Good Clinical Practice: A Question & Answer Reference Guide - May 2012 - (Page 271)

Section 7: Clinical Trial Protocols/Protocol Changes/ Protocol Violations 7.1 Q. How often are protocol-related issues cited as deficiencies in FDA bioresearch monitoring inspections today? A. The failure to adhere to the clinical protocol is consistently the most-commonly cited deficiency in CDER’s inspections of clinical investigators each year. In FY2010 (based on 422 inspection reports), 43% of all clinical investigators/sites inspected by CDER were cited for a failure to follow the investigational plan/protocol, a severalyear high (compared to 40% in FY2009, 32% in FY2008, 34% in FY2007, and 35% in FY2006). For the second consecutive year, a higher percentage of U.S.-based investigators were cited for protocol-related noncompliance in FY2010 (45%, compared to 41% in FY2009, and 32% in FY2008) than were foreign-based investigators (37%, compared to 37% in 2009, and 33% in FY2008,). As these numbers also suggest, protocolrelated citations have risen consistently in recent years for U.S. investigators. It is also important to note that, today, protocol-related issues continue to represent the most common among those issues that CDER terms “significant departures” from GCP standards. Of the clinical investigators cited for serious noncompliance in FY2010 (official action indicated, OAI), 94% were cited for a failure to follow the study protocol (compared to 91% in FY2009, 81% in FY2008, 86% in FY2007 and 81% in FY2006), according to CDER data. From January 2008 through February 2011, CDER issued more than two dozen warning letters to clinical investigators, the vast majority of which included protocol-related noncompliance among the listed citations. The protocol-related citations during this period included the following: • Clinical site failed to follow-up sufficiently with a patient who did not show up for a site visit. The protocol required the investigator to “make an attempt to contact those subjects who do not return for scheduled visits or follow-up.” Although source documents show that the subject dropped from the study after Visit 2 on November 15, 2005, a phone call attempting to contact this subject did not occur until August 17, 2006. • Study vaccine was dispensed by individuals not authorized to dispense the product. • Although the protocol specified that blood samples for chemistry and hematology should be drawn and the results (including Liver Function Test) be reviewed by the investigator or study staff within 24 hours prior to dose administration (for possible dose modification/withholding of treatment), there was no documentation that results were reviewed before subject dosing. Ultimately, the subject was taken for emergency medical care with symptoms of vomiting and fever, and was later pronounced dead by the attending physician with the cause of death being attributed to cardiac arrest due to severe metabolic acidosis related to multiple organ failure. • A cytotoxic agent, which the protocol required be prepared by the pharmacist or designee with training in the safe handling and administration of the agent, actually was prepared by an individual identified only by initials and with no documentation that he/she was the pharmacist or designee. • Seven of 17 subjects enrolled by a clinical investigator did not meet enrollment eligibility criteria established in the protocol. • Clinical examinations were performed by a physician who was not either the clinical investigator or a subinvestigator identified in the 1572-Investigator Statement. The protocol specified that clinical examinations were to be performed by the investigator. • Ten subjects were randomized into a study prior to surgery, contrary to the protocol and prior to the sponsor’s approval of an exemption for these subjects. • Clinical investigator failed to conduct a physical examination for each randomized subject, as required by the protocol. • Clinical investigator screened an additional subject for inclusion in a study after receiving a sponsor letter instructing him to suspend screening new subjects. 271

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