Clinical research is about generating data to support decisions for developing and changing medical products and practices while making sure the safety, rights, and well-being of participating subjects are protected, and resulting data are reliable. Decision making can only be as good as the processes used to manage the clinical trials.
Academic and industry driven clinical research is slowly adapting quality risk management processes for: early identification of factors with potential to affect subject safety and protocol compliance; training for those conducting, overseeing and monitoring the study; continual re-assessment of priorities; and CAPA. Perfect control of activities is rarely possible to achieve, but a quality controlled and prioritized risk-based approach can be next best to perfection.
In support of the emerging transformation in how clinical trials are managed, US FDA released the “Guidance for Industry: Oversight of Clinical Investigations - A Risk-Based Approach to Monitoring” (August 2013), and on its heels, the European Medicines Agency (EMA) issued the “Reflection Paper on Risk Based Quality Management in Clinical Trials” (November 2013).
Comparison of the two guidance documents reveals both overarching commonalities and different areas of focus.
The FDA guidance explicitly applies to drugs, biologicals, medical devices and combinations. The implied scope of the EMA paper is for medicinal products, but the purported concepts are universal and applicable to all other medical products.
The EMA reflection paper was developed taking into account the preceding FDA guidance and advisories from other groups in the field. EMA’s purpose is to encourage not just efficient monitoring, but facilitate the development of a more systematic, prioritized, step-by-step, risk-based approach to quality management of clinical trials. Emphasized are the importance of time and resource/cost management; how risk management contributes to and facilitates decision making throughout the lifecycle of the trial; and modernizing the concepts from the 1996 ICH GCP, when clinical research was largely paper based.
The FDA guidance embraces modernization by acknowledging that, historically, 100% verification of all data has been the preferred way to meet monitoring obligations. But now, alternative monitoring approaches including risk-based use of centralized monitoring, metrics to ensure accomplishment of the defined strategies, and reliance on technological advancements such as email, webcasts, and EDC, can meet statutory and regulatory requirements under the appropriate circumstances.
A common thread throughout both guidances is that a risk-based approach does not suggest less vigilance in oversight, but puts priority on preventing or mitigating important or likely risks to critical data and processes. Both regulators describe risk-based monitoring as a systematic and dynamic process over the lifecycle of the clinical trial that includes identification, assessment, communication and ongoing review of trial risks and priorities, and control through mitigation of significant and serious risks.
Tutelage from both regulators begins with prospective identification of critical data and processes followed by a risk assessment to identify and understand what could affect collection and performance. FDA expands by giving specific examples of what might be critical data and processes including informed consent, study blinding, and adherence to subject inclusion and exclusion criteria. The monitoring plan can then be developed focusing on the most important and likely risks. Both guidances describe factors to consider when developing a monitoring plan including complexity of the study design, study endpoints, study population, geography, site experience, EDC systems, stage of the study, features of the investigational product, and quantity of data generated. Periodic re-evaluation is encouraged for identification of emerging risks and whether monitoring activities need changing.
FDA clearly focuses on development of a monitoring plan, while the EU paper is more general in support of efforts to manage and mitigate risks across the entire clinical trial development and execution phases by, for example, attention to a well designed and articulated protocol early in the process.
The EMA document is organized by stages of risk management, beginning with “risk assessment”, followed by “risk control”, and then “risk review and reporting”. Quality reporting would include an assessment of deviations from tolerance limits or protocol requirements with a description of follow-up actions, and calling attention to any unexpected trends. FDA focuses on risk assessment, and does not include a section on mitigation and review as in the EMA document. Neither provides comprehensive detail on how to perform a risk assessment, although EMA refers to useful tools such as FMEA and fishbone diagrams.
Both address project related risks stratified by “product” (e.g., complexity, instructions for use); “Protocol” (e.g., trial design, population, recruitment difficulty); and “Site” (e.g., resources, experience, IT sophistication, location); however, EMA also addresses system related risks and mitigations. “System risks mitigations” might be detailed contracts between parties clearly defining roles, responsibilities, and tasks to be undertaken, and pre-established communication plans; whereas “project risk mitigations” might be protocol design with collaboration among expert functions, and well designed training materials.
FDA offers more insight into the capabilities of on-site and centralized monitoring practices, factors, and triggers to consider when choosing the types, frequency and proportion of each. Examples are given of activities that should be done on-site and of various centralized techniques that can be used to replace, supplement, and set targets for on-site visit activities.
The final section in the EMA paper addresses approaches for implementation of risk management methodologies and advises use of multiple tools and stratification based on the stage of product development/commercialization. FDA concludes by addressing the format and recommended components of the Risk-Based Monitoring Plan; commenting on documenting monitoring activities, and briefly addressing some additional strategies to ensure study quality such as a well designed CRF and completion instructions to facilitate consistent data collection across all sites.
In summary, two regulatory agencies have issued complementary documents giving guidance on how to better ensure quality, integrity and reliability of information generated from clinical research. EMA focuses on helping you understand the concepts and step-by-step approach to risk management, whereas FDA focuses on risk-based planning for clinical study monitoring. Both convey that risk-based monitoring is all about targeted, efficient, and intelligent monitoring to eliminate errors that matter. It is clear that FDA recognizes that monitoring is only one aspect of the processes needed to ensure clinical trial quality and integrity and subject safety and lets us know that it is considering the need for additional guidance describing a more over-reaching risk management approach. Adopting the EU reflection paper could be the sequel for FDA, as the EMA’s guidance on wider application of risk management processes for clinical trials may be what is needed to fill the gap.