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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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PART II - IMPLEMENTATION


A. OBJECTIVES

The objectives of the 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 sponsors, contract research organizations (CROs), and monitors, and recommending associated administrative/enforcement actions.

B. PROGRAM MANAGEMENT INSTRUCTIONS

1. Coverage

This program covers domestic and foreign inspections of:  

a. Sponsors
Such entities consist of those individuals, organizations, or corporations that initiate clinical investigations and have been so identified by FDA through receipt of an investigational exemption, or application for research or marketing permit for an article. A sponsor is defined in the regulations at 21 CFR 312.3(b), 510.3(k), and 812.3(n).  

b. Contract Research Organizations

Such entities consist of those organizations or corporations that have entered into a contractual agreement with a sponsor to perform one or more of the obligations of a sponsor (e.g., design of protocol, selection of investigators and study monitors, evaluation of reports, and preparation of materials to be submitted to FDA). In accord with 21 CFR 312.52 and 511.1(f), responsibility as well as authority may be transferred and thus the CRO becomes a regulated entity. [Note: As noted above, the medical device regulations (21 CFR Part 812) do not provide for the transfer of sponsor regulatory obligations to CROs. Device study sponsors are therefore held responsible for any regulatory noncompliance by a CRO.]  

c. Monitors

Such entities consist of those individuals who are selected by either a sponsor or CRO to oversee the clinical investigation. The monitor may be an employee of the sponsor or CRO, or an independent consultant to the sponsor or the CRO. The latter are commonly referred to as clinical research associates (CRAs).

2. Inspection Assignments

a. Center BIMO units issue inspection assignments of sponsors, CROs, and monitors.

i. Domestic inspection assignments are issued to the district offices.

ii. International inspections of sponsors are generally assigned when the sponsor is located outside of the United States (US) and an overall view of the conduct of the study, as provided at the sponsor site, is critical to decision-making on product approval. International inspection assignments are issued to the Division of Foreign Field Investigations (DFFI).

 

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 (and e-mail address, if available) of the sponsor/CRO/monitor to be inspected; for international inspections, the U.S. agent’s contact information.

iii. The type and purpose of the inspection;

iv. The background materials (e.g., study protocol and amendments, relevant sections of marketing applications/submissions, case report forms (CRFs), the sponsor’s/CRO’s/monitor’s compliance history) sent from the Center to facilitate the inspection. For investigational device studies, the Center should identify the type of study (i.e., 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; if the assignment requests review of information and/or data for one or more of the study sites, line data and protocol deviations submitted by the sponsor for the site(s) in question may be included in the background materials.

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, e-mail address, and fax number of the Center BIMO contact(s).
 

c. 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 (Office of Regulatory Affairs) Field Assignments - Guidelines for Issuance by Headquarters (http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm056651.htm)
 

d. If the sponsor has contracted out all or part of their responsibilities, the field investigator should notify the Center contact of this fact and continue the inspection. The Center will decide whether to follow up with an inspection at the CRO or monitor and issue any additional assignments.
 

e. Whether a study monitor is an employee of the sponsor or CRO or is an independent CRA, a monitor inspection will cover the monitor’s obligations for overseeing the investigation as instructed in Part III.
 

f. All headquarters and field personnel who become aware of complaints or problems related to a sponsor/CRO/monitor 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, address, and phone number (and e-mail address, if available) of the sponsor/CRO/monitor;
 

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 sponsor/CRO/monitor 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;

- 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 Centermayarrange 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 Biologics 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/she:

- 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 three (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, as agreed to with the Center) any 483 that is issued.  

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. Attending pre-inspection conferences if and when scheduled;

ii. Scheduling and conducting the assigned inspection;

iii. 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);

iv. Communicating inspectional issues and observations with the sponsor, CRO, or monitor during the course of the inspection, as appropriate;

v. Communicating inspectional observations and issues with the Center contact, as directed in the assignment memorandum;

vi. Preparing, issuing, and discussing the items listed on the 483 with the inspected party; and

vii. 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 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), Team Inspections, http://www.fda.gov/ICECI/Inspections/IOM/ucm151267.htm#5.1.2.5):

i. Attending pre-inspection conferences if and when scheduled;  

ii. Scheduling and coordinating the participation of team members;

iii. Discussing inspection plans and objectives with team members;

iv. Setting team policy regarding communications with the sponsor, CRO, or monitor;

v. 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;

vi. Discussing personal conduct with team members as necessary; and

vii. Resolving disputes or differences of opinion among team members, including items to be listed on the 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. Completing the Inspection Participation Form (Form FDA 2115, available at http://inside.fda.gov:9003/downloads/Administrative
/Forms/FDA/UCM030799.pdf) and submitting it to the Office of Security Operations (OSO, Special Programs Branch (White Oak, Building 1, Room 1201, 10903 New Hampshire Avenue, Silver Spring, MD 20993). The form may also be submitted electronically to FDA-ORO Credentials (located in Microsoft Global Address list). For further information see http://inside.fda.gov:9003/EmployeeResources/FDABadging/
GeneralInformation/ucm205502.htm;

iv. Obtaining inspection credentials as directed by OSO;

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.

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 the Division of Domestic Field Investigations (DDFI) for domestic inspections or DFFI for foreign inspections.

6. Inspections of the Veteran’s Administration (VA) as the sponsor of FDA-regulated clinical trials. (For example, the VA’s Cooperative Studies Program sponsors a number of FDA-regulated clinical trials.)

a. Pre-Inspection

Center. The BIMO unit in the assigning Center will provide the VA’s Office of Research Oversight (ORO) with written notification of FDA’s intention to inspect a VA sponsor program at the time an assignment is being issued to the field.

This notice should be sent to:  

Chief Officer
Office of Research Oversight (10R)
Veterans Health Administration
Department of Veterans Affairs
810 Vermont Avenue, N.W., Suite 574
Washington, D.C. 20420

Field. The field investigator will contact the VA sponsor program before the inspection, as they would any other sponsor they are assigned to inspect.

b. Post-Inspection

The Center will provide the VA’s ORO redacted copies of post-inspection correspondence issued to VA sponsored programs that include a discussion of deficiencies noted during the inspection (including the FDA-483s). Such materials should be sent to:

Chief Officer
Office of Research Oversight (10R)
Veterans Health Administration
Department of Veterans Affairs
810 Vermont Avenue, N.W., Suite 574
Washington, D.C. 20420

If, following receipt of the FDA correspondence, the VA-ORO requests a copy of the EIR, a redacted copy of the report will be provided to VA-ORO by the district office.