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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Compliance Program 7348.809 - Part II - Implementation

  1. OBJECTIVES

    The objectives of the BIMO Program are:

    1. To protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials;
    2. To verify the accuracy and reliability of clinical trial data submitted to FDA in support of research or marketing applications; and
    3. To assess compliance with FDA’s regulations governing the conduct of clinical trials.

    The purpose of this compliance program is to provide instructions to the field and Center personnel for conducting inspections of IRBs and recommending associated regulatory and/or administrative actions.

  1. PROGRAM MANAGEMENT INSTRUCTIONS
    1. Coverage -- This program provides for the inspection of domestic IRBs that review and approve investigational studies involving human subjects and FDA-regulated articles (e.g., drugs including biologics, food or color additives, and medical devices).
    2. Types of IRBs -- There are many types of IRBs. They can be categorized as government, independent, hospital, academic, or central.
    3. Due Dates -- All assignments will be issued by the Centers and will have a ninety (90) day completion date unless otherwise indicated.
    4. Centers should give consideration to the following factors when selecting IRBs for inspection:
      1. IRBs for which the previous inspection was classified Official Action Indicated (OAI) (e.g., sanctions imposed, Warning letter issued). These IRBs should be re-inspected within one year (i.e., soon after the last Warning Letter correspondence was issued);
      2. IRBs that have never been inspected before; and
      3. IRBs that were recently established or have limited experience reviewing FDA-regulated research (for example, an IRB that previously only reviewed social behavioral research begins to review investigations of FDA-regulated articles).
    5. Centers may pursue special IRB inspection initiatives, for example, inspecting IRBs that review particular types of studies, such as first-in-human trials, studies involving an exception from informed consent, or studies involving vulnerable populations (e.g., Alzheimer’s patients, pediatric populations). Any unique focus of an inspection will generally be discussed in the assignment.
  1. TYPES OF INSPECTIONS

    FDA will periodically inspect each IRB that reviews research involving FDA-regulated articles. The inspections will be either routine or directed.

    1. Routine Inspections
      The assigning Center will provide evidence of FDA jurisdiction over the IRB by consulting the IRB Registration database maintained by the Office for Human Research Protections (OHRP) for the name and address of the institution, and when available, the name of a contact person at the IRB. The assigning Center may provide a specific protocol to review during the inspection, when available.

      Those IRBs found to have no objectionable conditions (NAI classification) or objectionable conditions that do not meet the threshold for regulatory action (VAI classification) will usually be assigned for reinspection in 5 years.
    2. Directed Inspections
      A directed inspection may be assigned when the assigning Center receives information that calls an IRB’s practices into question. A directed inspection may be limited to one area of concern or assigned to cover the entire compliance program.

      IRBs found to have major deficiencies (OAI classification) will usually be assigned for reinspection within one year to confirm that adequate corrections have been made.
       
    3. Inspection Assignments
      1. Center BIMO units issue inspection assignments of IRBs. The Centers will identify IRBs to be inspected from sources such as the IRB’s Official Establishment Inventory (OEI) file maintained by ORA District offices, Center files (including complaints), the IRB Registration database5 maintained by the Office for Human Research Protections (OHRP), Web searches, journal articles, research permits, and marketing applications submitted to the Center.
      2. To ensure the appropriate and efficient use of FDA resources, IRB assignments will follow Field Management Directive (FMD) No. 17, ORA Field Assignments - Guidelines for Issuance by Headquarters, whether from an ORA headquarters unit or a Center. (http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/UCM056651).
      3. The assignment should identify:
        • The program assignment code (PAC), Field Accomplishments and Compliance Tracking System (FACTS) number, and Firm Establishment Identification (FEI) number, if known;
        • The name, address and phone number of the IRB, when available, to be inspected;
        • The type and purpose of the inspection (e.g., routine or directed inspection).
          Occasionally, some Centers will designate sub-types (e.g., Surveillance, For Cause, Complaint, or OAI follow-up);
        • The background materials that are being sent from the Center to facilitate the inspection (e.g., information obtained from OHRP’s IRB registry);
        • Specific issues or concerns (if applicable) that need to be addressed during the inspection;
        • The due date for the Center contact to receive the completed EIR;
        • The headquarters address where the EIR should be sent; and
        • The name, telephone number, and fax number of the Center contact(s).

        Note: For any inspection attempt where it is determined the IRB is out of business or it is been determined that FDA does not have jurisdiction (e.g., IRB is not reviewing FDA-regulated studies), please contact the Center that issued the assignment in order to discuss converting the inspection request (Operation 12) to an Operation 13 designation.

      4. Inspection of the Department of Veterans Affairs (VA) as the IRB of FDA-regulated clinical trials.
        • Pre-Inspection
          • Center. The BIMO unit in the assigning Center will provide the VA’s office of Research Oversight (ORO) with written notification of FDA’s intention to inspect a VA IRB program at the time an assignment is being issued to the field.
          • The notice should be sent to:

            Chief Officer
            Office of Research Oversight (10R)
            Veterans Health Administration
            Department of Veterans Affairs
            810 Vermont Avenue, N.W., Suite 574
            Washington, D.C. 20420

          • Field. The field investigator will contact the VA IRB program before the inspection, as they would any other IRB they are assigned to inspect.
        • Post-Inspection
          • The Center will provide the VA’s ORO redacted copies of post-inspection correspondence issued to VA IRB programs that include a discussion of deficiencies noted during the inspection (including the Form FDA 483). Such materials should be sent to:

            Chief Officer
            Office of Research Oversight (10R)
            Veterans Health Administration
            Department of Veterans Affairs
            810 Vermont Avenue, N.W., Suite 574
            Washington, D.C. 20420

          • If, following receipt of the FDA correspondence, the VA-ORO requests a copy of the EIR, a redacted copy of the report will be provided to VA-ORO by the District office.
      5. All headquarters and field personnel who become aware of complaints or problems related to an IRB are encouraged to refer them to the appropriate Center contact with a recommendation for inspection. All recommendations should include the following:
        • The name and address of the IRB;
        • If available, the name(s) of the test article(s) being investigated, and the application for research or marketing permit number(s); and
        • The basis for the recommendation and any relevant documentation.
    4. Communication between the Centers and the Districts

      Inspectional observations documenting that an IRB is not operating in compliance with the regulations in 21 CFR Parts 50 and 56 may be used as evidence for taking appropriate administrative and/or enforcement actions. Ensuring that the evidence collected to support such actions is both appropriate and adequate requires that communication lines between the ORA District office and the Center be established early and maintained throughout the entire process, i.e., until post-inspectional correspondence is issued by the Center. Contact between a Center and an ORA field investigator will respect District’s policy for direct contact between field investigators and Center personnel and may require ORA management participation.

      1. Prior to an Inspection
        • The Center issues an assignment that includes contact information for the BIMO reviewer.
        • The field investigator contacts the BIMO reviewer:
          • Upon receipt of the assignment, to establish initial contact and/or provide an inspection start date;
          • When the inspection date is firmly set, to alert the BIMO reviewer and/or a back-up to be available and to establish the most appropriate means of contact for both the investigator and the BIMO reviewer/back-up;
          • To obtain any new information that may change the focus of the inspection; and
          • To coordinate inspection arrangements if Center personnel plan to participate in the inspection.
      2. Special Considerations
        • In particular cases, the Center may arrange for a consultative teleconference immediately prior to the inspection(s) if, for example, the complexity of issues, urgency of feedback, compliance history, etc., trigger the need to discuss issues further. Such conference calls are most likely when the agency encounters special situations (e.g., directed inspections where pertinent information is either complex or needs discussion between the Center and the field). Unless information necessitating this discussion emerges after the assignment is issued, the assignment will usually include information as to when this teleconference will occur.
        • These teleconferences may include the following participants, as warranted and feasible:
          • BIMO reviewer (and supervisor/division director or other staff, as appropriate);
          • Lead application reviewer (along with branch and division chiefs, if appropriate) or other application reviewers as needed; and
          • Field investigator(s) assigned to the inspection(s), the BIMO coordinator (when not yet specifically assigned), and ORA management and staff, as appropriate.
      3. During an Inspection
        • The BIMO reviewer contacts the field investigator if significant new information becomes available.
        • The field investigator contacts the BIMO reviewer or designated back-up person if the field investigator:
          • Needs advice or clarification. The BIMO reviewer and field investigator should strive to be accessible to one another as much as possible during the time that the inspection is ongoing.
          • Uncovers other evidence of concern warranting discussion with Center staff.
      4. After an Inspection
        • As soon as possible but within three (3) business days after conclusion of the inspection, the field investigator forwards to the BIMO reviewer (by facsimile, e-mail, or placement in the appropriate shared drive folder) any Form FDA 483 (commonly referred to as a “483”) that is issued.
        • The field investigator/District will forward as soon as possible to the BIMO reviewer a copy of any written response to the 483 by the inspected party. The BIMO reviewer will forward to the field investigator, a copy of any response to a 483 that does not appear to have been shared with the inspecting District. If desirable, the field investigator provides Center contact information so that the response to the 483 can be sent directly to the Center for review in addition to sending it to the field inspector/District.
        • For general guidance for handling unsolicited responses resulting from the issuance of the 483, please see Field Management Directive #120.6
        • The BIMO reviewer consults with the field investigator/District representative as needed when reviewing the EIR.
        • If the Center’s final classification is different from the one recommended by the field, the Center should ensure that District personnel are aware of the change and reasons for the change. The Center promptly forwards to the field investigator and other appropriate District personnel by e-mail, if possible, copies of post-inspectional correspondence issued to the inspected party.
        • The Center enters the final classification into FACTS.
    5. Responsibilities of Field Investigators, Inspection Team Leaders, and Headquarters Participants
      1. When conducting solo inspections

        When conducting solo inspections, the field investigator’s responsibilities include, but are not limited to, the following:

        • Scheduling and conducting the assigned inspection;
        • Discussing with District management the need to adjust the workload in order to meet specific deadlines or goals (e.g., goals established as part of the Prescription Drug/Medical Device User Fee Acts);
        • Communicating inspectional observations with the institutional officials and IRB staff during the course of the inspection, as appropriate;
        • Communicating inspectional observations and issues with the Center contact during the course of the inspection and review, as appropriate;
        • Preparing, issuing, and discussing the items listed on the 483 with the IRB at the close of the inspection;
        • Preparing and submitting an EIR within FDA timelines; and
        • When appropriate, participating in discussions with the Center regarding potential changes in the EIR classification.
      2. When conducting team inspections

        When inspections are conducted by a team, a field investigator serves as inspection Team Leader who is responsible for the cooperative conduct of the inspection. The Team Leader’s responsibilities include, but are not limited to the following (see also Investigations Operations Manual (IOM) at http://www.fda.gov/ICECI/Inspections/IOM/default.htm , Chapter 5, section 5.1.2.5- Team Inspections 7):

        • Scheduling and coordinating the participation of team members;
        • Discussing inspection plans and objectives with team members;
          • Assuring that team members understand their roles and responsibilities in conducting the inspection, taking notes, collecting documentation, preparing sections of the inspection report and exhibits, and signing the report;
        • Setting team policy regarding communications with institutional officials and/or the IRB staff;
        • Discussing personal conduct with team members as necessary; and
        • Resolving disputes or differences of opinion among team members, including items to be listed on the 483. If an agreement cannot be reached during the inspection, the final items included on a 483 will be decided by the ORA field investigator.
      3. Headquarters Participants

        A headquarters participant is a member of the inspection team who serves in a compliance or scientific advisory capacity to the Team Leader. The headquarters participant’s responsibilities include, but are not limited to, the following:

        • Obtaining training on inspection conduct and behavior prior to participating in inspections;
        • Obtaining inspection credentials from the Division of Domestic Field Investigations (DDFI) (HFC-130);
        • Completing the Inspection Participation Form (Form FDA 2115) available at
          http://inside.fda.gov:9003/downloads/Administrative/Forms/FDA/UCM030799.pdf ;
        • Contacting the Office of Regional Operations (ORO) to request permission to participate in field inspections;
        • Providing information pertinent to the inspection;
        • Attending pre-inspection discussions, if and when requested by the Team Leader;
        • Participating in the on-site inspection as permitted by agency priorities; and
        • Providing guidance and expertise during the inspection and completing inspection tasks as directed by the Team Leader (e.g., auditing documents, preparing inspection notes and specific sections of the establishment inspection report within guidelines and timeframes).
    6. Resolution of Disagreements

      If there is disagreement among members of the inspection team, the issue should be discussed off-site and resolved cooperatively. Any difficulties in conducting team inspections should be discussed with both District management and the assigning Center, and, if not resolved, immediately referred to the Division of Domestic Field Investigations (DDFI) (HFC-130).
       


5http://www.hhs.gov/ohrp/assurances/status/index.html

6http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm096015.htm

7http://www.fda.gov/ICECI/Inspections/IOM/ucm151267.htm#5.1.2.5