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AIP Procedures

1-1-6 Administrative Considerations

  1. Communication among the Agency's Offices involved in decision-making about AIP issues should be open, clear, accurate, complete, and prompt.
  2. Managers of Offices routinely involved in AIP decision-making should develop and document procedures for delegating authority for these decisions.
  3. The time it takes to investigate the issues on which decisions are based will vary. To reach AIP decisions in a timely manner, managers involved in AIP decision-making should:
    1. assign AIP-related responsibilities to Agency personnel in a manner that promotes timely decisions that are consistent and of high quality;
    2. establish processes to monitor the progress of activities related to AIP decisions; and,
    3. expedite the flow of AIP-related documents and information.
  4. Each Center should establish a procedure to maintain a file system to contain the facts, circumstances, and rationale to support its AIP decision. Examples of other documentation include the memorandum from the district office (see "REVOKING THE AIP AS IT APPLIES TO A FIRM'S APPLICATIONS," item 4), and the supporting summary and analysis. Documentation serves the following two purposes:
    1. it becomes part of an administrative record; and,
    2. it provides carefully developed criteria that should be applied in subsequent cases with similar facts. The reasons for deviations from such precedent should be consistent both with the AIP and with prior instances of deviation, if any. Consider consulting the AIP-C or the OCC before finalizing the decision to deviate from precedent.

GENERAL CONSIDERATIONS BEFORE A CENTER INVOKES THE AIP

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Generally, the procedure set out below should be followed when the Agency suspects an applicant of committing wrongful acts that raise significant questions about data integrity.

  1. No application, during or after investigation, should be approved or cleared if the data are unreliable, or there are data integrity, safety, or efficacy concerns, until the Center is satisfied that the issues in question are resolved, or, (if the AIP is invoked) an exception to deferral of scientific review is granted
  2. After suspected wrongful acts come to the Agency's attention, the Field Office/ investigating unit should investigate to determine the scope and extent of the wrongful acts.

INVOKING THE AIP

  1. Generally, there should be evidence of a pattern or practice of wrongful conduct that raises a significant question about the reliability of data in an AIP application before the Center defers scientific review and invokes the validity assessment process under the AIP. When invoked, the AIP may cover one, some, or all the applications, including all applications from one or more facilities, that are affected, either directly or indirectly, by the wrongful acts that raise significant questions regarding reliability.

    A wrongful act includes, but is not limited to, submitting a fraudulent application, offering or promising a bribe or illegal gratuity, or making an untrue statement of material fact. A wrongful act also includes submitting data that are otherwise unreliable due to, for example, a pattern of errors whether caused by incompetence, negligence, or a practice such as inadequate standard operating procedures or a system-wide failure to ensure the integrity of data submissions. Usually, when the AIP is invoked, there are two or more applications affected.
  2. When the criteria in item 1 are met, the Center should be guided by the information set out below when deciding whether and to what extent to invoke the AIP.
    1. The Center should invoke the AIP on all of a firm's applications affected by a wrongful act, that is, whenever the wrongful act raises a significant question regarding the reliability of data in those applications. A wrongful act is any act that may subvert the integrity of the review process.
    2. When the pattern or practice of wrongful acts raises a significant question regarding the reliability of data in only a single application, the Center should continue to resolve the data integrity issues of that application through the review process (e.g., denial or withdrawal of approval). The Center need not invoke the AIP, as to that single application, unless the review process is inadequate to deal with the data integrity issues raised by the wrongful act. Generally, the review process alone is inadequate to deal with a single application when, for example, the firm's problems are either:
      1. system-wide, such as failure to have and implement:
        1. systems or procedures to ensure the quality and accuracy of submissions,
        2. standard operating procedures (SOP's) that will ensure compliance with the regulations or relevant court decisions, or otherwise ensure the integrity of the data; or,
      2. firm-wide, such as evidence that the firm's personnel are inadequately trained, perform work incompetently, repeatedly fail to follow the firm's SOP's, or are untrustworthy as it relates to the application or the approval process.

        These are examples of problems that undermine the Agency's confidence in the integrity of any application submitted by the applicant. As it relates to a single application, AIP, along with the review process, is better suited than review of the application alone, to address these types of data integrity problems.
    3. A Center may decide that the questions raised about the reliability of data in a single application can be resolved through the review process without invoking the AIP because the criteria in item 2.B. have not been met (also see "GENERAL CONSIDERATIONS BEFORE THE CENTER INVOKES THE AIP"). Such a decision does not preclude the Center from invoking an AIP action if the Center finds additional or new evidence that meets the criteria set forth in item 2.B., or if the firm submits other applications and the Center concludes that the wrongful conduct raises a significant question regarding the reliability of such data.
    4. A determination that an untrue statement (false statement, misstatement, or an omission) is material is necessary for purposes of invoking the AIP. The Center should make a written determination. This determination may involve discussions with OCC.
    5. A court order after either a civil finding of fact or a criminal conviction, each about a wrongful act related to the approval process, may be the basis for invoking the AIP. However, before the Center invokes the AIP, a determination about the extent to which the wrongful act affected approved or pending applications must be made.

GRANTING AN EXCEPTION TO DEFERRAL OF SCIENTIFIC REVIEW AFTER THE AIP IS INVOKED

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It may be appropriate to continue or resume substantive scientific review of an application in certain limited circumstances even though the AIP remains in effect as to that application. This situation is referred to as an "exception" to AIP. Generally, review may continue, with appropriate documentation of the reason and written concurrence by management according to Center procedure, for the reasons set out below. A Center may have additional reasons that justify continuing or resuming review.

Submissions for which review may continue or begin after the AIP is invoked.

  1. The Center may continue an ongoing review until a logical stopping point has been reached. However, the Center should not communicate with the firm about deficiencies found during the normal course of review of the application, or about the suspected wrongful acts.
  2. The Center may begin review of, and approve if warranted, the following types of applications with proper management concurrence if necessary (see "Authorization..." below). Document the decisions related to the exception. The Center does not need a firm's written request for an exception to the AIP to continue or begin review of applications in items 2.A. through E.
    1. Applications for products with public health significance. The application is for a product intended or expected to provide a significant scientific break-through (e.g., a product that yields important therapeutic or diagnostic gain), is medically necessary, or is otherwise critically needed. Applications relying upon a sole supplier of the product or where other firms are unable to maintain a sufficient supply of the product may also be considered for an exception.
    2. Applications regarding approved products.
      1. Supplements for class labeling, or changes that enhance the labeling or are protective in nature.
      2. Supplements for changes for post-approval applications that don't require pre-approval, such as "changes being effected " supplements to human drugs applications [21 CFR 314.70(c)]. The review should ensure that the change is fully described and meets regulatory criteria.
      3. Annual reports. The review should ensure that the change is fully described, meets regulatory criteria, and/or that the firm has met application commitments.
      4. Adverse experience/event reports.
    3. A protocol that is not provided as part of an application.
    4. IND's, INAD's or IDE's of the applicant whose applications are subject to AIP unless the wrongful acts raise a significant question regarding data integrity of the IND, INAD, or IDE.
    5. Applications not subject to the AIP even though they reference an application or a device, drug, or food master file subject to AIP. However, these applications should not be approved until the questions raised regarding data integrity in the referenced AIP file or application have been resolved. Generally, the referenced data from an AIP file or application should be replaced or, if used, audited and validated before the Agency considers approval of the non-AIP applicant's application. In some cases, where the applicant intends to rely upon the referenced AIP data, the application should not be approved until the AIP firm has submitted and substantially executed its CAP.
    6. Applications for changes that are required because of international law or federal law (such as the "Clean Air" Act) other than the Food and Drug Administration's, or state law.

Authorization to either begin review or approve the application.

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Each Center should develop and document the process and rationale by which management authorizes the decision to either begin review or approve an application(s) while it is still under the AIP. The procedure, including the level of authority, may vary depending on the type of submission, the significance of the change for which the firm requests review, the basis for granting the exception, or whether evidence of wrongful acts is known to exist in the application.
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