Description
This guidance provides recommendations to assist sponsors, clinical investigators, and institutional review boards (IRBs) in defining, identifying, and reporting protocol deviations in clinical investigations. FDA regulations do not include a definition of the term protocol deviation or provide a system for classifying the various types of deviations that may occur during the conduct of a clinical investigation. A system that applies consistent classification, reporting, and documentation standards is important to assure the most interpretable and useful information emerges from the reporting of protocol deviations. To address these considerations, this guidance includes definitions for protocol deviations and important protocol deviations, recommendations on the types of protocol deviations that sponsors should report to FDA in clinical study reports for drugs and devices, recommendations on the types of protocol deviations that investigators should report to sponsors and to IRBs, and recommendations for IRBs in their evaluation of protocol deviations.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3Clinical investigations of drugs, including human drugs and biological products
Requires analytical comparability per ICH Q5E
Clinical investigations of medical devices
Stakeholders
6Assist sponsors in the nonclinical evaluation
Governs top dose in clinical studies
Individuals responsible for monitoring and reporting protocol deviations
Bodies responsible for evaluating trial risks and benefits for pregnant participants.; IRBs experienced in this population may advise on compensation.
Responsible for qualifications, training, and trial conduct; Individual responsible for trial conduct and data governance at a site.; May delegate tasks but retains overall responsibility; Person responsible for the conduct of the clinical trial at a trial site; Responsible for trial conduct and participant safety; Responsible for trial conduct, data integrity, and investigational product management.; Individual responsible for trial conduct at a site and informing the institution.; maintaining
Entity responsible for submitting applications under section 524B
Regulatory Context
Regulatory Activities
5The conduct of trials where protocol deviations occur
IND for treatment use; Regulatory submission required for clinical trials and expanded access.
Rule does not apply to products marketed under an NDA
BLA for biological products
Marketing submission type requiring QMS information; Type of marketing submission requiring QMS information
Document Types
6Reports where sponsors should report protocol deviations
Reporting mechanism for certain device protocol changes
Plan used to minimize impact of deviations
A document describing changes made to the original clinical trial protocol.
Defines the standard of veterinary practice and limits for anesthetic regimens
CSR supported by ADaM datasets; Contains analysis results and animal listings
Attributes
2The accuracy and completeness of study data
A critical-to-quality factor in clinical research
Technical Details
Clinical Concepts
3The well-being and rights of clinical trial participants
confirming consent was obtained before participation
Serious and unexpected suspected reactions must be reported
Identified Hazards
Hazards
1Exception for prior IRB approval
ICH References (4)
document remedial actions in the clinical trial report; Structure and Content of Clinical Study Reports standards.
Questions and Answers (R1) defining protocol deviations
Integrated Addendum to ICH E6(R1) document
General Considerations for Clinical Studies
Related CFR Sections (12)
- 21CFR312.30§ 312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application. This section sets forth the provisions under which new protocols may be submitted and changes in previously submitted protocols maRead full regulation →
- 21CFR812.35§ 812.35 Supplemental applications.
(a) Changes in investigational plan —Read full regulation →
- 21CFR312.60§ 312.60 General responsibilities of investigators.
An investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of subjects under the investigator's care; and for the control of drugs Read full regulation →
- 21CFR812.100§ 812.100 General responsibilities of investigators.
An investigator is responsible for ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations, for protecting the rights, safety, and welfare of subjects under the investigator's care, and for the control of devices under inRead full regulation →
- 21CFR312.66§ 312.66 Assurance of IRB review.
An investigator shall assure that an IRB that complies with the requirements set forth in part 56 will be responsible for the initial and continuing review and approval of the proposed clinical study. The investigator shall also assure that he or she will promptly report to the IRB all changes in thRead full regulation →
- 21CFR812.140§ 812.140 Records.
(a) Investigator records. A participating investigator shall maintain the following accurate, complete, and current records relating to the investigator's participation in an investigation:Read full regulation →
- 21CFR812.150§ 812.150 Reports.
(a) Investigator reports. An investigator shall prepare and submit the following complete, accurate, and timely reports:Read full regulation →
- 21CFR312.50§ 312.50 General responsibilities of sponsors.
Sponsors are responsible for selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), ensuring that the investigation(s) is conducted in accordance with the general investigational plan Read full regulation →
- 21CFR312.32§ 312.32 IND safety reporting.
(a) Definitions. The following definitions of terms apply to this section:Read full regulation →
- 21CFR1301.18§ 1301.18 Research protocols.
(a) A protocol to conduct research with controlled substances listed in Schedule I shall be in the following form and contain the following information where applicable:Read full regulation →
- 21CFR56.102§ 56.102 Definitions.
As used in this part:Read full regulation →
- 21CFR56.108§ 56.108 IRB functions and operations.
In order to fulfill the requirements of these regulations, each IRB shall:Read full regulation →
Enforcement Impact
Deficiencies cited in Warning Letters referencing the same regulations
Related Warning Letters (10)
- 2025-09-23
Clinical Investigator/Sponsor
Ralph A. DeFronzo, M.D.
- 2025-09-09
Clinical Investigator
Shirish M. Gadgeel, M.D.
- 2025-07-15
Clinical Investigator
Mark J. Savant, M.D
- 2025-07-01
Clinical Investigator
Peter Michael, M.D.
- 2025-06-03
Bioresearch Monitoring Program
Amy Lightner, MD
- 2025-05-20
Bioresearch Monitoring Program/Institutional Review Board (IRB)
United Health Products, Inc.
- 2025-05-06
Clinical Investigator
Nana Barseghian, M.D.
- 2025-03-25
Clinical Investigator
Americo F. Padilla, M.D.
- 2025-03-18
Clinical Investigator
Mehran Michael Bahrami, M.D.
- 2024-12-03
Clinical Investigator
Han C. Phan, M.D.
See Also (8)
- Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics Guidance for Industry: Guidance for Industry (Status: Final)
- Changes or Modifications During the Conduct of a Clinical Investigation; Final Guidance for Industry and CDRH Staff (Status: Final)
- Considerations for the Conduct of Clinical Trials of Medical Products During Major Disruptions Due to Disasters and Public Health Emergencies (Status: Final)
- Dental Composite Resin Devices - Premarket Notification (510(k)) Submissions: Draft Guidance for Industry and Food and Drug Administration Staff (Status: Draft)
- Sponsor - Investigator - IRB Interrelationship: Guidance for Institutional Review Boards and Clinical Investigators (Status: Final)
- Non-local IRB Review : Guidance for Institutional Review Boards and Clinical Investigators (Status: Final)
- Institutional Review Boards Frequently Asked Questions: Guidance for Institutional Review Boards and Clinical Investigators (Status: Final)
- Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices: Guidance for Industry and Food and Drug Administration Staff (Status: Final)