Site-level input into trial design

Sponsors should seek and consider local input on trial design before finalization with central regulators.

Trial design and implementation are improved when informed by the local context at participating sites. Despite this, it can be challenging to incorporate local input on major trial design issues in the context of multi-site, international regulatory trials. Often a protocol for the trial is submitted and approved by central regulators (for example, the US FDA or the European Medicines Agency (EMA)) before sites for the trial are selected. And even when a trial protocol is amended after sites are selected, it may not be practical for the Sponsor to consult with all trial sites due to timing constraints and/or where the central regulator’s requirements are clear and overriding. Nevertheless, Sponsors should aim to maximize site-level consultation on major trial decisions, especially around trial regimens, sample exports and safety assessments. Although this could delay central approvals, it might also significantly improve implementation by avoiding decisions that will be unacceptable to country regulators and inappropriate in the local context of trial sites.

The importance of local consultation was evident on a number of occasions during STREAM. When version 8.0 of the protocol was introduced, it included significant changes related to treatment regimens and trial design that sites and local committees had not reviewed prior to finalization with the US FDA. In one country, the local regulator did not approve the change – resulting in prolonged recruitment to a secondary arm of the trial and extending overall recruitment timelines for the trial. Understanding the local regulator’s views prior to engaging central regulators (FDA/EMA) could have influenced proposals made and the ultimate decisions reached with the central regulators. In addition, even if the Sponsor had been unable to accommodate changes to account for local requirements/context, prior consultation may have improved buy-in to the centrally-approved design changes.

[I recommend that sites] … participate in the Protocol development (to ensure local regulator’s concerns regarding patient management and treatment regimens are accounted for) and ensuring that the clinical management guides (that also address issues raised locally) are in place.

Site Study Coordinator, STREAM Trial

A second aspect of the STREAM trial design that would have benefitted from prior local consultation was the requirement for central laboratory safety testing. It is a common requirement in multi-site, phase III trials to require central lab testing to ensure consistency of results across sites in multiple countries. However, this requirement can be misunderstood by sites and regulators, who sometimes interpret the requirement as a lack of confidence in local capacity, rather than being driven by the need for consistent results. Sponsor consultation with local partners on this issue before site selection could have improved interactions with local regulators and enhanced buy-in or – where local regulators were unwilling to permit central safety testing – informed the Sponsor’s site selection.

Recommended best practices

Sponsor should maximize site-level consultation on major trial design issues through the following measures:

  • Develop a standardized list of proposed trial characteristics (e.g., use of a central lab, import of supplies available locally, benefit sharing requirements arising from biodiversity laws, storing samples for future research, etc.) that might be controversial for local regulators

  • (Using the standardized list) consult with site-level stakeholders on key aspects of trial design before finalization with central regulators

  • Seek out opportunities to meet with local regulators to understand their requirements and align them better with requirements of international regulated trials