Clinical trials are conducted to allow safety and efficacy data to be collected for health interventions, including drugs, biologics, devices, and therapy protocols. These trials can only take place once satisfactory information has been gathered on the quality of the non-clinical safety. Good Clinical Practices (GCPs) provide a platform for the quality of the data and a unified standard for the conduct of clinical trials.
GCPs describe information to be included in the Investigator's Brochure (IB), a comprehensive document summarizing the body of information about an investigational product (IP) or study drug. The purpose of the IB is to compile data relevant to studies of the IP in human subjects gathered during preclinical and other clinical trials. GCPs define the essential documents necessary to permit evaluation of a clinical study and the quality of data generated.
The investigational product or study drug must be handled and prepared in accordance with Good Manufacturing Practices (GMPs) and used in accordance with the protocol instructions. Informed consent must be obtained from all subjects prior to participation in the clinical study.
In a clinical study, all data must be recorded, handled, and stored properly. Confidentiality of subject records must be maintained in accordance with applicable regulatory requirements. Patient rights, safety, and well-being are of primary concern. Foreseeable risks and inconveniences should be weighed against anticipated benefit. Clinical trials should be scientifically sound and clearly described in the study protocol. The clinical trial should be conducted in compliance with the study protocol.
The clinical study must be approved by an Institutional Review Board (IRB), a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the subjects. Most importantly, a qualified physician must conduct the clinical study.
These requirements describe the conditions under which clinical data from investigational studies would be acceptable in support of a regulatory submission for the approval and commercial use of a drug, biologic, or medical device. The data from the clinical trial is included in regulatory submissions.
These requirements form the basis of U.S. Food and Drug Administration (FDA) inspection activities for clinical trials. When the FDA inspects a clinical trial, they are looking at the following regulations and subparts, including the sections contained therein:
The data for the clinical trial can be electronic or paper-based. Whichever is used, it must be accurate, complete, legible, and recorded in a timely manner. Maintain trial documents during and after conclusion of the study for at least 10 years, as a review of the data will be done by the study sponsor, but it also may be done by the IRB, the FDA, or another regulatory agency.
The FDA conducts routine and for-cause inspections of IRBs, and the Division of Scientific Investigations, Center for Drug Evaluation and Research (CDER), maintains an inventory of IRBs that have been inspected. Sponsors can find out if an IRB has been inspected by the FDA, along with the results of the inspection, through Freedom of Information Act (FOIA) procedures.
Another area the FDA has been focusing on in recent years is ensuring compounded product quality, with traditional compounding facilities coming under greater scrutiny. Through enforcement actions, the agency has been addressing manufacturing quality issues at compounders’ facilities, particularly GMP compliance in outsourcing facilities.
The following are the most common issues cited in FDA inspections of clinical trials, based on my experience as an auditor of clinical trials for study sponsors:
Adherence to the study protocol is critical; too many waivers or deviations from the study protocol are unacceptable. If exceptions, protocol violations, and/or deviations are allowed by the study sponsor, they must be documented properly (with the appropriate signatures). Entering ineligible subjects in a study is a common citation; all subjects must meet the eligibility as defined in the protocol.
Records must confirm the diagnosis or the inclusion and exclusion criteria. There must be evidence of physician oversight (the principal investigator and the sub-investigator). The information within a subject's chart or medical history must be in agreement with the study records. Records must be secure at all times and cannot be lost, misplaced, or destroyed.
The informed consent must have the study subjects’ signatures and the date, and it must be signed and dated prior to any study procedures being performed. The most current, IRB-approved informed consent must be the consent signed. The consenting process must have adequate documentation describing the consent process. Most importantly, the informed consent must be written in a language understood by the study subject.
Drug accountability is an important component of a study. Records cannot be completed retroactively. Drug storage conditions must be monitored and access to the study drug must be limited to study personnel as documented on the study responsibility log.
The reporting of serious adverse events (SAEs) is very important to the FDA because study subjects’ safety is their primary focus. Therefore, it is critical to report all SAEs in a timely manner. They must be documented in subject source records, not only in the case report forms. Any and all laboratory abnormalities must be reviewed and addressed (clinically significant or not clinically significant) by the principal investigator.
What is important to remember is that the protection of the rights of subjects and the safety of the subjects is paramount. This can be obtained by thorough oversight by the sponsor, meticulous documentation, and excellent monitoring by the study monitor.
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