Clinical trials are conducted to allow safety and efficacy data to be collected for health interventions (e.g., drugs, biologics, devices, therapy protocols). These trials can only take place once satisfactory information has been gathered on the quality of the non-clinical safety. The regulations that provide a platform for the quality of the data are Good Clinical Practices or GCPs.
GCPs are an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve human subjects. The regulations applicable to GCPs are found in the Code of Federal Regulations. The Code of Federal Regulations (CFR) is the codification of the general and permanent rules and regulations published in the Federal Register by the executive departments and agencies of the Federal Government of the United States. The CFR is divided into 50 titles that represent broad areas subject to federal regulation. The enforcement of Title 21 is the responsibility of the US Food and Drug Administration (FDA). The regulations for GCPs are found in Title 21 and Part 50 - Informed Consent, Part 56 - Institutional Review Board. Rules are also in the Code of Federal Regulations, Title 21, and Part 312, subpart D-Responsibilities of Sponsors and Investigators. The CFR is also supported by multiple guidance documents generated by the FDA; these are entitled "Guidance for Industry." A large number of these documents are in place to support the requirements in 21 CFR.
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Always document internal training on the Study Protocol, SOPS, and GCPs.
A significant portion of FDA regulations/requirements and Industry Guidelines pertain to Good Clinical Practices (GCPs). That being said, what are the basic principles of these regulations as they pertain to clinical trials? Good Clinical Practices provide a unified standard for the conduct of clinical trials.
Briefly I will outline what these regulations require for the conduct of a clinical trial.
GCPs describe information to be included in the Investigator's Brochure (IB). The IB is a comprehensive document summarizing the body of information about an investigational product 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. Each professional involved in the clinical study must be qualified for his/her task by education, training and experience.
Informed consent must be obtained from all subjects prior to participation in the 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). An institutional review board is 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 these subjects. IRBs may be associated with a hospital or institution but may also be a private enterprise.
Most importantly, a qualified physician must conduct the clinical study.
What do these regulations/requirements mean and what does the clinical trial data impact?
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 (IND, NDA, or BLA).
These requirements form the basis of FDA Inspectional Activities for Clinical Trials. When the FDA inspects a clinical trial they are looking at the following regulatory criteria:
The Principle Investigator (PI) is the most critical part of the clinical trial. The PI must be qualified by education, training, and experience to assume the responsibility for the proper conduct of the trial. The PI must personally conduct and/or supervise the trial.
The PI must ensure that all persons involved in the study are qualified and properly trained. The names of the clinical trial staff, qualifications (CVs and licenses) and delegated tasks need to be documented. The PI must assure compliance with GCPs, SOPs and any other regulatory requirements. The PI must read and understand the Investigators' Brochure and the Study Protocol. During the trial the PI and clinical trial staff must assure adherence to Study Protocol.
Always document internal training on the Study Protocol, SOPS, and GCPs. Keep files of who attended and what was covered in the training sessions.
Document any delegation of authority by the PI to clinical trial staff.
One of the most important things in a study is adherence to the Study Protocol. In the eyes of the FDA, any deviation from the protocol is violative, whether or not the study sponsor has accepted the deviation or granted a waiver.
Another critical aspect is the clinical trial subjects; only recruit qualified study subjects. Ensure that each subject signs a current IRB-approved Informed Consent (IC) prior to any study procedure. Institutional Review Board (IRB) approval of protocol and the IC must be obtained prior to the start of the study. The IRB must also approve protocol amendments, advertisements for the study, and the Investigators' Brochure.
The IC must be reviewed with trial subjects and all questions must be answered, again prior to the start of the study.
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. A review of the data will certainly be done by the Study Sponsor but it also may be done by the IRB, the FDA or another regulatory agency. Maintain trial documents during and after conclusion of the study for at least 10 years. The Study Sponsor must be notified before any records related to the study are moved or scheduled to be destroyed.
The PI is also responsible for providing a written status summary to IRB, a written report to sponsor/IRB regarding significant study changes and a final study report to sponsor/IRB.
However, the most important responsibility of the PI is managing and reporting Serious Adverse Events to the Study Sponsor within 24 hours (of the event) by fax or phone.
The PI and clinical trial staff are responsible for the management, storage, security and administration of the study drug. The study drug must have secure, controlled access storage. It can only be administered under the supervision of the PI or a Sub-investigator. Maintain records of receipt and use of the study drug.
The Principal Investigator or the Sub-investigator who is directly involved in the treatment or evaluation of research subjects, including spouses and dependent children, cannot be compensated (financially) for an amount that could influence the outcome of the clinical trial.
Therefore, the Principal Investigator or the Sub-investigator cannot have equity interest in the study sponsor's company or the study drug itself greater than $50,000 US dollars.
The Principal Investigator or the Sub-investigator cannot have proprietary interest in the study drug.
So, as an experienced auditor of Clinical Trials for Study Sponsors, what have I seen as the most common issues cited by FDA in their inspections of clinical trials?
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 then they must be documented properly (with the appropriate signatures).
The entering of ineligible subjects in the study is a common citation; all subjects must meet the eligibility as defined in the Protocol. If follow-up visits are required, the schedule must be respected. All study staff including the Principal Investigator and the Sub-investigator must have a complete understanding of the study protocol.
Clinical 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 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 Signatures of the study subjects and the date. The Informed Consent must be signed and dated prior to any study procedures being performed. The most current (approved by the IRB) Informed Consent must be the consent signed. The consenting process must have adequate documentation describing the consent process and 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 retrospectively. 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 safety of study subjects is their primary focus. Therefore, it is critical to report all SAEs and report them timely. SAEs and AEs must be documented in subject source records (charges, study notes, etc) and 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.
In conclusion, 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.
Michelle Sceppa is the Principal at MSceppa Consulting, an established Consulting firm in its 14th year in Industry. MSceppa Consulting specializes in quality systems for Pharmaceutical and Biotechnology interests and has implemented and managed Preclinical, Clinical, and Manufacturing Quality Assurance Programs for numerous clients. As the lead auditor, MSceppa Consulting has conducted and managed more than 500 internal and external vendor audits for Drug and Biologic firms in the US and Europe. MSceppa Consulting is knowledgeable in the details of compliance with all U.S. Federal Regulations-Good Laboratory Practice (GLP), Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) for Drugs, Biologics and Medical Devices. Contact her at 617-620-2500 or via email at email@example.com or visit her website at msceppaconsulting.com.