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 1.Diverse adverse event reporting requirements 2.Confusion regarding roles and responsibilities of Data Safety and Monitoring Boards, IRBs, and other review mechanisms 3.Variable requirements for auditing and monitoring of clinical trials 4.Absence of uniform standards for electronic submission of safety and clinical research information

11. Priority Issues 5.Confusion regarding applicability of privacy requirements and HIPAA to clinical research 6.Variability in interpretation of the human subjects regulations 7.Central vs. local IRB review 8.Best practices in informed consent 9.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. Reporting Safety Information IRBs IBCs DSMBs OHRP NIH (various ICs) FDA All PIs conducting clinical research submit adverse events reports, protocol amendments, and annual reports to a variety of local and federal entities: Concern: Diverse reporting requirements and formats

14. Challenges Posed to Clinical 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 Event Reporting 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 Group Findings 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 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 (GeMCRIS)

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

32. 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 Overview

33. 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 Advantages for the IRB

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