Final FDA Guidance Reinforces the Importance of Sponsor Oversight and Quality Risk Management in All Clinical Trials

The new final guidance goes beyond the August 2013 guidance and March 2019 draft guidance in several important ways. These include the following:

• The new final guidance explicitly articulates the expectation that monitoring is just one component of a comprehensive quality risk management approach. For example, it states: “Monitoring is a quality control tool for determining whether study activities are being carried out as planned, so that deficiencies can be identified and corrected. Monitoring, or oversight, alone cannot ensure quality. Rather, quality is an overarching objective that must be built into the clinical trial enterprise. FDA recommends a quality risk management approach to clinical trials and is considering the need for additional guidance describing this approach.”⁴
• The guidance also describes the scope of expected monitoring by placing greater emphasis on the reevaluation of “risk assessment and management processes throughout the conduct of the investigation” and revision of “monitoring plans (and if necessary, protocol design) ... when needed to continue to protect the rights, safety, and welfare of participants in the clinical investigation and the integrity of data generated during the investigation.”⁵ FDA also provides more detail on centralized monitoring and highlights the benefits for sponsors, including the ability to “(1) review study-wide data for inconsistencies or omissions; (2) perform activities such as data checks, for completeness and consistency; (3) verify source data; (4) ensure that institutional review board and informed consent documents are current; and (5) determine which clinical sites need on-site review.”⁶
• Finally, the guidance puts increased emphasis on the monitoring expectations in situations where studies are run by a CRO. For example, it notes that “efforts to build quality into the design and execution of clinical investigations should be informed by representative study team members involved with conduct, monitoring, and/or reporting of the investigation,” which may include “contract service providers tasked with critical study functions.”⁷ Further, it mentions the need for communication of significant issues to CROs and potential modification of vendor service agreements if preventative or corrective actions are warranted.⁸

As noted above, it is perhaps most significant that the new final guidance aligns with growing attention on clinical trials by various stakeholders in the U.S. and globally, a general focus on patient protection and data integrity in clinical investigations, and signals of increased future enforcement. For example, the final guidance is consistent with the EU adoption of a risk-proportionate approach in clinical trials, which aims to account for differences in trials and works to “ensur[e] the protection of the participants in clinical trials as well as the quality and integrity of the trial outcomes.”⁹ In addition, in the U.S., the Department of Justice has noted its focus on clinical trial issues in a number of public statements.

In light of all this, clinical trial sponsors should view this new final guidance as significant and further evidence of FDA’s focus on clinical quality and data integrity. While the focus on a risk-based approach is not new, the guidance underlines the importance of robust quality management systems including vendor oversight in the clinical trial context. The consequences of lax oversight can be severe, both from an enforcement perspective and in terms of potential setbacks in development. Accordingly, sponsors should engage and assess their clinical trial vendors, including by conducting audits and monitoring for potential signals. If potential GCP, quality, or data integrity lapses are identified, sponsors should be proactive and take appropriate action to product trial participants and the quality of the clinical trial data.

¹ See, e.g., What Life Sciences Companies Can Expect for Enforcement in 2023: Enforcement Focused on Misconduct in Clinical Trials (Feb. 7, 2023), https://www.sidley.com/en/insights/newsupdates/2023/02/what-life-sciences-companies-can-expect-for-enforcement-in-2023.

² See FDA, Guidance for Industry, “A Risk-Based Approach to Monitoring of Clinical Investigations—Questions and Answers” (Apr. 2023) at 4 (available at https://www.fda.gov/media/121479/download) (Monitoring Guidance or final guidance).

³ See “A Risk-Based Approach To Monitoring of Clinical Investigations-Questions and Answers; Guidance for Industry; Availability,” 88 Fed. Reg. 22038, Apr. 12, 2023 (available at https://www.federalregister.gov/documents/2023/04/12/2023-07687/a-risk-based-approach-to-monitoring-of-clinical-investigations-questions-and-answers-guidance-for); see “A Risk-Based Approach To Monitoring of Clinical Investigations: Questions and Answers; Draft Guidance for Industry; Availability,” 84 Fed. Reg. 9531, Mar. 15, 2019 (available at https://www.federalregister.gov/documents/2019/03/15/2019-04814/a-risk-based-approach-to-monitoring-of-clinical-investigations-questions-and-answers-draft-guidance); see FDA, Guidance for Industry, “Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013) (available at https://www.fda.gov/media/116754/download) (RBM Guidance).

⁴ Monitoring Guidance, at 4.

⁵ Id. at 7.

⁶ Id. at 10.

⁷ Id. at 6, FN 9.

⁸ Id. at 12.

⁹ Regulation (EU) No 536/2014, Risk proportionate approaches in clinical trials, Apr. 25, 2017 (available at https://health.ec.europa.eu/system/files/2017-08/2017_04_25_risk_proportionate_approaches_in_ct_0.pdf).