NIH Perspectives on Adverse Event Reporting: Looking to the Future

1. NIH Perspectives on Adverse Event Reporting: Looking to the Future VA IRB Chair Training Session April 8, 2004

2. NIH Mission • Discover new scientific knowledge that will improve human health • NIH funds, conducts, and oversees biomedical research • Over 50,000 extramural scientists • Over 2,000 research institutions, including VA medical centers • Over 5,000 intramural scientists • 27 Institutes and Centers

3. Human Subjects Research: NIH Roles • Conduct: Investigator • Fund: Sponsor • Oversee: Steward

4. NIH Stewardship • Invest wisely taxpayer dollars entrusted to NIH for the support and conduct of biomedical research • To streamline and facilitate compliance with regulatory and administrative requirements for reporting clinical research information • Apply and communicate the knowledge gained from research • Improve design and conduct of studies • Advance development of new treatments and cures • Optimize patient safety

5. NIH Roadmap • A coordinated plan to guide NIH research into the coming decade and beyond.

6. Re-engineering the CR Enterprise • Facilitate translational research • Enhanced training • Clinical Research Corps • Integration of CR networks/CR Informatics • Pilot NECTAR network • Harmonization of CR policies and processes

7. Clinical Research: Navigating the Roadway • Clinical research impeded by multiple and variable requirements to address fundamentally the same oversight concerns • Variability among and within agencies • Creates uncertainty about how to comply • Hampers efficiency and effectiveness

8. Clinical Research Policy Analysis and Coordination Program • AIM • Promote clear, effective, and coordinated policies and regulations for the conduct and oversight of clinical research

9. Methods • Work in concert with sibling agencies and research communities to catalyze the federal-wide coordination of policies pertaining to clinical research • Maintain the integrity and enhance effectiveness of federal and institutional systems of oversight • Develop tools and resources to facilitate understanding of and compliance with clinical research policies and requirements

10. Priority Issues • Diverse adverse event reporting requirements • Confusion regarding roles and responsibilities of Data Safety and Monitoring Boards, IRBs, and other review mechanisms • Variable requirements for auditing and monitoring of clinical trials • Absence of uniform standards for electronic submission of safety and clinical research information

11. Priority Issues • Confusion regarding applicability of privacy requirements and HIPAA to clinical research • Variability in interpretation of the human subjects regulations • Central vs. local IRB review • Best practices in informed consent • Investigator financial disclosure and conflicts of interest (COI)

12. Priority Issues • Harmonize diverse adverse event reporting requirements • Identified as the highest priority among the many harmonization opportunities

13. IRBs IBCs DSMBs OHRP NIH (various ICs) FDA Reporting Safety Information • All PIs conducting clinical research • submit adverse events reports, protocol amendments, and annual reports to a variety of localand federal entities: • Concern: • Diverse reporting requirements and formats

14. Challenges Posed toClinical Research • Keeping track of multiple sets of requirements • Extra workload to report different information at different times to different agencies

15. Needs • Promote understanding • Ease administrative burdens • Facilitate compliance • Enable robust analysis and communication of information • Enhance participant safety • Maximize knowledge

16. Diversity in Adverse EventReporting Requirements NIH has already taken an introspective look at the problem...

17. NIH Working Group on Adverse Event Reporting • NIH conducted an “in-house” assessment of variability in AE reporting requirements • Established NIH Working Group on Adverse Event Reporting • First Step: Conducted survey of ICs

18. NIH AE Working Group Findings • Compliant with the regulatory “floor” or baseline • Wide variation among and within ICS with respect to: • AE definitions • AE severity grading • Expedited reporting timeframes • Reporting formats used

20. NIH AE Working GroupFindings • Variation is a tremendous obstacle for PIs, IRBs, and sponsors • NIH could make an important contribution were it to promote coordination and harmonization efforts

21. Harmonization of AE Reporting:Gene Therapy Example • Prior to January 2002: • Principal Investigators had to report to NIH all serious adverse events immediately • At variance with FDA requirements (21 CFR 312) • Current harmonized requirement: • Possibly associated, unexpected events reported within 15 days - or within 7 days if fatal or life threatening • Scope, timeframe, and definitions for safety reporting are now the same for NIH and FDA

22. Future Activities • Setting up a “Trans-Agency Task Force on Adverse Events” through OHRP to: • Study range of variability between agencies, • Prioritize opportunities for harmonization, and • Identify core data sets for shared, baseline reporting requirements.

23. Priority Issues • Develop standards for electronic submission of safety and clinical research information • Use of electronic systems to collect safety data • Facilitates investigator compliance and agency oversight • Facilitates data sharing • Common vocabularies and data transmission standards are essential to make this possible

24. Prevailing Paradigm • Paper-based reporting systems • Uncontrolled, “individualized” medical vocabularies • Diverse reporting formats and templates • Transmission and comparison of data cumbersome

27. Moving Toward a New Paradigm • Tools for streamlined and effective communication and analysis of safety data • One AE reporting format • Uniform “Core” data elements • Controlled medical vocabularies • On-line adverse event reporting • Objective: To facilitate • Investigator compliance • Agency oversight • Data sharing

28. Genetic Modification Clinical Research Information System (GeMCRIS) • Serve as an analytic tool for NIH and FDA CBER • Facilitate the evaluation and analysis of safety information from all gene transfer clinical trials • Provide database reports that can be routed to diverse user groups • IRBs, local DSMBs, co-investigators http://www.gemcris.od.nih.gov

30. Broader Utility • GeMCRIS adapted as an adverse event reporting system for NIH intramural clinical research • NIH CC’s Clinical Research Information System Adverse Events (CRIS-AE) • Launch December 2003 • Being used as a model for an adverse event reporting system for extramural clinical research

31. ProtoType / CRIS-AE Automated Protocol Writing and Adverse Event Reporting Two Web-based systems: One user interface and “feel”

32. Overview ProtoTypeCRIS-AE • An automated-system assist to: • Protocol writing and tracking • Standardized templates • Flexibility • Resource mapping • Leveraging protocol data for: • AE report writing • AE research support Automated assistance: • Report tracking

33. Advantages for the IRB • Flexible workflow maybe tailored by organization. • Centralized system management. • Add, modify, inactivate users and organizations • Define user roles and security access • Update intervention reference tables (drugs, labs, radiology, etc.) • Immediate access to protocols and status: • Automated alerts for pending reviews, late AERs • Visibility of resource requirements: • High level cost estimates • Identify resource constraints

34. Government Efforts Toward Standardization • Data Standards • Government-wide standards for health information • e-Gov • CHI (vocabulary) • Universal Data Model • Overarching principles for adverse event reporting • 3500 (MedWatch report) • HL-7 data model • ICH data model • Goal: Streamlined, yet robust, data model

35. Benefits of Standardization for Local Oversight • Improved electronic reporting to the IRB • Comparable language to describe a range of possible adverse events • More effective local management of adverse event data • Common adverse event reporting formats used by multiple sites • Facilitated analysis at the federal level • More efficient dissemination of federal findings to IRBs, PIs, and other at local level

36. Clinical Research Informatics • Another key NIH Roadmap initiative • Embodied in the National Electronic Clinical Trials and Research (NECTAR) Network • Provides the necessary infrastructure to advance coordination and harmonization • Research management tools • Connectivity between sites

37. NECTAR: Integration of Clinical Research Networks Establish interoperable networks where clinical studies and trials can be effectively conducted

38. Web-Based Suite of Tools for Clinical Research • Anticipated Functionality -- outcome of focus group meetings • Protocol Authoring Tool • IRB Review Management Tool • Adverse Event Reporting Tool • Development Process -- consultation and collaboration with other Federal agencies, IRB community, and Research communities to determine • Unified format and “core” data elements • Functions

39. Harmonization: Establishing the Foundation • Establish NIH program to provide concentrated attention to critical coordination and harmonization concerns • Create facile and efficient mechanisms for coordinating and collaborating with VA and other agencies • Conduct broad and ongoing stakeholder consultation (including IRBs) through: • Ad hoc expert panels • Focus groups • Education and outreach

40. Future Challenges • Addressing multiple needs • Many constituencies affected • Needs of each community may not be fully consonant • Continued input and consultation will be key • Catalyzing change • Inertia • Investment in current agency practices • Coordination

41. Overarching Principles • Elimination of unnecessary obstacles to the efficient and safe conduct of clinical research • Optimizing protections for research participants through a more coordinated, streamlined system of oversight