1. Preparing the IRB and Investigators for an External Audit/Site Visit
Cynthia Monahan, MBA, CIP
IRB Director
Boston University Charles River Campus IRB

2. Table of Contents
Office for Human Research Protections (OHRP) Compliance Oversight Evaluations
Food and Drug Administration (FDA) Inspections
Association for the Accreditation of Human Research Protection Programs (AAHRPP) Site Visit
Preparing and Navigating the Inspection/Visit

3. OHRP Compliance Oversight Evaluation
Division of Compliance Oversight (DCO) evaluates, at OHRP’s discretion, written substantive indications of noncompliance with HHS regulations
DCO also conducts a program of not-for-cause surveillance evaluations of institutions, and receives, reviews, and responds to incident reports from Assured institutions

4. OHRP Not-for-cause Evaluation
Visit is not initiated by a complaint or report of possible non-compliance
Institutions are selected based on:
Volume
History of low level of reporting to OHRP
Need to evaluate that corrective actions from a previous for-cause evaluation have been implemented
Geographic location
Accreditation status
Results of recent evaluations/audits by other regulatory agencies

5. OHRP Not-for-cause Evaluation
OHRP notifies Institutional Officials in writing of evaluation
Notice will include whether interviews will be conducted and if an on-site visit will be conducted
Institutional officials, IRB members, and investigators
OHRP requests the following information by a specified date:
Policies and procedures
Recent meeting minutes
List of active IRB protocols

6. OHRP For-Cause Evaluation
Evaluation is in response to an allegation of non-compliance
Sources of non-compliance include: research subjects, investigators, research staff, and Institutional Officials

7. OHRP For-Cause Evaluation
OHRP notifies institutional officials in writing of evaluation
Initial letter includes:
Description of the allegation
Request for the institution to conduct an investigation
Request for written response by a specified date
Corrective action plan if investigation reveals any non-compliance
Explanation of OHRP evaluation procedures

8. OHRP On-Site Visit
In most cases, on-site visits are not required; however, visit will be required if concerns cannot be resolved through correspondence
Majority of on-site visits are for-cause
Most on-site visits are announced 1-2 weeks in advance; however, there is no requirement that visit must be announced

9. OHRP On-Site Visit
Visits are conducted by a team of 2-5 OHRP professionals and 2-5 external consultants
Visits are usually announced by telephone and in writing
OHRP is informing the institution that the visit will occur NOT inquiring about scheduling an appointment
OHRP provides agenda for visit

10. OHRP On-Site Visit OHRP will request list of human subjects research
3-5 days in advance of visit, OHRP will identify specific protocols and request that they be available for review; medical records may also be requested
Minutes from the past 3 years will be reviewed
Visit usually lasts 3-5 days

11. OHRP On-Site Visit
Visit begins with an introductory meeting with the institutional officials and other appropriate officials
1 hour/day devoted to on-site review of the IRB
1 day devoted to meetings with IRB chairs, IRB members, administrators, investigators, and research staff
Exit interview at the end of the visit

12. OHRP On-Site Visit Exit interview:
Determinations and required corrective actions are presented
If immediate action is required, determination letter may be issued at exit interview
OHRP determination letters are publicly available and are posted on the OHRP website

13. Evaluation Outcomes OHRP does not identify any areas of non-compliance
OHRP recommends improvements
Institution is free to implement the recommendations or not

14. Evaluation Outcomes (cont’d)
OHRP determines that there is non-compliance
Institution is required to develop and implement corrective actions
Restricts or attaches conditions to its approval of the institutions FWA
Suspends its approval of the institutions FWA
Temporarily suspend or permanently remove an institution or investigator from specific projects
Notify scientific peer groups of non-compliance
Institution and/or investigator is debarred
Refer the matter to another Federal agency

15. FDA Inspections

16. Bioresearch Monitoring (BIMO) Program
FDA developed BIMO to ensure:
The protection of the rights, safety, and welfare of human research subjects
The quality and integrity of data submitted to the Agency
BIMO Program involves site visits to clinical investigators, sponsors, monitors, contract research organizations, IRBs, nonclinical (animal) laboratories, and bioequivalence analytical laboratories

17. FDA Inspections Routine Inspections Directed Inspections Every 5 years
FDA receives information that calls an IRB’s practices into question

18. FDA Inspections
FDA inspector will contact the institution with the notification of intent to inspect
FDA inspector is not calling to schedule an appointment; this is a notification that you will be inspected

19. FDA Inspections
The PI or his/her representatives should meet the inspector and receive and sign the FDA form 482 “Notice of Inspection.”
Request to see the inspector’s identification if he/she does not present it to you
Write down the inspector’s identification information—you cannot make a copy of the inspector’s badge!!

20. FDA Inspections What does the FDA inspect? IRB written procedures
IRB membership
IRB meeting minutes
Consent forms
Correspondence between the IRB and PI
Correspondence regarding unanticipated problems and serious and/or continuing non-compliance

21. FDA Inspections What does the FDA inspect (cont’d)
Non-significant risk (NSR)/Significant Risk (SR) device determinations
Study files
Documentation of approvals and waivers
Humanitarian use Devices (HUD)
Pediatric findings

22. After the FDA Inspection
The FDA inspector will hold an exit interview at the conclusion of the audit to discuss findings and deficiencies
Document the interview, specifically noting observations, comments, and commitments
Any deficiencies will be noted on the FDA form 483 and given to the PI
IRB should respond to the 483 in writing (within 15 days)

23. After the FDA Inspection
After the inspection, the inspector will write an Establishment Inspection Report (EIR) and submit it to FDA headquarters
After the report has been evaluated you will receive one of three letters:
No action indicated (NAI): No objectionable conditions or practices were found during the inspection, or the significance of the objectionable conditions does not justify further FDA action

24. After the FDA Inspection
Post-inspection letters (cont’d)
Voluntary Action Indicated (VAI): Objectionable conditions were found and documented, but the FDA is not prepared to take or recommend further regulatory action because the objectionable conditions are few and do not seriously impact subject safety or data integrity
Official Action Indicated (OAI): Regulatory violations uncovered during the inspection are repeated or deliberate and/or involve submission of false information to FDA or to the sponsor

25. FDA Actions for Non-Compliance
Administrative Actions
Re-inspect to verify corrective actions
Withhold approval of new studies
No new subjects can be enrolled into ongoing studies
Terminate ongoing studies
Disqualification

26. 2013 BIMO Metrics IRB Inspections: 174
Clinical Investigator Investigations: 664

27. Most Common IRB Deficiencies
Inadequate initial and/or continuing review
Inadequate SOPs
Inadequate membership rosters
Inadequate meeting minutes
Quorum issues
Subpart D issues
Inadequate communication with CI/institution
Lack of or incorrect SR/NSR determination

28. Most Common Clinical Investigator Deficiencies
Failure to follow the investigational plan and/or regulations
Protocol deviations
Inadequate recordkeeping
Inadequate accountability for the investigational product
Inadequate communication with the IRB
Inadequate subject protection-- failure to report AEs and informed consent issues

29. Association for the Accreditation for Human Research Protection Programs (AAHRPP)

30. Who is AAHRPP? Independent non-profit accrediting body
Voluntary, peer-driven, educational model
Site Visitors
Council Members
Ensures that HRPP meet rigorous standards for quality and protection
Tangible evidence of commitment to ethical research and continuous improvement
Policies, procedures, and practices
Provides assurance that HRPP is focused on excellence
Research subjects, researchers, sponsors, federal regulators

31. Why AAHRPP Accreditation?
Earn respect and meet expectations of peers
Over 60% of US research-intensive universities and over 65% of US medical schools have or are in the process of AAHRPP Accreditation
Leadership role in collaborative efforts
External IRB reviews
Competitive edge with sponsors/funders
Reduce the risk of non-compliance
Streamlined policies
Enhance standing with US federal agencies
Benefit from a common commitment to continuous quality improvement

32. Goals, Principles, and Standards
AAHRPP has adopted nine overarching principles for protecting human research participants, which serve as the foundation for the AAHRPP Accreditation Standards for Human Research Protection Programs.
The AAHRPP Accreditation Standards themselves describe what Organizations can do to consistently act on these principles by applying them to the diverse organizational and cultural contexts in which research is conducted and reviewed

33. AAHRPP Accreditation Standards
Domain I: Organization
Structural characteristics of the Organization
Domain II: Institutional Review Board/Ethics Committee
Review and oversight of research
Ensure independence of ethics review
Domain III: Researcher and Research Staff
Requirements for researchers and research staff involved in human subjects research

34. Accreditation Process
Application preparation (Step 1)
Submit Application to AAHRPP for review
On-site evaluation (Step 2)
Site visitors conduct on-site visit
Council Review
Council reviews the Application, Draft Site Visit Report, and response and determines accreditation status
Notification of accreditation status
Report sent to Organization detailing the status of the accreditation

35. Preparing for Accreditation
Conduct a self-assessment
Allows the Organization to review its HRPP and evaluate its compliance with the AAHRPP Accreditation Standards
Create list of supporting documents (forms, policies, checklists, etc.) and make copies (this becomes part of your Application)
Draft an element-by-element index to the supporting documents (this becomes part of your Application)
Use Evaluation Instrument for Accreditation
Provides direction on the meaning of each Standard and Element

36. Application Steps Step 1 (Application Review)
Submit Application including: 1) program overview, 2) copies of supporting documents (policies/procedures, checklists, forms, etc.), and 3) an index for the supporting documents
AAHRPP will review Application and provide feedback within 45 days
Address any issues with feedback

37. Application Steps (cont’d)
Step 2 (Site Visit)
Once all issues have been resolved, AAHRPP will schedule the site visit
Site visits are typically scheduled within 3 months after Application is considered to be complete

38. On-site Visit
Depending on size of the Organization, the visit will last 2-4 days
Four-Eight Weeks Before the Visit, AAHRPP will send the following:
Draft agenda
List of people to be interviewed
Explanation of the types of visits
List of the AAHRPP site visitors
Request for logistical and travel information
Request to set aside rooms to be used by site visitors
Request for additional info (e.g. electronic system, etc.)

39. On-site Visit
One week before the Visit, AAHRPP will send the following:
Final agenda
Logistical details
List of records and documents that must be ready
Protocol files
Average is files

40. On-Site Visit During the Visit: Introduction Session Program Overview
AAHRPP site visitors, lead contact from Organization, Organizational Official, other staff members
AAHRPP site team leader will describe the accreditation process
Program Overview
Opportunity for site visitors to ask questions
Organization provides overview of Program
File Review
Site visitors will review requested files

41. On-Site Visit During the Visit (cont’d) Interviews Closeout Session
Confidential and limited to individuals on the agenda
Closeout Session
Site team leader will provide high-level overview and specific observations about each Standard
Organization is provided with the comments that will be in the report
Site visitors may provide suggestions but they will not be included in the report
Organization attendees usually the same as Introduction session

42. After the Visit
AAHRPP will provide a Draft Site Visit Report to Organization within 30 days of the site visit
Organization must respond within 30 days
Once response has been completed and accepted, it is sent to Council for review

43. Council Review
Council on Accreditation makes the decision about accreditation
Accreditation Status
New Applicants
Full Accreditation
Qualified Accreditation
Accreditation Pending
Accreditation Withheld

44. Preparing and Navigating for the Inspection/Visit

45. Preparing for the Inspection/Visit
Ensure that all study documentation is available for review for the inspector/visitor
Review study documentation for:
Comprehensiveness, accuracy, and compliance
Weakness/gaps; correct those that can be corrected (i.e. file violations, notes-to-file, locate missing documents, etc.)
Unresolved or outstanding issues
Organize documents

46. Preparing for the Inspection/Visit
Notify all appropriate officials/individuals
Prepare work space for the inspector/visitor
Access to copy machine
Access to electronic systems
Involve IT Department
Issue Temporary passwords
Training session

47. During the Inspection/Visit
The Institutional representatives should meet the inspector/visitor
Arrive on time
Ask for identification

48. During the Inspection/Visit
If the inspector/visitor requests copies of documents:
Remove subject identifiers from the copies given to the inspector/visitor
Make a copy for yourself
The inspector’s/visitor’s copies should be stamped ‘Confidential’ and your copies should be stamped ‘Copy.’
Set aside time each day to talk with the inspector/visitor

49. During the Inspection/Visit
How to answer questions from the inspector/visitor:
Be concise; answer only the question that is asked
Always be clear with answers to questions
Answer honestly and openly
DO NOT volunteer information
DO NOT guess or speculate
DO NOT argue
If you don’t know the answer, write down the question and refer it to the appropriate person
Keep a log of questions asked by the inspector

50. Ongoing Preparation Process
Internal audits
Review FDA/OHRP determination letters
Adequate IRB Staffing
Continuing education for IRB members, IRB staff, and researchers
Maintain and update IRB policies

51. Resources
BIMO
OHRP: Compliance Oversight
AAHRPP