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AIP Procedures

1-1-1 Background

This section provides procedures for Food and Drug Administration (FDA) employees to carry out the Agency policy commonly known as the Application Integrity Policy (AIP). The policy focuses on the integrity of data and information in applications submitted for Agency review and approval. On September 10, 1991, the FDA published the Notice of this policy formally entitled, "Fraud, Untrue Statements of Material Facts, Bribery, and Illegal Gratuities; Final Policy" (Federal Register, 56 FR 46191). The AIP described the Agency's approach regarding the review of applications that may be affected by wrongful acts that raise significant questions regarding data reliability. FDA published the Federal Register (FR) Notice and a companion document, "Points to Consider for Internal Reviews and Corrective Action Operating Plans," in Compliance Policy Guide (CPG) 7150.09 (see Sec. 120.100 of the Compliance Policy Guides publication).

1-1-2 Purpose

The purpose of this section is to:

  1. provide clear and consistent instruction to FDA staff on the elements of the AIP, particularly, the deferral of scientific review. AIP decisions and the criteria on which they are based should not be arbitrary or vary dramatically from Center to Center;
  2. stress the importance of consistent application of the procedures set out in this section, FR Notice, CPG 7150.09, and the Center policy or procedure statements to carry out the policy, and
  3. emphasize the importance of following up on observations or concerns about the integrity of the applicant or its application. The Center makes the AIP decision based upon input from the Office of Compliance (OC), the Center's reviewing unit, the Field office or Center investigating unit, and, as appropriate, other parts of the Agency.

Although this guidance document does not create or confer any rights for or on any person and does not operate to bind FDA or the public, it does represent the Agency's current thinking on consistent implementation of the AIP.

This section is intended to supplement any Center policy or procedure statement on the AIP. This section is effective immediately.

1-1-3 Definitions

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  1. Applicant. The term "applicant" includes any person within the meaning of section 201(e) of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321(e)) who submits to FDA data or other information to influence or support an agency decision regarding approval [or clearance] to market an FDA-regulated product. Actions by an applicant's employees or agents are considered actions by the applicant.(56 FR 46191, at 46199).
  2. Application Integrity Policy Committee (AIP-C). The AIP-C is an Agency committee comprised of members, one of whom is a chairperson, from each Center, and the Office of Regulatory Affairs (ORA). The Office of Chief Counsel (OCC) advises on legal matters. Each member is known as an "AIP contact person" The purpose of the AIP-C is to meet regularly to discuss the AIP, including consistent implementation. The AIP-C prepared this section.
  3. Application. The term "application" includes "any application, petition, amendment, supplement, or other submission made by an applicant to an agency review process in support of the approval or marketing of a regulated product.... References to data in an application include all data and other information submitted in or in relation to, or incorporated by reference in the application." (56 FR 46191, at 46199). For purposes of this section, an application includes any submission of any type to the Agency, such as pending and approved applications or petitions, amendments, supplements, supplemental amendments, premarket notifications (510k's), annual reports, investigational new drug applications (IND's), investigational new animal drug applications (INAD's), and investigational device exemption applications (IDE's) upon which the application is based. An application also includes a drug, device, or food master file, correspondence, and any submission by any person to support the approval or marketing of a regulated product.
  4. Corrective action operating plan (CAP). The "corrective action operating plan" (CAP) is the applicant's written operating plan that describes its commitment, procedures, actions, and controls to ensure data integrity. The CAP should include, but not be limited to, an explanation of the circumstances surrounding the conduct of the wrongful act, information set out in the section below, "REVOKING THE AIP AS IT APPLIES TO A FIRM'S APPLICATIONS," CPG 7150.09, and the "Corrective Actions" section of the AIP (56 FR 46191, at 46200).
  5. Deferral of scientific review. The term "deferral of scientific review" indicates that the Center's review unit will not expend scientific review resources on an application until the Center is satisfied that the data or information in the application is reliable.
  6. Pattern or practice. The term "pattern" means more than one instance of errors or acts involving subject matter important to the evaluation of an application. The term "practice" means an act or process of doing something affecting subject matter important to the evaluation of an application. A practice can be one or more acts or processes. A pattern or practice can occur in one or more applications.
  7. Untrue statement of material fact. An "untrue statement of material fact" is a false statement, misstatement, or omission of a fact. A determination that an untrue statement is material is necessary for purposes of invoking the AIP. The Center should make a written determination. This determination may involve discussions with OCC.
  8. Validity assessment. The AIP and its accompanying preamble in the Federal Register Notice (56 FR 46191) frequently refer to the validity assessment. That term "validity assessment" includes the Agency's determination of the scope and extent of an applicant's suspected wrongful acts, an Agency inspection of the firm, and an Agency review of the applicant's audit. The Agency may assess the validity of any applications called into question by the wrongful acts, in addition to those directly affected. An Agency inspection may be initiated before scientific review of an application is deferred.
  9. Wrongful act. A wrongful act is any act that may subvert the integrity of the review process. 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. A wrongful act may be evidenced in a document, including informal documents such as correspondence or memoranda, or verbally, such as in telephone conversations or in one-on-one meetings. Regardless of the means, each suspected incident of a wrongful act should be reported and investigated to determine whether they raise significant questions regarding data integrity and reliability with respect to a regulated product. (See 56 FR 46191, at 46192).
  10. Invoking AIP. The phrase "invoking AIP" as used in this section means that the Agency will apply the Application Integrity Policy to one or more applications by deferring substantive scientific review pending a validity assessment of data and information in all of the affected applications.
  11. Revoking AIP. The phrase "revoking AIP" as used in this section means that the Agency will resume substantive scientific review of all of an applicant’s pending applications that have been subject to the Application Integrity Policy.

1-1-4 Education Program

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The Agency has taken the steps outlined below to ensure that its employees are aware of the AIP, and that those employees who are responsible for carrying out the AIP (see "RESPONSIBILITIES OF AGENCY PERSONNEL" below) do so in a complete and consistent manner:

  1. The FDA Orientation Program for new employees will contain a written introduction to the AIP.
  2. The Director, Office of Enforcement, Office of Regulatory Affairs, and the Director, Division of Ethics and Program Integrity, issued a joint memorandum dated June 4, 1997, to Agency employees describing the AIP.
  3. The AIP-C is committed to identifying methods to educate Agency staff about the AIP. Each AIP contact person ensures that his or her Center or Office has a procedure for distributing information about the AIP.
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