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SOP Protocol Deviations Handling and Reporting Procedure for Clinical Trials

 Title: Protocol Deviations Handling and Reporting Procedure

Introduction and Purpose:

  • Protocol deviations in clinical research, whether from the clinical research protocol, Good Clinical Practice (GCP) guidelines, or applicable federal regulations, have the potential to jeopardize the safety and rights of study participants and compromise the scientific integrity of the study. Therefore, it is crucial to identify, address, and correct deviations when possible, as well as to establish preventive measures to mitigate future occurrences.
  • Deviations must be documented in accordance with GCP guidelines and reported to the Institutional Review Board (IRB) following the procedures outlined in this Standard Operating Procedure (SOP) and in compliance with IRB policies and procedures. The deviation reporting guidelines provided in this SOP pertain to studies overseen by the clinical site IRB. For studies under a Central IRB (CIRB) or another IRB of record, both the CIRB or IRB-specific deviation reporting requirements and local clinical site Human Research Protections Program (HRPP) requirements must be adhered to.
  • The Principal Investigator (PI) bears the responsibility for conducting clinical research in accordance with the current IRB-approved protocol, GCPs, and relevant federal regulations. The PI may not make any changes to the protocol treatment or procedures without prior IRB approval, except when necessary to protect the safety, rights, or welfare of study participants.

Definitions and Acronyms:

  • Clinical Research: Encompasses all research involving human participants. It does not include secondary studies using existing biological specimens or data collected without identifiers or publicly available data.
  • Clinical Trial: Refers to clinical research studies involving human participants assigned to an intervention designed to evaluate the effect(s) of the intervention on the participant and the effect being evaluated is a health-related biomedical or behavioral outcome.
  • CAPA: Corrective and Preventive Action
  • CFR: Code of Federal Regulations
  • CIRB: Central IRB
  • ERICA: Electronic Research Integrity and Compliance Administration program
  • FDA: United States Food and Drug Administration
  • GCP: Good Clinical Practice
  • ICH: International Council on Harmonization
  • IRB: Institutional Review Board
  • PI: Principal Investigator
  • SOP: Standard Operating Procedure

Procedure:

i) Identification of Protocol Deviations:

  • Clinical research investigators and staff must be familiar with the study protocol, GCPs, and applicable federal regulations and ensure adherence during the conduct of clinical research.
  • Deviations should be identified promptly by the PI or research staff as they occur. When a deviation is suspected, it should be cross-checked against the study protocol, relevant regulations, or applicable GCP principles.
  • Protocols often establish visit windows for completing scheduled procedures and assessments. Procedures and assessments conducted outside these predefined windows are considered deviations.
  • In cases where the protocol does not specify windows and exact timelines for procedures or assessments, reasonable windows may be determined by the investigator to avoid multiple deviations.
  • Deviations may come to light during routine monitoring visits or clinical research record audits. These deviations should be verified as described above and presented to the PI for assessment and potential IRB reporting.

ii) Documentation of Deviations:

  • All deviations, regardless of their severity or outcome, must be documented. Deviations can be recorded electronically (using systems like OnCore, REDCap, Microsoft Excel databases, etc.) or on paper forms (e.g., Protocol Deviation Log).
  • Deviation records should include a clear and concise description of the deviation, including details about which regulatory requirement, GCP principle, or protocol procedure was not followed.
  • The deviation record must contain sufficient attribution, including the date of the deviation, study identification, subject ID, study visit, date of deviation identification, and the identity of the person documenting the information.
  • If corrective actions were taken to address the deviation, the record should also detail these corrective measures.

iii) Deviation Review and Reporting:

  • The PI is responsible for reviewing and assessing all deviations.
  • Any deviations identified by study staff or monitors should be communicated to the PI promptly.
  • Study staff should notify the PI of serious deviations impacting subject safety within 48 hours whenever possible. If the PI is not immediately available, staff should report serious deviations as soon as possible.
  • Other deviations of lesser severity may be communicated to the PI during a monitoring visit close-out meeting or a regular study team meeting following discovery.
  • For industry-sponsored clinical research, the protocol typically outlines requirements for deviation documentation and reporting to the sponsor. Protocol-specific requirements should be followed accordingly.
  • The PI must determine whether the deviation meets any of the following IRB reporting criteria:
  • Intended to eliminate an apparent immediate hazard to a research participant (e.g., changing medication dosage due to toxicity).
  • May have caused possible harm to participants or others, or increased the risk of harm, including physical, psychological, safety, economic, or social harm, such as a breach of confidentiality.
  • Possible serious or continued non-compliance.
  • Serious non-compliance refers to deviations that result in significant harm (physical, psychological, safety, or privacy) or significantly increase the possibility or likelihood of harm to the health, rights, or welfare of study participants.
  • Continuing non-compliance involves a pattern of repeated actions or omissions (either serious or non-serious) that indicates a future likelihood of recurrence and suggests a deficiency in the ability or willingness to comply with the protocol, GCPs, or regulations.
  • The PI, relying on clinical expertise and consideration of the clinical research protocol, subject safety, and applicable regulations, should determine whether the deviations meet the IRB reporting criteria.
  • The PI's assessment of IRB reporting should be documented in the electronic or paper-based record, signed or initiated, and dated by the investigator.
  • If the deviation meets the criteria for IRB reporting, the study coordinator or clinical research coordinator should collaborate with the PI to complete the deviation report in ERICA.
  • Each section of the report template should provide sufficient detail to effectively describe the deviation to IRB administration and board reviewers.
  • The section outlining the plan to prevent the deviation from recurring is particularly crucial. Corrective and preventive action plans (CAPA) should be carefully developed to address the root cause of the problem and prevent further occurrences. If re-training is part of the CAPA, it should be documented.
  • The PI must submit the complete report in ERICA within 10 working days from the date the deviation is identified or the study team becomes aware of it.
  • If the deviation report is not submitted to the IRB within the 10 working days, an accompanying written explanation for the delay must be provided with the report. Late reports may be considered additional non-compliance by the IRB.
  • The IRB will evaluate the deviation report to determine whether it significantly affected the risk to study participants' safety, rights, or welfare, or the integrity of scientific data.
  • The IRB review may lead to requests for additional information, to which the PI must respond within the requested timeframe.
  • After the IRB review is completed, the PI will be notified of the outcome, which may include determinations of "Serious Non-Compliance" and/or "Continued Non-Compliance." Such determinations may necessitate additional corrective and preventative actions by the PI and study team.
  • IRB deviation reports and supporting documents should be retained with the study records.
  • If the study falls under the review and approval authority of a CIRB or another IRB of record, the deviation reporting requirements of that IRB must be followed. Local deviations meeting the IRB's prompt reporting criteria must also be submitted for review by the HRPP.

Materials Required:

  • IRB-approved protocol and informed consent form.
  • Protocol Deviation Log or other department-specific or study-specific deviation documentation form, or an electronic data capture system.
  • Access to ERICA (IRB electronic application and document system).

References:

  • 45 CFR Part 46.103(b)(5)
  • ICH Guidance for Industry E6(R2): Good Clinical Practice, Section 4.5
  • IRB SOP: Protocol Deviations

Document Approval:

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