Clinical Safety Management

Ensuring patient safety is a critical aspect of clinical development, starting with the initiation of risk management must commence no later than the decision to begin human trials. The systematic approach to identifying and managing risks involves creating a procedure that outlines the structure and responsibilities of a multidisciplinary team. This team, comprising representatives from various medical functions, is accountable for promptly reviewing and evaluating safety data.

It is advisable to initiate the formulation of components for risk assessment and risk minimization plans early in development. Specific concerns or interests in adverse events may prompt the implementation of special monitoring procedures based on factors such as therapeutic or pharmaceutical class, animal toxicology studies, or the known mechanism of action. Safety reviews focus on issue identification, determining implications, deciding on appropriate actions, and monitoring and assessing results. Meetings involve a clear assessment to determine new issues or recent developments related to previously identified issues.

The Individual Case Safety Report (ICSR) is the fundamental unit for safety analysis, providing insights, especially regarding serious adverse events (SAE) and adverse events of special interest (AESI) during clinical development. Understanding the evolving safety profile, detecting potential signals, and evaluating aggregate data (DSUR, Annual reports, etc.) require a thorough understanding of existing safety data, patient populations, and risk factors. Sponsors may establish an independent Data and Safety Monitoring Board (DSMB) for ongoing safety data review, commonly for a single large clinical trial.

The sponsor is responsible for the ongoing safety evaluation of the Investigational Medicinal Product(s) used in a Clinical Trial of Investigational Medicinal Products.

The following safety information must be communicated to regulatory bodies.

• Expedited Safety Reporting: Most of the regulations that describe safety reporting from clinical trials focus on the expedited reporting of individual case safety reports (ICSRs). The sponsors should submit suspected adverse drug reactions that are both serious and unexpected to regulators within 7 (if fatal or life-threatening) or 15 calendar days in an appropriate format.
• Annual Safety Reporting: Most of the authorities accept Development Safety Update Report (DSUR) as outlined in the ICH E2F Guidelines along with regional specific appendix like in the U.S., the FDA IND regulations define an “annual IND report” which includes line listings of the most serious and the most frequent adverse events as well as reasons for discontinuation.
• Urgent safety measures: Measures taken to protect clinical trial subjects due to an unexpected event that is likely to seriously affect the benefit-risk balance of the clinical trial.

Analysis of Safety Information

• The frequent review of serious and special interest adverse events, as well as overall assessment of all AEs, regardless of seriousness, causality, or expectedness, should be performed periodically:
  > Ad hoc, for serious and special interest AEs,
  > Routine, periodic, general review of all data, whose frequency will vary from trial to trial and from development program to development program and depend on many factors, and
  > Reviews triggered by specific milestones established for a trial or a program (e.g., numbers of completed patients, end-of-trial, end-of-program, preparation of integrated summary of safety, and a marketing application).
• Appropriate analyses should also be conducted periodically for safety-related information other than AEs, including physical examination findings, vital signs, clinical laboratory tests, cardiac electrophysiology, and other evaluations.
• Aggregate safety data should be monitored and evaluated periodically during the course of the overall developmental program, during each study, and at the end of every study to provide an ongoing appraisal of benefit- risk balance.
• Each time a study is completed and unblinded, all safety information, not limited to clinical AEs but ideally including emerging efficacy endpoints, vital signs, and clinical investigation results, should be assessed and evaluated relative to previous knowledge; product information should be updated as needed (investigator brochure, development core safety information, informed consent, company core safety information, local datasheets).

Following eCTD modules will used as source document for RMP Authoring

• Module 2.3 Quality overall summary
• Module 2.4 Non-clinical overview
• Module 2.5 Clinical overview
• Module 2.6 Non-clinical written and tabulated summaries
• Module 2.7 Clinical summary
• Module 3 Quality
• Module 4 Non-clinical study reports
• Module 5 Clinical Study reports

Yes, the marketing authorization holder may publish the educational material(s) on a specifically dedicated (or other suitable) website, provided that the marketing authorization holder respects the following:

• The way in which dissemination via the website occurs should be agreed with the competent authority of the Member State, i.e. as primary or as an additional way for dissemination.
• The website address should be given to the competent authority of the Member State.
• A statement that the information of the website is consistent with the educational material approved by the competent authority should be submitted to the competent authority of the Member State.
• The specific website should not include any reference to documents or to other websites/pages or weblinks not agreed with the competent authority of the Member State.
• All elements and information on the specific website should be expressed in the official language(s) as required by the Member State or, in exceptional cases with the agreement of the competent authority of the Member State, in English.
• The specific website should not contain references to or information about medicinal products not marketed in that Member State.

Other relevant documents such as the SmPC, the PL and the summary of the RMP may be referred to.