# Presentation: 412715

## Human Subjects Working Group Spring WorkshopMay 7th, 2008

- Department of Health and Human Services (HHS)
-  Office for Human Research Protections (OHRP)
- Division of Education and Development
- Lyndi Lahl, MS, RN
- Michelle Feige, MSW

## Overview

- OHRP’s QIP
- Assurance of Compliance
- IRB Membership
- Investigator Responsibilities

## OHRP’s Quality Improvement Program (QIP) 

## OHRP’s QI Program (QIP)

- OHRP initiated QIP 2002 to assist institutions in assessing and improving their human research protections program
- QIP includes two separate components:
- A Guided Self Assessment Tool
- OHRP QA Consultation – Division of Education and Development staff

## Goals of OHRP’s QIP

- Provide tools to help an institution identify strengths and areas for improvement
- Provide detailed review of IRB written procedures and meeting minutes
- Clarify regulatory requirements
- Explore ways to improve the quality, efficiency, and effectiveness of the human research protection program

## Attributes of OHRP’s QIP

- Voluntary
- No Cost
- Choice of components:
-     1) independent self assessment
- online guided self assessment tool
-     2) consultation with OHRP
- modes of interaction: on-site visit, videoconference or teleconference

## 

QA Self Assessment Tool

*QA Self Assessment Tool*

## QA Self Assessment Tool

- EVALUATES: Human Research Protection Program
- General information about the program including organizational structure
- Disclosure and management of conflicts of interest
- Handling noncompliance
- Workload of the IRB, staffing and resources
- General information about the IRB
- Education of Chair, members, staff,  & investigators

## QA Self Assessment Tool

- EVALUATES: The Institutional Review Board
- Review process
- Minutes
- Post IRB review processes
- Approval
- Written procedures
- Submission process for IRB review
- Preparation for full committee review
- Preparation for continuing review

## 

OHRP QA Consultation

*OHRP QA Consultation*

## Why Seek an OHRP QA Consultation?

- A site has made improvements to their HRPP and seeks an OHRP consultation to assess the current status of their program
- A site has reached the level of continuing quality improvement of their HRPP and plans to seek accreditation

## Agenda for an On-Site Consultation

- DAY 1: DATA COLLECTION
- Interviews
- 		- Institutional Official
- 		- IRB members, Chair(s)
- 		- IRB office director(s), administrator,
-            staff
- 		- Investigators
- Records review
- - Written policies & procedures & IRB minutes
- - Research protocol files

## Agenda for an On-Site Consultation

- DAY 2: OHRP FEEDBACK
- Detailed review of written procedures, IRB minutes, and IRB records
- Question and answer period
- Exit interview with Institutional Official

## Agenda for a Video/Teleconference Consultation

- Detailed records review
- Written policies & procedures and
- 	IRB minutes
- Limited interaction with personnel
- Debriefing of Institutional Official & staff

## Frequently Discussed Topics

- IRB written procedures
- IRB minutes
- Continuing review
- Expedited review, use of exempt categories
- Informed consent: documentation of waiver
- IRB review of adverse events for multicenter trials
- Review of Subparts B, C, D

## How the OHRP QA Team Handles Noncompliance

- Procedural non-compliance
- - QA team clarifies regulatory requirements and works with institution to develop its corrective action plan
- - QA team may offer a follow-up interaction
- Serious or systemic noncompliance that has or may put the rights and welfare of subjects at risk
-     -  Same Steps as above
- 	- Recommend self-reporting to OHRP
-    - Notification of Institutional Official & OHRP
-      Director

## Key Points OHRP’s QIP 

- Available to all institutions engaged in  HHS conducted or supported nonexempt human subjects research
- Various methods of conducting consultation
- Helps institution to identify areas to improve current human research protections progarm

## Assurance of Compliance

## HHS Regulations  (45 CFR part 46)

- HHS will conduct or support non-exempt
- human subject research only if:
- the institution has an OHRP-approved assurance, and
- the institution has certified to HHS
- research was reviewed and approved by IRB, and
- the research will be subject to continuing review**	**
**	****	****	****	****	****	****   **§46.103(b) & (f)
**	****	****	****	****	****	**

## Institution is Generally Engaged in Human Subjects Research 

- When employees or agents obtain, for research purposes:
- data about the subjects of the research through intervention or interaction with them; or
- identifiable private information about them
- 					§46.102(d) & (f)
- Draft Guidance at: _[http://www.hhs.gov/ohrp/requests/engage.html](http://www.hhs.gov/ohrp/requests/engage.html)_

## Institutions Generally Engaged, Examples:

- Administer research interviews or questionnaires
- Perform invasive or non-invasive procedures
- Manipulate a subject’s environment
- Receive or access identifiable private information

## Institutions Generally Not Engaged, Examples:

- Release individually identifiable private information/specimens to another institution
- Permit investigators from another institution to use their facilities for research
- Provide information about research to prospective subjects
- Perform commercial or non-collaborative service

## Institutional Responsibilities

- Protect Human Subjects in Research
- Responsibilities shared by
-       Institutional Officials, IRBs, and Investigators

## Institutional Assurance

- Documentation of institution’s commitment to comply with applicable regulations §46.103(b) & (f)
- Generally recognized by other federal departments & agencies
- Method of compliance oversight for OHRP
- Federalwide Assurance (FWA) – only assurance option

## Assurance Applications – Extending FWA

- Individual Investigator Agreement
- independent investigators
- investigators at another institution
- Assured institution responsible for oversight of research
- Sample agreement and guidance available
- at the OHRP website

## IRB Authorization Agreement

- Detail which institution responsible for:
- project(s) that will be reviewed by external IRB
- monitoring and oversight
- Consider including details on termination of agreement
- Signed by each institution’s authorized official
- Document kept by institutions – must be made available to OHRP, if requested

## FWA Covers 

- Institutional components* *
- Institution’s employees and agents, including students
- Under limited circumstances, FWA may be extended to *individual investigators*

## Assurance Applications - Relying on External IRB

- Institution responsibility
- Written agreement
- IRB authorization agreement
- 	_[http://www.hhs.gov/ohrp/humansubjects/assurance/iprotsup.rtf](http://www.hhs.gov/ohrp/humansubjects/assurance/iprotsup.rtf)__ _
- Ensure research conducted per IRB approved plan
- Procedures for reporting to OHRP

## Institutional Official’s Responsibilities

- Assure compliance with the:
- Terms of the Federalwide Assurance

## Institutional Official’s Responsibilities (cont’d)

- Set the "tone" for an institutional culture promoting ethical conduct of research
- Support IRB actions & determinations
- Ensure that investigators fulfill their responsibilities
- Support training/education opportunities for staff

## Additional Administrative Considerations

- Applicability of assurance
- Staffing and support
- Administrative conflict of interest
- Review by additional committees

## Key PointsAssurance of Compliance

- There are many institutional responsibilities when engaged in human subjects research
- OHRP holds FWA-holding institution responsible for compliance
- Read and understand the terms of FWA assurance
- Protecting human subjects is a shared responsibility

## IRB Membership	

## Members

- Minimum of 5 members
- Experience and Expertise
- Diversity of Members

## Regulatory Membership Requirements

- Minimum one scientist member
- Minimum one non-scientist member
- Roles of scientist vs. non-scientist
- Minimum one nonaffiliated member

## Special IRB Members

- Prisoner representatives
- Alternate members
- identify pairing of alternate and primary member(s)
- appropriate expertise
- substitute for entire meeting or any portion of meeting
- Expert Consultant

## IRB Member Conflict of Interest

- Investigators on the protocol, financial conflict, other
- Conflicted members do not contribute to the quorum
- May provide information requested by the IRB
- Recusal from IRB’s deliberations and voting

## IRB Membership Selection & Retention

- Who makes selection
- Length of tenure
- Reasons for termination
- Retention strategies

## IRB Roster (IRB Registration)

- Members identified by:
- Name
- Earned degree
- Representative capacity
- Indication of experience
- Employment or other relationship between member and institution
- 					   §46.103(b)(3)

## Key PointsIRB Membership

- Meet regulatory membership requirements
- Alternate member paired to primary member
- IRB member conflict of interest must be addressed
- Update IRB Roster with OHRP

## Investigator Responsibilities

## Protecting Human Subjects is a Shared Responsibility

**Subjects**

**Sponsor**

**Advocates**

**IRB**

**Research Team**

**Institution**

**        **

**Government**

**Public**

**Family**

**Investigator**

##  Investigator Responsibility #1

*  *
***Comply with relevant ***
***Federal regulations ***

## Regulations for Protection of Human Subjects 45 CFR part 46

**Subpart A** – basic HHS Policy - “The Common Rule” or Federal Policy
- Other federal departments & agencies have adopted
**Subpart B** - Pregnant Women, Human Fetuses,  and Neonates
**Subpart C** - Prisoners
**Subpart D** - Children

- 6

##     Investigator Responsibility #2

*   *
***Recognize when the ***
***regulations apply ***
***to planned activities***

## Investigator Responsibility #3

***Initial Review***

## Materials Submitted to the IRB

- Protocol, grant proposal, informed consent(s)
- Recruitment materials and plan
- Any IRB mandated or other related documents

## Considerations for IRB Review and Approval

- Understand IRB expectations and policies
- Provide sufficient information and materials
- Recognize and manage conflicts of interest
- Comply with IRB decisions and requirements
- Respond to IRB requests in a timely fashion

## Investigator Responsibility #4

***Prospective IRB review of proposed changes to research******	***
***No Changes to Research ******Without IRB Review and Approval***

## Investigator Responsibility #5

***Continuing Review***

## Continuing Review

- Status Reports
- Lapse in Continuing Review

##     Investigator Responsibility #6

*  ****Obtain and document legally effective informed consent, assent, and parental permission in accord with §46.116 and applicable subpart(s) and as approved by the IRB.***

## Investigator Responsibility #7

***Realize ***_***your role***_*** when reporting certain incidents***

## What is an Unanticipated Problem?

- Incident, experience, or outcome that is:
- Unexpected (nature, severity, frequency)
- Related or possibly related to research, AND
- Suggests greater risk of harm than previously known or recognized

## Investigator Responsibility #8

***Fulfill responsibilities when study is completed ***

## Study Completion

- When is the study completed?
- Responsibilities for study completion?

## Key Points Investigator Responsibilities

- Follow Belmont Report, Federal regulations, IRB & institutional procedures and policies
- Promptly report changes to the IRB
- Obtain, document, and retain legally effective informed consent
- Ensure ongoing protections
- Understand role when reporting incidents to OHRP

## Human Subjects Working Group MeetingMay 7th, 2008

- The Office for Human Research Protections
- Lyndi Lahl, MS, RN
- Michelle Feige, MSW

## Overview

- Required written procedures
- Additional considerations
- Written procedures
- IRB records

## IRB Written Policies and Procedures

## 7 Required Written Elements

- “Magnificent 7” required elements & operational procedures

## 
 Required Elements of  
Written IRB Procedures
§46.103(b)(4-5) 

* **Required Elements of  *
*Written IRB Procedures*
- §*46.103(b)(4-5) *

## Required Element 1

-    Procedures IRB will follow for conducting
- 	initial review of research
- 					 §46.103(b)(4)(i)

## Required Element 2

- Procedures IRB will follow for conducting
- continuing review of research
- 							 							    §46.103(b)(4)(i)

## Initial & Continuing Review

- Description of
- Method of review
- Reviewer system
- Documents received and distributed for review
- IRB review, findings, & determinations
- Range of possible actions by IRB
- Further review by institution

## Method of Review

- Convened IRB Meeting
- Expedited** **

## Convened IRB Meeting

- Convened meeting (telephone, videoconference participation OK)
- Quorum
- majority of IRB members present
- at least one non-scientist present
- Approval by majority present

## Expedited Review

- Minor changes to previously approved research
- No greater than minimal risk *and*  on “list” at 63 FR 60364-60367 _[http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm](http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm)__ _

##   Expedited Review (cont’d)

- Description of
- Assignment of reviewers
- IRB chair designates
- criteria for assignment
- IRB chair or experienced IRB member reviews
- Documents distributed for review
- Communication of approval action to all IRB members

## Reviewer System

- Primary or other reviewer system
- Initial review
- Continuing review
- Review of protocol changes
- Review of required reports
- Documents distributed for review

## Primary Reviewer System

- Assignment of reviewer(s)
- criteria for assignment
- who assigns reviewer(s)
- Responsibilities of primary reviewer(s)

## Documents for Initial Review

- Protocol summary and/or full protocol
- Proposed informed consent document
- Relevant HHS application or proposal
- Recruitment and data collection materials
- Multi-center trials (HHS supported)
- complete approved protocol and informed consent document

## Documents for Continuing Review

- Protocol summary and/or full protocol,
- include modifications previously approved
- Current informed consent document
- Status report:
- number of subjects accrued
- summary of unanticipated problems, available AE information, withdrawal of subjects, & complaints
- literature summary, amendments, & modifications since last review
- relevant multi-center trial reports
- All other documents available

## Document Distribution- Convened IRB Review

- No primary reviewer system
- One member -- HHS proposal
- All members -- all other materials

## Document Distribution- Convened IRB Review (cont’d)

- Primary reviewer system
- One member -- HHS proposal
- Primary reviewer(s) -- all other materials
- All other members receive summary of protocol, informed consent document, and recruitment materials (continuing review to also include status report)
- Complete documentation available to
-    all members

## IRB Review, Findings, & Determinations

- Description of process:
- Criteria for approval under §46.111 & applicable subparts
- Informed consent considerations
- basic & additional elements §46.116(a & b)
- altering or waiving §46.116(c or d), §46.408(c), & §46.101(i)
- waiving written documentation §46.117(c)

## Range of Possible IRB Actions

- Description of action:
- Approve research
- Require modifications in order to secure approval
- Disapprove research (convened IRB only)
- Suspend or terminate previously approved research

## Documentation of IRB Review Process

- OHRP recommends institutions have
- written procedures for documenting
- IRB findings, determinations, actions,
- and other IRB requirements.

## Further Review by Institution

- Who is responsible for further review
- institutional committees, e.g., COI, Privacy Board, Radiation, Biosafety
- other
- Institutional policies relevant to review
- Actions that may be taken by institution
- institution may _not_ _override_ IRB disapproval

## Required Element 3

- Procedures the IRB will follow for reporting
- its findings and actions to the investigator
- and the institution
- 						§46.103(b)(4)(i)

## Reporting IRB Actions

- To investigator
- Written communication
- Request for modifications or clarifications
- Reviewing and acting upon investigator’s response

## Reporting IRB Actions (cont’d)

- To institution
- Written communication
- Which institutional official(s) notified
- How notification accomplished** **

## Required Elements 4

-    Procedures the IRB will follow for determining which projects require review more often than annually
- 					    		 §46.103(b)(4)(ii)

## Determining Frequency of IRB Review

- Specific criteria used to make these determinations
- Document approval period**	**

## Required Elements 5

-    Procedures the IRB will follow for determining which projects need verification from sources other than the investigator that no material changes have occurred since previous IRB review
- 					    §46.103(b)(4)(ii)

## Verifying No Changes Since IRB Review  

- Specific criteria, e.g.,
- Random selection of projects
- Complexity of project
- History or concerns re: investigator compliance

## Required Element 6 

**   **Procedures for ensuring prompt reporting to the IRB of proposed changes in a research activity *and *ensuring that such changes in approved research may not be initiated without IRB review and approval except when necessary to eliminate apparent immediate hazards to the subject    						§46.103(b)(4)(iii)

## Ensuring Protocol Changes Made in Accordance with Regs 

- Steps to ensure compliance, e.g.,
- training programs for investigator,
- specific directives included in approval letters to investigators,
- random or targeted audits of research
- Exception - eliminate apparent immediate hazards to subjects

## Required Element 7 

-    Procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, the Department or Agency head, and OHRP of any
- unanticipated problems involving risks to subjects or others
- any serious or continuing noncompliance
- any suspension or termination of IRB approval							§46.103(b)(5)

## Reporting Requirement

- Who is responsible for prompt reporting
-  to whom/which office(s) or official(s)
- Time frames for accomplishing reporting requirement
- Range of possible actions taken by the IRB in response to reports

## OHRP Guidance

- Reporting Incidents to OHRP:
-     _[http://www.hhs.gov/ohrp/policy/incidreport_ohrp.htm](http://www.hhs.gov/ohrp/policy/incidreport_ohrp.htm)_
- Reviewing and Reporting Unanticipated Problems ...  and Adverse Events: _[http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm](http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm)__ _

## Key PointsRequired Elements of Written IRB Procedures

- Institutions must have written procedures  comprised of the seven required elements
- Include step-by-step operational details that are user friendly and effective
- Implement throughout the organization
- OHRP guidance is available

## 

Additional Considerations

_***Additional Considerations***_

## Subparts B, C, and D

- Categories of permissible research
- Research not otherwise approvable (Secretarial panel process)
- Additional criteria for IRB approval
- Special requirements for informed consent, parental permission, and assent
- Other considerations

## Informed Consent Process

- Facilitate informed consent
- “Long” and “short-form” consent options and considerations
- Methods for ensuring use of proper informed consent document
- Who may be/must be involved in consent process

## Informed Consent Process (cont’d)

- Other considerations
- distinguish between “informed consent” and “documentation” of informed consent
- IRB’s role in monitoring informed consent process

## Ensuring IRB Knowledge of Local Context

- Methods for ensuring IRB knowledge of local research context
- See guidance document at:** **_**[http://www.hhs.gov/ohrp/humansubjects/guidance/local.htm](http://www.hhs.gov/ohrp/humansubjects/guidance/local.htm)**__ _

## Other Relevant Authorities

- Other Federal laws/regulations
- State & local laws/regulations
- Foreign laws/regulations/regulatory standards  _[http://www.hhs.gov/ohrp/international/HSPCompilation.pdf](http://www.hhs.gov/ohrp/international/HSPCompilation.pdf)__ _
- Other
- institutional commitments & policies
- funding entities

## Determining Applicability and Exemptions

- Considerations:
- Institutional locus (e.g., IRB office)
- Institutional person – someone with good foundation of human subjects’ protection regulations
- Mechanism for ensuring no changes in research

## Lapse in Continuing Review

- Notification of investigator that IRB approval has lapsed
- Process used by IRB to determine whether individual subjects’ continued participation is in their best interest
- Generally not reported to OHRP

##  Conflict of Interest (COI)

- Recognize
- Manage
- HHS guidance on Conflict of Interest:
-    _[www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf](http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf)__ _

## Institutional Educational Requirements

- Training and education program considerations
- for IRB members, investigators, & staff
- Who
- How often
- Documentation
- Resources

## Other Issues for Possible Inclusion 

- Important definitions
- Preparing for review/meeting
- IRB meeting attendance
- IRB fees
- IRB member responsibilities
- External IRB

## Other Issues for Possible Inclusion (cont’d)

- Investigator responsibilities
- Handling allegations of non-compliance
- Maintenance of IRB records and meeting minutes
- Emergency research
- Description of FDA-related responsibilities
- Institution-specific practices

## IRB Records

- Copies of
- research proposals reviewed
- scientific evaluations, if any
- approved sample consent documents
- progress reports submitted by investigator
- reports of injuries to subjects
**                 ****	****	****	**** **§46.115(a)(1)

## IRB meeting minutes 
Records of continuing review activities
Correspondence between IRB and investigators
				            §46.115(a)(2-4)

- Records of continuing review activities
- Correspondence between IRB and investigators
**	****	****	****	****            **§46.115(a)(2-4)

- IRB Records (cont’d)

## List of IRB members
Written IRB procedures 
Statement of significant new findings provided to subjects 					 	    						§46.115(a)(5-7) 

- Written IRB procedures
- Statement of significant new findings provided to subjects** ****	****	****	****	****	**** ****	****    ****	****	****	****	****	****	**§46.115(a)(5-7)

- IRB Records (cont’d)

## Regulatory requirements - §46.115(a)(2) 
Objective 
Too much or too little:  It’s always a balancing act! 

- Objective
- Too much or too little:  It’s always a balancing act!

- IRB Meeting Minutes

## IRB Meeting Minutes to Describe

- Regulatory requirements
- Attendance
- IRB actions
- IRB vote
- Basis for requiring changes in or disapproving research
- Controverted issues

## Attendance at Meeting

- Document attendance
- members
- others
- Entry/Exit/Recusals
- Document quorum
- Loss of quorum = no further IRB action

## IRB Actions and Votes

- Minutes to reflect actions taken by convened IRB
- regulatory
- institutional
- Vote on IRB actions
- voting for
- against
- abstaining

## Basis for Requiring Changes in or Disapproving Research

- Why IRB required changes to specific proposed research
- Why IRB disapproved research

## Controverted Issues

- Written summary
- discussion and
- resolution
- Dictionary definition of controverted:
- 	- to dispute or oppose by reasoning
- 	- to engage in controversy

## Remember:  Waiver of Informed Consent

- 	Alteration or waiver of informed consent must be documented under §46.116(c) & (d)

## Additional Considerations

- 	If you think documentation will enhance your IRB’s decision-making process when reviewing research...

## Consider documenting each IRB finding, determination, and requirement - including protocol-specific information justifying each decision 
in the minutes of the IRB meeting (or, e.g., checklists, reviewer sheet) 
alternative documentation for expedited review

- in the minutes of the IRB meeting (or, e.g., checklists, reviewer sheet)
- alternative documentation for expedited review

- Considerations for Documentation

## Considerations for Documentation (cont’d)

- Protocol-specific information justifying the IRB’s
- decision re:
- Waiving written documentation of informed consent 			§46.117(c)
- Approving research
- criteria and rationale under §46.111
- criteria and rationale under applicable subpart(s)

## Considerations for Documentation (cont’d)

- Protocol-specific information justifying the IRB’s
- decision re:
- Approval period
- Requiring modifications in research
- Disapproving research
- Suspending or terminating IRB approval

## Retention of IRB Records

- Minimum three years
- Accessible for inspection and copying
- 				 		§46.115(b)
- Check state and local laws

## Key PointsAdditional Considerations

- Many institutions develop comprehensive procedures that go beyond what is required
- Provide helpful resource for all involved in human subject research
- Maintain records in compliance with regulations

## OHRP Contact Information

- Website:  _[www.hhs.gov](http://www.hhs.gov/ohrp)__[/ohrp](http://www.hhs.gov/ohrp)_
- Email:  _[OHRP@HHS.GOV](mailto:OHRP@HHS.gov)_
- Toll-free phone #:  1-866-447-4777
- Main phone #:  240-453-6900
- Join Listserv:
- 	 _[http://](http://www.hhs.gov/ohrp/news/index.html)__[www.hhs.gov/ohrp/news/index.html](http://www.hhs.gov/ohrp/news/index.html)_