• Decrease font size
  • Return font size to normal
  • Increase font size
U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

  • Print
  • Share
  • E-mail

PART V - REGULATORY/ADMINISTRATIVE STRATEGY

 

A.  ADMINISTRATIVE GUIDANCE
 

  1. District EIR Classification Authority

    The District is encouraged to review and initially classify EIRs under this compliance program as outlined in item 3 below.

  2. Center EIR Classification AuthorityThe Center has final classification authority for all EIRs generated under this compliance program.  If the Center is considering a classification that differs from the District’s recommended classification, the Center will contact the District to discuss the issues (see Part II B. 3. c) as soon as possible to avoid delays in the final classification process.  In addition, the Center will provide the District with notice of all final classifications, including the rationale for any that differ from the District’s initial classification.
  3. EIR Classifications The following guidance is to be used in conjunction with the instructions in FMD-86 for initial District and Center classification of EIRs generated under this compliance program:
    1. NAI - No Action Indicated.  No objectionable conditions or practices were found during an inspection (or the objectionable conditions found do not justify further regulatory action);
    2. VAI - Voluntary Action Indicated.  Objectionable conditions or practices were found, but the agency is not prepared to take or recommend any administrative or regulatory action; and
    3. OAI - Official Action Indicated.  Regulatory and/or administrative actions will be recommende
  4. Administrative/Civil/Criminal Actions will be in accordance with 21 CFR Parts 312, 511, and 812.  FDA can invoke other legal sanctions under the FFDCA and/or Title 18, USC where appropriate.
    1. Administrative Actions.  The following administrative actions are available:
      1. Untitled Letters
      2. Warning Letters
      3. Reinspection to verify corrective actions
      4. Regulatory meetings
      5. For a study subject to 21 CFR 312, placing a clinical hold on the study
      6. If inspection involves a study subject to 21 CFR 812, withdrawal of approval of IDE application
      7. If inspection involves a study subject to 21 CFR 511, termination of exemption.
      8. Rejection of data from that site
      9. Initiation of Disqualification Proceedings
      10. Consent agreements
      11. Device detention
      12. Referral of pertinent matters, with headquarters concurrence, to other Federal, state, or local agencies for such action as that agency deems appropriate.
      13. For Sponsor-Investigators, additional administrative/enforcement actions that may be applicable are described in the Sponsors, Contract Research Organizations and Monitors Compliance Program (7348.810)
    2. Civil/Criminal Actions.  The following actions are available: 
    1. Seizure of test articles
    2. Injunction
    3. Civil Money Penalties
    4. Prosecution under the FFDCA or other Federal statutes, e.g., 18 U.S.C. 2, 371, 1001, and 1341.

 

.
B.  REGULATORY GUIDANCE
The following criteria are relevant to FDA’s classification of inspections of clinical investigator sites:

No Action Indicated (NAI). No objectionable conditions or practices (e.g., violations of 21 CFR Parts 50, 54, 56, 312, 511, 812) were found during the inspection, or the significance of the documented objectionable conditions found does not justify further FDA action.

Any post-inspectional correspondence acknowledges the investigator’s basic compliance with pertinent regulations.

Voluntary Action Indicated (VAI).  Objectionable conditions were found and documented, but the Center is not prepared to take or recommend any further regulatory (advisory, administrative, or judicial) action because the objectionable conditions do not meet the threshold for regulatory action (i.e., regulatory violations uncovered during the inspection are few and do not seriously impact subject safety or data integrity).
 

Post-inspectional correspondence will identify the issues and, when needed, state that FDA expects prompt, voluntary corrective action by the investigator.

Official Action Indicated (OAI). If objectionable conditions were found, one of the actions listed below should be recommended.  Specifically, regulatory violation(s) uncovered during the inspection is/are repeated13 or deliberate14 and/or involve submission of false information to FDA or to the sponsor in any required report.  The regulatory violation(s) uncovered is/are significant/serious and/or numerous, and the scope, severity, or pattern of violation(s) support a finding that:

a) Subjects under the care of the investigator would be or have been  exposed to an unreasonable and significant risk of illness or injury. OR

b) Subjects' rights would be or have been seriously compromised. OR

c) Data integrity or reliability is or has been compromised. 

Post-inspectional correspondence should be either a Warning Letter (WL) or a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). 

Once an OAI decision is reached, additional information (e.g., previous inspectional findings, correspondence, or other information about the clinical investigator) may assist the Center in determining which type of post-inspectional correspondence is appropriate.   If the Center chooses to issue a WL and allow the clinical investigator to submit a detailed corrective action plan or alternate approach that is acceptable to FDA, the Center should nevertheless be prepared to initiate disqualification proceedings should the clinical investigator not respond appropriately (i.e., fails to respond, fails to develop an adequate corrective action plan, or is found, during a subsequent inspection, to have failed to comply with a corrective action plan). 

 
A Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE) May be Considered When:

An investigator (including a sponsor-investigator) has

1) Repeatedly or deliberately failed to comply with the requirements for conducting clinical trials (21 CFR 312, 511, 812, 50, or 56); or

2) Repeatedly or deliberately submitted false information to FDA or to the sponsor in any required report.

A Warning Letter may be considered when the violations can be corrected through specific action(s) by the investigator (e.g., preparation of, and compliance with, a detailed corrective action plan, that is acceptable to FDA) and adherence to the corrective action plan has a high probability of preventing similar or other violations from occurring in the future. 

EXAMPLES

The following are intended to serve as examples of violations that, alone or in combination, would be considered significant and may warrant OAI classification.  This list is not all inclusive; other circumstances may also merit OAI classification.  

Violations included under "Data Integrity" categories could apply to studies conducted under 21 CFR 312, 511, or 812.  Violations included under "Inadequate Human Subject Protection" would apply only to studies involving human subjects (i.e., conducted under 312 or 812).

When applying the classification criteria, Center reviewers will generally evaluate the impact of the investigator's actions (number, scope, and severity of the regulatory violations) on the protection of the subjects in the study, and the reliability and acceptability of the data. There are gradations in the severity of each example, and the specific observation(s) should support the seriousness of the violation(s) and the effect(s) on physical harm to subjects, compromise to subjects' rights, and/or the reliability and acceptability of data for FDA decision-making purposes.

Inadequate Human Subject Protection

Violation/Related CitationExamples
Failed to inform subjects that they could refuse to participate
21 CFR 50.25(a)(8); 50.20; 50.27
No documentation to show that subjects received either oral or written information about their right to refuse to participate
Repeated or deliberate failure to obtain informed consent in accordance with 21 CFR Part 50
21 CFR 50.20; 50.27;
21 CFR 312.60; 312.62(b);
21 CFR 812.100; 812.140(a)(3)(i); 812.150(a)(5)
Missing consent documents; omission of a description of one or more required elements when obtaining consent
Prevented subject from withdrawing from study
21 CFR 312.60;
21 CFR 50.25(a)(8);
Study or institutional records indicate subject's request to withdraw was denied
No documentation to show that subjects were informed they could withdraw without penalty
Repeated or deliberate failure to provide study information in language understandable to the subject(s) or his legally authorized representative (LAR)
21 CFR 50.20
Evidence of non-English speaking subjects but no translated informed consent document or short form and summary was provided to the subject or his LAR

Failure to supervise the clinical trial, such that subjects are or would be exposed to unreasonable and significant risk or injury
21 CFR 312.60;
21 CFR 812.100;  812.110(c)

 

Records showing the CI failed to appropriately delegate study related duties to qualified personnel  (e.g., physical exams, serious sdverse event [SAE] evaluations), with resultant exposure of subjects to unreasonable and significant risk or injury
Failure to ensure that study has IRB review and approval; failure to ensure that IRB has reviewed and approved changes in the research when such changes are not necessary to eliminate hazard to the subject
21 CFR 312.66;
21 CFR 812.150(a)(4);  812.110(a)
No documentation of IRB approval of protocol or amendments
Enrolled subjects before IRB approval obtained
21 CFR 312.66;
21 CFR 812.110(a)
Date of IRB approval after first subject(s) enrolled into study
Protocol Violations 
21 CFR 312.60; 312.66;
21 CFR 812.100; 812.110(b)
Enrolling subjects who do not meet the entrance criteria because they have conditions that put them at increased risk
Failure to report serious or life-threatening adverse events to the sponsor
21 CFR 312.64(b)
No evidence that SAEs were reported to the IRB and/or sponsor

Failure to report to the IRB, and for devices, to the sponsor, unanticipated problems involving risk to human subjects or others
21 CFR 312.66;
21 CFR 812.150(a)(1)

 

 

 

 

 

 

 

 

 

 

No evidence that unanticipated problems were reported to the IRB or sponsor

 

Data Integrity:  Submission of False Information to FDA or the sponsor

Violation/Related CitationExamples
Study records are fabricated, altered, or concealed
 21 CFR 312.70; 312.62(b);
21 CFR 511.1(c); 511.1(b)(7)(ii);
21 CFR 812.119; 812.140(a)
CRFs for study subjects who did not exist or did not participate in the study
Falsified consent documents (signatures do not match)
Falsified records of IRB review and/or approval (human studies
CRFs include results about protocol-required procedures that were never done
Specimens and/or analytical results characterized as being from a study subject that were from a different individual
False or misleading reports were prepared and/or submitted  
21 CFR 312.70; 312.64;
21 CFR 511.1(c);
21 CFR 812.119, 812.150(a)
False safety data or reports are submitted

Inadequate supervision of study personnel who, in turn, fabricated, altered, or contributed false information to study records or reports 
21 CFR 312.60;
21 CFR 812.100; 812.110(c)

 

 

 

 

 

 

 

 

 

Signatures on CRFs and/or other study documents do not match

        


Data Integrity:  Repeated or Deliberate Failure to Comply with the Regulations
Violation/Related CitationExamples
Failure to supervise the clinical trial, such that data collected are unreliable
21 CFR 312.60;
21 CFR 812.100; 812.110(c)
Records showing the CI failed to appropriately delegate study related duties to qualified personnel  (e.g., physical exams, SAE evaluations)
Repeated or deliberate deviation from the investigational plan, investigator statement/agreement, FDA regulations, or condition imposed by FDA or the reviewing IRB
21 CFR 312.60; 312.61; 312.66; 312.68;
21 CFR 812.110(b);
Enrolling subjects who do not meet the entrance criteria because they have conditions that put them at increased risk
Administration of the test article to persons not authorized to receive it
Failure to perform protocol-required procedures
No documentation of required IRB review of study changes
No documentation of IRB continuing review, where required
Refusal to allow FDA inspection
Inadequate and/or inaccurate case histories; inadequate study records
21 CFR 312.62(b);
21 CFR 812.140(a)(3)
Incomplete subject records (e.g., missing records or evidence records have been deliberately discarded or destroyed)
Inadequate accountability for the investigational product
21 CFR 312.60, 312.61, 312.62(a);
21 CFR 511.1(b)(7)(ii);
21 CFR 812.100, 812.110(c); 812.140(a)(2)
Use of investigational product by an unauthorized individual
No or inadequate records on receipt, preparation, use, and/or disposition of the investigational product
Promotion or commercialization of investigational products
21 CFR 312.7;
21 CFR 812.7
Fliers, brochures, etc. that do not indicate investigational nature of product, or claim safety and/or efficacy for the indication under study
Evidence study subjects were charged for the investigational drug without FDA approval

C.  FOLLOW-UP INSPECTIONSollow

1.  Centers should evaluate whether the violations found indicate systemic problems with the conduct of the study or the reliability of the data and whether additional inspection assignments should be issued (e.g., IRB, sponsor, CRO, monitor, other CIs).

2.  Following issuance of a Warning Letter, Centers should periodically review their clinical investigator databases for entries indicating that a Warning Letter recipient is actively conducting other clinical investigations.  If such entries are found, the Center should schedule follow up inspections to verify if the clinical investigator is fulfilling the terms of any corrective action plans and in compliance with applicable HSP and GCP regulations. 


 

13Repeated violation means more than one violation, including the same violation, in one or more studies. See Commissioner's Decision, Regulatory Hearing on the Proposal to Disqualify Layne O. Gentry, M.D. (2008).

14Deliberate Violation is defined as a willful action that need not entail knowledge that it is a violation of law as long as there is some perception of wrongdoing or of reckless disregard for obvious or known risks. See Commissioner's Decision, Regulatory Hearing on the Proposal to Disqualify Layne O. Gentry, M.D. (2008).