# Presentation: 302415

## Presentation of Maureen Donahue Hardwick, Esquire on behalf of the IRB-Sponsor Roundtable

**FDA Public Hearing on Reporting of Adverse Events to Institutional Review Boards ****(21 March 2005)**

## Introduction

- Pleased to speak today on behalf of the IRB-Sponsor Roundtable
- The Roundtable commends FDA for organizing this hearing on this critical issue
- Purpose of this presentation is to share Roundtable’s thoughts on possible best practices and potential new processes to the current challenge of AE reporting in multi-site clinical studies
- Roundtable views expressed are still a “work in progress”

## Presentation Overview

- Provide background on the IRB-Sponsor Roundtable
- Provide feedback on FDA’s questions (70 Fed. Reg. 6693; February 8, 2005)
- IRB’s responsibilities in multi-site trials versus single-site trials
- Types of AEs that IRBs should receive
- How to enhance IRB’s ability to assess implications of AEs for study subjects
- Consolidated reports of AEs

## IRB-Sponsor Roundtable:Background (I)

- In 2003, two meetings on HIPAA and clinical research issues brought IRBs and sponsors together
- Two communities engaged in productive dialogue
- Consensus that increased communication on broader clinical research issues needed to enhance protection of human research subjects
- Both the IRB and sponsor communities, and the research enterprise in general, will benefit from a neutral and constructive venue outside of individual trials to address overarching and recurring issues
- Formed in 2004, the Roundtable is comprised of representatives from IRBs and Sponsors
- Independent of existing organizations (*e.g.,* P*h*RMA, PRIM&R, ARENA, DIA)
- Goal is equal representation from both communities

## IRB-Sponsor Roundtable:Background (II)

- The Roundtable is the first organization where sponsors and IRBs have come together as equal partners to address issues of mutual concern in a sustained and task-oriented manner
- This new paradigm for communication may improve the functioning of IRBs and sponsors in their respective roles in large and increasingly complex research projects
- The current challenges associated with AE reporting in multi-site trials is a Roundtable priority

## Roundtable’s Mission

- Facilitate constructive communications between sponsors and IRBs on significant clinical research issues and, where possible,
- propose practical strategies for improving clinical trial processes and human subject protections
- engage other affected stakeholders to facilitate broader dialogue and consensus building
- _Overarching objective_: Enhance protection of human research subjects

## Roundtable Participants

- IRBs:
- Sponsors:
- Pfizer (Justin McCarthy, Co-Chair)		Novartis
- Sanofi-Aventis		Schering-Plough

- Marianne Elliott                      		Felix Gyi
*      **Navy Medical Research**	**	**	**Chesapeake Research Review, Inc*
- Karen Hansen		John Isidor
*     **	**Fred Hutchinson Cancer Research Ctr**	**	**Schulman Associates IRB*
-  Moira Keane	 	Daniel Nelson (Co-Chair)
*	**University of Minnesota**	**	**	**University of  North Carolina*
- Pearl O’Rourke 		Ernest Prentice
*	**Partners Healthcare System**	**	**	**University of Nebraska*
- Ada Sue Selwitz
*	**University of Kentucky*

## Current Context

- Clinical investigation of FDA-regulated products are frequently conducted at numerous sites across the US and around the world
- Often each study site is overseen by a different IRB; IRB receives individual reports of expedited AEs (including possible unanticipated problems involving risks to human subjects and others) reported in subjects enrolled in: its institution _and_ other institutions in the same trial
- Sheer number and disaggregated nature of reports make it difficult, particularly for IRBs, to effectively evaluate significance and the implications for study subjects

## Current Context, Cont.

- Existing regulatory framework developed before multi-site trials were commonplace
- Regulatory definitions and processes for AE reporting differ among FDA and other agencies
**Process would benefit from clear regulatory guidance relevant to multi-site trials**

## Some Definitions

- “Adverse Event” or “Adverse Experience” (AE)
- Multiple definitions exist (e.g., FDA’s IND regulation, ICH guidelines)
**External AE**: In a multi-site trial an AE that occurs at an institution other than the one for which the IRB is directly responsible
**Internal AE**: In a multi-site trial, an AE that occurs at the local IRB’s institution, not one of the other sites involved in the trial
- “Unanticipated problems involving risks to human subjects or others” (21 CFR 56.108 and 45 CFR 46.103): broader than AEs, but significant overlap exists

## Definitions, Cont.	

- Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC): Formal committees charged with reviewing the accumulating data as the trial progresses to:
- Monitor safety, effectiveness, and trial conduct issues
- Provide a set of recommendations to study Sponsor

## Goals of a New AE Model	

- Enhance protection of human subjects by ensuring that medically relevant data on AEs is communicated to IRBs in a meaningful way
- Clearly highlight medically relevant events that are more likely to change risk/benefit relationship from other AEs
- Promote responsible and effective AE reporting through a multi-party process (IRBs, Principal Investigators and Sponsors) which includes appropriate checks and balances
- Reinforce active participation by all parties in identifying potential unanticipated problems

## IRB’s Review of AEs in Multi-site Trials

- IRBs are not intended to function as safety oversight committees for multi-site trials
- IRBs do not have access to the relevant information necessary to evaluate large volumes of disaggregated “external” AE reports in order to put them in proper context
- At present, the signal to noise ratio is unfavorably dominated by noise for review by IRBs
**The process for sending routine expedited “external” AE reports to IRBs should be eliminated**

## Possible Elements of Solution

- In context of identifying unanticipated problems  involving risks to human subjects, **Investigators** should identify “relevant” external AE reports that require notification to IRB
**Proposed criteria** for “relevant” reports:
- Reports leading to study protocol modification
- Reports leading to revisions to informed consent form
- Reports reflective of (other) major concerns impacting the study
- _Note_:
- PI’s obligation to submit all appropriate internal AEs _is unchanged_
- Sponsors should continue to submit expedited AE reports to FDA pursuant to existing regulatory requirements

## Possible Elements of a Solution (II)

**Sponsors **should clearly identify to PI those external AE reports that meet criteria
- Supplements Sponsors’ existing safety reporting obligations to FDA and PI
- Best practice (as such reports are usually singled out)
- _Importantly:_
- PIs should provide AE reports to IRBs that they believe meet the criteria for notification of IRBs, even if sponsor does not identify them as such
- If PI believes AE reports not meeting the criteria should be sent to the IRB, they should do so providing justification for the transmission
- If the Sponsor concludes that an external report warrants immediate referral to IRB, it should highlight to PIs

## Other Best Practices &Checks and Balances

- Sponsors and Principal investigators should document their analysis of all external AEs
- This analysis and associated documentation would be subject to audit by the IRB (or designated compliance arm) for Investigator site and by FDA for both Sponsors and Site Investigators
- Sponsor should develop and justify a plan and schedule for communicating aggregate AE reports as part of the study protocol

## Plan for Communicating AEs

- In the study protocol submitted to IRBs, the Sponsor should specify a “communication plan” for providing periodic aggregate summaries of external AEs
- Elements of the plan *could* include:
- Proposed frequency for submission of aggregate safety information (*i.e., *quarterly, semi-annual, or annual)
- Proposed format for the submission of periodic qualitative assessment reports covering all safety information relevant to the trial, including all expedited AEs and other relevant safety information
- Description of the functioning of a DSMB, if used for the study, and the method & frequency of communication of DSMB reviews to Investigators/IRBs
- Should be developed and implemented in a flexible manner to meet the specific needs of an individual clinical trial/Investigational product

## Suggested Next Steps

- The Roundtable will:
- Continue to discuss and further refine thinking on AE reporting and role of IRBs in multi-site trials
- Reflect on submissions during this Hearing
- Consider existing proposal by CIOMS VI
- Conduct outreach to interested stakeholders (e.g., P*h*RMA, ARENA, PRIM&R, investigators) to obtain feedback
- Particularly important to obtain input from investigators
- As appropriate, continue dialogue with interested government agencies
- Priority: submission of written comments by 21 April 2005
- The Roundtable encourages FDA/OHRP to clearly articulate – in official guidance – best practices for reporting of external AEs in multi-site clinical trials

## Conclusions

- If a more workable AE reporting model for multi-site trials is put in place:
- IRBs will be able to more effectively evaluate risk/benefit issues
- Both Investigators and Sponsors will be better equipped to fulfill their regulatory and ethical responsibilities
_**Subject protection will be enhanced**_