Best practices for reviewing and finalizing clinical protocols

Introduction to the PRC

The Protocol Review Committee (PRC) is a multidisciplinary body established to facilitate the internal review and finalization of clinical trial protocols prior to regulatory submission. Although not required by the FDA, many sponsors assemble a PRC to serve as a quality gate to systematically identify protocol gaps ensuring that all supporting elements, from study design to safety monitoring, are in place before advancing to the Investigational New Drug (IND) submission stage. Typically, the PRC process is driven by Clinical Operations (ClinOps) or a lead Principal Investigator (PI) who oversees protocol development, determines the study budget and timeline, and sets the stage for subsequent activities. The PRC enables cross-functional review, bringing together clinical, statistical, patient advocacy, and regulatory perspectives to ensure protocols meet study goals and regulatory expectations.

The BGTC aims to implement a PRC for all NCATS’ sponsored gene therapy clinical protocols and has successfully completed one full PRC process, presented herein as an example. We describe the PRC procedures used by BGTC which are intended only as a guide rather than a standard. Templates and tools referenced are available in this playbook’s resources section.

Establishing and Conducting a PRC

The key phases of the BGTC PRC process are outlined below.

1. Drafting the PRC Charter

   1. Define purpose, authority, and review scope of the PRC.

   2. Establish clear roles and responsibilities (e.g., chair, reviewers, scientific lead, admin support).

   3. Develop an activity timeline outlining different milestones.

2. Creating the Scoring Rubric and Guidelines

   1. Develop a standardized scoring framework to evaluate key protocol sections (e.g., study design, endpoints, safety monitoring, statistical plan, feasibility).

   2. Consider adding qualitative guidance on what constitutes “acceptable,” “needs revision,” or “major concern” for each scoring category.

   3. Encourage reviewers to provide narrative justification alongside scores to support actionable feedback.

3. Establishing Review Process Logistics

   1. Ensure consistent scheduling and clear communication timelines between PIs and the PRC.

   2. Define criteria for PRC membership selection (subject-matter expertise, independence, and balanced representation of clinical, statistical, and regulatory perspectives).

   3. Recommend scheduling the PRC review and activities in a way that builds in sufficient time for revision / alignment. Create agenda templates to standardize review flow (e.g., presentation of protocol, discussion of key risk areas, scoring, consensus summary)

The following BGTC documents are offered as examples:

• Scoring rubric

• Scoring guidelines

• Consolidated feedback template

• Protocol checklist

Practices for Finalizing Protocols

• Before finalizing a PRC-reviewed protocol, the following may be considered:

• Confirm that all regulatory-critical components (objectives, endpoints, safety assessments, statistical plan) have been PRC-reviewed and authorized.

• Conduct a final cross-functional review, involving clinical, regulatory, biostatistics, and manufacturing teams.

• Incorporate the patient voice in protocol review.

• Ensure version control and documentation of changes resulting from PRC feedback.

• Archive PRC outputs and decisions for traceability.