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  • NIH Perspectives on Adverse Event Reporting: Looking to the Future

    VA IRB Chair Training Session April 8, 2004

  • NIH Mission Discover new scientific knowledge that will improve human health

    NIH funds, conducts, and oversees biomedical researchOver 50,000 extramural scientists Over 2,000 research institutions, including VA medical centersOver 5,000 intramural scientists27 Institutes and Centers

  • Human Subjects Research: NIH Roles

    Conduct: Investigator

    Fund: Sponsor

    Oversee: Steward

  • NIH StewardshipInvest 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 studiesAdvance development of new treatments and curesOptimize patient safety

  • NIH RoadmapA coordinated plan to guide NIH research into the coming decade and beyond.

  • 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

  • Clinical Research: Navigating the RoadwayClinical research impeded by multiple and variable requirements to address fundamentally the same oversight concerns

    Variability among and within agenciesCreates uncertainty about how to complyHampers efficiency and effectiveness

  • Clinical Research Policy Analysis and Coordination Program

    AIMPromote clear, effective, and coordinated policies and regulations for the conduct and oversight of clinical research

  • MethodsWork 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

  • Priority IssuesDiverse 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

  • Priority IssuesConfusion 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)

  • Priority IssuesHarmonize diverse adverse event reporting requirements

    Identified as the highest priority among the many harmonization opportunities

  • Reporting Safety InformationIRBsIBCsDSMBs

    OHRPNIH (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

  • Challenges Posed to Clinical Research

    Keeping track of multiple sets of requirements

    Extra workload to report different information at different times to different agencies

  • NeedsPromote understanding

    Ease administrative burdens

    Facilitate compliance

    Enable robust analysis and communication of information

    Enhance participant safety

    Maximize knowledge

  • Diversity in Adverse Event

    Reporting RequirementsNIH has already taken an introspective look at the problem...

  • NIH Working Group on

    Adverse Event ReportingNIH 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

  • 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 timeframesReporting formats used

  • NIH AE Working Group


    Variation is a tremendous obstacle for PIs, IRBs, and sponsors

    NIH could make an important contribution were it to promote coordination and harmonization efforts

  • Harmonization of AE Reporting:Gene Therapy ExamplePrior to January 2002: Principal Investigators had to report to NIH all serious adverse events immediatelyAt 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 threateningScope, timeframe, and definitions for safety reporting are now the same for NIH and FDA

  • 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, andIdentify core data sets for shared, baseline reporting requirements.

  • Priority Issues

    Develop standards for electronic submission of safety and clinical research informationUse of electronic systems to collect safety data Facilitates investigator compliance and agency oversightFacilitates data sharing Common vocabularies and data transmission standards are essential to make this possible

  • Prevailing ParadigmPaper-based reporting systems

    Uncontrolled, individualized medical vocabularies

    Diverse reporting formats and templates

    Transmission and comparison of data cumbersome

  • Moving Toward a New ParadigmTools for streamlined and effective communication and analysis of safety dataOne AE reporting format Uniform Core data elementsControlled medical vocabulariesOn-line adverse event reporting

    Objective: To facilitateInvestigator complianceAgency oversightData sharing

  • Genetic Modification Clinical Research Information System

    Serve as an analytic tool for NIH and FDA CBERFacilitate the evaluation and analysis of safety information from all gene transfer clinical trials

    Provide database reports that can be routed to diverse user groupsIRBs, local DSMBs, co-investigators

  • Broader Utility GeMCRIS adapted as an adverse event reporting system for NIH intramural clinical research NIH CCs 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

  • Two Web-based systems: One user interface and feelProtoType / CRIS-AEAutomated Protocol Writing and Adverse Event Reporting

  • ProtoTypeCRIS-AE An automated-system assist to:Protocol writing and trackingStandardized templatesFlexibility Resource mapping

    Leveraging protocol data for: AE report writing AE research supportAutomated assistance: Report tracking


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

  • Government Efforts Toward StandardizationData StandardsGovernment-wide standards for health informatione-GovCHI (vocabulary)

    Universal Data ModelOverarching principles for adverse event reporting3500 (MedWatch report)HL-7 data modelICH data modelGoal: Streamlined, yet robust, data model

  • Benefits of Standardization for Local OversightImproved electronic reporting to the IRBComparable language to describe a range of possible adverse eventsMore effective local management of adverse event dataCommon adverse event reporting formats used by multiple sitesFacilitated analysis at the federal levelMore efficient dissemination of federal findings to IRBs, PIs, and other at local level

  • Clinical Research InformaticsAnother key NIH Roadmap initiative

    Embodied in the National Electronic Clinical Trials and Research (NECTAR) Network

    Provides the necessary infrastructure to advance coordination and harmonizationResearch management tools Connectivity between sites

  • NECTAR: Integration of Clinical Research Networks

    Establish interoperable networks where clinical studies and trials can be effectively conducted

  • Web-Based Suite of Tools for Clinical Research Anticipated Functionality -- outcome of focus group meetingsProtocol Authoring ToolIRB Review Management ToolAdverse Event Reporting Tool

    Development Process -- consultation and collaboration with other Federal agencies, IRB community, and Research communities to determineUnified format and core data elementsFunctions

  • Harmonization: Establishing the FoundationEstablish 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 groupsEducation and outreach

  • Future ChallengesAddressing multiple needsMany constituencies affectedNeeds of each community may not be full


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