Introducing the need for a consensus-based framework for protocol modifications to improve trial trustworthiness

Area of Science:

• Clinical Trials
• Research Integrity
• Biostatistics

Background:

• Randomized controlled trials (RCTs) transparency has improved via registration and public protocols/statistical analysis plans (SAPs).
• Reporting of protocol and SAPs modifications lacks standardization, hindering identification of changes, rationale, and impact on results.
• Existing transparency initiatives leave gaps in understanding the implications of modifications for trial trustworthiness.

Purpose of the Study:

• Advocate for a consensus-based framework for reporting protocol modifications in RCTs.
• Address the tension between the necessity of modifications and their potential risks (bias, undermined confidence).
• Highlight challenges faced by readers, reviewers, and decision-makers in evaluating protocol changes.

Main Methods:

• Review empirical evidence on the prevalence and nature of protocol modifications.
• Discuss the implications of these modifications for trial validity, interpretation, and credibility.
• Analyze the difficulties in identifying and assessing protocol changes due to dispersed information.

Main Results:

• Protocol modifications are common and necessary but can introduce bias if not properly justified.
• Lack of standardized reporting burdens stakeholders in evaluating the impact of changes.
• Current practices make it difficult to ascertain the trustworthiness of RCT findings when modifications occur.

Conclusions:

• Standardized and transparent reporting of protocol modifications is essential for critical evaluation.
• Advocate for a consensus-based reporting framework, potentially using a Delphi process.
• Improved reporting will enhance transparency, facilitate critical appraisal, and strengthen confidence in RCT findings.