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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 V - Regulatory/Administrative Strategy

  1. ADMINISTRATIVE GUIDANCE
    1. District EIR Classification Authority

      The District must follow the procedures for assigning District Office inspection conclusions and decisions to an Establishment Inspection Report (EIR) within established timeframes as defined in Field Management Directive, Establishment Inspection Report Conclusions and Decisions (FMD #86).

    2. Center EIR Classification Authority

      The Center has final classification authority for all EIRs generated under this compliance program. If the Center is considering a classification that differs from the District’s recommended classification, the Center will contact the District to discuss the issues as soon as possible to avoid delays in the final classification process. In addition, the Center will provide the District with notice of all final classifications, including the rationale for any that differ from the District’s initial classification.

    3. EIR Classifications

      The following guidance is to be used in conjunction with the instructions in FMD-86 for initial District and Center classification of EIRs generated under this Compliance Program:

      1. NAI - No Action Indicated -- No objectionable conditions or practices were found during an inspection (or the objectionable conditions found do not justify further regulatory action);
      2. VAI - Voluntary Action Indicated -- Objectionable conditions or practices were found, but the agency is not prepared to take or recommend any administrative or regulatory action; and
      3. OAI - Official Action Indicated – Regulatory and/or administrative actions will be recommended.
    4. Administrative/Civil/Criminal Actions will be in accordance with 21 CFR Parts 50, 56, 312, and 812. FDA can invoke other legal sanctions under the FD&C Act and/or Title 18, USC, where appropriate.
      1. Administrative Actions for noncompliance -- If apparent noncompliance with FDA regulations (21 CFR 56.120), the FDA can move forward with the following regulatory actions:
        • Untitled Letters
        • Warning Letters
        • Reinspect to verify corrective actions
        • Regulatory meetings
        • Withhold approval of new studies that are conducted at the institution or reviewed by the IRB
        • Direct that no new subjects may be recruited for ongoing studies
        • Terminate ongoing studies
        • Refer pertinent matters, with headquarters concurrence, to other Federal, State, or local agencies for such action as that agency deems appropriate
      2. Disqualification of an IRB or institution (21 CFR 56.121)

        If an IRB or the institution has failed to take adequate steps to correct the noncompliance stated in the letter sent by the agency under 21 CFR 56.120(a), FDA may institute proceedings in accordance with the requirements for a regulatory hearing set forth in Part 16 (21 CFR 56.121(a)).

        Disqualifications may occur if:

        • the IRB has refused or repeatedly failed to comply with any of the regulations set forth in 21 CFR Part 56 (21 CFR 56.121(b)(1)), and
        • the noncompliance adversely affects the rights or welfare of the human subjects in a clinical investigation (21 CFR 56.121(b)(2)).

        FDA will issue an order that explains the basis for the determination and will send a notice of disqualification to the IRB or institution. FDA will not approve an application for a research permit for a clinical investigation that is to be under the review of a disqualified IRB or that is to be conducted at a disqualified institution, and may refuse to consider in support of a marketing permit the data from a clinical investigation that was reviewed by a disqualifized IRB.

    5. Communications

      The District should promptly inform Headquarters/Centers about any written or oral communication from the institution following the inspection. Similarly, Headquarters/Centers should promptly inform the District of communication (including any written correspondence) with the institution following the inspection, including any judicial/administrative actions. Copies of any written communications should be shared.

  2. REGUATORY GUIDANCE

    The following criteria are relevant to FDA’s classification of inspections of IRBs:

    1. No Action Indicated (NAI)

      No objectionable conditions or practices (e.g., violations of 21 CFR Parts 50, 56, 312, and 812) were found during the inspection, or the significance of the documented objectionable conditions found does not justify further FDA action.

      Any post-inspectional correspondence acknowledges the IRB’s basic compliance with pertinent regulations.

    2. Voluntary Action Indicated (VAI)

      Objectionable conditions were found and documented, but the Center is not prepared to take or recommend any further regulatory (advisory, administrative, or judicial) action because the objectionable conditions do not meet the threshold for regulatory action (i.e., regulatory violations uncovered during the inspection are few and do not seriously impact subject safety or data integrity).

      Post-inspectional correspondence may identify the issues and, when needed, state that FDA expects prompt, voluntary corrective action by the IRB.

    3. Official Action Indicated (OAI)

      An OAI recommendation is appropriate when regulatory violation(s) uncovered is/are significant/serious and/or numerous, and the scope, severity, or pattern of violations(s) support a finding that:

      Subjects participating in studies approved by the IRB would be or have been exposed to an unreasonable and significant risk of illness or injury; or

      Subjects’ rights would be or have been seriously compromised; or

      Data integrity or reliability is or has been compromised.

      Once an OAI decision is reached, additional information (e.g., previous inspectional findings, correspondence, or other information about the IRB) may assist the Center in determining the type of post-inspectional correspondence that is appropriate. If the Center chooses to issue a Warning Letter and allow the IRB to submit a detailed corrective action plan or alternate approach that is acceptable to FDA, the Center should nevertheless be prepared to initiate disqualification proceedings should the IRB not respond appropriately (i.e., fails to respond, fails to develop an adequate corrective action plan, or is found, during a subsequent inspection, to have failed to comply with a corrective action plan).

      A Warning Letter may be considered when the violations can be corrected through specific action(s) by the IRB (e.g., preparation of, and compliance with, a detailed corrective action plan, that is acceptable to FDA) and adherence to the corrective action plan has a high probability of preventing similar or other violations from occurring in the future.

    EXAMPLES:

    The following are examples of violations that, alone or in combination, would be considered significant and may warrant an OAI classification. This list is not all inclusive; other circumstances may also merit an OAI classification.

    When applying the classification criteria, Center reviewers will generally evaluate the impact of the IRB’s actions (number, scope, and severity of the regulatory violations) on subjects’ rights, safety and welfare. There are gradations in the severity of each example, and the specific observation(s) should support the seriousness of the violation(s) and the effect(s) on subjects’ safety and welfare and/or the reliability and acceptability of data for FDA decision-making purposes. The Center should also consider whether FDA has cited the IRB for the same or similar violations during a previous inspection.

    Inadequate Human Subject Protection

    Violation/Related Citation

    Examples

    Failure of the IRB to register with OHRP
    (http://ohrp.cit.nih.gov/efile)

    21 CFR 56.106

    IRB is not registered on OHRP’s Registration Web site.

    The initial IRB registration must occur before the IRB begins to review clinical investigations and must be updated as required by the regulation.

     

    Failure to conform to membership criteria listed in 21 CFR 56.107

     

     

     

     

    • IRB has fewer than 5 members
    • IRB fails to have an unaffiliated member OR at least one member whose primary concerns are scientific OR at least one member whose primary concerns are non-scientific
    • IRB is composed entirely of one sex or members of one profession
    • Conflicted member votes on his/her own study
    • Invited consultant votes on study

     

    Failure to conform to meeting participation criteria as listed in 21 CFR 56.107(e)

    • IRB has a member participate in the IRB’s initial and continuing review of a project in which the member has a conflicting interest

    Failure to follow written procedures

    21 CFR 56.108(a)

    IRB does not follow written procedures that state the IRB will conduct continuing review at least annually. For example, if a clinical investigator failed to submit a periodic report, the IRB did not detect the omission. 

    Failure to have minutes of IRB meetings in sufficient detail to show attendance at the meetings

    21 CFR 56.115(a)(2)

     

    IRB records of meetings (e.g., minutes) are missing or do not have sufficient detail to show who attended, actions taken, and the votes, including the number of members for and against, and abstentions.
    Note: Please contact the BIMO reviewer for clarification on the frequency of the missing minutes to warrant an OAI classification.

    Failure to have records of continuing review activities

    21 CFR 56.115(a)(3)

    Records of continuing review activities are missing or incomplete.
    Note: Please contact the BIMO reviewer for clarification on the frequency of the missing or incomplete records to warrant an OAI classification.

    Failure to make a risk determination regarding an investigation presented for approval as NSR

    21 CFR 812.66

    The IRB failed to determine whether an investigation presented for approval as NSR is a SR or NSR study.

    Failure to determine that the research study is in compliance with 21 CFR Part 50 Subpart D when some or all of the subjects in a study are children

    21 CFR 56.109(h)

    The IRB failed to determine at the time of initial review that studies involving children were in compliance with 21 CFR Part 50 Subpart D --  “Additional Safeguards for Children in Clinical Trials”

    Failure to conduct continuing review of research at intervals appropriate to the degree of risk

    21 CFR 56.109(f)

    The IRB failed to conduct continuing review of research at intervals of not less than once per year

    Failure to evaluate that all conditions for exception of informed consent and requirements for emergency research were satisfied.

    21 CFR 50.24

    The IRB failed to determine and document that:

    • The human subjects were in a life-threatening situation that necessitated urgent intervention
    • Available treatments were unproven or unsatisfactory
    • Collection of valid scientific evidence was necessary to determine the safety and effectiveness of the intervention
    • Informed consent was not feasible
    • Participation in research held out the prospect of direct benefit to the subjects
    • The clinical investigation could not practicably be carried out without a waiver
    • The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a LAR for each subject within that window of time and, if feasible, to asking the LAR contacted for consent within that window rather than proceeding without consent
    • The IRB has reviewed and approved informed consent procedures and an informed consent document consistent with 50.25
    • Additional protections of the rights and welfare of the subjects will be provided  (e.g., community consultation and public disclosure)
  3. FOLLOW-UP INSPECTIONS
    1. Centers should evaluate whether the violations found indicate systemic problems with the conduct of the study or the reliability of the data and whether additional inspection assignments should be issued (e.g., sponsor, CRO, monitor, clinical investigator(s)).
    2. Following issuance of a Warning Letter, Centers should schedule a follow-up inspection to verify if the IRB is fulfilling the terms of any corrective action plan and is in compliance with applicable regulations. Such follow-up inspections should take place within one year after the date of the last Warning Letter correspondence, depending on the nature of the violations.
  4. POST-INSPECTION INFORMATION SHARING

    Per the September 07, 2010, agreement between the Department of Veterans Affairs (VA) and the FDA Office of Regulatory Affairs (ORA) and upon the written request by the Office of Research Oversight, VA, the Center contacts are authorized to provide to the Office of Research Oversight, VA, and its staff, redacted copies of FDA-reviewed EIRs and any post-inspection correspondence issued to VA facilities or employees following any inspection (including the 483s).

    Post inspection documents 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
     

    Responses are subject to FDA priority and available resources, and are pursuant to ORA, VA’s June 18, 2010, non-disclosure agreement.