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Bioresearch Monitoring Agreement for PMAs and PDPs
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February 23, 1998
Director
Office of Device Evaluation (HFZ400)
Bioresearch Monitoring Agreement for
PMAs and PDPs
ODE Review Staff
Purpose
The purpose of this interoffice agreement
is to provide guidance to the Office of Device Evaluation (ODE)
and the Office of Compliance, Division of Bioresearch Monitoring
(DBM) staff, regarding bioresearch monitoring inspections in the
routine evaluation of premarket approval (PMA) applications and
product development protocols (PDP). This agreement outlines
the responsibilities of the PMA Staff, ODE reviewers and managers
and the Office of Compliance, Division of Bioresearch Monitoring,
for these programs.
Agreement
The full agreement on PMA/PDP bioresearch
monitoring is embodied in the Attachment. It sets forth the respective
responsibilities of the Office of Device Evaluation and the Office
of Compliance.
Effective Date
This guidance is effective immediately.
Susan Alpert, Ph.D., M.D. |
PMA Guidance Menorandum #P98-1
Purpose
The purpose of this interoffice agreement is to provide guidance
to the Office of Device Evaluation (ODE) and Division of Bioresearch
Monitoring (DBM) staff regarding bioresearch monitoring audits
in the routine evaluation of premarket approval (PMA) applications.
This agreement outlines each office's responsibility for the
PMA/DBM programs. Specifically it outlines the responsibilities
of the PMA Staff, ODE reviewers and managers and the DBM within
the Office of Compliance (OC). The bioresearch monitoring inspectional
process is separate and distinct from the pre-approval manufacturing
facility inspection process associated with the Quality System
Regulation (21 CFR Part 820). The manufacturing facility inspection
was the subject of Blue Book Memorandum #P91-3.
A detailed discussion of the bioresearch monitoring process is
provided in Attachment A and is also available on the Internet
at http://www.fda.gov/cdrh/comp/bimo.html.
Agreement
It is important for all ODE managers and reviewers to understand
the impact that the bioresearch monitoring program has on the
PMA and PDP evaluation process. The following ODE/DBM agreement
outlines the respective roles of the ODE and DBM staff in routinely
assuring the integrity of the data in PMA applications.
This agreement does not cover issues, policies and procedures
that arise under the Application Integrity Policy (AIP), which
is the subject of Blue Book Memorandum #I91-2, Integrity of
Data and Information Submitted to ODE. The AIP includes the
evaluation of potential fraud, untrue statements of material facts,
bribery and illegal gratuities.
The validity of the clinical data submitted in PMAs and PDPs through
routine onsite data audits must be assured through the bioresearch
monitoring process. Responsibilities under this agreement are
as follows:
In cases where CDRH grants expedited review status during the
IDE phase, the responsible ODE review division will promptly provide
a copy of the expedited review decision letter to the PMA Staff
and DBM. Early and frequent interaction between ODE and DBM
is critical to identify appropriate sites for inspection and validation
of the submission's clinical data and information. DBM will develop,
schedule, or assess the results of these inspections prior to
the submission of the expedited review PMA application, whenever
possible.
Because of resource limitations, DBM may not complete the inspectional
process by the time ODE is prepared to issue a final decision
letter. If this occurs, the ODE will consider any available bioresearch
monitoring information in its final decision on a PMA, PDP, or
panel-track supplement.
If ODE has completed the review, but the bioresearch monitoring
audit has revealed a serious problem which impacts on the evaluation
of the safety and effectiveness of the device, ODE will delay
the final decision until the problem is resolved.
The DBM will provide the Summary of Findings memo to ODE for inclusion in the PMA or PDP administrative record at least 5 days prior to ODE's final decision whenever possible. This will ensure that ODE properly considers all the DBM inspectional findings prior to the final decision.
If you have questions regarding any aspects of the interoffice
agreement or how the agreement will impact upon the applications
in your division, please contact the PMA Staff at (301) 594-2186.
Any questions from the regulated industry regarding the PMA bioresearch
monitoring program other than questions relating to ODE procedures
and responsibilities, should be referred to DBM at (301) 594-4718.
Effective Date
This policy is effective immediately.
_____________________________ | _____________________________ | |
Susan Alpert, Ph.D., MD | Lillian J. Gill | |
Director | Director | |
Office of Device Evaluation | Office of Compliance |
Attachment A
What is the Bioresearch Monitoring Program?
INTRODUCTION
The Food and Drug Administration's (FDA) bioresearch monitoring program was established in 1977 by a task force which included representatives from the drug, biologics, medical device, veterinary medicine, and food areas. The need for such a program was evident in a survey of the conduct of studies involving FDA-regulated products by the FDA field inspection operation between 1972 and 1974. Following a review of the inspectional findings, the Congress mandated that FDA develop and implement an agency-wide program.
The bioresearch monitoring program at the Center for Devices and
Radiological Health (CDRH) was expanded in June 1992. In May
1993 the Bioresearch Monitoring Branch became the Division of
Bioresearch Monitoring in the reorganization of the Office of
Compliance. The Division of Bioresearch Monitoring is responsible
for monitoring sponsors, institutional review boards, clinical
investigators, and nonclinical laboratories involved in the testing
of investigational devices.
PROGRAM OBJECTIVES
The objectives of the bioresearch monitoring program are twofold:
(1) 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 (2)
to ensure that human subjects taking part in investigations are
protected from undue hazard or risk. DBM 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.
PROGRAM FUNCTIONS
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 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 also reviewed. If the
advertisements or articles deviate from the requirements set forth
in 21 CFR 812.7 (Prohibition of promotion and other practices),
DBM 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:
21 CFR 812 -Investigational Device Exemptions
21 CFR 50 - Protection of Human Subjects
21 CFR 56 - Institutional Review Boards
21 CFR 58 - Good Laboratory Practice for Nonclinical Laboratory
Studies
INSPECTION PROGRAMS
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 non-clinical 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 DBM.
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, DBM 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. 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.
For additional information about the bioresearch monitoring program
in CDRH, contact:
Charma A. Konnor, R.Ph., Director
Division of Bioresearch Monitoring (HFZ-310)
Office of Compliance
Center for Devices and Radiological Health
2094 Gaither Road Rockville, Maryland 20850
Telephone (301) 594-4718
Updated 3/11/1998
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