MHRA Guidelines on Risk-based Quality Management (RBQM) in Clinical Trials

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Apr 14, 2022

This blog was authored by Fiona Maini, Global Compliance and Strategy Principal, Medidata.

On January 28th, 2022, the UK Medicines & Healthcare products Regulatory Agency (MHRA) published guidance on clinical trials regarding risk-adapted approaches, risk assessments, oversight, and monitoring activities in two individual documents: Risk-adapted Approach to Clinical Trials and Risk Assessments¹ and Oversight and Monitoring of Investigational Medical Product Trials.² These documents emphasize the use of risk-based strategies in clinical trials and align with more modern clinical trial design and study conduct approaches.

As trusted advisors in the life sciences industry, Medidata welcomes these guidelines and has observed the evolution of these topics. Our regulatory strategy experts provided practical insights to the discussion via presentations to the MHRA Innovation Office regarding our own experiences in the practical, operational risk-based monitoring processes and technologies already established. Through these discussions (going back more than three years), it was acknowledged that risk-adapted approaches in clinical trials could be highly beneficial. But wider adoption across the industry remains slow.

The guidelines provide a comprehensive overview of clinical trial risk management and monitoring approaches with the fundamental perspective that ‘one size does not fit all.’ Not all trials are the same, and some only pose minimal risk to safety and data integrity. The MHRA discusses the benefits of adopting a risk-adapted approach, which they cite can potentially reduce costs, drive more effective utilization of resources, reduce duplication of efforts, and shift the focus onto reliability of results rather than the correctness of data points that are not critical to a trial.^1,2,3

Risk-Adapted Approach to Clinical Trials and Risk Assessments

The Risk-adapted Approach to Clinical Trials and Risk Assessments guidance takes a dual strategic approach:

First, this defines the stratification and categorization of trials into type A, B, or C depending upon the use of the investigational medicinal product (IMP) in relation to its marketing authorization or an unlicensed IMP, i.e., the risks associated with the IMP. This would impact the MHRA authorization process, indicate potential changes to trial documentation requirements, inform the safety monitoring plan and trial results, and protect trial patients' safety, rights, and well-being¹
The second strategic requirement is to have a risk assessment specific to the trial to identify specific vulnerabilities and risks in the trial conduct that could impact the trial results and the patients' safety, rights, and well-being.

This risk assessment would document the mitigations for specific identified risks and any adaptations from traditional Good Clinical Practice (GCP). These would then be developed to have risk proportionate management and monitoring of the trial. The risk assessment covers risk-based design and management of the trial, not just monitoring; therefore, when considering the development of the risk assessment, the importance of starting early and involving all the relevant resources is emphasized. The guidance indicates the auditors will be reviewing the risk assessment as part of inspections.

Oversight and Monitoring of Investigational Medical Products

The MHRA simultaneously published companion guidance on the Oversight and Monitoring of Investigational Medical Products.² This document lists significant areas in determining the oversight and monitoring strategy, indicating that sponsors should establish processes that reflect the known risks of a trial and make sure the risk assessment determines this strategy.

The oversight and monitoring strategy could be a single document or be contained in a range of documents. Regardless of how it is performed, there needs to be a clear link to the risk assessment to identify the areas that matter to the result's reliability, patient safety and rights, and compliance with the legislation.

The MHRA also outlines specific oversight and monitoring considerations across a broad range of clinical trial activities; some of these areas are outlined below:

Central monitoring in clinical trials is emphasized within the MHRA guidance. Traditionally, monitoring has been performed on-site, but centralized or remote monitoring mechanisms can cover many of the tasks carried out on-site. Central monitoring activities will typically focus on the areas that matter as identified in the monitoring strategy. Sponsors can leverage an on-site, off-site, or a mixture of both approaches. The MHRA highlighted the need to document centralized monitoring, "There should be a formal process for dealing with issues and data queries identified during central monitoring and data management activities, including an escalation process. Any generated evidence of identification of the issue(s), review and discussion, and subsequent actions must be retained."
Statistical monitoring is an aspect of central monitoring which uses statistical approaches and modeling methods to examine and monitor clinical and performance data as it accumulates. With these statistical techniques, site comparisons can be made to identify unusual or irregular patterns, variances distributions, etc., occurring in the clinical trial. These may determine whether increased monitoring is required at a site. The MHRA indicates that these techniques can potentially highlight issues that on-site monitoring might not reveal, referencing the potential to highlight fraudulent behaviors.
Quality metrics and performance indicators were highlighted by the MHRA such that there is currently no general industry standardized list. Still, they do outline the key metrics used by sponsors that have been typically seen, notably serious adverse events reporting, recruitment rates, and number of subject withdrawals/dropouts.
Source data verification (SDV) was also a key topic explained by the MHRA and one that the industry has had many questions about.
- The MHRA recommends that any SDV performed focus on data that matters to the reliability of the trial results.
- The MHRA and industry are aligned in that performing 100% SDV may not be an efficient and effective use of a monitor's time.
- The MHRA indicates that if a monitor is performing 100%, they may not have much time for anything else and may miss other critically important issues.
- The risk-based approach to SDV is discussed. The amount of SDV to be performed is based on the risk categorization, and there may be more SDV performed with a Type C versus a type A profiled clinical trial. The MHRA recommends that the SDV planned checks are to be kept in the protocol, SOPs, or monitoring strategy.
- GCP inspectors may inspect the SDV, but based on what is outlined in the trial documentation outlined above. The GCP inspectors will generally take a risk-based approach to select the data to inspect. If discrepancies are seen in the risk-based verified data, then this may result in a significant finding.
- With increasing use of electronic systems and reduction in SDV, it is likely to emphasize computer system validation checks.
- Within the SDV section, the MHRA highlights that source data can be accessed and verified remotely, but is restricted to authorized users and where a patient has explicitly consented, and according to data protection and data privacy laws.
- In general, the MHRA guidance gravitates away from the typical, traditional approach of looking to assess compliance with every detail of the protocol and checking every data point against source documents.

Several points were repeatedly emphasized across the two guidances and the MHRA's New Clinical Trial Legislation⁵ : 1) ensure the risk assessment is performed early with the relevant multi-disciplinary team, 2) focus on the areas that matter, and 3) focus on the data that is critical to the reliability of the trial results.

Medidata's approach is in complete alignment with this recent guidance. By unifying RBQM and clinical trial management, Medidata delivers the ability to define and execute a holistic, end-to-end risk-based quality management and monitoring strategy from initial protocol development to database lock. As the application of risk-based principles in clinical trials evolves, our regulatory strategy experts continue to assist customers in successfully navigating the regulatory landscape and promoting the adoption of RBQM methodologies in their trials.

Medidata’s RBQM process consists of Medidata Risk Management, Medidata Detect, Medidata Rave TSDV (Targeted Source Data Verification), and Medidata Remote Source Review powered by Rave CTMS for robust issue management and reporting capabilities to enable digital oversight. Designed to support customers' adherence to ICH E6 (R2) and ICH E8 (R1) recommendations, Medidata RBQM provides inspection-ready status and full transparency to regulatory authorities while maintaining continuous application of risk management and centralized statistical monitoring methodologies.