough document and version control, and more robust quality controls within the organisation.
Having teams collaborating and working in alignment and breaking down the silos that often lead to inconsistencies can help sponsors to limit the RFIs they receive from the regulators. Simple solutions such as starting with a detailed submission compliance checklist, including version history tables in core documents, or adding a change control step that includes cross-document consistency checks before a new version is finalised, can all help avoid some of the most common causes of delay to study approval.
“An analysis of RFIs shows the most frequent causes of an RFI are protocol gaps … (often) due to missing required regulatory language, lack of clarity with the study design, or insufficient detail in the safety monitoring plan.”