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GCP Guideline published by Turkish Medicine and Medical Device Agency

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GCP Guideline published by Turkish Medicine and Medical Device Agency

GCP Guideline published by Turkish Medicine and Medical Device Agency

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  • 1. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 1. INTRODUCTION Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, performing, recording and reporting clinical studies that involve participation of human subject which is 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 subjects 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 guides the users on generating clinical trial data that are intended to be Submitted to the Ministry of Health and Turkish Medicine and Medical Device Agency, and describes the principles and details of conducting or planned to be conducted clinical trials in our country. 2. DEFINITIONS 2.1. Adverse Event: Any undesired medical event in a trial subject who participated in The clinical trial 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. 2.2. Adverse Reaction: All undesired and unintended responses occurred in trial subject who participated in the clinical trial. 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. 2.3. Investigator: Any individual member of the clinical trial team supervised by the investigator. 2.4. Investigator Brochure: Documentation consisting of all clinical and non-clinical data for the investigational product or administration. 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 which is being tested or used as a reference in a clinical trial. 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
  • 2. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether t continue, modify, or stop a trial. 2.9. Unexpected Serious Adverse Reaction: Any serious adverse reaction which is not consistent with the nature, severity or the result of the reference safety information. 2.10. Informed Consent Form (ICF): It's a document that proves the obtaining of written consent by giving detailed and clear information about the research. 2.11. Bioequivalence: Similarity of the two products which are pharmaceutical equivalent so that their bioavailability and effect in terms of efficacy and safety are substantially similar after administration in the same molar dose. 2.12. Bio-availability: The degree and speed at which the active substance or its therapeutic portion is absorbed from the pharmaceutical form, reached the systemic circulation and thus becomes available at the site of action or in body fluids, usually in serum or plasma. 2.13. Serious Adverse Event or Reaction: Any adverse event or reaction 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. 2.14. 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 its two different pharmaceutical forms. 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. 2.15. 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. 2.16. Inspection: The act by the Institution of conducting a review of the places where clinical trials are conducted, the sites owned by the sponsor or the contract research organization, the study documents and records, quality assurance regulations, and all other institutions, committees and organizations, related with the trial, including the Ethics Committee, with respect to compliance with the relevant regulations, with or without prior notice. 2.17. Inspection Report: The report issued by the relevant health authority at the end of the inspection. 2.18. Sponsor: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. 2.19. Direct Access: Permission to examine, analyze, verify, and reproduce any records and reports for evaluation of a clinical trial. Ministry of Health and Turkish Medicine and Medical Device Agency 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 subjects' identities and sponsor's proprietary information. 2.20. 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. 2.21. Ethics Committee: The independent committees to be approved by the Turkish
  • 3. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April Medicine and Medical Device Agency, whose responsibility is to provide scientific and ethical opinion on other matters related to the trial as well as the methods and material to be used in obtaining and documenting informed consent of the trial subjects in order to ensure the protection of the rights, safety and well-being of subjects. 2.22. Vulnerable Subjects: 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 subjects 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. 2.23. Essential Documents: Documents which individually and collectively permit evaluation of conduction of a study and the quality of the data produced. 2.24. Confidentiality: Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity. 2.25. Subject: Patients or healthy individuals who participate in a clinical trial, by obtaining consent from the subject or his/her legal representative. 2.26. Subject Code: A code assigned by the principal investigator or other investigators to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events or other trial related data. 2.27. Good Clinical Practices (GCP): 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 subjects, 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. 2.28. Permission (Turkish Medicine and Medical Device Agency Permission): The positive decision of the Turkish Medicine and Medical Device Agency that the trial can be conducted in relevant sites within limits determined in accordance with Good Clinical Practices and other relevant regulations. 2.29. 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. 2.30. Monitoring Report: A written report from the monitor to the sponsor after each site visit or other trial-related communication prepared based on according to the sponsor's standard operating procedure. 2.31. 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. 2.32. 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. 2.33. Legal Representative: In accordance with the legislation in force, on behalf of the potential subject, the person authorized to provide consent for participation in the clinical trial. 2.34. Comparator: An investigational product or placebo, used as a reference in a clinical trial.
  • 4. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 2.35. Source Documents: Hospital records, laboratory notes, memoranda, subjects' 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, subject files, and records kept at the pharmacy, laboratories and medico-technical departments involved in the clinical trial and original documents. 2.36. 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. 2.37. Clinical Trial: Any investigation in subjects intended to discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more investigational products; to define adverse events or reactions; to study absorption, distribution, metabolism, and excretion; to confirm the safety and efficacy of an investigational product. 2.38. Interim Clinical Trial Report: A report of intermediate results and their evaluation based on analyses performed during the course of a trial. 2.39. Clinical Trial Report: A written description of a trial of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report. 2.40. 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 ethics committee, the sponsor or legal representative of the sponsor and Turkish Medicine and Medical Device Agency, if required. 2.41. Blinding (Masking): A procedure in which one or more parties to the trial such as the principal investigator or other investigator, subject or monitor are kept unaware of the treatment assignment. Single-blinding usually refers to the subject being unaware, and double-blinding usually refers to the subject, principal investigator or other investigator, monitor, and, in some cases, data analyst being unaware of the treatment assignment. 2.42. Site Organization 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 subjects, arranging study files. 2.43. 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 subject. 2.44. Approval (Ethics Committee’s Approval): The positive decision of the Ethics Committee that the trial can be conducted at relevant sites within limits determined by relevant regulations and good clinical practices. 2.45. Primary Endpoint: The most important end-point in the trial, which provides primary data. 2.46. Randomization (Random Assignment): The process of assigning subjects to treatment or control groups using an element of chance in order to reduce bias. 2.47. 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 site organization management service. 2.48. Secondary Endpoint: One end-point which is less important than the primary end-point
  • 5. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April in the trial. 2.49. 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. 2.50. Principal Investigator: A medical doctor or dentist responsible for conduction of the clinical trial, who has a specialty degree on the field related with the trial. 2.51. 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 trial protocol may serve as the basis of a contract. 2.52. 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. 2.53. Standard Operating Procedures (SOPs): Detailed, written instructions to provide complementary guidance and support to the relevant regulations and Good Clinical Practices. 2.54. Impartial Witness: A person, who is independent of the trial and not a part of the clinical trial team, who should not be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject's legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject. 2.55. Compliance: Adherence to all the trial-related requirements, Good Clinical Practice Requirements and the applicable regulatory requirements. 2.56. 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 procedure or to make important trial-related decisions 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. 3. 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 subject 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. 3.3. The rights, safety, and well-being of the clinical trial subjects are the most important considerations. The issues should prevail over interests of science and society.
  • 6. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 3.4. The available nonclinical and clinical information on an investigational product should be adequate to support the clinical trial. 3.5. Clinical trials should be described in a scientifically appropriate, scientifically valid, applicable and clear, detailed protocol. 3.6. A clinical trial should be conducted in compliance with the approved trial protocol. 3.7. The medical care given to and medical decisions made on behalf of any subjects should always be under responsibility of a qualified physician or a qualified dentist. 3.8. Each individual involved in conducting a trial should be qualified by education, training and experience to perform his or her respective tasks. 3.9. Freely given informed consent should be obtained from every subject prior to starting the clinical trial in accordance with the relevant regulation. 3.10. All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. 3.11. The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirements. 3.12. Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice. These products should be used in accordance with the approved trial protocol. 3.13. Quality systems that assure the quality of every aspect of the trial should be implemented. 4. ETHICS COMMITTEE 4.1. The Ethics Committee should have the qualifications to review and evaluate the science, medical aspects, and ethics of the proposed trial. 4.2. The Ethics Committee should consist of minimum seven members and maximum fifteen members pursuant to relevant regulation, should at least one member is a subject with non-medical profession and another one member is a lawyer and most of members are healthcare professionals with education level of doctorate or medical specialty. 4.3. When the Ethics Committee is established, the members of the Ethics Committee are preferred to exhibit an equal gender distribution. 4.4. An Ethics Committee should safeguard the rights, safety, and well-being of all trial subjects. Special attention should be paid to trials that may include vulnerable subjects. 4.5. The Ethics Committee should ensure that documents and information required to be submitted in clinical trial applications are complete. 4.6. The Ethics Committee should review the proposed clinical trial within the time period and provide the decision to applicant indicated in the applicable regulations. 4.7. Ethics Committee should pay attention to following issues and it should document them in writing: 4.7.1. The title of the trial, 4.7.2. List of the documents reviewed if available, including date and version number, 4.7.3. A member list of ethics committee, where specialty branches of the members are listed, 4.7.4. The approval if a favorable opinion is made and its date, 4.7.5. If a negative opinion is made, the reason and date for this, 4.7.6. If a previously given favorable opinion is cancelled or temporarily
  • 7. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April suspended, the reason and date for the same. 4.8. The Ethics Committee should consider the qualifications of the principal investigator and the other investigators if required for the proposed trial, as documented by a current curriculum vitae or by any other relevant documentation the Ethics Committee requests. 4.9. The Ethics Committee may request more information than is given in the informed consent form, when, in the judgment of the Ethics Committee, the additional information would add meaningfully to the protection of the rights, safety and/or well being of the subjects. 4.10. When a non-therapeutic trial is to be carried out with the consent of the subject's legally acceptable representative, the ethics committee should determine that the proposed trial protocol or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials. 4.11. Where the protocol indicates that prior consent of the trial subject or the subject's legally acceptable representative is not possible, such as if the trial subject represents an emergency for the subject's health and in cases where the subject is unconscious and his/her legal representative or relative is not available to get consent at the time of intervention required, the ethics committee should determine that the proposed trial protocol or other documents adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such trials. 4.12. The Ethics Committee should review both the amount and method of the expenditures such as transportation and meal, arising from participation of subjects to the trial, to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should not be wholly contingent on completion of the trial by the subject. 4.13. The ethics committee may request information regarding the way payment will be prorated. 4.14. The Ethics Committee should ensure that information regarding payment of expenditures such as transportation and meal to subjects, is set forth in the written informed consent form and any other written information to be provided to subjects. 4.15. The Ethics Committee should review and evaluate on information and documents such as annual report forms, in regular intervals, but not less than once a year, the ongoing clinical trials with consideration to the degree of risk on trial subjects. 4.16. The Ethics Committee performs review of clinical trial applications when the application is submitted and also throughout the trial period. 4.17. Members of Ethics Committee are obligated to respect confidentiality principles for any and all types of information received by them. 4.18. It is forbidden that members of the Ethics Committee disclose any and all types of documents and information provided to them in relation with the clinical trial. Such documents and information can be submitted to the authorized person only if requested by legally authorized subjects and institutions. 4.19. Members of ethics committee will start operation after they undersign a confidentiality letter and commitment letter to be issued by Turkish Medicine and Medical Device Agency and published at web site of Turkish Medicine and Medical Device Agency. 4.20. In order to ensure standard operation of Ethics Committees, standard operating procedures will be determined by by Turkish Medicine and Medical
  • 8. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April Device Agency and published at web site of by Turkish Medicine and Medical Device Agency. Ethics Committee should perform its functions in accordance with standard operating procedures. 4.21. The Ethics Committee should operate in compliance with applicable regulations, good clinical practices and standard operation procedures and they should retain written records of all activities. 4.22. Whenever necessary, an ethics committee may request for recommendation from members with expertise in special areas or invite these people to the meeting as counselors. 4.23. Only members who participate in the ethics committee review and discussion should vote, provide their opinion or advise. 4.24. Only those ethics committee members who are independent of the staff or the sponsor of the trial should vote or provide opinion on a trial-related matter. Those ethics committee members who are related to the reviewed trial or responsible for the trial cannot participate in discussions and voting of the trial, cannot sign ethics committee decision. 4.25. Coordinator, the principal investigator, the investigator or the sponsor may be invited to an ethics committee meeting to provide information on any aspect of the trial. Coordinator, the principal investigator, the investigator or the sponsor should not participate in the deliberations of the ethics committee or in the vote/opinion of the ethics committee. 4.26. A current list should be retained, which includes name and qualification of each Ethics Committee’s member. 4.27. Name and qualification of Ethics Committee’s members can be informed to relevant parties, when necessary. 4.28. An Ethics Committee should hold a meeting which at least a two-thirds quorum is present, and it should adopt its decisions by simple majority. 4.29. The tenure of an Ethics Committee’s member is two years and a member whose tenure has expired can be re-elected. 4.30. The membership of the committee’s member, who fails to attend sequential three meetings or five meeting in intervals without a justification, will be spontaneously void. If membership of members tenure has expired or becomes null and void, replacement with be made with be made with a member with same qualifications. 5. THE PRINCIPAL INVESTIGATOR AND THE INVESTIGATOR 5.1. Coordinator, the principal investigator and the other investigators should be qualified by education, training, and experience to assume responsibility for the proper conduction of the trial. 5.2. The curriculum vitae of coordinator, the principal investigator and the other investigators should be in accordance with the form published at the web site of by Turkish Medicine and Medical Device Agency, up-to-date and signed. The investigator should provide evidence of such qualifications through documentation requested by Turkish Medicine and Medical Device Agency, the Ethics Committee or the Sponsor. 5.3. Physicians or dentists responsible for conduction of the trial, who have received education on the relevant expertise, can be assigned as principal investigator. The principal investigator should have obtained the degree of doctorate or medical
  • 9. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April specialty. 5.4. Phase I drug clinical trials and studies for bio-availability/bioequivalence are conducted by an appropriate team which has adequate training regarding good clinical practices and medical doctor who obtained the degree of doctorate or medical specialty with degree of pharmacology expertise. 5.5. Coordinator, the principal investigator and sub-investigator should have adequate and detailed information on the investigational products, as described in the current protocol, in the current Investigator Brochure, and in other information sources provided by the sponsor. 5.6. Coordinator, the principal investigator and sub-investigator should be aware of, and should comply with, Good Clinical Practices, the current version of the Helsinki Declaration and the applicable regulatory requirements. 5.7 Coordinator, the principal investigator and sub-investigator should permit monitoring and auditing by the Ethics Committee and/or the sponsor, and inspection by Turkish Medicine and Medical Device Agency or appropriate regulatory authorities in all respects including investigation site, trial documentation. 5.8 Provided that by Turkish Medicine and Medical Device Agency and the Ethics Committee is notified, the principal investigator may delegate trial nurse, field officer, sub-investigator or a qualified person to aid conduction of the trial. Principal investigator should keep records of those delegations. Turkish Medicine and Medical Device Agency may cancel this delegation with providing justification. 5.9. The principal investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial in a proper and safe manner. 5.10. Coordinator, the principal investigator should have sufficient time to properly perform and complete the trial within the agreed trial period. Coordinator, the principal investigator and other investigators may perform a certain number of trials at the same time as per nature of the trial, should the justification on that subject is submitted. However Turkish Medicine and Medical Device Agency and Ethics Committee may impose restrictions, provided that the justification is mentioned. 5.11. The principal investigator should be able to demonstrate a potential for recruiting the required number of subjects with suitable qualifications within the recruitment period. 5.12. Coordinator and the principal investigator should ensure that the study team is adequately informed about the trial protocol, the investigational products, and their trial related duties and functions. 5.13. A qualified physician or dentist, who is a principal investigator or a sub-investigator for the trial, should be responsible for all trial-related medical or dental decisions. 5.14. During and following a subject's participation in a trial, the principal investigator and sub-investigator and the investigational site should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. 5.15. The principal investigator or sub-investigator should inform a subject when medical care is needed for other illnesses of which the principal investigator or
  • 10. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April sub-investigator becomes aware, occurring during or after a clinical trial, in addition to an ongoing disease. 5.16. It is recommended that the principal investigator or sub-investigator inform the subject's primary physician about the subject's participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed. 5.17. A subject is not obliged to give his/her reasons for withdrawing prematurely from a trial. However, the principal investigator or sub-investigator should make a reasonable effort to ascertain the reasons, while fully respecting the subject's rights. 5.18. Before initiating a trial, coordinator or the principal investigator should have approval from the Ethics Committee and permission from by Turkish Medicine and Medical Device Agency for the trials within scope of relevant regulations. 5.19. The principal investigator or sub-investigator should conduct the trial in compliance with the trial protocol approved by the Ethics Committee; for the trials where permission is necessary according to the relevant regulation, the trial should be conducted in compliance with the protocol permitted by Turkish Medicine and Medical Device Agency. 5.20. Coordinator or the principal investigator and the sponsor should sign the protocol to confirm agreement. 5.21. Coordinator or the principal investigator should not implement any deviation from or changes of the protocol without review and written approval from the Ethics Committee; for the trials where permission is necessary according to the relevant regulation; a protocol amendment should not be implemented without the permission of the Turkish Medicine and Medical Device Agency. However, the Ethics Committee and the Turkish Medicine and Medical Device Agency should be notified of the matter and its justification as soon as possible if any deviation from or changes of the protocol has/have happened to eliminate an immediate hazard. 5.22 Coordinator, the principal investigator or sub-investigator should document and explain any deviation from the approved protocol and its justification. Violations of the protocol should be submitted if requested by the Ethics Committee and Turkish Medicine and Medical Device Agency. 5.23. The receipt, storage, written request or distribution in accordance with the trial protocol, inventory control, the procedures for the remained portion and record keeping of the investigational product are the responsibility of the principal investigator at all trial sites. Principal investigator delegates a pharmacist for these responsibilities. 5.24. The pharmacist, who is designated by the principal investigator, should maintain the inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of unused products. These records should include dates, quantities, batch/serial numbers, expiration dates and the code numbers assigned to the investigational products and trial subjects. 5.25. The pharmacist who is designated by the principal investigator should ensure that the investigational products are stored in accordance with applicable regulatory requirements. 5.26. The principal investigators or sub-investigator should maintain records that document adequately that the subjects were provided the doses specified by the trial protocol and reconcile all investigational products received from the sponsor.
  • 11. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 5.27. The principal investigator or sub-investigator should ensure that the investigational products are used only in accordance with the approved trial protocol. 5.28. The principal investigator or sub-investigator or appropriate person or pharmacist designated by the principal investigator, should explain the correct use of the investigational products to each subject and should check, at intervals appropriate for the trial, that each subject is following the instructions properly. 5.29. The principal investigator should follow the trial's randomization procedures, if any, and should ensure that the code is broken only in accordance with the trial protocol. If the trial is blinded, the principal investigator should promptly document and explain to the sponsor reasons of any premature unblinding of the investigational products. 5.30. In obtaining and documenting informed consent, the principal investigator or an investigator who is a medical doctor or dentist should comply with the applicable regulatory requirements and the ethical principles. 5.31. Prior to the beginning of the trial, coordinator or the principal investigator should ensure that the informed consent of each subject is obtained. 5.32. The principal investigator should retain copy of the signed informed consent forms. 5.33. The principal investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to the sponsor in the Case Report Forms and in all required reports. 5.34. Data reported on the Case Report Form, which are derived from source documents, should be consistent with the source documents. Any discrepancies should be explained. 5.35. Any change or correction to a case report form should be dated, initialed, and explained if necessary. This should not obscure the original data entry; this applies to both written and electronic changes and corrections. Sponsor should provide guidance to principal investigator and/or the principal investigators' designated sub-investigator, on making such corrections. Sponsor should have written procedures to assure that changes or corrections in case report forms are required and necessary and that such changes are necessarily approved by the principal investigator or sub-investigator. The principal investigator should retain records of the changes and corrections. 5.36 The principal investigator should maintain the trial documents as required by the applicable regulatory requirements; the investigator should take measures to prevent accidental or premature destruction of these documents. 5.37. Documents related with the trial should be retained for minimum fourteen years following the end of the trial at all trial sites. These documents should be retained for a longer period if required by an agreement with the sponsor. It is the responsibility of the sponsor to inform the principal investigator as to when these documents no longer need to be retained. 5.38. The financial aspects of the trial should be documented in an agreement between the sponsor and the principal investigator. 5.39. Upon request of the monitors, auditors, Ethics Committee, or Turkish Medicine and Medical Device Agency or other related health authorities, the principal investigator should make available for direct access to all requested trial-related records. 5.40. The principal investigator should submit written summaries of the trial status to the Ethics Committee and Turkish Medicine and Medical Device Agency
  • 12. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April at least annually, or more frequently, if requested by the Ethics Committee and Turkish Medicine and Medical Device Agency. 5.41. The principal investigator should promptly provide written reports to the sponsor, the Ethics Committee and Turkish Medicine and Medical Device Agency on any changes significantly affecting conduction of the trial, and/or increasing the risk to subjects. 5.42. The principal investigator should inform all related parties when new information is obtained which may adversely affect the health of the subjects or conduction of the trial. 5.43. The principal investigator should respect the timelines described in applicable regulations in safety notifications of the trial and he should meet his obligations. 5.44. All serious adverse events should be reported by the principal investigator or designated investigator immediately to the sponsor except for those SAEs that the trial protocol or other document (e.g., Investigator Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify subjects by code numbers assigned to the trial subjects; the subjects' names, personal identification numbers or addresses should not be used. 5.45. Adverse events or laboratory abnormalities identified in the trial protocol as critical to safety evaluations should be reported to the sponsor by the principal investigator or designated investigator according to the reporting requirements and within the time periods specified in the trial protocol. 5.46. For reported deaths, the principal investigator should supply Turkish Medicine and Medical Device Agency or the Ethics Committee with any additional requested information such as autopsy reports and terminal medical reports. 5.47. If the trial is prematurely terminated or suspended for any reason, the principal investigator should promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects. 5.48. If the principal investigator terminates or suspends a trial without obtaining prior agreement of the sponsor, the principal investigator should inform the institution where the trial is conducted to the sponsor and the Ethics Committee, and should provide Turkish Medicine and Medical Device Agency, the sponsor and the Ethics Committee a detailed written explanation of the termination or suspension. 5.49. If the sponsor, the Ethics Committee or Medicine and Medical Device Agency terminates or suspends a trial, the principal investigator should promptly inform the institution where the trial is conducted. 5.50. The principal investigator should ensure that the institution where the trial is conducted, the Ethics Committee and Medicine and Medical Device Agency is notified after the trial is completed. 5.51. All references to the principal investigator in this guideline also apply to coordinator. 6. SPONSOR 6.1. The sponsor is responsible for implementing and maintaining quality
  • 13. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April assurance and quality control systems with written standard operating procedures to ensure that trials are conducted and data are generated, documented, and reported in compliance with the protocol, principles of the Good Clinical Practices, and the applicable regulatory requirements. 6.2. The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by Medicine and Medical Device Agency and the regulatory authorities. 6.3. The sponsor should ensure it is specified in the protocol and other written agreements that the investigator will allow monitoring, auditing and inspection related with the trial by allowing direct access to the source data. 6.4. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly. 6.5. Agreements, made by the sponsor with the investigator or any other parties involved with the clinical trial, should be in writing, as part of the trial protocol or in a separate agreement. 6.6. A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a contract research organization. Selection of contract research organization is under responsibility of the sponsor. However, the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The contract research organization should implement systems related with quality assurance and quality control. 6.7. Any trial-related duty and function that is transferred to and assumed by a contract research organization should be specified in writing. 6.8. Any trial-related duties and functions not specifically transferred to or assumed by a contract research organization are retained by the sponsor. 6.9. All references to a sponsor in this guideline also apply to a contract research organization to the extent that a contract research organization has assumed the trial related duties and functions of a sponsor. 6.10. The sponsor should utilize qualified individuals as appropriate, throughout all stages of the trial process, from designing the trial protocol and case report forms and planning the analyses to analyzing and preparing interim and final clinical trial reports. 6.11. The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose. 6.12. The sponsor should utilize appropriately qualified individuals to supervise conduction of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports. 6.13. The sponsor may consider establishing an independent data-monitoring committee, to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The independent data monitoring committee should have written operating procedures and the independent data monitoring committee should maintain written records of all its meetings. 6.14. When necessary, ethics committee or Medicine and Medical Device Agency may request from the sponsor to establish an independent data monitoring
  • 14. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April committee. 6.15. When using electronic trial data handling or remote electronic trial data systems, the sponsor should: 6.15.1. Ensure and document that the electronic data processing systems conforms to the sponsor's established requirements for completeness, accuracy, reliability, and consistent validation. 6.15.2. Maintains standard operating procedures for using these systems, 6.15.3. Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data such as to maintain an audit trail, data trail, or edit trail. 6.15.4. Maintain a security system that prevents unauthorized access to the data, 6.15.5. Maintain a list of the individuals, who are authorized to make data changes, 6.15.6. Allow and maintain adequate backup of the data, 6.15.7. If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data. 6.15.8. Safeguard the blinding, if any. 6.16. The sponsor should use a subject code that allows identification of all the data reported for each subject. 6.17. The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents. 6.18. The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirements of the countries where the product is approved or where the sponsor intends to apply for approval. 6.19. If the sponsor discontinues the clinical development of an investigational product the sponsor should maintain all sponsor-specific essential documents for at least 14 years after formal discontinuation or in conformance with the applicable regulatory requirements. 6.20. If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators, the Ethics Committee and Turkish Medicine and Medical Device Agency. 6.21. Any transfer of ownership of the data should be reported to Medicine and Medical Device Agency and the Ethics Committee. 6.22. The sponsor should inform the principal investigator in writing of the need for record retention or should notify the principal investigator in writing when the trial related records are no longer needed. 6.23. The sponsor is responsible for selecting the principal investigators and other investigators and investigational sites. 6.24. For multi-center studies, selection of coordinator is also the sponsor's responsibility. 6.25. Before entering an agreement with investigators to conduct a trial, the sponsor should provide the principal investigator or other investigators with the trial protocol and an up-to-date Investigator Brochure, and should provide sufficient time for the principal investigator or other investigators to review these. 6.26. The sponsor should obtain the investigator's agreement and sign the study protocol or an alternative document together with the principal investigator or other investigators to approve this agreement regarding the subjects below: 6.26.1. to perform the trial in compliance with Good Clinical Practices, with the applicable regulatory requirements, and with the protocol given approval
  • 15. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April by the Ethics Committee and permitted by Medicine and Medical Device Agency 6.26.2., to comply with procedures for data recording/reporting, 6.26.3. To permit monitoring, auditing and inspection, 6.26.4. To retain the trial related essential documents until the sponsor informs the principal investigator these documents are no longer needed. 6.27. Prior to a trial, the sponsor should define and implement all trial-related duties and functions. 6.28. If required by the applicable regulatory requirements, the sponsor should provide insurance with legal and financial coverage or should indemnify the principal investigator and other investigators against claims/needs arising from the trial, except for claims that arise from malpractice or negligence. 6.29. The treatment expenses of events such as the trial-related injuries which may result from complications arising from the trial should be specified in the standard operating procedures of the sponsor. 6.30. When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirements. 6.31. The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator. 6.32. Before initiating the clinical trial, the sponsor should submit any required applications to Medicine and Medical Device Agency in accordance with the format in Medicine and Medical Device Agency web site for review, acceptance or permission to begin the trials. Any notification/submission should be dated and contain sufficient information to identify the protocol. 6.33. The sponsor is responsible for notifying, at first applications of the clinical trial, the Ethics Committee and Medicine and Medical Device Agency the total number of subjects planned to be enrolled to the trial from our country. When the number of the subjects specified in the application cannot be reached, the number of subject can be increased at the sites which approved by ethics committee and are permitted by Medicine and Medical Device Agency, provided that related up-to-date documents such as current insurance and budget together with the justification are provided to the Ethics Committee and Medicine and Medical Device Agency; however, the Ethics Committee and Medicine and Medical Device Agency may request cancellation of increasing number of subjects, should the justification is notified. 6.34. In multi-center trials, the investigative sites should be notified by the sponsor that the trial is to be performed at these sites. This notification should include the Ethics Committee’s approval on the trial, the permission of Medicine and Medical Device Agency, synopsis of the trial protocol, the informed consent form and biological material transfer form, if any. 6.35. When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies or clinical trials are available to support the route, the dosages, the duration, and the trial population to be studied. 6.36. The sponsor should update the Investigator Brochure as supplemental significant new information becomes available. 6.37. The sponsor should ensure that the investigational product is appropriate to the stage of development of the product, is manufactured in accordance with applicable Good Manufacturing Practices, and is coded and labeled in a manner that protects the blinding, if applicable. In addition, the labeling should comply with applicable regulatory requirements.
  • 16. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 6.38. The sponsor should provide for the investigational products, acceptable storage conditions, storage temperature, storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties of these. 6.39. The sponsor should ensure that the investigational products should be packaged to prevent contamination and unacceptable deterioration during transport and storage. 6.40. In blinded trials, the coding system for the investigational product should include a mechanism that permits rapid identification of the product in case of a medical emergency, but does not permit breaks of the blinding. 6.41. If significant formulation changes are made in the investigational or comparator product during the course of clinical trial, the results of any additional studies of the product needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be made available by the sponsor prior to the use of the new formulation in clinical trials. 6.42. The sponsor is responsible for supplying the principal investigator and investigative sites with the investigational products. 6.43. The sponsor should not supply an investigative site with the investigational product until the sponsor obtains approval from Ethics Committee and permission from Medicine and Medical Device Agency. 6.44. Sponsor has the obligation after manufacture or import of investigational product the storage, distribution and delivery of investigational product to the investigative sites in accordance with the characteristics of the investigational product and the continuation of these conditions at investigative sites, ensuring the return of unused products from investigative sites or proper disposal and to keep records of all the process. 6.45. The sponsor should ensure that written procedures include instructions that the principal investigator and pharmacist designated by principal investigator should follow for the handling and storage of investigational products for the trial and documentation thereof. The said procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational products to the sponsor or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirements. 6.46. The sponsor should ensure timely delivery of investigational products to the investigators. 6.47. The sponsor should maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim). 6.48. The sponsor should maintain a system for the disposition of unused investigational products and for the documentation of this disposition. 6.49. The sponsor should take steps to ensure that the investigational products are stable over the period of use. 6.50. The sponsor should maintain sufficient quantities of the investigational products used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. Pursuant to the applicable regulation requirements, the responsibility rests with
  • 17. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April the manufacturing company for maintaining sufficient quantities of the investigational products (including drugs of comparative arm) marketed or available in the market in our country for serial sample analysis, the sponsor conducting the clinical trial may not be held responsible. 6.51. To the extent stability permits, the sponsor should retain samples domestically or abroad either until the analyses of the trial data are complete or as required by the applicable regulatory requirements (whichever represents the longer retention period) in accordance with the relevant regulation. 6.52. The sponsor should ensure that it is specified in the protocol or other written agreement that the principal investigators and other investigators provide direct access to source data or source documents for trial-related monitoring, audits, Ethics Committee review, Turkish Medicine and Medical Device Agency and regulatory authority inspection. 6.53. The sponsor should verify that each subject has consented, in writing, to direct access to his/her original medical records for trial-related monitoring, audit, review and inspection. 6.54. The sponsor is responsible for the ongoing safety evaluation of the investigational products. 6.55. The sponsor should promptly notify all concerned the principal investigators and investigators, investigative sites and Turkish Medicine and Medical Device Agency and the Ethics Committee of findings that could affect adversely the safety of subjects, impact conduction of the trial, or alter the favorable opinion to continue the trial. 6.56. The sponsor should expedite the reporting of both serious and unexpected adverse drug reactions to all concerned the principal investigators and investigators, to the Ethics Committee and to Medicine and Medical Device Agency, where required. 6.57. The sponsor should submit to Medicine and Medical Device Agency all safety updates and periodic reports in accordance with relevant regulation. 6.58. The sponsor should ensure that the trial is appropriately monitored. 6.59. The sponsor should monitor the trial in order to verify that the rights and well-being of human subjects are protected, the reported trial data are accurate, complete, and verifiable from source documents, conduction of the trial is in compliance with the currently approved trial protocol, with Good Clinical Practices, and with the applicable regulatory requirements. 6.60. The sponsor may conduct an audit separately and independently from the routine monitoring and quality control functions. The purpose is to assess whether conduction of the trial is in compliance with the trial protocol, standard operating procedures, Good Clinical Practices and applicable regulation requirements. 6.61. The sponsor should select officers, to conduct the audit, who are independent from the clinical trial and data collection systems. 6.62. The sponsor should ensure that education and experience of the auditing subjects are sufficient to appropriately conduct the audit. It is necessary to document qualifications of auditing subject. 6.63The sponsor should have written methods for audits of clinical trials and systems, which indicate what, how and how often an issue will be audited and also indicates format and content of audit reports. The audit report submitted to Medicine and Medical Device Agency or the relevant health authorities should include significance of the
  • 18. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April trial, number of volunteers in the trial, type of the trial and the degree of complexity as well as the level of risk on the volunteers and the determined outcomes of the risk. Moreover, observations and findings of the auditing volunteers should be documented. Medicine and Medical Device Agency and the relevant health authorities should not routinely request audit reports in order to protect the independency and the value of the audit procedure. If there are serious violations of Good Clinical Practices or during a legal condition or investigation, Turkish Medicine and Medical Device Agency or the relevant health authorities may access the case-based audit report during the audit. 6.64. The sponsor should take necessary steps to remove the non-compatibility, if the sponsor personnel, the principal investigator or other investigators or people involved in the trial do not follow the protocol, standard operating procedures, Good Clinical Practices and/or applicable regulations. 6.65. If serious or repetitive non-compatibility of the principal investigator or other investigators or people involved in the trial is found following a monitoring or an audit, the sponsor should end the participation of the investigator to the trial and the sponsor should immediately notify Medicine and Medical Device Agency and the Ethics Committee. 6.66. In case that a trial is prematurely terminated or suspended, the Sponsor should notify the cancellation and suspension and its justification to the principal investigators, the Ethics Committee and Turkish Medicine and Medical Device Agency. 6.67. The sponsor is responsible for issuing trial reports and submitting them to the Ethics Committee and Medicine and Medical Device Agency when the trial is completed or prematurely terminated. 6.68. In multi-center trials, the sponsor is responsible for designing the case report forms such that they include all necessary data for all investigational sites and for submitting the additional case report forms designed in order to collect additional data to the investigators collecting additional data. 6.69. Responsibilities of the coordinator, principle investigators, other sub-investigators and people involved in the trial should be documented by the sponsor before conduction of a trial. 6.70. Coordinators, the principal investigators and sub-investigators should be informed by the sponsor that they should follow uniform standards specified for respecting the protocol and evaluating clinical and laboratory findings and that they should fill in the case report forms and records must be kept. 6.71. The sponsor should ensure the communication between the principal investigators, coordinator, sub-investigators and responsible people participating to the trial. 6.72. The sponsor should ensure that the trial is appropriately monitored. 7. MONITORING 7.1. Monitors should be appointed by the sponsor. 7.2. Monitors should be appropriately trained, and should have the scientific or clinical knowledge needed to monitor the trial adequately. 7.3. The qualifications of the monitor should be documented. 7.4. Monitors should be thoroughly familiar with the investigational products, the protocol, written informed consent form and any other written information to be provided to volunteers, the sponsor's standard operating procedures, Good Clinical Practices, and the applicable regulatory requirements. 7.5. The sponsor should consider issues such as determination of the extent and nature of monitoring, objective, purpose, design, complexity, blinding, size, and endpoints of the trial. 7.6. In general there is a need for on-site monitoring, before, during, and after the trial.
  • 19. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 7.7. The monitors in accordance with the sponsor's requirements should carry out the following activities when relevant and necessary to the trial and the trial site. 7.7.1. Acting as the main line of communication between the sponsor and the principal investigator or other investigators, 7.7.2. Verifying that the principal investigator and sub-investigators have adequate qualifications and resources and remain adequate throughout the trial period, those facilities, including laboratories, equipment, and staff, is adequate to safely and properly conduct the trial and remain adequate throughout the trial period. 7.7.3. Verifying, for the investigational products: 7.7.3.1. That storage times and conditions are acceptable, 7.7.3.2. Supplies are sufficient throughout the trial, 7.7.3.3. That the investigational products are supplied only to subjects who are eligible to receive it and at the trial protocol specified doses and for protocol specified durations, 7.7.3.4. Those subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational products. 7.7.3.5. That the receipt, use, and return of the investigational products at the trial sites are controlled and documented properly, 7.7.3.6. That the disposition of unused investigational products at the trial sites complies with applicable regulatory requirements. 7.7.4. Verifying that the principal investigator and other investigators follow the approved protocol and all approved amendments, if any, 7.7.5. Verifying that the written informed consent was obtained before each subject's participation in the trial, 7.7.6. Ensuring that the principal investigator and other investigators receive the current Investigator Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirements, 7.7.7 Verifying that coordinator, the principal investigator and other investigators are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the principal investigator, and have not delegated these functions to unauthorized individuals, 7.7.8. Verifying that the investigator who is principal investigator and doctor or dentist is enrolling only eligible subjects, 7.7.9. Reporting the subject recruitment date, 7.7.10. Verifying that source data/documents and other trial records are accurate, complete, kept up-to-date and maintained, 7.7.11. Verifying that the investigator who is principal investigator and doctor or dentist provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial. 7.7.12. Checking the accuracy and completeness of the Case Report Form (CRF) entries, source documents and other trial-related records against each other. 7.8. The monitor specifically should verify that: 7.8.1. The data required by the trial protocol are reported accurately on the CRFs and are consistent with the source data/documents, 7.8.2. Any dose or therapy modifications are well documented for each of the trial subjects, 7.8.3. Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol and the CRFs, 7.8.4. Visits that the subjects fail to make, tests that are not conducted, and examinations that are
  • 20. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April not performed are clearly reported as such on the CRFs, 7.8.5. All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs, 7.8.6. Informing the investigator who is principal investigator and doctor or dentist of any CRF entry error, omission, or illegibility, 7.8.7. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained if necessary, and are made by the principal investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator, 7.8.8. Determining whether all safety reports are appropriately reported in compliance with the Good Clinical Practices, the applicable regulatory requirements to Turkish Medicine and Medical Device Agency, the Ethics Committee and the sponsor, 7.8.9. Determining whether the principal investigator is maintaining the essential documents, 7.8.10. Communicating deviations from the study protocol, standard operating procedures, Good Clinical practices, and the applicable regulatory requirements to the principal investigator and taking appropriate action designed to prevent recurrence of the detected deviations, 7.9. The monitor should follow the sponsor's established written standard operating procedures as well as applicable regulation requirements and those procedures that are specified by the principal investigator for monitoring a specific trial. 7.10. The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication. Reports should include the date, site, name of the monitor, and name of the principal investigator or other individuals contacted. Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance. 7.11. The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor's designated representative. 8. CLINICAL STUDY PROTOCOL AND PROTOCOL AMENDMENTS The contents of a trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol pages, or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as a Investigator Brochure: 8.1. Trial protocol title, protocol number, and date, 8.2. Any amendments should also bear the amendment number and date, 8.3. Name and address of the sponsor and monitor, if other than the sponsor, 8.4. Name and title of the person authorized to sign the trial protocol and the protocol amendments for the sponsor, 8.5. Name, title, address, and telephone numbers of the sponsor's medical expert or dentist when appropriate for the trial, 8.6. Name and title of the investigators, who are responsible for conducting the trial, and the address and telephone numbers of the trial sites, 8.7. Name, title, address, and telephone numbers of the qualified physician or
  • 21. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April dentist, who is responsible for all trial-site related medical or dental decisions, 8.8. Addresses of the clinical laboratories and other medical or other departments and/or institutions involved in the trial, 8.9. Name and description of investigational products, if applicable, 8.10. A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial, 8.11. Summary of the known and potential risks and benefits to subjects, 8.12. Description of and justification for the route of administration, dosage, dosage regimen, and treatment periods, 8.13. A statement that the trial will be conducted in compliance with the trial protocol, Good Clinical Practices and the applicable regulatory requirements, 8.14. Description of the population to be studied, 8.15. References to literature and data that are relevant to the trial and that provide background for the trial, 8.16. A detailed description of the objectives and the purpose of the trial, 8.17. The scientific integrity of the trial and the credibility of the data from the trial depend substantially on the trial design. A description of the trial design should include: 8.17.1. A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial, 8.17.2. A description of the type/design of trial to be conducted and a schematic diagram of trial design, procedures and stages, 8.17.3. Description of the measures taken to minimize/avoid bias, 8.17.4. A description of the trial treatments and the dosage and dosage regimen of the investigational products. 8.17.5. Include a description of the dosage form, packaging, and labeling of the investigational products, 8.17.6. The expected duration of subject participation, and a description of duration of all trial periods, including follow-up, if any, 8.17.7. A description of the "stopping rules" or "discontinuation criteria" for individual subjects, as parts of trial and for the entire trial, 8.17.8. Drug accountability log procedures for the investigational product, if any, 8.17.9. Maintenance of trial treatment randomization codes and procedures for breaking codes, 8.17.10. The identification of any data to be recorded directly on the case report forms (i.e. no prior written or electronic record of data), and to be considered to be source data. 8.18. Subject inclusion criteria, 8.19. Subject exclusion criteria, 8.20. Subject withdrawal criteria and procedures specifying 8.20.1. When and how to withdraw or be drawn subjects from the trial, 8.20.2. The type and timing of the data to be collected for withdrawing or withdrawn subjects, 8.20.3. Whether and how subjects are to be replaced, 8.20.4. The follow-up for subjects withdrawing or withdrawn from the trial. 8.21. The treatments to be administered, including the name of all the products, the dose, the dosing schedule, the route of administration, and the treatment period, including the follow-up periods for subjects for each investigational product treatment/trial treatment group/arm of the trial,
  • 22. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 8.22. Medications/treatments permitted (including rescue medication) and not permitted before or during the trial, 8.23. Procedures for monitoring subject compliance, 8.24. Specification of the efficacy parameters, 8.25. Methods and timing for assessing, recording, and analyzing of efficacy parameters, 8.26. Assessment of safety: 8.26.1. Specification of safety parameters, 8.26.2. The methods and timing for assessing, recording, and analyzing safety parameters, 8.26.3. Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses, 8.26.4. The type and duration of the follow-up of subjects after adverse events. 8.27. Statistics: 8.27.1. A description of the statistical methods to be employed, including timing of any planned interim analyses, 8.27.2. The number of subjects planned to be enrolled. 8.27.3. In multicentre trials, the numbers of enrolled subjects projected for each trial site, 8.27.4. Reason for choice of sample size, including evaluations on the power of the trial and clinical justification, 8.27.5. The level of significance to be used, 8.27.6. Criteria for the termination of the trial, 8.27.7. Procedure for accounting for missing, unused, and spurious data, 8.27.8. Procedures for reporting any deviations from the original statistical plan (any deviations from the original statistical plan should be described and justified in protocol or in the final report, as appropriate), 8.27.9. The selection of subjects to be included in the analyses (e.g. all legible subjects, all evaluable subjects, all randomized subjects, subjects who have received investigational drug). 8.28. Specifications of persons or institutions authorized to directly access to source data. 8.29. Explanations of the ethical assessments related with the trial. 8.30. Processing and recording the data. 8.31. The information regarding the finance and insurance, if not addressed in a separate agreement, 8.32. Publication policy, if not addressed in a separate agreement. 9. INFORMED CONSENT FORM 9.1. When the informed consent is obtained from the subjects and it is documented, the Good Clinical Practices and the ethical principles based on the current Helsinki Declaration should be followed. 9.2. The approval of the Ethics Committee and the permission of Turkish Medicine and Medical Device Agency should be obtained prior to conduction of the trial for the written informed consent form given to the subjects participating to the trial. 9.3. The written informed consent form to be provided to the subjects should be reviewed in the light of new information obtained, with respect to the consent given by the subject. Before any revised written informed consent form is used, the approval of the Ethics Committee and the permission of Turkish Medicine and Medical Device Agency should be obtained. The subject or the
  • 23. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April legal representative of the subject should be immediately informed whenever new information is obtained, which may possibly influence the will of the subject to continue the trial. It should be necessarily documented that such information is shared. 9.4. The principal investigator or any person from the trial staff should not either force or improperly influence the subject for participating to a trial or continuing an existing trial. 9.5. None of the verbal information or written information pertaining to the investigator, including the written informed consent form may include any provision or statement which voids the legal rights of the subject or the legal representative and moreover, they may not also include any provision or statement which may release the principal investigator, any person from the trial staff, the site, the sponsor or their representatives from any obligations arising from their own negligence. 9.6. The subject and legal representatives should be informed about all aspects of the trial. 9.7. The verbal and written words and the language of the documents related with the trial, including the written informed consent, should be clear, understandable and free of terminological terms such that they should be satisfactorily understood by the subject or the legal representative or the impartial witness. 9.8. When the written informed consent is obtained, the subject and the legal representative should be allowed sufficient time in order to ask questions about details of the trial and make decisions on whether the subject will participate to the study. All questions about the trial should be satisfactorily answered to the subject or the legal representative by the qualified person providing the information. 9.9. Before the subject takes part in the trial, the written informed consent should be personally signed and dated by the subject, the qualified investigator or dentist who conducts the informed consent interviews and is a member of the research team, and when necessary, the legal representative and impartial witness with hair own handwriting. The initials of the subject or the legal representative, and of the impartial witness, should be present on each page of the written informed consent. 9.10. If the subject or the legal representative is illiterate, or if the subject is visually impaired, the entirety of the written informed consent interview should be made in the presence of an impartial witness, who is not a member of trial staff. After the written informed consent and other written explanations, required to be given to the subject, are read and explained to the subject or the legal representative, the impartial witness should sign and date the written informed consent after the subject or the legal representative gives verbal consent about the participation to the trial and after said persons sign the approval form, if possible. Signing the written informed consent, the witness testifies and confirms that information in the written informed consent and other written explanations are clearly instructed to the subject or the legal representative, they are understood by the subject or the legal representative and the informed consent is given based on the free will of the subject or the legal representative. 9.11. The informed consent interview, the written informed consent given to the subjects as well as other written information should include explanations for at least the following issues: 9.11.1. The trial is an investigational study,
  • 24. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 9.11.2. The aim of the trial, 9.11.3. Treatments to be administered in the trial, the possibility that subjects can be randomized to trial groups for different treatments, 9.11.4. All methods to be followed or administered to the subject including the invasive methods to be performed during the trial, 9.11.5. Responsibilities of the subject, 9.11.6. Experimental parts of the trial, 9.11.7. The anticipated risks and discomforts the subject will be exposed (if the trial is conducted on pregnant or puerperal women, the risks and discomforts to the embryo, fetus or infant, 9.11.8. The subject is informed about the possibility that there may be no clinical benefit in part of the subject in relation with benefits the reasonably anticipated from the trial, 9.11.9. The alternative methods, which may be possibly applied to the subject, or the treatment schedule and their possible risks and benefits, 9.11.10. In case of injury related with the trial, the indemnity or the treatment to be paid/provided to the subject, 9.11.11. The information regarding the payments to be made to the subject for expenditures such as transportation and meals, 9.11.12. The fact that participation of the subject to the trial is voluntary and the subject may refuse participation to and withdraw from the study at any time without any penalty or sanctions and losing any rights otherwise entitled, 9.11.13. The monitors, auditors, the Ethics Committee, Turkish Medicine and Medical Device Agency and the other relevant health authorities will have direct access to the original medical records of the subject, but such information will be kept confidential, and by signing the written informed consent form, the subject or the legal representative consents the said access, 9.11.14. Pursuant to the applicable regulation requirements, the records directly identifying the subject will be kept confidential, they will not publicly disclosed and the identity of the subject will be still kept confidential even if results of the trial are published, 9.11.15. When new information is obtained in relation with the study, which may influence the will of the patient to continue the trial, the subject or the legal representative will be informed in timely manner, 9.11.16. Persons as well as 24-hour available phone numbers of such persons whom the subject can contact in order to have further information on the trial, the subject's own rights or any adverse event related with the trial, 9.11.17. Conditions or reason requiring termination of the subjects’ participation to the trial, 9.11.18. The estimated time for the subject to maintain participation to the trial 9.11.19. Number of subjects expected to participate to the trial. 9.12. Prior the participation to the trial, a copy of the signed and dated written informed consent form and of other written examinations, which are provided to the subject, should be given to the subject or the legal representative of the subject. Throughout the participation of the subject to the trial, a copy of updates in signed and dated written informed consent forms and also of the changes in the written information, which are previously provided to the subject, should be given to the subject or its legal representative. This written informed consent forms; a copy should be retained by the principal investigator, while the other copy is kept by the subject.
  • 25. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 9.13. If the clinical trial is characterized with the requirement that the subject may be only enrolled into the study based on consent of the legal representative, the subject should also be informed to the extent of the subject's perceptional capacity and the written informed consent form is approved, signed and dated by the subject itself if possible. 9.14. Excluding the Conditions specified in Article 9.15, a non-therapeutic study (a study where no direct clinical benefit to the subject is expected) should be conducted on subjects who may personally consent, sign and date the written informed consent form. 9.15. For non-therapeutic trials, they may be also conducted on subjects with consent given by the legal representative, provided that following conditions are met: 9.15.1. Inability to realize the aims of the trials with a trial conducted on subjects who may personally give the informed consent, 9.15.2. The low level of risks the subjects will be exposed, 9.15.3. Minimizing and the low level of the adverse effects, which may occur in the health of the subject, 9.15.4. The trial is not forbidden legally, 9.15.5. Obtaining approval of the Ethics Committee for the participation of such subjects and the written opinion covers this issue. Unless an exceptional conditions with reasonable justification occurs, such trials should be conducted on patients with a disease or a condition, which the investigational product targets. Subjects participating to such trials should be closely monitored and they should be immediately withdrawn from the trial, if they are exposed to any discomfort in any manner. 9.16. In emergencies where the consent of the subject cannot be obtained, prior to conduction of the trial, in order to protect rights, safety and health of the subject and ensure compliance to the applicable regulation, written consent of the subject's legal representative, if available, should be requested. When the legal representative of the subject is not available, the conditions included in the trial protocol, which is previously approved by the Ethics Committee and permitted by Turkish Medicine and Medical Device Agency, should be followed in relation with the participation of the subject to the trial. Later, the subject or the legal representative of the subject should be informed as soon as possible and the written consent of the subject or the legal representative of the subject should be obtained in order to determine whether the subject continues to participate or he withdraws from the trial on his free will. 9.17. For the clinical trials which will be conducted in children if the child has the ability to disclose his/her consent as well as his/her consent his/her mother and father, if under custody the tutor should be informed in accordance with relevant regulation and then written consent is obtained. 9.18. For the clinical trials which will be conducted in intensive care and unconscious people, if any legal representative, or else the relatives should be informed in accordance with relevant regulation and then written consent is obtained. If none of these are available, the investigator who is the principal investigator or doctor or dentist can be involved in the trial. 9.19. For the written information and documents other than the informed consent form, patient card and patient diaries which will be given to the subjects, Turkish Medicine and Medical Device Agency permission need to be obtained after ethics
  • 26. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April committee approval. 10. INVESTIGATOR BROCHURE 10.1. The Investigator Brochure is a compilation of the clinical and nonclinical data on the investigational products. This guideline provides guidance on the minimum information that should be included in investigator brochures and gives advice on the design. 10.2. The purpose of the investigator brochure is to provide the principal investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency or interval, methods of administration, and safety monitoring procedures. 10.3. The investigator brochure also provides insight to support the clinical management of the study subjects during the course of the clinical trial. The information should be presented in a concise, simple, objective, balanced, and non promotional form that enables a clinician, or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. 10.4. A medically qualified person may generally participate in the editing of an Investigator Brochure, but this should be approved by the disciplines that generated the described data. 10.5. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. 10.6. If the investigational product is marketed in our country and its pharmacology is widely understood by medical practitioners, an extensive Investigator Brochure may not be necessary. Where permitted by Turkish Drug and Medical Devices Institution, a basic product information brochure may be an appropriate alternative to the package leaflet, or labeling, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the principal investigator. If a marketed product is being studied for a new use (indication), an Investigator Brochure specific to that new use should be prepared. 10.7. The Investigator Brochure should be reviewed at least annually and revised as necessary in compliance with a sponsor's written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information. However this new information should be communicated to the Ethics Committees for approval. If it requires an amendment in the informed consent form or the trial protocol permission should be obtained from Turkish Medicine and Medical Device Agency in addition to ethics committee approval. 10.8. The sponsor is responsible for ensuring that an up-to-date Investigator Brochure is made available to the principal investigators. In the case of an investigator sponsored trial, the investigator should determine whether an investigator brochure is available from the commercial manufacturer. If the Investigator Brochure is provided by the investigator, then he or she should provide the necessary information to the trial personnel. 10.9. The Investigator Brochure should include a title page and a confidentiality statement: 10.9.1. Title page: This should provide the sponsor's name, the identity of
  • 27. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April each investigational product (i.e., research number, chemical or approved generic name and trade name(s) where legally permissible and desired by the sponsor). It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided. 10.9.2. Confidentiality Statement: The sponsor may wish to make a statement instructing the investigators to treat the Investigator Brochure as a confidential document for the sole information and use of the investigator's team, Turkish Medicine and Medical Device Agency and Ethics Committee. 10.10. The Investigator Brochure should contain the following sections, each with literature references where appropriate. 10.10.1. Contents: An example of the Table of Contents is given in Article 10.12. 10.10.2. Summary: A short summary (preferably not exceeding two pages) should be given, highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product. 10.10.3. Introduction: A brief introductory statement should be provided that Contains the chemical name (and generic and trade names when approved) of the investigational products, all active ingredients, the investigational products pharmacological class and its expected position within this class (e.g. advantages), the rationale for performing research with the investigational products, and the anticipated prophylactic, therapeutic, or diagnostic indications. Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product. 10.10.4. Physical, Chemical, and Pharmaceutical Properties and Formulation: A description should be provided of the investigational product substances (including the chemical or structural formulas), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties. To permit appropriate safety measures to be taken in the course of the trial, a description of the formulations to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage forms should also be given. Any structural similarities to other known compounds should be mentioned. 10.10.5. Non-clinical Studies: The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product metabolism studies should be provided in summary form. This summary should address the methodology used, the results, and a discussion of the relevance of the findings to the investigated therapeutic and the possible unfavorable and unintended effects in humans. The information provided may include the following, as appropriate, if known/available: 10.10.5.1. Animal species tested, 10.10.5.2. Number and sex of animals in each group, 10.10.5.3. Unit dose (e.g., mg/kg, ml/kg) 10.10.5.4. Dose interval, 10.10.5.5. Route of administration, 10.10.5.6. Duration of dosing 10.10.5.7. Information on systemic distribution, 10.10.5.8. Duration of post-exposure follow-up,
  • 28. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April 10.10.5.9. Results, including the following aspects: 10.10.5.9.1. Nature and frequency of pharmacological or toxic effects, 10.10.5.9.2. Severity or intensity of pharmacological or toxic effects, 10.10.5.9.3. Time to onset of effects, 10.10.5.9.4. Reversibility of effects, 10.10.5.9.5. Duration of effects 10.10.5.9.6. Dose response Tabular format/listings should be used whenever possible to ensure the clarity of the presentation. The following sections should discuss the most important findings from the studies, including the dose response of observed effects, the relevance to humans, and any aspects to be studied in humans. If applicable, the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic index should be discussed). The relevance of this information to the proposed human dosing should be addressed. Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis. a) Nonclinical Pharmacology: A summary of the pharmacological aspects of the investigational product and, where appropriate, its significant metabolites studied in animals, should be included. Such a summary should incorporate studies that assess potential therapeutic activity (e.g. efficacy models, receptor binding, and specificity) as well as those that assess safety (e.g., special studies to assess pharmacological actions other than the intended therapeutic effects). b) Pharmacokinetics and Product Metabolism in Animals: A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in all species studied should be given. The discussion of the findings should address the absorption and the local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the pharmacological and toxicological findings in animal species. c) Toxicology: A summary of the toxicological effects found in relevant studies conducted in different animal species should be described under headings single dose, repeated dose, carcinogenicity, special studies (e.g., irritancy and sensitization), reproductive toxicity, and genotoxicity (mutagenicity). 10.10.6. Effects in Human: A thorough discussion of the known effects of the investigational products in humans should be provided, including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities. Where possible, a summary of each completed clinical trial should be provided. Information should also be provided regarding results of any use of the investigational products other than from in clinical trials (such as from experience during marketing). 10.10.7. Pharmacokinetics and Product Metabolism in Humans: A summary of information on the pharmacokinetics of the investigational products should be presented, including the following, if available: 10.10.7.1. Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, and elimination) 10.10.7.2. Bioavailability of the investigational product (absolute, where Possible, or relative) using a reference dosage form, 10.10.7.3. Population subgroups (e.g., gender, age, and impaired organ function), 10.10.7.4. Interactions (e.g., product-product interactions and interaction with food), 10.10.7.5. Other pharmacokinetic data (e.g., results of population studies
  • 29. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April performed within clinical trials). 10.10.8. Safety and Efficacy: A summary of information should be provided about the investigational products' (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in subjects. In cases where many clinical trials have been completed, the use of summaries of safety and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular summaries of adverse drug reactions for all the clinical trials (including those for all the studied indications) should be provided. Differences in adverse drug reaction patterns/incidences across indications or subgroups should be discussed. The Investigator Brochure should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis of prior experiences with the product under investigation and with other products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the products. 10.10.9. Marketing Experience: The Investigator Brochure should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarized (e.g., formulations, dosages, routes of administration, and adverse product reactions). The Brochure should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration. 10.10.10. Summary of Data and Guidance for the Investigator: This section should provide an overall discussion of the nonclinical and clinical data, and should summarize the information from various sources on different aspects of the investigational products, wherever possible. In this way, the principal investigator can be provided with the most informative interpretation of the available data and with an assessment of the implications of the information for future clinical trials. Where appropriate, the published reports on related products should be discussed. This could help the principal investigator or sub-investigators to anticipate adverse drug reactions or other problems in clinical trials. The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational products. Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that are based on previous human experience and on the pharmacology of the investigational product. 10.11. Following details are the examples of the Investigator Brochure’s title page: Name of the sponsor Product Number of the Trial Names: Chemical name, Generic name (if approved) Commercial names (if legally permitted and requested by the
  • 30. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April sponsor) Publication Number of the Investigator Brochure Issue Date of the Investigator Brochure The previous Issue Number and Date replaced by the Investigator Brochure 10.12. Following details are the examples of the Investigator Brochure’s content table: Confidentiality Statement (optional) Signature Page (optional) Content Table Summary Introduction Physical, Chemical, and Pharmaceutical Properties and Formulation Non-clinical Studies Nonclinical Pharmacology Pharmacokinetics and Product Metabolism in Animals Toxicology Effects in Human Pharmacokinetics and Product Metabolism in Humans Safety and Efficacy Marketing Experience Summary of Data and Guidance for the Investigator References to Publications and Reports: These references should be included at the end of each section. Annexes (if available) 11. ESSENTIAL DOCUMENTS FOR CONDUCTION OF A CLINICAL TRIAL 11.1. Essential Documents are those documents which individually and collectively permit evaluation of conduction of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the principal investigator and other investigators, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. 11.2. Providing these documents to the investigator and sponsor in a timely manner can greatly assist in the successful management of a trial by the principal investigator, other investigators, sponsor and monitor. 11.3. These documents are also audited at the sponsor's independent audit function and inspected by Turkish Medicine and Medical Device Agency as part of the process to confirm the validity of the trial conducted and the integrity of data collected. 11.4. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated. The minimum list of essential documents required to be prepared is as follows: before the clinical phase of the trial commences, during the clinical performance of the trial, after completion or termination of the trial. 11.5. A description is given of the purpose of each document. It is specified whether it should be filed in either the principal investigator or sponsor files, or both. It is acceptable to combine some of the documents, provided the
  • 31. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April individual elements are readily identifiable. 11.6 Trial master files should be established at the beginning of the trial, both at the principal investigator and at the sponsor. A final close-out of a trial can only be done when the monitor has reviewed both principal investigator and sponsor files and confirmed that all necessary documents are in the appropriate files. 11.7. Any or all of the documents addressed in this guideline should be subject to, and therefore available for, audit by the sponsor's auditor and inspection by Turkish Medicine and Medical Device Agency or the regulatory health authority. Therefore, these documents should be available. 11.8. Before the clinical phase of the trial commences, the following documents should be generated and should be on file before the trial formally starts. 11.8.1. The investigator brochure for documenting that relevant and up-to-date information about the investigational product is provided to the investigator, 11.8.2. The study protocol and its amendments, if any, and the CRF (this may be draft CRF, however, the approval of the Ethics Committee should be obtained until first subject is enrolled into the trial) signed in order to document that the investigator and the sponsor accepts the study protocol, amendments and the CRF, 11.8.3. The ICF, other written information and the advertisement used for enrolling patients to the trial, if any, in order to document that subjects are provided the informed consent form, subjects are provided written information for supporting the completely informed consent of the subject and the measures for enrolling subjects to the trial are proper and not compulsory, 11.8.4. Financial issues related with the study, 11.8.5. Insurance policy, if necessary, 11.8.6. Agreements signed between relevant parties, 11.8.7. Approval of the Ethics Committee, 11.8.8. The permission of Turkish Medicine and Medical Device Agency as specified in applicable regulatory requirements, 11.8.9. Curriculum vitas of the principal investigators and other investigators, 11.8.10. Normal values or rates of tests specified in the trial protocol and laboratory related documents, if any, 11.8.11. The investigational product’s label issued as specified in applicable regulatory requirements, 11.8.12. The handling instructions of the investigational products, if they are not addressed in the trial protocol or Investigator Brochure, in order to document instructions for proper storage, packaging, distribution and disposition of the investigational products and the trial-related supplies, 11.8.13. Shipment records of the investigational products and trial-related supplies in order to document shipment dates of investigational products and trial-related supplies, their serial numbers and shipment methods, 11.8.14. Analysis certificate of the investigational product shipped, 11.8.15. Un-blinding methods in blinded trials, 11.8.16. The randomization list, 11.8.17.The pre-trial monitoring report in order to document that the investigational site is appropriate, 11.9. When the clinical phase of the trial is conducted, in addition to the document specified in Article 11.8, at least following documents should be
  • 32. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April included in the files as the evidence of all relevant new information, if available: 11.9.1. Investigator Brochure updates, 11.9.2. Amendments made in the study protocol, ICF, CRF etc in relation with the trial throughout the study period, 11.9.3. The approval of the Ethics Committee and the permission of Turkish Medicine and Medical Device Agency for the amendments, when necessary, 11.9.4. Amendments made by coordinator, the principal investigator or other investigators, 11.9.5. Changes in normal values or rates of tests specified in the trial protocol and laboratory related documents, if any, 11.9.6. Monitoring reports, 11.9.7. Other important communication notes, other than visits to the investigational sites (phone call notes, meeting notes etc.) 11.9.8. ICF signed and obtained as specified in applicable regulatory requirements, source documents, 11.9.9. Signed, dated and filled CRF, 11.9.10. Corrections in CRF, 11.9.11. Safety notices, 11.9.12. The subject screening record, 11.9.13. The subject identity code list, 11.9.14. Related records in order to document that investigational products are used in compliance with the trial protocol, 11.9.15. The signature page in order to document signatures and initials of subjects authorized to make entries or corrections on CRF, 11.10. Following the completion or termination of the trial, in addition to the documents specified in Articles 11.8 and 11.9, following documents should be included in the files: 11.10.1. Records retained in the investigational site in relation with the investigational product, account details on use, 11.10.2. Documents indicating disposal of investigational products in compliance with the applicable regulatory requirements, 11.10.3. The filled subject identity code list, 11.10.4. Final close monitoring report of the trial, 11.10.5. Documents of audits and inspections, if any, 11.10.6. If the status of blindness is later removed, relevant documents, 11.10.7. The final report to be submitted to the Ethics Committee and Medicine and Medical Device Agency, 11.10.8. Clinical trial report. 12. OTHER PROVISIONS 12.1. When an extension is made on insurance documents, which were previously approved by the Ethics Committee and permitted by Medicine and Medical Device Agency, it is sufficient to inform the Ethics Committee and Turkish Medicine and Medical Device Agency. 12.2. Study nurse, site coordinator, sub-investigator, monitor or qualified person can be delegated to help conducting the trial provided that Turkish Medicine and Medical Device Agency, Authority and ethics committee are informed. However, Turkish Medicine and Medical Device Agency or ethics committee may cancel the delegation with justification. 12.3. The pharmacist assigned for the trial can be delegated in accordance with the relevant regulation provided that Turkish Medicine and Medical Device Agency and ethics committee are
  • 33. GOOD CLINICAL PRACTICES GUIDELINES 2013 17 April informed. However, Turkish Medicine and Medical Device Agency or ethics committee may cancel the delegation with justification. 12.4. The change of the principal investigator involved in the trials that have the previous approval of ethics committee and permission of Turkish Medicine and Medical Device Agency, can be made provided that Turkish Medicine and Medical Device Agency and Ethics Committee are informed. However, Turkish Medicine and Medical Device Agency or Ethics Committee may cancel the delegation with justification. 12.5. With regards the international multi-center clinical trials, it is sufficient to only inform the Ethics Committee about the changes which will not be applied in our country and does not include information about any safety notice, concerning the documents such as the investigator brochure, the protocol and ICF, 12.6. In order to conduct a clinical trial the CRF should be submitted for the initial submission to obtain approval from ethics committee and permission from Turkish Medicine and Medical Device Agency, approval and permission should be obtained. However, it is sufficient to inform ethics committee for the further changes in CRF to be made. 12.7. For some technical changes (changes in a CRF version approved by Ethics Committee and Turkish Medicine and Medical Device Agency which does not alter the quality or quantity of data; such as changes that facilitates answering the data in the CRF, changes that insert automatic queries in case of incorrect data entry or interface modifications in the program used) which does not affect the validation of electronic CRFs, it is sufficient to inform ethics committee. 13. REGULATIONS SUPERSEDED The Good Clinical Practices Guideline, which was put into force based on the Approval No. 10990, dated 06.12.2011, is superseded. 14. EFFECTIVE DATE This Guideline comes into effect on the date of approval.