The objectives of the bioresearch monitoring program are twofold: (I) to ensure the quality and integrity of data and information submitted in support of investigational and marketing clearance applications or submissions [IDEs, PMAs, and 510(k)s]; and (ii) to ensure that human subjects taking part in investigations are protected from undue hazard or risk. The Division is also charged with the implementation of the FDA's Application Integrity Policy (AIP) for medical devices and radiological health products.
The program objectives are achieved by several means which are discussed in the program functions and inspection program sections below.
The Division of Bioresearch Monitoring's (DBM) operations are directed toward several program areas. These include (1) audits of clinical data contained in PMA and some 510(k) submissions, ordinarily prior to approval; (2) audits of IDE sponsor submissions; (3) inspections of nonclinical laboratories that perform medical device-related safety testing; (4) inspections of Institutional Review Boards that monitor investigational device studies; (5) enforcement of the prohibition against commercialization of investigational devices; (6) providing education, training and guidance to regulated industry and (7) implementation of the FDA's Application Integrity Policy (AIP). Descriptions of some of these activities are summarized below:
- PMA data audits are conducted through comprehensive on-site inspections by FDA field office staff. Source data generated and collected by clinical investigators are compared with the data and information submitted by the sponsor to FDA in support of such applications. These audits help to ensure the quality and integrity of the information used by the FDA to render safety and effectiveness decisions. Additionally, FDA field staff review the appropriate records to ensure protection of the rights and welfare of the clinical research subjects participating in these studies. Where clinical data exists in 510(k) submissions, assignments may be issued requesting audits of that data.
- When indicated, inspections of clinical investigators participating in IDE studies are conducted.
- Good Laboratory Practice (GLP) inspections are undertaken to investigate compliance with regulations promulgated under 21 CFR Part 58, Good Laboratory Practice for Nonclinical Laboratory Studies. Compliance with these regulations is intended to ensure the quality and integrity of safety data obtained from animal studies submitted to FDA.
- Surveillance information received from district offices, the public, the industry, and other sources related to commercialization or promotion of investigational devices is reviewed. If the advertisements or articles deviate from the requirements set forth in 21 CFR 812.7 (Prohibition of promotion and other practices), the Division follows up by means of a letter to the promoter or a request for inspection of the responsible party.
- Implementation of the FDA's Application Integrity Policy involves investigations of sponsors that are suspected of submitting false or misleading data to the FDA. It also includes the review, evaluation, and monitoring of validity assessments required to be completed by sponsors found guilty of fraudulent activities.
The regulations enforced by the bioresearch monitoring program for medical devices are found in four sections of the CFR:
FDA's inspection programs include two types of assignments: routine inspections and directed inspections (sometimes termed "for cause"). The routine assignments include inspections of clinical investigators, sponsors, IRBs, or nonclinical laboratories that are randomly selected for coverage under one of four compliance programs. These assignments are issued to monitor adherence to FDA regulations.
A directed inspection is requested when some specific problem has been identified within one or all entities of the program. The problem may be observed during the review of sponsor submissions related to ongoing IDE investigations or following evaluation of clinical data submitted in a PMA or 510(k) application. Verbal or written complaints from patients, physicians, or competitors may also result in a directed inspection. Inspections issued for PMA data audits also fall into this category.
Deviations revealed during inspections are presented in writing and discussed with the responsible individual at the close of the inspection. Once an inspection has been completed, an establishment inspection report (EIR) is prepared and submitted by the district office. This report is then reviewed and classified by the Division of Bioresearch Monitoring.
Classifications assigned to inspections indicate whether or not the establishment is operating in compliance with the regulations. The classification scheme used by FDA is as follows:
NAI - No Action Indicated
VAI - Voluntary Action Indicated
OAI - Official Action Indicated
Depending upon the assigned classification, the Division may issue an untitled letter or warning letter based upon the severity of the deviations. These letters are intended to communicate the FDA's position on a matter, but do not commit the FDA to take further enforcement action. They are issued for the purpose of achieving voluntary compliance with the expectation that a majority of firms and individuals will comply with the regulations and implement corrective actions to prevent recurrence of the deviations.
When deviations are flagrant or significantly impact the quality and/or integrity of the research data, various actions have been used by the Division to achieve compliance in the bioresearch monitoring program area. Data audits have resulted in the Division's recommendation to invoke the Application Integrity Policy against the sponsor or reject clinical research data used to support a PMA. Data audits for 510(k)s that disclosed improprieties have led the sponsor to withdraw submissions. Monitoring efforts of IDE studies have led to the Division's recommendation for withdrawal of IDEs. Inspections of violative IRBs have resulted in administrative sanctions that suspend the institution's authority to approve new studies and/or add new subjects to existing studies.