Monitoring of Clinical Investigations: FDA´s Q&As on Data Integrity

The U.S. Food and Drug Administration, FDA, released additional guidance on risk-based monitoring for effective oversight. The guidance expands on the 2013 guidance Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring (the RBM guidance) by providing additional guidance to facilitate sponsors’ implementation of risk-based monitoring.

In particular, the guidance provides Questions and Answers regarding

• the Monitoring Approach,
• the Monitoring Plan Content,
• the Follow-Up and Communication of Monitoring Results.

Risk Based Monitoring

Sponsors of clinical investigations of human drugs, biological products, medical devices, and combination products are required to provide oversight to ensure adequate protection of the rights, welfare and safety of human subjects and the quality of the data submitted to the FDA. However, the regulations are not specific about how sponsors are to conduct such monitoring; a range of approaches to monitoring are compatible with the regulations.

"Traditional on-site monitoring of each clinical site to evaluate study conduct and perform 100 % source data verification is highly resource intensive and may account for up to a third of the total clinical trial cost", says the FDA. But traditional on-site monitoring that is overly focused on source data verification doesn’t guarantee data quality. Therefore, a risk-based monitoring, as a component of a sponsor’s overarching quality system and trial-specific quality by design (QbD) program, can help to provide more efficient oversight of trials, while still protecting human subjects and assuring data integrity (DI).

According to FDA, the Q&A paper can help sponsors tailor monitoring plans to the needs of the clinical investigation, while focusing on those risks that have the greatest potential to adversely affect study quality. For example, as identified in the RBM guidance, for investigations in which blinding will be used for interventions and/or outcome assessments, ensuring that the investigation blind is maintained is a critical process that sponsors should consider in their risk assessment.

In addition, risk based monitoring can be accomplished through the incorporation of more computerized systems for effective oversight that can be used to monitor DI as a trial is in process. 

Questions on Data Integrity (DI)

Should sponsors monitor only risks that are important and likely to occur?

A risk-based approach to monitoring should focus sponsor oversight activities on preventing or mitigating important and likely risks to investigation quality, including risks to human subject protection and DI. Sponsors also should consider monitoring risks that are less likely to occur but could have a significant impact on the investigation quality. Sponsors should therefore determine the types and intensity of monitoring activities best suited to address the identified risks. In addition, monitoring plans should permit monitoring activities to evolve based on additional issues and risks that may be identified during the conduct of an investigation.

How should sponsors follow up on significant issues identified through monitoring, including communication of such issues? 

According to FDA, significant issues identified through monitoring (for example, significant non-compliance with the protocol) should be thoroughly evaluated in a timely manner at the appropriate level (for example, sponsor, CI (clinical investigator) site(s)) as described in the monitoring plan. Appropriate corrective and preventative actions (CAPAs) should be taken. Deviations from the investigational plan should be documented, tracked, and escalated to relevant personnel, as appropriate. Related systemic issues should be identified and resolved promptly to ensure that investigation quality, including DI, is maintained. Some examples of CAPAs that may be needed include retraining CI and site staff; clarifying protocol requirements through protocol amendment(s); or revision(s) to informed consent documents or procedures.

For more information please see FDa`s draft Guidance for Industry A Risk-Based Approach to Monitoring of Clinical Investigations: Questions and Answers.