GOOD CLINICAL PRACTICE (GCP): A REVIEW
Development of support systems and tools
Appropriate support systems and tools facilitate the conduct of the study and collection of data required by the protocol. Support systems and tools include, but are not limited to, trial-related information documents (e.g., investigator’s brochure, case report forms [CRFs], checklists, study flow sheets, drug accountability logs; computer hardware and software, electronic patient diaries, and other specialized equipment. The sponsor is generally responsible for developing, maintaining, modifying, and ensuring the availability of support systems and tools for conducting the trial and collecting and reporting required data. For example, the sponsor may consider developing/designing/providing/ designating:
· diagnostic or laboratory equipment required by the study protocol, and procedures/schedules for servicing the equipment according to the manufacturer’s specifications;
· computer systems (hardware and software) to be used in the clinical trial (e.g., statistical or other software, electronic patient diaries, coding of personal data), and software validation systems, as needed;
· facsimile or other communications equipment to facilitate reporting of serious adverse events;
· information and training tools for clinical investigators and site personnel.
Generation and approval of trial-related documents
Development of trial-related documents may facilitate the conduct of the study, collection and reporting of study-related data, and analysis of study results. The sponsor generally develops, designs, and provides various standardized forms and checklists to assist the clinical investigator and his/ her staff in capturing and reporting data required by the protocol.
Examples of trial information documents include, but are not limited to:
· investigator’s brochure;
· checklists to identify and document the required steps for each of the various clinical trial activities (e.g., investigator selection, approvals and clearances, monitoring, adverse event reporting and evaluation, analysis of interim data);
· investigational supplies accountability forms to document the amount and source of investigational product shipped and received, the amount dispensed to subjects, and the return/destruction, as appropriate, of any unused product;
· signature logs and other forms to document by whom activities are completed, when, and the sequence in which they are carried out;
· case report forms (CRFs) for each scheduled study visit to capture all of the necessary data collected from and reported for each subject;
· informed consent documents;
· adverse event or safety reporting forms;
· administrative forms to track research funds and expenses;
· forms to disclose information about the investigator’s financial, property, or other interests in the product under study, in accordance with national/local law or regulations;
· formats for reports of monitoring visits;
· formats for progress reports, annual reports, and final study reports.
Selection of trial sites and the selection of properly qualified, trained, and experienced investigators and study personnel
Clinical investigators must be qualified and have sufficient resources and appropriately trained staff to conduct the investigation and be knowledgeable of the national setting and circumstances of the site and study population(s). Sponsors should review the requirements of the study protocol to determine the type(s) of expertise required and identify clinical investigators who have the particular medical expertise necessary to conduct the study and who have knowledge, training and experience in the conduct of clinical trials and human subject protection.
Ethics committee review and approval of the protocol
Within GCP, studies must be reviewed and receive approval/ favourable opinion from an Independent Ethics Committee (IEC)/ Institutional Review Board (IRB) prior to enrollment of study subjects. The investigator generally assumes responsibility for obtaining IEC/ IRB review of the study protocol. Copies of any approval/favourable opinion are then provided to the sponsor.
Review by regulatory authorities
Within GCP, studies must undergo review by regulatory authority(ies) for use of the investigational product or intervention in human subjects and to ensure that the study is appropriately designed to meet its stated objectives, according to national/regional/local law and regulations. [Note: Some countries may not have systems in place for reviewing research or may depend on external review. Also, some countries may have additional requirements for the review and approval of trial sites and/or investigators.] The sponsor is generally responsible for ensuring that the applicable regulatory authority(ies) review and provide any required authorizations for the study before the study may proceed. The sponsor should also list the trial in applicable and/or required clinical trial registry(ies).
Enrollment of subjects into the study: recruitment, eligibility, and informed consent
The clinical investigator has primary responsibility for recruiting subjects, ensuring that only eligible subjects are enrolled in the study, and obtaining and documenting the informed consent of each subject. Within GCP, informed consent must be obtained from each study subject prior to enrolment in the study or performing any specific study procedures.
The investigational product(s): quality, handling and accounting
Quality of the investigational product is assured by compliance with Good Manufacturing Practices (GMPs) and by handling and storing the product according to the manufacturing specifications and the study protocol. GCP requires that sponsors control access to the investigational product and also document the quantity(ies) produced, to whom the product is shipped, and disposition (e.g., return or destruction) of any unused supplies. GCP also requires investigators to control receipt, administration, and disposition of the investigational product.
Trial data acquisition: conducting the trial
Research should be conducted according to the approved protocol and applicable regulatory requirements. Study records documenting each trial-related activity provide critical verification that the study has been carried out in compliance with the protocol. .
Safety management and reporting
All clinical trials must be managed for safety. Although all parties who oversee or conduct clinical research have a role/responsibility for the safety of the study subjects, the clinical investigator has primary responsibility for alerting the sponsor and the IEC/IRB to adverse events, particularly serious/life-threatening unanticipated events, observed during the course of the research. The sponsor, in turn, has primary responsibility for reporting of study safety to regulatory authorities and other investigators and for the ongoing global safety assessment of the investigational product. A data and safety monitoring board (DSMB) may be constituted by the sponsor to assist in overall safety management.
Monitoring the trial
Sponsors generally perform site monitoring of a clinical trial to assure high quality trial conduct. The sponsor may perform such monitoring directly, or may utilize the services of an outside individual or organization (e.g., contract research organization [CRO]). The sponsor determines the appropriate extent and nature of monitoring based on the objective, purpose, design, complexity, size, blinding, and endpoints of the trial, and the risks posed by the investigational product. The “on site” monitors review individual case histories in order to verify adherence to the protocol, ensure the ongoing implementation of appropriate data entry and quality control procedures, and verify adherence to GCP. In blinded studies, these monitors remain blinded to study arm assignment. For an investigator-initiated study, the sponsor-investigator should consider the merits of arranging independent, external monitoring of the study, particularly when the study involves novel products or potential significant risks to subjects.
Managing trial data
Within GCP, managing clinical trial data appropriately assures that the data are complete, reliable and processed correctly, and that data integrity is preserved. Data management includes all processes and procedures for collecting, handling, manipulating, analysing, and storing/archiving of data from study start to completion. The sponsor bears primary responsibility for developing appropriate data management systems. The sponsor and the investigator share responsibility for implementing such systems to ensure that the integrity of trial data is preserved. Data management systems should address (as applicable):
· data acquisition;
· confidentiality of data/data privacy;
· electronic data capture (if applicable);
· data management training for investigators and staff;
· completion of CRFs and other trial-related documents, and procedures for correcting errors in such documents;
· coding/terminology for adverse events, medication, medical histories;
· safety data management and reporting;
· data entry and data processing (including laboratory and external data);
· database closure;
· database validation;
· secure, efficient, and accessible data storage;
· data quality measurement (i.e., how reliable are the data) and quality assurance;
· management of vendors (e.g., CROs, pharmacies, laboratories, software suppliers, off-site storage) that participate directly or indirectly in managing trial data.
Quality assurance of the trial performance and data
Quality assurance (QA) verifies through systematic, independent audits that existing quality control systems are working and effective. Quality assurance audits may be performed during the course of the clinical trial and/or upon trial completion. Sponsors bear primary responsibility for establishing quality systems and conducting quality assurance audits.
Reporting the trial
The results of each controlled study involving an investigational product should be summarized and described in an integrated clinical study report containing clinical data and statistical descriptions, presentations, and analyses. The report should be complete, timely, well-organized, free from ambiguity, and easy to review. The sponsor is responsible for preparing clinical study reports. Such reports should generally include:
· a description of the ethical aspects of the study (e.g. confirmation that the study was conducted in accordance with basic ethical principles);
· a description of the administrative structure of the study (i.e. Identification and Qualifications of investigators/sites/other facilities);
· an introduction that explains the critical features and context of the study (e.g. rationale and aims, target population, treatment duration, primary endpoints);
· a summary of the study objectives;
· a description of the overall study design and plan;
· a description of any protocol amendments;
· an accounting of all subjects who participated in the study, including all important deviations from inclusion/exclusion criteria and a description of subjects who discontinued after enrolment;
· an accounting of protocol violations;
· a discussion of any interim analyses;
· an efficacy evaluation, including specific descriptions of subjects who were included in each efficacy analysis and listing of all subjects who were excluded from the efficacy analysis and the reasons for such exclusion;
· a safety evaluation, including extent of exposure, common adverse events and laboratory test changes, and serious or unanticipated or other significant adverse events including evaluation of subjects who left the study prematurely because of an adverse event or who died;
· a discussion and overall conclusions regarding the efficacy and safety results and the relationship of risks and benefits;
· tables, figures, and graphs that visually summarize the important results or to clarify results that are not easily understood;
· a reference list. Where permitted, abbreviated or less detailed reports may be acceptable for uncontrolled or aborted studies.
PRINCIPLES OF GCP:
Principle 1: Research involving humans should be scientifically sound and conducted in accordance with basic ethical principles, which have their origin in the Declaration of Helsinki. Three basic ethical principles of equal importance, namely respect for persons, beneficence, and justice, permeate all other GCP principles.
Principle 2: Research involving humans should be scientifically justified and described in a clear, detailed protocol.
Principle 3: Before research involving humans is initiated, foreseeable risks and discomforts and any anticipated benefit(s) for the individual trial subject and society should be identified. Research of investigational products or procedures should be supported by adequate non-clinical and, when applicable, clinical information.
Principle 4: Research involving humans should be initiated only if the anticipated benefit(s) for the individual research subject and society clearly outweigh the risks. Although the benefit of the results of the trial to science and society should be taken into account, the most important considerations are those related to the rights, safety, and well-being of the trial subjects.
Principle 5: Research involving humans should receive independent ethics committee/institutional review board (IEC/IRB) approval/ favourable opinion prior to initiation.
Principle 6: Research involving humans should be conducted in compliance with the approved protocol
Principle 7: Freely given informed consent should be obtained from every subject prior to research participation in accordance with national culture(s) and requirements. When a subject is not capable of giving informed consent, the permission of a legally authorized representative should be obtained in accordance with applicable law.
Principle 8: Research involving humans should be continued only if the benefit-risk profile remains favourable.
Principle 9: Qualified and duly licensed medical personnel (i.e., physician or, when appropriate, dentist) should be responsible for the medical care of trial subjects, and for any medical decision(s) made on their behalf.
Principle 10: Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s) and currently licensed to do so, where required.
Principle 11: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.
Principle 12: The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
Principle 13: Investigational products should be manufactured, handled, and stored in accordance with applicable Good Manufacturing (GMP) and should be used in accordance with the approved protocol.
Principle 14: Systems with procedures that assure the quality of every aspect of the trial should be implemented.
These principles are self-explanatory and, when summarized, simply mean: All clinical trials should be conducted in accordance with ethical principles, sound scientific evidence and clear detailed protocols. The benefits of conducting trials should outweigh the risks. The rights, safety and well being of trial participants are of paramount importance and these should be preserved by obtaining informed consent and maintaining confidentiality. The care must be given by appropriately qualified personnel with adequate experience. Records should be easily accessible and retrievable for accurate reporting, verification and interpretation. Investigational products should be manufactured according to Good Manufacturing Practice . It is also important to mention the participants of GCP in clinical trials and their respective responsibilities.
The events that led up to the culmination of the GCP guidelines brought forth public awareness that there was a need to control and regulate clinical trials dealing with drugs and human subjects lies in historical background that led to the formulation of GCP guidelines in the United States and Europe and also to the formation of the ICH. The violation of human rights played a large role and that is why the Declaration of Helsinki and The Nuremberg Code remain as the framework of the present guidelines. Today the GCP guidelines are become a global law which safeguards humanity.
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4. Office of Human Subjects Research. The Nuremberg Code, 1949, ohsr.od.nih.gov/guidelines/nuremberg.
5. The Doctors Trial (the Medical Case of the Subsequent Nuremberg Proceedings), ushmm.org/research/doctors/Nuremberg_Code.htm.
6. The World Medical Association. Declaration of Helsinki, 2004, wma.net/e/policy/b3.htm.
7. Vadivale M: ICH-GCP Guidelines for Clinical Trials. Berita MMA. 1999, 7:29
8. ICH E6: Good Clinical Practice: Consolidated Guideline 1996. ich.org/
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