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

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

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

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

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

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

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

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

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

OHRP On-Site Visit OHRP will request list of human subjects research 3-5 days in advance of visit, OHRP will identify 50-100 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

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

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

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

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

FDA Inspections

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

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

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

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!!

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

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

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)

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

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

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

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

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

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

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

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

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

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

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 http://www.aahrpp.org/apply/process-overview/standards

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

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

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

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

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.)

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 20-30 files

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

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

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

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

Preparing and Navigating for the Inspection/Visit

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

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

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

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

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

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

Resources BIMO http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/default.htm OHRP: Compliance Oversight http://www.hhs.gov/ohrp/compliance/index.html AAHRPP http://www.aahrpp.org/