# Presentation: 285235

## 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 research**
**Over 50,000 extramural scientists **
**Over 2,000 research institutions, including VA medical centers**
**Over 5,000 intramural scientists**
**27 Institutes and Centers**

## Human Subjects Research: 

**NIH Roles**
**Conduct:  Investigator**
**Fund:  Sponsor**
**Oversee:  Steward**

## 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**

## NIH Roadmap

**NIH Roadmap**

**A 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 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**

## Clinical Research Policy Analysis and Coordination Program

**AIM**
**Promote clear, effective, and coordinated policies and regulations for the conduct and oversight of clinical research**

## 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 **

## 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**

## 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)**

## Priority Issues

**Harmonize diverse ****adverse event reporting requirements**
**Identified as the **_**highest**_** priority among the many harmonization opportunities **

## 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**

## Challenges Posed to Clinical Research

**Keeping track of multiple sets of requirements**
**Extra workload to report different information at different times to different agencies**

## Needs

**Promote understanding**
**Ease administrative burdens**
**Facilitate compliance**
**Enable robust analysis and communication of information**
**Enhance participant safety**
**Maximize knowledge**

## Diversity in Adverse EventReporting Requirements

**	****NIH has already taken an introspective look at the problem...**** **

**Notes:**
NIH decided to take an introspective look at this problem.

## 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**

**Notes:**
We conducted an in-house assessment of variability in AE reporting requirements.  

## 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**

**Notes:**
We found, that while all of the NIH Institutes and Centers were compliant with the regulations, there was nonetheless considerable variation among and within ICs with respect to definitions, severity grading, expedited reporting timeframes and reporting formats. Some of these differences make sense– they are a reflection of different clinical settings and research needs. However, some of the differences are more rooted in history and rather than in medicine.

## 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**

**Notes:**
This variation is a tremendous obstacle for PI’s, IRBs, and sponsors.

We could make an important contribution by promoting coordination and harmonization efforts..

This is the perfect segue to a high priority initiative in the NIH Roadmap that I’d like to talk to you about.

## 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**

## 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.**

**Notes:**
This variation is a tremendous obstacle for PI’s, IRBs, and sponsors.

We could make an important contribution by promoting coordination and harmonization efforts..

This is the perfect segue to a high priority initiative in the NIH Roadmap that I’d like to talk to you about.

## 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**

## Prevailing Paradigm

**Paper-based reporting systems**
**Uncontrolled, “individualized” medical vocabularies**
**Diverse reporting formats and templates**
**Transmission and comparison of data cumbersome**

## Slide 25

## Slide 26

## 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**

## 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)**

## Slide 29

## 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**** **

## ProtoType / CRIS-AE

**Two Web-based systems:  **
***One user interface and “feel”***

**ProtoType / CRIS-AE**
**Automated Protocol Writing and Adverse Event Reporting**

##        ProtoType		CRIS-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**

## Advantages for the IRB

**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**

## 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**

## 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 **

## 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**

## 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 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**

## 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**

## 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**

## 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**

## Slide 42