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SOP on Safety Events Reporting In Clinical Trials

Title: Standard Operating Procedure for Collection, Evaluation, Documentation, and Reporting of Safety Events in Clinical Trials

Introduction and Purpose

The assessment of safety events and the accurate reporting of these events are fundamental aspects of conducting clinical trials. These processes are crucial for ensuring the safety and well-being of research participants. This Standard Operating Procedure (SOP) outlines the procedures for collecting, evaluating, documenting, and reporting safety events, including Adverse Events (AE), Serious Adverse Events (SAE), Unanticipated Problems (UP), and other relevant safety events during the course of a clinical trial.

The Principal Investigator (PI) holds the primary responsibility for the overall conduct of the trial, safeguarding the rights, safety, and welfare of study subjects, and ensuring that the investigation adheres to the protocol, Good Clinical Practice (GCP), Institutional Review Board (IRB), Food and Drug Administration (FDA), and all other applicable regulations. Safety events must be collected and reported following the protocol and the guidelines presented in this SOP, as applicable.

Definitions and Acronyms

  • Adverse Event (AE): Any unfavorable medical occurrence or worsening of an existing condition in a clinical trial participant, which may or may not have a causal relationship with the study treatment.
  • Suspected Adverse Reaction: An adverse event for which there is a reasonable possibility that the drug caused the adverse event.
  • Serious Adverse Event (SAE): An adverse event or suspected adverse reaction is considered "serious" if it results in specific outcomes such as death, life-threatening conditions, hospitalization, significant incapacity, congenital anomalies, or other significant medical events.
  • Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on the health or safety of a participant, including life-threatening issues or death, caused by or associated with a device not previously identified in the investigational plan or application, or any other unanticipated serious problem related to the device's impact on the rights, safety, or welfare of subjects.
  • Safety Event Evaluation Criteria: Safety events must be evaluated based on criteria relevant to the study protocol and applicable regulatory authorities. Common evaluation criteria include:
  • Severity: The intensity of the adverse event and its impact on the participant's health, categorized on a scale such as Mild, Moderate, Severe, Life-threatening, or Death.
  • Attribution or Relatedness: The determination of whether there is a causal relationship between an adverse event and the investigational product or intervention. This may be rated on a scale like Unrelated, Unlikely Related, Possibly Related, Probably Related, or Definitely Related.
  • Expectedness: Whether the adverse event and its characteristics are anticipated based on the current understanding of the research intervention or the expected progression of the participant's underlying condition.
  • Prompt Reporting: The urgency and speed required for reporting events that meet specific criteria, which may be defined by the IRB, Human Research Protection Program, study sponsor, or applicable oversight agencies.

Procedure

Collection of Safety Events

  • The PI and study staff should familiarize themselves with the safety profile of the investigational product by reviewing the study protocol, informed consent documents, Investigator's Brochure, package insert, safety reports related to the investigational product, and safety event evaluation criteria specified by the IRB, Human Research Protection Program, study sponsor, or oversight agencies.
  • Safety events should be collected according to the protocol-defined reporting window or, if not specified, until one of the following conditions is met: completion of the safety follow-up window, withdrawal of consent by the participant, or resolution or stabilization of safety events related to the investigational product.
  • A baseline assessment of the participant's medical history and comorbidities should be conducted before any clinical research intervention, including a review of the participant's systems and medical history.
  • Throughout the study, safety information should be collected from various sources, including participant reports, investigator observations, abnormal laboratory or imaging findings, and non-study-related medical encounters.

Evaluation of Safety Events

  • After identifying an adverse event, the PI or a qualified study team member should assess its severity, attribution, expectedness, seriousness, and, if applicable, whether it meets protocol-defined stopping rules such as Dose Limiting Toxicity (DLT).
  • Severity should be assessed based on the relevant scale specified in the protocol or by regulatory authorities.
  • Attribution or relatedness should be determined based on the policy of the reviewing IRB, the institution's Human Research Protection Program, the study sponsor, or oversight agencies. If the study involves multiple interventions, attribution should be assessed independently for each.
  • Expectedness should be determined by comparing the event to the information provided in the protocol, Investigator's Brochure, informed consent forms, product labeling, and the natural progression of the participant's underlying condition.

Documentation of Safety Events

  • Safety events for each participant should be recorded cumulatively and accurately, either in an adverse event log, source documents, or Case Report Forms (CRFs).
  • The assessment of each safety event, including severity, attribution, expectedness, seriousness, and whether it meets DLT criteria, should be documented, signed, and dated by the investigator or a designated team member.

Reporting Safety Events

  • Safety information must be reported to the relevant parties, including the Sponsor, Contract Research Organization (CRO) if applicable, IRB, Data Safety Monitoring Committee/Board, FDA, or other sponsoring agencies, as specified in the protocol.
  • Reporting methods and timelines may vary by study and should be outlined in the protocol or separate guidance documents. Common reporting methods include paper-based forms, Electronic Data Capture (EDC) systems, or other designated formats.
  • The reporting frequency and extent depend on the characteristics of the event, such as expectedness, relatedness, and seriousness. Expedited reporting is typically required for certain events, with initial notification within 24 business hours and follow-up reporting as necessary.

Institutional Review Board (IRB) Reporting

  • The IRB of record should be consulted for guidance on reporting safety information, including unanticipated problems or events.
  • The PI or a qualified team member should review and confirm safety events that meet IRB reporting requirements.
  • The IRB requires reporting of adverse events that are unexpected, definitely or probably related to the research, and place participants or others at greater risk of harm than previously known.
  • Reporting requirements and timeframes can be found on the IRB website.

Food and Drug Administration (FDA) Reporting

  • For studies falling under FDA regulations, adverse events meeting specific criteria must be promptly reported to the FDA. These criteria include events that are serious, unexpected, and related (definitely, probably, or possibly).
  • Reporting timeframes for FDA-regulated studies are provided in this SOP and may vary based on the characteristics of the event.
  • Responsibilities for reporting to the FDA depend on whether the study is industry-sponsored or investigator-initiated. The SOP provides guidance for both scenarios.

Reporting External Safety Events

  • External safety events, such as those from sponsors, coordinating centers, or IP manufacturers, should be reviewed and assessed for their impact on the study's conduct, informed consent document, or investigator brochure.
  • The sponsor is responsible for notifying investigators of important safety information and unanticipated problems that affect the research.
  • Investigators are not required to actively monitor external sources for safety information but should promptly report relevant safety events to the IRB.

Materials Required

  • Study protocol
  • IRB of record safety event reporting requirements
  • Template adverse event log (available at provided link)

References

  • 21 CFR Part 312.32 IND Safety Reporting
  • 21 CFR Part 812 Investigational Device Exemptions
  • FDA Guidance for Industry: Safety Reporting Requirements for INDs and BA/BE Studies
  • ICH Guidance for Industry E2: Clinical Safety Data Management
  • NCI Common Terminology Criteria for Adverse Events

Document Approval

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