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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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PART II - IMPLEMENTATION

 

A. 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 clinical investigators and sponsor-investigators,and recommending associated administrative/enforcement actions.

B. PROGRAM MANAGEMENT INSTRUCTIONS

  1. Coverage

    This program covers domestic and foreign inspections of:

    1. Clinical Investigators

      A clinical investigator is the individual who actually conducts the clinical investigation. 1 The investigator is responsible for overall conduct of the study at the study site, including directing the administration or dispensing of the test article to the subject, and ensuring that data are collected and maintained in accordance with the protocol and regulatory requirements.  When the investigation is conducted by a team of individuals, the clinical investigator is the leader of the team.
    2. Sponsor-Investigators

      A sponsor-investigator is an individual who initiates and also conducts the clinical investigation. A sponsor-investigator must comply with regulatory requirements applicable to both sponsors and clinical investigators.2 While inspections of sponsor­-investigators are assigned under CP 7348.811, CP 7348.810 (Sponsors, Contract Research Organizations and Monitors) should also be consulted for areas applicable to the sponsor responsibilities of the sponsor-investigator.
  2. Inspection Assignments
    1. Center BIMO units issue inspection assignments of clinical investigator sites.
      • Domestic inspection assignments are issued to the district offices.  
      • International inspections are generally assigned when the studies covered are part of a marketing application to FDA and provide data critical to decision-making on product approval.  Such assignments may include studies that are conducted under an FDA application for research (e.g., Investigational New Drug Application [IND], Investigational Device Exemption [IDE], Investigational New Animal Drug Application [INAD]), as well as non-U.S. sites or studies that are not conducted under an FDA application for research.  Such assignments are issued to the Division of Field Investigations (HFC-130).
    2. The assignment should identify:
      • The program assignment code (PAC) and Field Accomplishments and Compliance Tracking System (FACTS) number;
      • The name, address and phone number of the clinical investigator or sponsor-investigator, and the study site(s) to be inspected;
      • The type and purpose of the inspection;
      • The background materials (e.g., study protocol; tables; sampling plan3 for review of informed consent documents, case report forms (CRFs) or specific data, if appropriate) that are being sent from the Center to facilitate the inspection. For investigational device studies, the Center should identify the type of study (e.g., significant risk (IDE), non-significant risk (abbreviated requirements), or IDE exempt).
      • 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).
    3. If the inspection involves a Veterans Administration (VA) facility, please see section B.6 for additional instructions.
    4. When requesting expedited inspections, the Center should provide justification. If a Center’s assignment needs high priority, follow Field Management Directive (FMD) No. 17, ORA Field Assignments - Guidelines for Issuance by Headquarters  (http://www.fda.gov/ora/inspect_ref/fmd/fmd17.htm). 
    5. If, during the course of a clinical investigator or sponsor-investigator inspection, field personnel identify an institutional review board (IRB) that has never been inspected or has not been inspected within the past 5 years, the field investigator may request that the Center issue an inspection assignment for that IRB. All headquarters and field personnel who become aware of complaints or problems related to a clinical investigator or sponsor-investigator are encouraged to refer the name(s) to the appropriate Center with a recommendation for inspection. 
    6. All recommendations should include the following:
      • The name and address of the clinical investigator or sponsor-investigator;
      • 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.
  3. Communication between Centers and Districts

    Inspectional observations documenting that a clinical investigator is not operating in compliance with regulations governing the conduct of clinical trials 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 field investigator and the Center be established early and maintained throughout the entire process, i.e., until post-inspectional correspondence is issued by the Center.
    1. Prior to an Inspection

      • The Center issues an assignment (B. 2. above) 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 information that may change the focus of the inspection;
        • To coordinate inspection arrangements if Center personnel plan to participate in the inspection.
      • Special Considerations

      In particular case, the Center may arrange for a consultative teleconference immediately prior to the inspection(s) if, for example, the complexity of the product or study, data concerns, urgency of feedback, compliance history, etc., trigger the need to discuss issues further.  Such conference calls are most likely when the agency is reviewing Biologic License Applications (BLAs), New Drug Applications (NDAs), Premarket Approval Applications (PMAs), or New Animal Drug Applications (NADAs), for novel or complex products, or in “for cause” inspections where pertinent information is either complex or needs discussion between the Center and the field.  The assignment will usually state that this teleconference will occur, unless information necessitating this discussion emerges after the assignment is issued. 

      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, as appropriate) and other application reviewers as needed; and
      • Field investigator(s) assigned to the inspection(s) and/or the BIMO coordinator (when not yet specifically assigned).  Other district staff may also participate.
    2. 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 he:
        • 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 going on.
        • Uncovers other evidence of concern warranting discussion with Center staff.
    3. After an Inspection
      • Within 3 business days of concluding the inspection, the field investigator forwards to the BIMO reviewer (by facsimile, e-mail, or placement in the appropriate shared drive folder) any 483 that is issued. 
      • The field investigator forwards as soon as possible to the BIMO reviewer a copy of any response to the 483 by the inspected party.  The BIMO reviewer forwards to the field investigator, a copy of any response to a 483 that does not appear to have been shared with the inspecting district.
      • The BIMO reviewer consults with the field investigator as needed when reviewing the EIR.
      • The Center consults with appropriate District personnel if contemplating an EIR classification different from the one recommended by the District.
      • 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.
  4. Responsibilities of Field Investigators, Inspection Team Leaders, and    Headquarters Participants

    1. 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 (e.g., deadline imposed for review of the application by the Prescription Drug/Animal Drug/Medical Device User Fee Act);
      • Communicating inspectional issues and observations with the clinical investigator and the study staff during the course of the inspection, as appropriate;
      • Communicating inspectional observations and issues with the Center contact, as directed in the assignment memorandum;
      • Preparing, issuing, and discussing the items listed on the 483; and
      • Participating in discussions with the Center regarding potential changes in the EIR classification.

    2. Inspection Team Leader

      When inspections are conducted by a team, a field investigator serves as inspection Team Leader and 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; http://www.fda.gov/ora/inspect_ref/iom/default.htm), Team Inspections):

      • Scheduling and coordinating the participation of team members;
      • Discussing inspection plans and objectives with team members;
      • Setting team policy regarding communications with the clinical investigator or study staff;
      • Assuring that team members understand their roles in conducting the inspection, taking notes, collecting documentation, preparing sections of the inspection report and exhibits, and signing the report;
      • 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 FDA 483.

    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:

    • Identifying specific objectives to be covered by the inspection;
    • Providing information pertinent to the inspection;
    • Contacting the Office of Regional Operations (ORO) to request permission to participate in field inspections; and
    • Obtaining inspection credentials from the Division of Field Investigations (DFI, HFC-130);
    • Attending pre-inspection conferences if and when scheduled;
    • Participating in the on-site inspection as permitted by agency priorities; and
    • Providing guidance and expertise during the inspection, and preparing specific sections of the inspection report within timeframes established by the Team Leader.

  5. 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 DFI (HFC-130).
  6. Inspections of facilities under the jurisdiction of the Veteran’s Administration (VA)

    a. Pre-Inspection

    Center.  The assigning Center will provide the VA Project Officer with written notification of FDA’s intention to inspect a clinical investigator at a VA facility at the time an assignment is being issued to the field, per the terms of FDA/VA Memorandum of Understanding (MOU) FDA-225-82-8400  (http://www.fda.gov/oc/mous/domestic/225-82-8400.html).

    This notice should be sent to:

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

    Field. The field investigator should contact the VA Medical Center Director before an inspection of a clinical investigator or sponsor-investigator at a VA facility.  For inspections of military installations, the field investigator should contact the Chief of Professional Services at the facility to be inspected


    b. Post-Inspection.

    The Center contacts are authorized to provide redacted copies of post-inspection correspondence issued to VA facilities or employees following any BIMO inspection (including the FDA-483s).4 Such materials should be sent to:

    Chief Officer
    Veterans Health Administration
    Department of Veterans Affairs
    Office of Research Oversight
    811 Vermont Avenue, N.W.
    Suite 574 (10R)
    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 should be obtained from the district office and provided to VA-ORO.

Centers should contact the Director, Division of Compliance Policy, Office of Enforcement (HFC-230) for detailed instructions for such disclosures and key contact information. (This activity is subject to 21 CFR 5.23(a)(4), 20.85, and supported by FDA’s continuing MOU with the VA (FDA-225-07-4300, (http://www.fda.gov/oc/mous/domestic/225-07-4300.html), which provides for the exchange of information between the two agencies.).
 

121 CFR 312.3, 21 CFR 812.3(i)

221 CFR 312.3; 21 CFR 812.3(o)

3A sampling plan provides instructions about the amount of data or number of documents to be reviewed, and how to select specific records for this purpose. Generally, a sampling plan will identify the minimum number of subjects’ records (relative to the total number of subjects in the study) to be reviewed in order to provide a reasonable level of confidence that any problems at the site would be found (i.e., have a high probability of being detected).

4This authorization, has been renewed every two years, and  currently extends to November 28, 2009.