# Presentation: 613745

## Adverse Event Reporting in Clinical Research:  Trans-Federal Policy Coordination 

**Population Health and Clinical Care Connections Workgroup**
**American Health Information Community**
**Amy P. Patterson, M.D.             Office of Science Policy,           Office of the Director, NIH**

## Adverse Events: Potential Lessons

**Signal to attend to safety and well-being of research participant**
**Call for changes to:**
**Protocol **
**Monitoring plan, and/or**
**Informed consent **
**Offer insights into:**
**Mechanism of drug action **
**Metabolic and genomic pathways**
**New therapeutics or applications**

## Adverse Events:  Hurdles to Learning 

**Current reporting paradigm impedes extraction of knowledge from these events**
**Variation in regulatory terms and medical vocabularies frustrates comparison of data across studies and agencies**
**Diverse reporting policies, timeframes, and content complicates and slows investigator communication of key information**
**Volume of information received by IRBs hampers detection of important “signals” from background “noise”**

## Current Adverse Event Reporting

**Issues**
**Divergent federal reporting requirements**
**Threshold**
**Scope**
**Timeframe**
**Divergence creates confusion, non-compliance, increased costs**
**Poor quality of information**
**No standards**
**Incomplete reports**
**Deluge of AERs that cannot be interpreted in multi-site trials**
**Negative effect on protection of human subjects**

## PIs Must Report Same Event to Multiple Entities

**IRB**

**DSMB**

**Sponsor**

**NIH**
**	**

**FDA**

**OHRP**

**CDC**

**VA**

**DoD**

**CMS**

**PI**

## Practice

**Practice**

**Clinical Research**

## IRBs Must Assess Safety Information from Multiple IRBs and Other Sources

**IRB #1**

**IRB #2**

**IRB #3**

**IRB #n**

**DSMB**

**PI**

**Sponsor**

**IRB**

## Federal Adverse Event Task Force 

**Charge**
**Propose specific means for promoting harmonized and streamlined federal requirements for reporting, analyzing, and communicating adverse events in clinical ****research**
**Member Agencies:**

**FDA**
**OHRP**
**CDC**
**AHRQ**

**NIH (chair) **
**VA **
**DoD**

## FAET Objectives

**Agencies will speak the same language**
**Reduce variability in terms and definitions**
**Alignment**** of federal AE reporting policies**
**Develop *****best practices blueprint***** for reporting, analysis, and application of ****saf****ety information**
**One ****core**** ****AE report**** that PIs can sent to multiple agencies**
**Basal Adverse Event Report (BAER)**

**Notes:**
1. Agencies will speak the same language
Reduce variability in terms and definitions
Examples 

Unanticipated vs. unexpected
Related vs. associated
Adverse event vs. unanticipated problem vs. adverse effect
2. Develop best practices blueprint for reporting, analysis, and application of safety information

Harmonize reporting policies and criteria

Identify “Best Practices”

Use controlled vocabularies to support analysis

Promote standardized reporting to IRBs and DSMBs

3.  One core AE report that PIs can sent to multiple agencies

Basal Adverse Event Report (BAER)
	Features
Baseline set of core information adopted by all agencies
Incorporates HHS standards for data transmission and vocabularies
Can also be used for “unanticipated problems”

## Terms and Definitions Overview

***Scope***
**Reduce variability in the terms, definitions, and rules for expedited reporting**
**adverse event vs. adverse effect**
**associated vs. related**
***Process***
**Collect agency terms, definitions, and policies**
**Characterize along a gradient based on difficulty/ease to change**
**Assess concepts and policies and identify opportunities for harmonization**

**Notes:**
Changed examples to something more substantive.

## Terms and Definitions Activities

**Convened focus groups to identify key concepts for harmonization and validation of agency terms**
**Administered survey**
**Assessed and synthesized information**
**Currently identifying opportunities for harmonization based on source gradient**

**Notes:**
The purpose of this slide is to show where we are in the methodology and to introduce the “fundamental concept” approach.  Also, this is where we mention that we will visit them again to coordinate the changes and/or mapping to preferred terms.

## Findings

**Disparity in term use and meaning **
**Different terms or combination of terms**
**Adverse event versus adverse drug reaction**
**Adverse event versus unanticipated problem**
**Different definitions**
**Disparity in the criteria for expedited reporting of adverse events**
**Differing criteria (rules for reporting)**
**Different timelines**
**Despite different rules, one or more of three fundamental concepts are often used when reporting adverse events**
**Expectedness/unexpectedness, frequency**
**Relatedness/association**
**Seriousness, severity**

**Notes:**
What did we discover.  Introduces concepts chosen for harmonization and why.

## Concepts of an Adverse Event

**Three Fundamental Dimensions:**
**Is the event expected/anticipated to occur, and occur at the observed frequency?**
**Is the event related to the clinical research?**
**How serious is the event?**

**Notes:**
This is the “so what” slide.  It is supposed to say why harmonization is important and what needs to be harmonized.

## Disparity in Expedited Reporting Policy-- Examples 

**OHRP**

**VA (VHA)**

**FDA / CDER**

**FDA / CBER**

**CDC**

**Navy**

**Army**

**Army**

**Org**

**Related**

**Serious**

**Unexpected**

**Death**

**FDA / CDRH**

**VA (VHA)**

**Life-**
**Threat**

**Reference**

- 

- 

- 

- 

- 21 CFR 812.3(s)
- 21 CFR 812.150(a)(1), *Reports*

- 

- 

- 

- 

- 

- 

- 21 CFR 312.32

- 21 CFR 312.32

- Draft Guidance on Reporting &
- Reviewing AEs/UPs (10/11/05)

- 

- 

- VHA Handbook 1058.1
- - Substantive action by IRB

- VHA Handbook 1058.1
- – Unexpected deaths

- SECNAVINST 3900-39C:
_*Protection of Human Subjects*_

- 

- 

- 

- 

- Promptly

- ASAP, NLT
- 10 workdays

- 24 hours

- 24 hours

**Time **
**Frame**

- ASAP/ NLT 7/15 days

**“****ASAP”** [CDER/CBER]:
-   NLT 7/15 days for death, life-threatening/other serious events

**“****Promptly”** [OHRP]:  couple Weeks (written rpt)

**“****Promptly”** [CDC]:
-   2 Work Days

- 

- ASAP/ NLT 7/15 days

- 

- W/i 10
- workdays

## Disparity in Expedited Reporting Policy-- Examples

**Disparity in Expedited Reporting Policy-- Examples**

**OHRP**

- 2 weeks

**VA (VHA)**

- 24 hours

**FDA / CDER**

**FDA / CBER**

**CDC**

- 10 workdays

**Navy**

**Army**

- 24 hours

**Army**

**Org**

**Related**

**Serious**

**Death**

**Time **
**Frame**

**FDA / CDRH**

**VA (VHA)**

**Life-**
**Threat**

**Reference**

- 

- 

- 

- 

- 

- 

- ASAP

- ASAP

- 21 CFR 312.32

- 21 CFR 312.32

- Draft Guidance on Reporting &
- Reviewing AEs/UPs (10/11/05)

- 

- VHA Handbook 1058.1
- (Reporting AEs)

- SECNAVINST 3900-39C:
_*Protection of Human Subjects*_

- 

- 

- 

- 

**Unexpected**

- 

- 

- 

- 

- 

- 

- 21 CFR 812.3(s)
- 21 CFR 812.150(a)(1), *Reports*

- W/i 10
- workdays

- VHA Handbook 1058.1
- (Reporting AEs)

- 

**Not described in Investigator’s Brochure **[ICH, FDA]

**...****not previously identified in ...the investigational plan or application...**
- [FDA]

**Not previously known from interventions and interactions used in the research.... **[OHRP]

## Basal Adverse Event Report (BAER) Overview

***Scope***
**Fundamental set of medical information adopted by all agencies**
**Span pre- and post market**
**Used by PI and practitioner**
**Incorporation of HHS standards for data transmission and vocabularies**
***Aims*****	**
**Offer utility for reporting at local and federal level **
**Offer standards for full spectrum of clinical research**

## How was the Basal Adverse Event Report Developed?

**How was the Basal Adverse Event Report Developed?**

- CDC

- DOD

- FDA

- NIH

- OHRP

- VA

**Collect Data**
**Requirements**

**ICH E2B, MedWatch, VAERS, Selected NIH Templates; NCI DE Repository; AER systems**

**OHRP Guidance May 2005**

**MedWatch, VAERS,**
**VA Form 10-0420**

**ICH E2B, MedWatch,**
**VAERS, CDC Form 1254 and 1254.S**

**MedWatch, VAERS,**
**Army HSRRB Report Form**

**ICH E2B, MedWatch, VAERS**

## DRAFT Basal Adverse Events Report 

**DRAFT Basal Adverse Events Report **

**Unanticipated Problems**

**Dynamic Data Elements **

## Utilizes existing data standards for AE reporting
International Conference on Harmonization (ICH) E2B 
Health Level 7 (HL7) Individual Case Safety Report (ICSR)

Encompasses all forms of clinical research 
Draw upon a single streamlined data set to report

Safety information to multiple agencies, IRBs, and DSMBs

Unanticipated problems to OHRP
Pre and Post-market adverse events to FDA

**International Conference on Harmonization (ICH) E2B **
**Health Level 7 (HL7) Individual Case Safety Report (ICSR)**
**Encompasses all forms of clinical research **
**Draw upon a single streamlined data set to report**
**Safety information to multiple agencies, IRBs, and DSMBs**
**Unanticipated problems to OHRP**
_**Pre and Post-market**_** adverse events to FDA**

**Key Features of the Basal Adverse Event Report **** **

## Optimizing Analysis and Application of Safety Data

**Enhances knowledge-to-data ratio through uniform, standardized approach to adverse event reporting**
**Promotes completeness of data**
**Improves quality of data**
**Facilitates analysis of information**
**Enables translation of data into knowledge to:**
**Inform the design and conduct of ongoing and future studies**
**Efficiently advance development of new treatments and cures**
**Optimize patient safety**

## FAET has actively coordinated with Government, standards organizations, and industry 

HL7 clinical trial data modeling (BRIDG)
Merging CDISC and NCI data models

AHRQ’s Patient Safety Data Elements Common Formats 

NCI’s caAERS/caBIG

CDISC Clinical Research Data Collection Standardization

Clinical Data Acquisition Standards Harmonization Initiative (CDASH)
Development of a set of content standards (element name, definition, metadata) for a core set of global data collection fields that will support clinical research studies

**HL7 clinical trial data modeling (BRIDG)**
**Merging CDISC and NCI data models**
**AHRQ’s Patient Safety Data Elements Common Formats **
**NCI’s caAERS/caBIG**
**CDISC Clinical Research Data Collection Standardization**
**Clinical Data Acquisition Standards Harmonization Initiative**** (CDASH)**
**Development of a set of content standards (element name, definition, metadata) for a core set of global data collection fields that will support clinical research studies**

**Coordination With Other Initiatives**

## BAER’s Contribution to CDASH

**Adverse Event Data Stream**
**Proposed new data elements**
** ****(e.g. expectedness)**
**Team lead for definitions group**
**BAER definitions were used as a starting point**
**Concomitant and Prior Medications Stream**
**Contributed definitions from BAER**
**Demographics Stream**
**Contributed definitions from BAER and HL7**

## BAER Validation

**Mappings to 25 existing adverse event data formats (forms, applications, standards)**

**Documentation sent to FAET participating agencies for review and comment, beginning Feb 2006**

**Agencies **
**  ****CDC Incident Report**
**  ****CDC IR Supplement**
**  ****FDA MedWatch**
**  ****VAERS**
**  ****VA AE**
**  ****DoD HSRRB**
**  ****NIH OHSR SAE**
**  ****OHRP Guidance**

**Institutes**
**  ****NINDS SAE Form**
**  ****NINDS AE Core Form**
**  ****NIDA Form 23**
**  ****NICHD SAR**
**  ****NICHD Medical Review Form**
**  ****NIAID EAE Form**
**  ****NCI DCP SAE Form**
**  ****NCI DCP AE Cumulative**
**  ****NEI Annual Reporting**
**  ****NIDDK PRP Study**
**  ****NHGRI SAE Form**

**Standards  **
**  ****E2B**
**  ****HL7/ICSR**
**  ****CDISC SDTM**

**Applications**
**  ****NCI AdEERS**
**  ****GeMCRIS**
**  ****CRIS-AE**

## Current Status of BAER 

**Federal Adverse Event Task Force members (NIH, FDA, OHRP, CDC, VA, DoD, AHRQ) agree that the draft BAER represents a single, baseline set of core information acceptable to their agency**
**Contains the information needed for adverse event and unanticipated problem reporting across all types of clinical research**
**Briefed the Secretary’s Advisory Committee on Human Research Protections (July 31, 2006)**

## BAER Beta Test

**Web-based test application**
**Series of focus groups**
**Testing participants to include broad range of stakeholders**

## Slide 28

## 2007 Emphasis
Conduct BAER Beta Test and integrate feedback into BAER
Coordinate terms and definitions
Begin focus on workflow

**2007 Emphasis**
**Conduct BAER Beta Test and integrate feedback into BAER**
**Coordinate terms and definitions**
**Begin focus on workflow**

**Current FAET Schedule**** **** **

**FAET –**
**PI/Industry Focus Groups –**
**SACHRP –**

-  Jan  -  June      July  - Dec       Jan  -  Mar       Apr  - June       July  -  Sep      Oct  - Dec

**Initial and**
**follow-on**
**analysis**

** ****Begin focus on **
**   ****workflow**
** ****Continue with:**
**   ****- BAER validation**
**   ****- T&D coordination**
**   ****- Harmonize with**
**     ****other initiatives**

** ****Continue Focus Groups**
** ****Coordinate T&Ds and HL7**
**   ****extensions**
** ****Continue to participate**
**   ****in other initiatives**

**CY 2006**

**CY 2007**

***Today***

** ****Conduct BAER Beta Test**

## Moving Forward

**Propose candidate terms and definitions for harmonization of federal reporting policies**
**Further engage stakeholder community**
**IRB**
**Investigators**
**Industry**
**Research community consultation and beta-testing**
**Seek formal HHS clearance**

## Slide 31