1. INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, performing, recording and reporting clinical studies that involve participationof human volunteers.
Good Clinical Practices are based on principles laid down in the Declaration of Helsinki.
Good Clinical Practices provide public assurance that the rights, safety, well-being and privacy of trial volunteers are protected and data obtained from the trials are safe.
The objective of Good Clinical Practice Guideline is to provide a single standard to facilitate the mutual acceptance of clinical data internationally.
This guideline guidesthe users on generating clinical trial data that are intended to be submitted to the Ministry, and describes the principles and details of conducting clinical trials in our country.
2. DEFINITIONS
2.1.Adverse Effect: It is the undesired effect which occurs in the trial volunteer with any dose of the investigational product administered, or with the use of the investigational medical device.
2.2.Adverse Event: Any undesired medical event in a trial volunteer occurring irrespective of whether there is a causal relationship with the treatment applied.Adverse event includes any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal investigational product, whether or not related to the medicinal product.
2.3.Adverse Reaction: In the pre-registration clinical trials with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be determined yet, all adverse events against a medicinal product related to any dose, including the status of the medicinal product, which is found to have logical causal relationship with the medicinal product, should be considered adverse reactions.The term of “logical causal relationship” is used for stating the presence of evidence or an opinion to suggest a causal relationship.Adverse reaction regarding authorized medicinal products refers to a reaction to a drug which is harmful and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis, treatment of diseases or for modification of physiological function.
2.4.Study Brochure: Documentation consisting of all clinical and non-clinical data for the investigational product/medical device or products/medical devices.
2.5.Study Protocol: A document that describes the objective, design, statistical methodology, and organization of a trial.
2.6.Study Protocol Amendment: Documentation of a change to a study protocol.
2.7.Investigational Product: A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial or the medical devices for clinical trial.It includes a product with a marketing registration when used or assembled (formulated or packaged) in a way that is different than the approved form, or when used for an unapproved indication, or used to gain further information about an approved use.
2.8.Independent Data Monitoring Committee (Data Monitoring Group or Data Safety Monitoring Committee):A committee, comprised of specialists independent from the trial, that may assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
2.9.Unexpected Adverse Effect: The adverse reaction of the investigational product, that's not included in the Summary of product characteristics for an authorized product, in the instructions for use for an approved product and in the study brochure for a non-authorized product.The adverse reaction which is not stated in the operating instructions of the investigational medical device in the medical device clinical trials.
2.10.Informed Consent Form (ICF):It's a document that reveals the written consent of the volunteer showing that the volunteer has decided to participate in the trial completely by his/her own will and handed her/his signature and written the date, or if the volunteer is visually impaired and if the volunteer or the legal representative is not literate, the verbal consent of the volunteer obtained in the presence of at least one independent witness and by obtaining the signature of the witness, after all information on the trial, the importance of the administration with respect to human health and the related risks have been fully explained to the volunteer or his/her legal representative, whenever necessary.
2.11.Serious Adverse Event or Effect: Any adverse event or effect that leads to death, life-threatening condition, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or a congenital anomaly/birth defect.
2.12.Double Dummy: It is a blinding method used for masking the products administered to the study groups in blinded trials, where an investigational product is compared with another product, if it is not possible that both groups of products have similar appearance.Accordingly, the study groups are administered the investigational products by for example administering placebo tablet and the ampoule containing the active substance to one group and administering the tablet containing the active substance and placebo ampoule to the other group.
2.13.Multi-Center Clinical Study: A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one principal investigator.
2.14.Inspection: The act by the Ministry of conducting an inspection of the study documents and records and places where they archived, quality assurance regulations, domestic and foreign trials, the trials sites previously approved by the Ministry, the sites owned by the sponsor and the contract research institution or the manufacturing and storage places of the investigational products,the laboratories performing trial-related analyses and all other institutions, committees and organizations, related with the trial, including the Ethics Committee, with respect to compliance with the relevant regulations, by notifying in advance or not.
2.15.Inspection Report: The report issued by the relevant health authority at the end of the inspection.
2.16.Sponsor: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial; or if the trial will be conducted in collaboration with the scientific research projects of Turkish Scientific and Technical Researches Institution (TUBITAK), State Planning Organization (DPT) or universities, directly the principal investigator of the project; or if there's no sponsor, the study coordinator in multi-center trials and the principal investigator in single-center trials.
2.17.Direct Access: Permission to examine, analyze, verify, and reproduce any records and reports for evaluation of a clinical trial.Any party (e.g., the Ministry of Health (the Ministry) and relevant health authorities) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirements to maintain the confidentiality of volunteers' identities and sponsor's proprietary information.
2.18.Documentation: All documents in any form including written, electronic, magnetic records and scans, x-rays and electrocardiograms that describe and record the methods, conduction, and/or results of a trial, the factors affecting a trial, and the actions taken.
2.19.Ethics Committee: The independent committees to be constituted according to clinical research fields and approvedby the Ministry, whose responsibility is to evaluate all clinical trials in ethical respects to ensure volunteer safety, conducting and monitoring the trial in accordance with the relevant regulations and to provide scientific and ethical opinion on the trial protocol, the suitability of the investigator, facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial volunteers in order to ensure the protection of the rights, safety and well-being of volunteers involved in a trial.
2.20.Vulnerable Volunteers:Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether accepted or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, soldiers and persons kept in detention.
Other vulnerable volunteers include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, and patients in emergency situations, children, and those incapable of giving consent.
2.21.Essential Documents:Documents which individually and collectively permit evaluation of conduction of a study and the quality of the data produced.
2.22.Non-invasive Clinical Trial: All observational studies, the survey studies, retrospective archive screenings such as files and imaging records, studies conducted with biochemistry, microbiology, pathology and radiology collection materials such as blood, urine, tissue and radiological image or with materials obtained during routine examination, test, analysis and treatment procedures as well as cell or tissue culture studies; definitive trials conducted with genetic material other than gene therapy clinical trials, trials conducted within scope of nurse care activities, diet studies conducted with food additives, studies related with body physiology such as exercise, studies based on anthropometric measurements and all studies conducted “without requiring direct intervention of a physician to the volunteer” such as trials examining life habits.
2.23.Confidentiality:Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a volunteer's identity.
2.24.Volunteer:Patients or healthy individuals who participate in a clinical trial, by obtaining consent from the volunteer or his/her legal representative.
2.25.Volunteer Code:A code assigned by the investigator to each trial volunteer to protect the volunteer's identity and used in lieu of the volunteer's name when the investigator reports adverse events and/or other trial related data.
2.26.Good Clinical Practices: Rules including the regulations on the design, conduct, monitoring, budgeting, assessment and reporting of the clinical trial, protection of the rights, and body integrity of trial volunteers, and confidentiality and reliability of trial data to ensure conduction of the trial as per international scientific and ethical standards, which are required to be observed by the participants.
2.27.Monitoring:The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted in accordance with the protocol, Standard Operating Procedures (SOP), Good Clinical Practice, and the applicable regulatory requirements.
2.28.Monitoring Report: A written report from the monitor to the sponsor after each site visit and/or other trial-related communication prepared based on according to the sponsor's standard operating procedure.
2.29.Permission (Ministry’s Permission):The positive decision of the Ministry that the trial can be conducted in relevant site(s) within limits determined in accordance with Good Clinical Practices and other relevant regulations.
2.30.Quality Assurance:All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented, recorded and reported in compliance with Good Clinical Practice and the applicable regulatory requirements.
2.31.Quality Control:The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
2.32.Comparator: An investigational product or placebo, used as a reference in a clinical trial.
2.33.Source Documents: Original documents, data and records. For example, hospital records, laboratory notes, memoranda, volunteers' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, photographic negatives, microfilm or magnetic media, x-rays, volunteer files, and records kept at the pharmacy, laboratories and medico-technical departments involved in the clinical trial.
2.34.Source Data: All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial.Source data are contained in source documents.
2.35.Clinical Trial: Any and all types of trials conducted on humans.
2.36.Clinical Drug Trial: Any investigation in volunteers performed at one or more sites intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational products, and/or to define adverse effects of an investigational products and/or to confirm the safety and/or efficacy of an investigational products, and/or to study absorption, distribution, metabolism, and excretion of an investigational products.
2.37.Interim Clinical Trial Report:A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
2.38.Clinical Trial Report: A written description of a trial of any therapeutic, prophylactic, or diagnostic agent conducted in human volunteers, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report.
2.39.Coordinator: An investigator, with the degree of medical specialty or doctorate, assigned the responsibility for the coordination of investigators at different centers participating in a multicentre trial and the Ministry, the Ethics Committee and the Sponsor.
2.40.Blinding (Masking):A procedure in which one or more parties to the trial such as the investigator, volunteer or monitor are kept unaware of the treatment assignment.Single-blinding usually refers to the volunteer being unaware, and double-blinding usually refers to the volunteer, investigator, monitor, and, in some cases, data analyst being unaware of the treatment assignment.
2.41.SiteOrganization Management Service: The entirety of services provided by a contracted research organization, independent from the sponsor, to the trial sites upon request of the principal investigator in order to perform the trial procedures such as preparing the volunteers, counting drugs and arranging study files, which are within scope of the siteorganization management service.
2.42.Case Report Form (CRF):A printed, optical, or electronic document designed to record all of the information as defined by the protocol information to be reported to the sponsor on each trial volunteer.
2.43.Approval (Ethics Committee’s Approval):The positive decision of the Ethics Committee that the clinical trial is inspected by the Ethics Committee pursuant to the relevant regulations and the trial can be conducted within limits determined by relevant regulations and good clinical practices.
2.44.Primary Endpoint: The most important end-point in the trial, which provides primary data.
2.45.Randomization (Random Assignment):The process of assigning volunteers to treatment or control groups using an element of chance in order to reduce bias.
2.46.Site Coordinator: The qualified person assigned independently from the sponsor pursuant to request of the principal investigator in the trial site in order to provide siteorganization management service.
2.47.Secondary Endpoint: One (or more than one, if possible) end-point which is less important than the primary end-point in the trial.
2.48.End-point:It can be defined as a variable, which is one of the main fields of interest of the trial. This variable may be related with efficiency and safety. End-point may be used as synonym of the efficiency variable and the safety variable; however, it may not be used as synonym of demographic variability.
2.49.Principal Investigator:A physician or dentist responsible for conduction of the clinical trial, whois a medical specialist or has doctorate degree on the expertise related with the volunteer of the trial in interventional trials or someone whois a medical specialist or has doctorate degree responsible for conduction of the clinical trial, in non-interventional trials.
2.50.Contract:A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.
2.51.Contract Research Organization (CRO):An independent organization contracted by the sponsor to perform one or more of a sponsor's trial-related duties and authorizations in accordance with principles of Good Clinical Practices.
2.52.Standard Operating Procedures (SOPs):Detailed, written instructions to provide complementary guidance and support to the relevant regulations and Good Clinical Practices.
2.53.Impartial Witness: A person, who is independent of the trial and not a part of the clinical trial team, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the volunteer or the volunteer's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the volunteer.
2.54.Compliance:Adherence to all the trial-related requirements, Good Clinical Practice requirements, and the applicable regulatory requirements.
2.55.Sub-investigator: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions
2.56.Legal Representative: An individual authorized under applicable law to consent, on behalf of a potential volunteer, to the volunteer's participation in the clinical trial.
2.57.Audit:A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures, Good Clinical Practice, and the applicable regulatory requirements.
2.58.Audit Certificate: A declaration of confirmation by the auditor that an audit has taken place.
2.59.Audit Report: A written evaluation by the sponsor's auditor of the results of the audit.
2.60.Audit Trail:Documentation that reveals the course of events.
- BASIC PRINCIPLES OF GOOD CLINICAL PRACTICES
Basic principles of Good Clinical Practices are as follows:
3.1.Clinical trials should be conducted in accordance with the Good Clinical Practice and the applicable regulatory requirements and ethical principles that have their origin in the current Declaration of Helsinki.
3.2.Before a clinical trial is initiated, any foreseeable probable risks should be weighed against the anticipated benefit for the individual trial volunteer and society. A clinical trial should be initiated and continued only if the anticipated benefits justify the risks.
A clinical trial should be initiated and continued only if the benefits anticipated from a clinical trial justify the risks.