FOOD AND DRUG ADMINISTRATION
COMPLIANCE PROGRAM GUIDANCE MANUAL PROGRAM 7348.811
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DATE OF ISSUANCE 12/08/08 COVER - PAGE 1 of 2
FORM FDA 2438g (electronic-09/2003)
PROGRAM 7348.811
CHAPTER 48- BIORESEARCH MONITORING
CLINICAL INVESTIGATORS AND SPONSOR-INVESTIGATORS
Date of Issuance: December 8, 2008
Guidance for FDA Staff
SUBJECT: Clinical Investigators and Sponsor Investigators
IMPLEMENTATION DATE
December 8, 2008
REVISION: COMPLETION DATE
Continuing
DATA REPORTING
PRODUCT CODES PROGRAM ASSIGNMENT CODES
FACTS does not require product codes for
Bioresearch Monitoring Inspections 09811 Food Additives
41811 Biologics ( Cell; Gene Transfer)
42811 Biologics (Blood)
45811 Biologics (Vaccines)
48811 Human Drugs
68811 Animal Drugs
83811 Medical Devices
FIELD REPORTING REQUIREMENTS:
For domestic inspections, copies of all establishment inspection reports (EIRs), complete with
attachments, exhibits, and any related correspondence are to be submitted promptly to the Center
contact, who is generally the reviewer in the Center’s Bioresearch Monitoring (BIMO) program
identified in the assignment.
For foreign inspections, all original EIRs, complete with attachments, exhibits and any related
correspondence are to be submitted promptly to the Center contact identified in the assignment.
All EIRs should be completed in accordance with FMD No. 86, Establishment Inspection Report (EIR) -
Inspection Conclusions and District Decisions (http://www.fda.gov/ora/inspect_ref/fmd/fmd86.htm).
When a Form FDA 483, “Inspectional Observations” (483), is issued, a copy should be faxed to the
Center contact, generally no later than 3 business days.
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PART I - BACKGROUND
Since the Investigational New Drug (IND) Regulations went into effect in 1963, the Food and Drug
Administration (FDA) has exercised oversight of the conduct of clinical studies involving FDA
regulated products. The BIMO Program was established in 1977 by a task force that included
representatives from the drug, biologic, device, animal drug, and food areas.
Compliance programs (CP) were developed to provide uniform guidance and specific instructions for
inspections of Clinical Investigators (CP 7348.811), Sponsors (CP 7348.810), In-Vivo Bioequivalence
facilities (CP 7348.001), Institutional Review Boards (CP 7348.809), and Non-Clinical Laboratories
(CP 7348.808).
Regulations addressing requirements of clinical investigators, sponsors and monitors (21 CFR Parts 312,
314, 511, and 514) were published on March 19, 1987, and became effective on June 17, 1987.
Regulations for clinical investigations of devices (21 CFR Part 812) became effective January 18, 1980,
and for premarket approval of medical devices (21 CFR Part 814) on July 22, 1986.
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PART II - IMPLEMENTATION
A. OBJECTIVES
The objectives of BIMO Program are:
1. To protect the rights, safety, and welfare of subjects involved in FDA-regulated clinical trials;
2. To verify the accuracy and reliability of clinical trial data submitted to FDA in support of
research or marketing applications; and
3. To assess compliance with FDA's regulations governing the conduct of clinical trials.
The purpose of this compliance program is to provide instructions to the field and Center personnel
for conducting inspections of clinical investigators and sponsor-investigators,and recommending
associated administrative/enforcement actions.
B. PROGRAM MANAGEMENT INSTRUCTIONS
1. Coverage
This program covers domestic and foreign inspections of:
a. Clinical Investigators
A clinical investigator is the individual who actually conducts the clinical investigation.1 The
investigator is responsible for overall conduct of the study at the study site, including directing
the administration or dispensing of the test article to the subject, and ensuring that data are
collected and maintained in accordance with the protocol and regulatory requirements. When
the investigation is conducted by a team of individuals, the clinical investigator is the leader of
the team.
b. Sponsor-Investigators
A sponsor-investigator is an individual who initiates and also conducts the clinical investigation.
A sponsor-investigator must comply with regulatory requirements applicable to both sponsors
and clinical investigators.2 While inspections of sponsor-investigators are assigned under CP
7348.811, CP 7348.810 (Sponsors, Contract Research Organizations and Monitors) should also
be consulted for areas applicable to the sponsor responsibilities of the sponsor-investigator.
1
21 CFR 312.3, 21 CFR 812.3(i)
2
21 CFR 312.3; 21 CFR 812.3(o)
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2. Inspection Assignments
a. Center BIMO units issue inspection assignments of clinical investigator sites.
i. Domestic inspection assignments are issued to the district offices.
ii. International inspections are generally assigned when the studies covered are part of a
marketing application to FDA and provide data critical to decision-making on product
approval. Such assignments may include studies that are conducted under an FDA
application for research (e.g., Investigational New Drug Application [IND],
Investigational Device Exemption [IDE], Investigational New Animal Drug
Application [INAD]), as well as non-U.S. sites or studies that are not conducted under
an FDA application for research. Such assignments are issued to the Division of Field
Investigations (HFC-130).
b. The assignment should identify:
i. The program assignment code (PAC) and Field Accomplishments and Compliance
Tracking System (FACTS) number;
ii. The name, address and phone number of the clinical investigator or sponsor-
investigator, and the study site(s) to be inspected;
iii. The type and purpose of the inspection;
iv. The background materials (e.g., study protocol; tables; sampling plan3 for review of
informed consent documents, case report forms (CRFs) or specific data, if
appropriate) that are being sent from the Center to facilitate the inspection. For
investigational device studies, the Center should identify the type of study (e.g.,
significant risk (IDE), non-significant risk (abbreviated requirements), or IDE
exempt).
v. Specific issues or concerns (if applicable) that need to be addressed during the
inspection;
vi. The due date for the Center contact to receive the completed EIR;
vii. The headquarters address where the EIR should be sent; and
viii. The name, telephone number, and fax number of the Center contact(s).
3 A sampling plan provides instructions about the amount of data or number of documents to be reviewed, and how to select
specific records for this purpose. Generally, a sampling plan will identify the minimum number of subjects’ records (relative
to the total number of subjects in the study) to be reviewed in order to provide a reasonable level of confidence that any
problems at the site would be found (i.e., have a high probability of being detected).
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c. If the inspection involves a Veterans Administration (VA) facility, please see section B.6
for additional instructions.
d. When requesting expedited inspections, the Center should provide justification. If a
Center’s assignment needs high priority, follow Field Management Directive (FMD) No.
17, ORA Field Assignments - Guidelines for Issuance by Headquarters
(http://www.fda.gov/ora/inspect_ref/fmd/fmd17.htm).
e. If, during the course of a clinical investigator or sponsor-investigator inspection, field
personnel identify an institutional review board (IRB) that has never been inspected or has
not been inspected within the past 5 years, the field investigator may request that the Center
issue an inspection assignment for that IRB.
f. All headquarters and field personnel who become aware of complaints or problems related to
a clinical investigator or sponsor-investigator are encouraged to refer the name(s) to the
appropriate Center with a recommendation for inspection. All recommendations should
include the following:
i. The name and address of the clinical investigator or sponsor-investigator;
ii. If available, the name(s) of the test article(s) being investigated, and the application
for research or marketing permit number(s); and
iii. The basis for the recommendation and any relevant documentation.
3. Communication between the Centers and the Districts
Inspectional observations documenting that a clinical investigator is not operating in compliance
with regulations governing the conduct of clinical trials may be used as evidence for taking
appropriate administrative and/or enforcement actions. Ensuring that the evidence collected to
support such actions is both appropriate and adequate requires that communication lines between
the field investigator and the Center be established early and maintained throughout the entire
process, i.e., until post-inspectional correspondence is issued by the Center.
a. Prior to an Inspection
i. The Center issues an assignment (B. 2. above) that includes contact information for the
BIMO reviewer.
ii. The field investigator contacts the BIMO reviewer:
− Upon receipt of the assignment, to establish initial contact and/or provide an
inspection start date;
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− When the inspection date is firmly set, to alert the BIMO reviewer and/or a
back-up to be available and to establish the most appropriate means of contact
for both the investigator and the BIMO reviewer/back-up;
− To obtain any information that may change the focus of the inspection;
− To coordinate inspection arrangements if Center personnel plan to participate in
the inspection
iii. Special Considerations.
In particular cases, the Center may arrange for a consultative teleconference
immediately prior to the inspection(s) if, for example, the complexity of the product or
study, data concerns, urgency of feedback, compliance history, etc., trigger the need to
discuss issues further. Such conference calls are most likely when the agency is
reviewing Biologic License Applications (BLAs), New Drug Applications (NDAs),
Premarket Approval Applications (PMAs), or New Animal Drug Applications
(NADAs), for novel or complex products, or in “for cause” inspections where pertinent
information is either complex or needs discussion between the Center and the field.
The assignment will usually state that this teleconference will occur, unless information
necessitating this discussion emerges after the assignment is issued.
These teleconferences may include the following participants, as warranted and
feasible:
− BIMO reviewer (and supervisor/division director or other staff, as appropriate);
− Lead application reviewer (along with branch and division chiefs, as appropriate)
and other application reviewers as needed; and
− Field investigator(s) assigned to the inspection(s) and/or the BIMO coordinator
(when not yet specifically assigned). Other district staff may also participate.
b. During an Inspection
i. The BIMO reviewer contacts the field investigator if significant new information becomes
available.
ii. The field investigator contacts the BIMO reviewer or designated back-up person if he:
− Needs advice or clarification. The BIMO reviewer and field investigator should
strive to be accessible to one another as much as possible during the time that the
inspection is going on.
− Uncovers other evidence of concern warranting discussion with Center staff.
c. After an Inspection
i. Within 3 business days of concluding the inspection, the field investigator forwards to the
BIMO reviewer (by facsimile, e-mail, or placement in the appropriate shared drive folder)
any 483 that is issued.
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ii. The field investigator forwards as soon as possible to the BIMO reviewer a copy of any
response to the 483 by the inspected party. The BIMO reviewer forwards to the field
investigator, a copy of any response to a 483 that does not appear to have been shared with
the inspecting district.
iii. The BIMO reviewer consults with the field investigator as needed when reviewing the EIR.
iv. The Center consults with appropriate District personnel if contemplating an EIR
classification different from the one recommended by the District.
v. If the Center's final classification is different from the one recommended by the field, the
Center should ensure that District personnel are aware of the change and reasons for the
change.The Center promptly forwards, to the field investigator and other appropriate
district personnel, by e-mail if possible, copies of post-inspectional correspondence issued
to the inspected party.
vi. The Center enters the final classification into FACTS.
4. Responsibilities of Field Investigators, Inspection Team Leaders, and Headquarters Participants
a. The field investigator's responsibilities include, but are not limited to, the
following:
i. Scheduling and conducting the assigned inspection;
ii. Discussing with District management the need to adjust the workload in
order to meet specific deadlines (e.g., deadline imposed for review of the
application by the Prescription Drug/Animal Drug/Medical Device User
Fee Act);
iii. Communicating inspectional issues and observations with the clinical
investigator and the study staff during the course of the inspection, as
appropriate;
iv. Communicating inspectional observations and issues with the Center
contact, as directed in the assignment memorandum;
v. Preparing, issuing, and discussing the items listed on the 483; and
vi. Participating in discussions with the Center regarding potential changes in the
EIR classification.
b. Inspection Team Leader
When inspections are conducted by a team, a field investigator serves as inspection team
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leader and is responsible for the cooperative conduct of the inspection. The team leader's
responsibilities include, but are not limited to, the following (see also Investigations
Operations Manual (IOM; http://www.fda.gov/ora/inspect_ref/iom/default.htm), Team
Inspections):
i. Scheduling and coordinating the participation of team members;
ii. Discussing inspection plans and objectives with team members;
iii. Setting team policy regarding communications with the clinical investigator or
study staff;
iv. Assuring that team members understand their roles in conducting the inspection,
taking notes, collecting documentation, preparing sections of the inspection report
and exhibits, and signing the report;
v. Discussing personal conduct with team members as necessary; and
vi. Resolving disputes or differences of opinion among team members, including
items to be listed on the FDA 483.
c. Headquarters Participants
A headquarters participant is a member of the inspection team who serves in a compliance or
scientific advisory capacity to the Team Leader. The headquarters participant’s
responsibilities include, but are not limited to, the following:
i. Identifying specific objectives to be covered by the inspection;
ii. Providing information pertinent to the inspection;
iii. Contacting the Office of Regional Operations (ORO) to request permission to
participate in field inspections; and
iv. Obtaining inspection credentials from the Division of Field Investigations (DFI,
HFC-130);
v. Attending pre-inspection conferences if and when scheduled;
vi. Participating in the on-site inspection as permitted by agency priorities;
and
vii. Providing guidance and expertise during the inspection, and preparing specific
sections of the inspection report within timeframes established by the Team
Leader.
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5. Resolution of Disagreements
If there is disagreement among members of the inspection team, the issue should be discussed
off-site and resolved cooperatively. Any difficulties in conducting team inspections should be
discussed with both District management and the assigning Center, and, if not resolved,
immediately referred to DFI (HFC-130).
6. Inspections of facilities under the jurisdiction of the Veteran’s Administration (VA)
a. Pre-Inspection
Center. The assigning Center will provide the VA Project Officer with written notification of
FDA’s intention to inspect a clinical investigator at a VA facility at the time an assignment is
being issued to the field, per the terms of FDA/VA Memorandum of Understanding (MOU)
FDA-225-82-8400 (http://www.fda.gov/oc/mous/domestic/225-82-8400.html).
This notice should be sent to:
Chief Officer
Office of Research Oversight (10R)
Veterans Health Administration
Department of Veterans Affairs
811 Vermont Avenue, N.W., Suite 574
Washington, D.C. 20420
Field. The field investigator should contact the VA Medical Center Director before an
inspection of a clinical investigator or sponsor-investigator at a VA facility. For inspections
of military installations, the field investigator should contact the Chief of Professional
Services at the facility to be inspected
b. Post-Inspection.
The Center contacts are authorized to provide redacted copies of post-inspection
correspondence issued to VA facilities or employees following any BIMO inspection
(including the FDA-483s).4 Such materials should be sent to:
Chief Officer
Veterans Health Administration
Department of Veterans Affairs
4
This authorization, has been renewed every two years, and currently extends to November 28, 2009.
PROGRAM 7348.811
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Office of Research Oversight
811 Vermont Avenue, N.W.
Suite 574 (10R)
Washington, D.C. 20420
If, following r
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