Good Clinical Practice: A Question & Answer Reference Guide - May 2012 - (Page 325)

by James Nickas, PharmD Ex. Dir., Pharmacovigilance & Medical Writing, BioMarin As much as any aspect of clinical trials regulation, safety reporting principles and requirements have been in a state of evolution through much of the last decade. This evolution has been driven by several factors, including international harmonization efforts, continuing efforts to transition to the electronic submission of regulatory filings, and an ever-increasing focus on product safety due to high-profile drug withdrawals. In accordance with GCP and industry standards, investigators participating in clinical trials of an investigational medicinal product (IMP) are generally instructed to expeditiously report all serious adverse events, regardless of causal attribution, to the sponsor. In addition, adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations are also required to be reported to the sponsor in accordance with protocol instructions. Sponsors are responsible for the ongoing safety evaluation of IMPs and to inform investigators and applicable regulatory authorities of any new information that, based upon appropriate medical judgment, might materially influence the benefit-risk assessment of the IMP or that would be sufficient to consider changes in either product administration or in the overall conduct of a clinical investigation. This includes preclinical findings that suggest significant risk for human subjects, such as reports of mutagenicity, teratogenicity or carcinogenicity. With the continuing emergence of global medical product development programs, sponsors must be aware of, and develop procedures that enable compliance with, applicable international safety reporting regulations. In the United States (US), requirements for safety reporting during clinical trials involving IMPs are set forth in the Code of Federal Regulations (CFR), specifically sections 21 CFR 312.32, 312.33 and 312.64. On March 28, 2011, the United States implemented revisions to 21 CFR 312 and 320 that modify investigational new drug (IND) safety reporting requirements for human drug and biological products and for bioavailability and bioequivalence studies in humans. In the European Community (EC), requirements for clinical trial safety reporting are set forth in Directive 2001/20/EC, specifically Articles 16 (Notification of adverse events) and 17 (Notification of serious adverse reactions). The sponsor’s reporting requirements under Directive 2001/20/EC are further detailed in the European Commission documents entitled, “Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use” (ENTR/CT3 revision 2, April 2006) and “Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions” (Eudravigilance—Clinical Trial Module) (ENTR.CT4 revision 1, April 2004). Safety reporting regulations in the United States, ICH directives, and guidance documents in each region refer to and distinguish between several terms that are critical in establishing clinical trial safety reporting requirements: adverse event; adverse drug experience; adverse (drug) reaction; serious adverse event; serious adverse reaction; suspected adverse reaction; suspected unexpected serious adverse reaction; treatment emergent adverse event; and unexpected adverse event or unexpected suspected adverse reaction. These terms are defined below (with commentary) and are used extensively throughout the questions explored in this section. Adverse Event (AE). The ICH E2A and E6 guidance documents define an AE as “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.” This globally accepted definition of an AE implies that, to be regarded as an AE for drug safety analyses and reporting purposes, the unfavorable or unintended event must occur after exposure to a medicinal product. Some protocols define an AE more broadly as any unfavorable or unintended event associated with any protocol-imposed research intervention, which can include untoward events occurring prior to any IMP exposure. Another AE definition commonly found in today’s protocols is “any change from baseline.” Section 9: Drug/Study Safety and Safety Reporting 325

Table of Contents for the Digital Edition of Good Clinical Practice: A Question & Answer Reference Guide - May 2012

Good Clinical Practice: A Question & Answer Reference Guide - May 2012
Table of Contents
Introduction
Section 1: GCP Regulations, Standards and Guidelines for Clinical Research
Section 2: Investigators/Sites
Section 3: Form FDA-1572/Statement of the Investigator
Section 4: Study Sponsors and Clinical Trial Monitoring
Section 5: Informed Consent
Section 6: Source Data/Documentation
Section 7: Clinical Trial Protocols/Protocol Changes/Protocol Violations
Section 8: Institutional Review Boards
Section 9: Drug/Study Safety and Safety Reporting
Section 10: FDA Inspections, Quality Assurance Activities, and Study Auditing
Section 11: Computerized Systems, e-Clinical Trials, and Electronic Records Rules
Section 12: Patient Recruitment
Section 13: Conflicts of Interest/Financial Disclosure
Section 14: The HIPAA Privacy Rule and FDA-Regulated Clinical Trials
Section 15: Drug Accountability, Administration, and Labeling
Section 16: Fraud, Negligence, and Regulatory Non-Compliance
Section 17: Subject Diaries
Section 18: GCP and Clinical Research Standards in the European Union and An Interview with Fergus Sweeney, Ph.D., EMA Head of Sector, Compliance and Inspection
Section 19: Clinical Trial and GCP Standards in Selected Leading Countries/Regions: Latin America, China, Russia, Ukraine, and India
Section 20: GCP Compliance Statistics and Trends
21 CFR Part 11 — Electronic Records; Electronic Signatures
21 CFR Part 50 — Protection of Human Subjects
21 CFR Part 54 — Financial Disclosure by Clinical Investigators
21 CFR Part 56 — Institutional Review Boards
21 CFR Part 312 — Investigational New Drug Application
ICH Consolidated Guideline on Good Clinical Practice (E6)
ICH Guideline on Clinical Safety Data Management (E2A)
European Union Clinical Trials Directive
European Union Good Clinical Practice Directive

Good Clinical Practice: A Question & Answer Reference Guide - May 2012