Addressing RWE Challenges in Real-Time: The ‘Clean Room Committee’ Approach Works to Handle Research Hurdles without Bias

OBJECTIVES: While there are accepted standards for demonstrating rigor, reproducibility, and transparency in randomized controlled trials, best practices for operationalizing Real-world evidence (RWE) studies intended for regulatory decision-making are still being established. Examining data can often lead to unexpected considerations that require deviation from the pre-specified statistical analysis plan (SAP). In practice, investigators have the option to formally amend the SAP as documentation of methodological deviations in real-time. While SAP amendments address transparency concerns, they do not safeguard against introducing investigator bias. There are no established best practices for quickly and efficiently proceeding in these settings while also maintaining study rigor. To address the competing needs of mitigating the potential for bias in these unexpected settings without introducing costly delays, we developed and implemented a novel process of an independent Clean Room Committee (CRC).

METHODS: In the fields of semiconductor manufacturing and the life sciences, cleanrooms are regulated spaces designed to control contamination and aid in the removal of airborne particles. We viewed potential investigator biases, such as the desire for statistically significant results, as analogous to a contaminant, and our CRC process was born. The process includes selection of a committee independent of the study team and procedures for revising the SAP while remaining blinded.

RESULTS: We recently used a CRC in a study using electronic health records to analyze the safety of cefazolin administered perioperatively. Upon receipt of the data, a substantial degree of missingness among the covariates was discovered, rendering the pre-specified analyses infeasible. The CRC reviewed the missing data patterns and recommended revisions to the SAP to enable the analysis to proceed.

CONCLUSIONS: As RWE plays a growing role in regulatory decision-making, principled processes are needed to build trust in the evidence without imposing costly delays—the Clean Room Committee fulfills this need.