• 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 Authority  

The 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[10] for initial District and Center classification of EIRs generated under this Compliance Program:  

a. 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);  

b. 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  

c. OAI – Official Action Indicated. Regulatory and/or administrative actions will be recommended.

 4. Administrative/Civil/Criminal Actions will be in accordance with 21 CFR Parts 312, 511, and 812. FDA may invoke other legal sanctions under the FFDCA or Title 18 of the United States Code where appropriate.  

a. Administrative Actions. The following administrative actions are available:  

i. Untitled Letters  

ii. Warning Letters  

iii. Reinspection to verify promised corrective actions  

iv. Regulatory meetings  

v. For a study subject to 21 CFR Part 312, placing a clinical hold on the study (21 CFR 312.42)  

vi. If the inspection involves a study subject to 21 CFR Part 812, withdrawal of approval of the IDE application (21 CFR 812.30(b))  

vii. If the inspection involves a study subject to 21 CFR Part 511, termination of the exemption  

viii. Refusal to approve or license  

ix. Withdrawal of approval (PMA, NDA, NADA)  

x. Determination of not substantially equivalent (21 CFR 807.100(a)(2)) or rescission of a 510(k) (see 21 CFR 10.33 and 10.75) for devices  

xi. Implementation of the Application Integrity Policy  

xii. For Sponsor-Investigators, additional administrative/enforcement actions that may be applicable are described in the Compliance Program Guidance Manual for Clinical Investigators and Sponsor-Investigators (CPGM 7348.811), as referenced in Part I - Background above.  

b. Civil/Criminal Actions. The following actions are available:  

i. Seizure of test articles  

ii. Injunction  

iii. Prosecution under the FFDCA and other Federal statutes, i.e., 18 U.S.C. 2, 371, 1001, and 1341  

iv. Referral of pertinent matters with headquarters’ concurrence to other Federal, state, and local agencies for such action as that agency deems appropriate.

B. REGULATORY GUIDANCE

The following criteria are relevant to FDA’s classification of inspections of sponsors/CROs/monitors:

No Action Indicated (NAI). No objectionable conditions or practices (e.g., violations of 21 CFR Parts 50, 54, 56, 58, 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 sponsor’s/CRO’s/monitor’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 may identify the issues and, when needed, state that FDA expects prompt, voluntary corrective action by the sponsor/CRO/monitor.

Official Action Indicated (OAI). An OAI recommendation is appropriate when 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 participating in studies conducted by the sponsor/CRO or overseen by the monitor 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 would usually be a Warning Letter (WL). Implementation of the agency’s Application Integrity Policy (AIP) is also possible. AIP may be considered when there is evidence of a pattern or practice of wrongful conduct that raises a significant question about the reliability of data in studies conducted to support an application(s) for marketing. (See information regarding AIP at http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/default.htm.)  

The Centers may rely on information from inspections of CROs and/or monitors that were contracted to assume some or all sponsor responsibilities, as well as information from inspected study sites, to determine whether the sponsor/CRO/monitor is compliant. If an OAI decision is reached, additional information (e.g., previous inspectional findings, correspondence, or other information about the sponsor/CRO/monitor) may assist the Center in preparing appropriate post-inspectional correspondence. If the Center believes that the violations can be corrected through specific action(s) by the sponsor/CRO/monitor (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, the Center may choose to issue a WL. Nevertheless, the Center should be prepared to take further action if the sponsor/CRO/monitor does 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.)

When applying the classification criteria, Center reviewers will evaluate the impact of the sponsor’s deficiencies on the general conduct of their clinical trials, with particular attention to the safety, rights, and welfare of study subjects and the integrity of the resulting data. 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 and other circumstances may also merit OAI classification. Each example can have gradations in severity and the specific observation(s) should support the seriousness of the violation(s) and its impact on subject protection and/or data integrity.

Violation/Related Citation

Examples/supporting evidence

Lack of a signed 1572/investigator agreement for one or more clinical sites

21 CFR

312.53(c)(1)

812.43(c)

Evidenced by absence of required documentation.

Failure to select qualified clinical investigators

21CFR

312.53(a), 312.53(c)(1)(iii) and (iv)

812.43(a), 812.20(b)(7)

Monitoring reports, Form FDA 1572s, and/or investigator agreements indicate that one or more clinical investigators did not have appropriate training and/or experience to perform their responsibilities in the study.

Monitoring reports, Form FDA 1572s, and/or investigator agreements indicate that one or more clinical investigators did not have access to the facilities necessary to conduct the study.

Failure to select qualified monitors

21 CFR

312.53(d)

511.1(b)(8)(ii)

812.43(d)

Non-compliance and/or data issues evidenced at study sites were not discovered by the study monitor and/or included in monitoring reports.

One or more sites were not trained to properly conduct the study (for example, required QC tests were not performed).

There is no documentation that one or more study monitors had clinical trial experience.

Lack of a required IND/IDE or failure to submit a “Notice of Claimed Investigational Exemption for a New Animal Drug”

21 CFR

312.20

812.20

511.1(b)(4)

NOTE: This citation requires consultation with the Center for a definitive conclusion before inclusion on a 483

Failure to provide investigators with the information they need to conduct the investigation.

21 CFR

312.50, 312.55

812.40, 812.45

The sponsor failed to provide one or more investigators with the study brochure and/or other information pertinent to the conduct of the study prior to initiation of the study at the site(s) in question.

Significant new adverse effects or risks were reported by the investigators to the sponsor, but the sponsor failed to promptly report them to all investigators.

The sponsor misrepresented the correct IDE/IND status of the study to one or more investigators.

Failure to ensure that IRB approval was obtained.

21 CFR

312.53(c)(v)

812.40, 812.42

The investigation was initiated at one or more sites prior to or without sponsor receipt of evidence of IRB approval for the site(s) in question.

Failure to notify FDA of all investigators participating in the study.

21 CFR

312.23(a)(6)(iii)(b), 312.30(c)

511.1(b)(4)(iii)
514.1(b)(8)(vi)

812.20(b)(4), 812.150 (b)(4)

814.20(b)(6)(ii)

One or more investigators who participated in the study were not included in the initial IND/IDE application, the Notice of Claimed Investigational Exemption for a New Animal Drug, required study updates, and/or the marketing application/submission.

Failure to obtain required financial disclosure information prior to a clinical investigator’s participation in the study

21 CFR

312.53(c)(4)

812.43(c)(5)

Dates on financial disclosure reports from one or more study investigators are after their initial participation in the study.

Lack of financial disclosure information from one or more investigators participating in the study.

Failure to adequately monitor the study

21 CFR

312.50, 312.53(d), 312.56(a)

511.1(b)(8)(ii)*

812.40, 812.43(d), 812.46


*Specific language differs: “provide for current monitoring”

One or more study sites had significant protocol deviations, informed consent violations, IRB reporting violations, and/or discrepancies that were not documented during monitoring, or monitoring reports were inaccurate.

Correspondence between the sponsor and one or more sites noted ongoing noncompliance with completion, review, and/or submission of CRFs, but monitoring reports did not include information regarding CRF issues or were inaccurate or inconsistent.

The sponsor did not conduct or arrange for monitoring activities.

The sponsor, monitor, or CRO instructed one or more sites to violate the protocol or instituted ad hoc protocol changes without IRB approval or notifying FDA.

Failure to bring non-compliant investigators into compliance

21 CFR

312.56(b)

812.46(a)

The sponsor failed to take action to correct continuing significant noncompliance documented in monitoring or other reports.

Failure to maintain or inadequate accountability for the investigational product

21 CFR

312.57(a), 312.59

511.1(b)(3), 511.1(b)(7)

812.43(b), 812.140(b)(2)

No or inadequate records of distribution and/or retrieval or disposition of the investigational product.

Investigational product was shipped to individuals for whom the sponsor lacks a signed 1572 (for drug and biologics studies) or a signed investigator agreement (for device studies) or who were not named in the Notice of Claimed Investigational Exemption for a New Animal Drug.

Failure to report adverse events

21 CFR

312.50, 312.56(c)[references 312.32]

314.50(d)(5)(vi)(a)

511.1(b)(8)(ii)

514.1(b)(8)(iv)

807.92(b)(2)

812.46(b)

812.150(b)(1)

814.20(b)(6)(ii)

Evidence of adverse events reported by sites but not included in the marketing application/submission; lack of evidence for submission of adverse events reports for ongoing studies.

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., clinical investigators participating in the study(s) or IRBs).

2. Following issuance of a Warning Letter, Centers should be alert to information indicating that a Warning Letter recipient is the sponsor/CRO/monitor responsible for the conduct of other clinical investigations. If such information becomes available, the Center should schedule follow-up inspections to verify if the sponsor/CRO/monitor is fulfilling the terms of any corrective action plans and in compliance with applicable GCP regulations.


 


[10] See http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061430.htm