PART V - REGULATORY/ADMINISTRATIVE STRATEGY
A. ADMINISTRATIVE GUIDANCE
The District is encouraged to review and initially classify EIRs under this compliance program as outlined in item 3 below.
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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:
The inspectional findings meet the criteria for OAI above, indicating that 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); and/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 |
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Violation/Related Citation |
Examples |
Failed to inform subjects that they could refuse to participate |
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 |
Missing consent documents; omission of a description of one or more required elements when obtaining consent |
Prevented subjects from withdrawing from study |
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 |
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Repeated or deliberate failure to provide study information in language understandable to the subject(s) or his legally authorized representative (LAR) |
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
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Records showing the CI failed to appropriately delegate study related duties to qualified personnel (e.g., physical exams, Serious Adverse 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 |
No documentation of IRB approval of protocol or amendments |
Enrolled subjects before IRB approval obtained |
Date of IRB approval after first subject(s) enrolled into study |
Protocol Violations |
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 |
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
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No evidence that unanticipated problems were reported to the IRB or sponsor |
Data Integrity: Submission of False Information to FDA or the sponsor |
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Violation/Related Citation |
Examples |
Study records are fabricated, altered, or concealed |
CRFs for study subjects who did not exist or did not participate in the study |
Falsified consent documents (signatures do not match) |
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Falsified records of IRB review and/or approval (human studies |
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CRFs include results about protocol-required procedures that were never done |
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Specimens and/or analytical results characterized as being from a study subject that were from a different individual |
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False or misleading reports were prepared and/or submitted |
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
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Signatures on CRFs and/or other study documents do not match |
Data Integrity: Repeated or Deliberate Failure to Comply with the Regulations |
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Violation/Related Citation |
Examples |
Failure to supervise the clinical trial, such that data collected are unreliable |
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 |
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 |
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Failure to perform protocol-required procedures |
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No documentation of required IRB review of study changes |
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No documentation of IRB continuing review, where required |
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Refusal to allow FDA inspection |
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Inadequate and/or inaccurate case histories; inadequate study records |
Incomplete subject records (e.g., missing records or evidence records have been deliberately discarded or destroyed) |
Inadequate accountability for the investigational product |
Use of investigational product by an unauthorized individual |
No or inadequate records on receipt, preparation, use, and/or disposition of the investigational product |
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Promotion or commercialization of investigational products |
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 Inspections.
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).
Hypertext updated January 08,2009 by ksj