Worldwide Medical Device Regulatory Updates

New guidance from the US Food and Drug Administration recommends adoption of more risk-based methods by sponsors to monitor clinical investigations including investigational device exemptions (IDEs) and Investigational New Drugs (INDs).

Existing regulations require sponsors to monitor the conduct and progress of their clinical investigations, but do not prescribe specific steps to follow in order to comply. Although various methods of effective monitoring practices are available, sponsors have primarily relied on on-site evaluations of study sites to review clinical data. The FDA’s new guidance emphasizes the use of risk-based methods such as focusing on the most critical data elements of a clinical investigation would better ensure protection of human subjects as well as study quality. Centralized off-site monitoring of multiple clinical study sites would also make sponsors’ efforts to ensure quality and integrity of clinical data more efficient.

The guidance recommends two types of clinical investigation monitoring, including on-site monitoring at study sites to identify data entry errors, verify existence of study documentation and assess staff compliance with study protocols. This method should be used to assess critical study data and identify major risks. Second, centralized monitoring of clinical investigations by off-site personnel can assess data quality and verify source data in real time, as well as perform aggregate statistical analyses and keep track of performance metrics. Sponsor ability to utilize centralized monitoring will depend on accessibility to electronic record and data capture systems.

Sponsors should also identify which of their data and study procedures are the most critical to the reliability of their study results: data supporting primary and secondary endpoints, serious adverse event information, processes tied to subject safety and ethical treatment, and processes supporting data integrity.

The guidance identifies the following types of data and processes that typically require more rigorous monitoring from sponsors:

• Staff conduct and documentation of procedures for critical study endpoints, protocol-required safety assessments and serious adverse events
• Compliance with protocol eligibility criteria to include only subjects identified as appropriate to a clinical investigation’s scope
• Staff conduct and documentation of procedures to maintain study blind at both site and sponsor levels
• Verification that informed consent was properly obtained
• Procedures for documenting accountability and administration of investigational product being studied

Once a sponsor has identified critical data and processes according to risk assessment, the FDA guidance recommends developing a comprehensive plan covering the types, frequency and intensity of clinical study monitoring. Factors shaping a monitoring plan should include:

• Study design complexity: more complex designs may require more intensive monitoring efforts
• Study endpoint types: more interpretive or subjective endpoints may require on-site rather than centralized assessments by sponsors, whereas objective endpoints facilitate remote verification
• Study population’s clinical complexity: subjects with serious diseases or vulnerabilities require more on-site, intensive monitoring to ensure proper protections
• Geography: study sites located in areas with different medical standards or clinical trial infrastructures require more intensive monitoring
• Investigator’s experience: lack of experience among investigators in conducting clinical studies or dealing with cutting-edge medical devices may require more intensive monitoring from sponsors
• Electronic data capture: access to EDC tools in order to evaluate quality metrics in real time can help sponsors determine which study sites require more hands-on monitoring and which can be remotely monitored
• Relative safety of investigational product: investigational devices with major safety concerns or little to no past experience in clinical trials require more intensive monitoring
• Stage of study: initial stages of clinical studies may require more intensive monitoring, while later stages may require less hands-on monitoring
• Quantity of data: For studies that generate higher volumes of data, centralized monitoring tools are more efficient for sponsors

Monitoring plans can include components such as descriptions of monitoring approaches, communication processes for monitoring results, management processes for noncompliance, and monitoring plan amendments. Documentation procedures for monitoring plans should also be established, according to the guidance.

In order to clarify its current stance on clinical investigation monitoring, the FDA has withdrawn its 1988 guidance on the topic, and states that bioresearch monitoring compliance program guidance manuals for sponsors, monitors and clinical research organizations will be amended to reflect the agency’s new recommendations.

As usual, interested parties have 90 days to submit comments on this guidance.

The International Organization for Standards (ISO) recently published a revision of its ISO 14155 rule governing clinical trials for medical devices, ISO 14155:2011, and manufacturers will have several new requirements to address in order to comply. (An overview of the revised standard is available from Excel Translations.)

ISO 14155:2011 follows ISO 14155:2003 and ISO 14155:2009, European standards applied to medical device clinical investigations. The new standard is entitled Clinical Investigation of Medical Devices for Human Subjects—Good Clinical Practices, and applies globally to all medical device manufacturers conducting clinical studies.

The revised standard’s new requirements pertain primarily to sponsor responsibilities, informed consent rules, ethics committees, study monitoring and data and risk management. Risk management features particularly strongly in ISO 14155:2011, which frequently references another medical device risk management standard, ISO 14971.

Once ISO 14155:2011 is published in the Official Journal of the European Union, mandatory compliance will go into effect. Each ISO member nation will have the opportunity to modify ISO 14155:2011 before adopting the standard—thus, actual requirements may vary from market to market. As such, manufacturers should pay close attention to ISO 14155:2011 requirements particular to the countries in which they plan to conduct clinical investigations.