Inspections, Compliance, Enforcement, and Criminal Investigations
5-9 - DISQUALIFICATION OF CLINICAL INVESTIGATORS
5-9 - DISQUALIFICATION OF CLINICAL INVESTIGATORS
5-9-1 - Purpose
5-9-2 - Criteria for Initiating Disqualification Proceedings
5-9-3 - Initiating the Disqualification Process
5-9-4 - Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)
5-9-5 - Consent Agreements
5-9-6 - Informal Conference with the Clinical Investigator
5-9-7 - The Notice of Opportunity for Hearing (NOOH)
This procedure describes the process, including timeframes, for initiating disqualification proceedings - from completion of the inspection to issuance of the Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) to the clinical investigator. In addition, it includes the processes and timeframes for follow-up to a response to a NIDPOE, through issuance of a Notice of Opportunity for Hearing (NOOH)2. This procedure is intended for use by center Bioresearch Monitoring (BIMO) Program Units, staff in the Office of the Commissioner (OC), the Office of Regulatory Affairs (ORA), and the Office of the Chief Counsel (OCC). Adherence to the procedures described in this chapter will assist the agency in achieving a uniform approach to the disqualification process.
Criteria for initiating disqualification proceedings are found at 21 CFR 312.70, 511.1(c), and 812.119 and are discussed in the clinical investigator CPGM, as noted in footnote 1. As discussed in the clinical investigator CPGM (7348.811, Part V. B.), a decision to initiate disqualification proceedings often starts with a decision to classify the Establishment Inspection Report (EIR) as Official Action Indicated (OAI).
When a clinical investigator inspection reveals serious noncompliance, communication with the center is essential, as noted in the CPGM (7348.811 Part II, B.3.), since collection of appropriate supporting evidence is vital. In addition, this will allow the center to provide advance notice to OCC and other appropriate offices if it appears a recommendation for disqualification may be considered. It is also recommended that the district investigator contact the Bioresearch Monitoring Specialist in the Medical Products and Tobacco Policy Staff (MPTPS) in the Office of Policy and Risk Management (OPRM), ORA, who can provide assistance with the process and serve as an additional resource. The resulting EIR, with violations indexed to the supporting evidence and exhibits appropriately tabbed for easy reference, should be forwarded to the center BIMO Program Unit within 30 days3 of completion of the inspection.
Because center BIMO Program Units need to expeditiously review inspectional findings that warrant initiation of disqualification proceedings, center BIMO Program Units should review and prioritize within fourteen (14) days of receipt all EIRs with a district office recommendation of OAI, with or without a recommendation for clinical investigator disqualification. Center BIMO Program Units should review and prioritize EIRs with Referred to Center (RTC) designations within a similar timeframe to determine if any warrant an OAI designation and therefore possible initiation of disqualification proceedings. EIRs with district office recommendations other than OAI or RTC may also support initiation of disqualification proceedings. When a BIMO reviewer identifies such an EIR, the timeframes discussed below would apply.
Once the potential for initiating disqualification proceedings is identified, the assigned BIMO reviewer analyzes the inspectional findings and determines if the findings are supported by sufficient evidence of regulatory significance. The BIMO reviewer also determines if the district office has received any response to the Form FDA 483 and requests a copy of all responses. After reviewing all materials associated with the most recent inspection, as well as any information available in the center’s inspectional files/databases, the BIMO reviewer drafts his/her rationale for or against initiation of disqualification proceedings. Consultation with office/center regulatory personnel and/or OCC attorneys during this review may be warranted. If initiation of disqualification proceedings is not deemed warranted, the BIMO reviewer prepares a document explaining that conclusion, for review by his/her supervisor, and initiates other appropriate actions. If initiation of disqualification proceedings is deemed warranted, the BIMO reviewer prepares appropriate documentation for the administrative record which will support all subsequent steps in the process. The portion of the administrative record supporting issuance of a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) will include such documents as:
- A chart and/or memo summarizing the significant inspectional findings and regulatory violations supporting the disqualification action;
- A chronology/inspectional history of the clinical investigator;
- A draft NIDPOE (see Exhibit 5-21 for sample); and
- A draft Consent Agreement (see Exhibit 5-22 for sample)
The NIDPOE file should be appropriately indexed to facilitate review by center management, OCC, and ORA. For example, violations cited in the NIDPOE should be indexed to the supporting evidence supplied with the EIR. During preparation of the NIDPOE file, the BIMO Program Unit should alert all relevant center and agency offices that this file is in preparation to ensure timely review. Review of the NIDPOE file should proceed according to center-specific procedures. The NIDPOE file should be ready for OCC review within four (4) months from receipt of the EIR. OCC should concur, with comments/suggested edits as necessary, or arrange for a discussion with appropriate center BIMO personnel if non-concurrence is considered, within four (4) months of receipt of the draft NIDPOE.
Upon receipt of OCC concurrence, the BIMO Program Unit incorporates any changes and/or additions to the NIDPOE letter and routes the entire NIDPOE file to the appropriate center official for signature of the NIDPOE. This signature should be affixed within fourteen (14) days of receipt of OCC concurrence. The NIDPOE file and signed NIDPOE are returned to the BIMO Program Unit. The BIMO Program Unit should issue the signed NIDPOE, with the consent agreement, to the clinical investigator within 1 working day of receipt and distribute copies to the appropriate agency units, as described below.
The NIDPOE directs the clinical investigator to write or call the center, within fifteen (15) working days, to arrange for an informal conference or to indicate the intent to respond to the allegations in writing. If the clinical investigator chooses to submit a written response, the NIDPOE directs him/her to respond within 30 working days of receipt of the NIDPOE.
A NIDPOE should be sent by certified mail (return receipt requested), or other method that documents transmission and receipt of delivery. If such delivery is unsuccessful, the center should contact the Director, Investigations Branch (DIB) in the appropriate district office and request that the NIDPOE be hand delivered by agency personnel. The Center will provide the district with addresses and alternative locations for delivery.
The issuance of a NIDPOE is a significant regulatory action and appropriate agency units should be promptly advised of its issuance. These include:
[To blind copy electronically, send to the relevant party at email@example.com; for hardcopy distribution at the White Oak (WO) campus, include the building and room numbers]
ORA, Division of Enforcement; WO32
[Originating Center- Center files and distribution]
[Relevant District Office- District Personnel, including the District Director; Director, Investigations Branch; and the District investigator(s)]
CDER, OSI; WO51
CBER, BIMO Group; HFM-664
CVM, BIMO Group; HFV-234
CDRH, BIMO Group; WO66, BIMO@cdrh.fda.gov
CFSAN, BIMO Group; HFS-205
The Center will forward the NIDPOE to the Center’s FOI program for redaction and posting on FDA’s webpage [www.fda.gov/DisqualificationProceedings].
After issuance of the NIDPOE, the clinical investigator may choose to enter into a consent agreement with FDA. A finalized consent agreement between FDA and the clinical investigator terminates the administrative proceedings in this matter. The option of entering into a consent agreement with the agency is available at any time throughout the disqualification proceedings, up to the issuance of the Commissioner's Decision under 21 CFR 16.95 or issuance of a notification of disqualification under 21 CFR 312.70, 511.1(c), or 812.119. The consent agreement may be signed by an FDA official as listed in Staff Manual Guide 1410.21- General Redelegations of Authority, Paragraph 1.P, at http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/StaffManualGuides/UCM273783.pdf. As noted above, a sample consent agreement is included in Exhibit 5-22.
In the NIDPOE, the center will offer the investigator the opportunity to submit an explanation in writing, or at the investigator's option, in an informal conference. If the clinical investigator submits a written response, the regulations do not require the center to hold an informal conference but the center may choose to do so. If an informal conference is requested, the center should schedule it as soon as possible, usually within thirty (30) days of the request. At the informal conference, the clinical investigator may be accompanied by a representative of his/her choosing and may provide documents for the record. A clinical investigator may submit written materials to FDA within 15 days after the informal conference.
At a minimum, FDA personnel attending the conference will include staff from the center BIMO Program Unit and counsel from OCC who reviewed the NIDPOE. FDA may also include other personnel with appropriate expertise or relevant experience with the case (e.g., a Medical Officer from the review team for the study involved, the FDA district investigator who conducted the inspection at the clinical investigator’s site). The center should make arrangements for the informal conference, notify all pertinent parties of the specifics, and arrange to have the discussion transcribed for the administrative record. These informal meetings should be scheduled for up to two (2) hours. Because the meeting is informal, there is no prescribed format, but the meeting should address all allegations listed in the NIDPOE.
Following the informal conference, the center will provide a copy of the written transcript to the clinical investigator. The center, in consultation with OCC, should promptly review any new explanation or evidence provided by the clinical investigator. If it no longer appears that disqualification is warranted, alternatives such as a detailed corrective action plan may be considered. The center BIMO Program Unit should notify the clinical investigator in writing within thirty (30) days of the informal conference of this decision not to proceed with the disqualification and include the specifics of any such alternative corrective action plan.
If the clinical investigator's explanation is not accepted by the Center, disqualification is still warranted and the center should issue a Notice of Opportunity for Hearing (NOOH) to the clinical investigator.
If a clinical investigator fails to respond to a NIDPOE or the center determines that the clinical investigator’s written or oral explanation is inadequate, the regulations provide that the clinical investigator be given an opportunity for a regulatory hearing under 21 CFR part 16 on the question of whether the investigator is eligible to receive test articles and eligible to conduct any clinical investigation that supports an application for a research or marketing permit for products regulated by FDA. Center BIMO Program Units should prepare an NOOH using the sample document provided in Exhibit 5-23. The NOOH should be prepared within 30 days of a center’s decision that a clinical investigator’s written or oral explanation is inadequate, or after it is clear the clinical investigator has chosen not to respond to the NIDPOE. The center should consult with OCC during the preparation of the NOOH and clear the NOOH in accordance with center procedures. The center-approved NOOH and the administrative record (which includes the NIDPOE file and all follow-up information/documents) should be forwarded to OCC for review and clearance. Within thirty (30) working days of receipt, OCC should concur or provide comments to the BIMO Program Unit as to what is necessary to achieve concurrence with the NOOH.
Within five (5) working days of OCC concurrence, after incorporating any OCC additions/changes, the BIMO Program Unit forwards both the paper and electronic copies of the NOOH and the administrative record to the Division of Enforcement (DE). DE has five (5) working days to review and clear the NOOH for signature. If DE, during its review, proposes substantive changes to the NOOH, DE will clear their proposed changes with OCC, who will consult with the BIMO Program Unit when necessary. Within five (5) working days, after clearing any substantive DE additions/changes with OCC as necessary (OCC will consult with the Center as necessary and notify the center about any changes); DE forwards the NOOH and the administrative record to the Associate Commissioner for Regulatory Affairs (ACRA) in the Office of Regulatory Affairs (ORA) for review and signature; and, requests redaction of the NOOH by the Center's FOI office and posting of the redacted NOOH on FDA's website. The ACRA should sign the NOOH, or provide comments to DE as to what is necessary to achieve his/her signature, within five (5) working days of receipt. Upon receipt of the signed NOOH (within one (1) working day), DE date stamps and issues the NOOH to the clinical investigator and/or his/her counsel by certified mail (return receipt requested) or other documented method of transmission. If delivery of the NOOH cannot be confirmed, the Director, DE, will contact the local district office and request that the NOOH be delivered by FDA personnel. The Center will provide the district with addresses and alternative locations for delivery. Upon issuance of the NOOH, DE provides a copy of the signed NOOH to the center BIMO Program Unit, which is responsible for appropriately distributing copies of the NOOH within FDA (see NIDPOE distribution list above). The Center will forward the NOOH to the Center's FOI program for redaction and posting on FDA's webpage [www.fda.gov/DisqualificationProceedings].
The NOOH provides that the investigator has ten (10) working days from receipt of the NOOH to request a hearing. If the clinical investigator does not respond within this time frame, the clinical investigator will be deemed to have waived the right to a regulatory hearing and the agency will make a decision on the matter based on the facts available to the agency.
DE will advise the center BIMO Program Unit of the response (or lack thereof) to the NOOH letter after ten (10) working days. Subsequent actions are discussed and determined by the center BIMO Program Unit, OCC, and DE as outlined in the Sample Notice of Opportunity for Hearing in Exhibit 5-23. The center BIMO Program Unit is responsible for preparing a memo for summary decision regarding the disqualification.
See SMG 7711 for details of the process to be followed after issuance of a NOOH (http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm052928.htm).
The clinical investigator disqualification proceedings described above are summarized in the flowchart found in Exhibit 5-20.
1Criteria for initiation of disqualification proceedings are included in the Compliance Program Guidance Manual (CPGM)(available at http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm) for the inspection of clinical investigators, 7348.811, Part V. B.
2Procedures for the hearing process initiated by issuance of an NOOH are described in the FDA Staff Manual Guides (SMG), Volume IV – Agency Program Procedures, specifically SMG 7711 (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/ucm052928.htm).
3All timeframes are in calendar days unless specified otherwise.