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楼主: BLUE_KAIKAI

[分享] 新手经验不够的进来。《ICH-GCP英文版加中文版》

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 楼主| 发表于 2009-3-8 21:50 | 显示全部楼层
5.3 Medical Expertise
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.
5.4 Trial Design
5.4.1 The sponsor should utilize qualified individuals (e.g. biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.
5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and conduct.
5.5 Trial Management, Data Handling, and Record Keeping
5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.
5.5.2 The sponsor may consider establishing an independent data-monitoring committee (IDMC) 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 IDMC should have written operating procedures and maintain written records of all its meetings.
5.5.3 When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
(a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
(b) Maintains SOPs for using these systems.
(c) 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 (i.e. maintain an audit trail, data trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to the data.
(e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g. maintain the blinding during data entry and processing).
5.5.4 If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.
5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all the data reported for each subject.
5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).
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 楼主| 发表于 2009-3-8 21:51 | 显示全部楼层
5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor intends to apply for approval(s).
5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e. for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation or in conformance with the applicable regulatory requirement(s).
5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators/institutions and all the regulatory authorities.
5.5.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).
5.5.11 The sponsor specific essential documents should be retained until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.
5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed.
5.6 Investigator Selection
5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor's responsibility.
5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.
5.6.3 The sponsor should obtain the investigator's/institution's agreement:
(a) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s) (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see 4.5.1);
(b) to comply with procedures for data recording/reporting;
(c) to permit monitoring, auditing and inspection (see 4.1.4) and
(d) to retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
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 楼主| 发表于 2009-3-8 21:52 | 显示全部楼层
The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.
5.7 Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.
5.8 Compensation to Subjects and Investigators
5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.
5.8.2 The sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).
5.9 Financing
The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.
5.10 Notification/Submission to Regulatory Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the applicable regulatory requirement(s)) should submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information to identify the protocol.
5.11 Confirmation of Review by IRB/IEC
5.11.1 The sponsor should obtain from the investigator/institution:
(a) The name and address of the investigator's/institution’s IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol, written informed consent form(s) and any other written information to be provided to subjects, subject recruiting procedures, and documents related to payments and compensation available to the subjects, and any other documents that the IRB/IEC may have requested.
5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as modification(s) of the protocol, written informed consent form and any other written information to be provided to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.
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 楼主| 发表于 2009-3-8 21:52 | 显示全部楼层
5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion.
5.12 Information on Investigational Product(s)
5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.
5.12.2 The sponsor should update the Investigator's Brochure as significant new information becomes available (see 7. Investigator's Brochure).
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.
5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.
5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.
5.14 Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
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 楼主| 发表于 2009-3-8 21:53 | 显示全部楼层
5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable opinion.
5.12 Information on Investigational Product(s)
5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.
5.12.2 The sponsor should update the Investigator's Brochure as significant new information becomes available (see 7. Investigator's Brochure).
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g. protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g. monitors, investigators, pharmacists, storage managers) of these determinations.
5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.
5.13.5 If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials.
5.14 Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational product(s).
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 楼主| 发表于 2009-3-8 21:53 | 显示全部楼层
5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s) until the sponsor obtains all required documentation (e.g. approval/favourable opinion from IRB/IEC and regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of investigational product(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).
5.14.4 The sponsor should:
(a) Ensure timely delivery of investigational product(s) to the investigator(s).
(b) Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
(c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g. for deficient product recall, reclaim after trial completion, expired product reclaim).
(d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition.
5.14.5 The sponsor should:
(a) Take steps to ensure that the investigational product(s) are stable over the period of use.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period.
5.15 Record Access
5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.
5.15.2 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, IRB/IEC review, and regulatory inspection.
5.16 Safety Information
5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the
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 楼主| 发表于 2009-3-8 21:54 | 显示全部楼层
safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
5.17 Adverse Drug Reaction Reporting
5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and unexpected.
5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required by applicable regulatory requirement(s).
5.18 Monitoring
5.18.1 Purpose
The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s).
5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional circumstances the sponsor may determine that central monitoring in conjunction with procedures such as investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.
5.18.4 Monitor's Responsibilities
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 楼主| 发表于 2009-3-8 21:55 | 显示全部楼层
The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly by carrying out the following activities when relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff, are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that supplies are sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
(d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
(e) Verifying that written informed consent was obtained before each subject's participation in the trial.
(f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial.
(h) Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator/institution, and have not delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling only eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
(l) Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
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 楼主| 发表于 2009-3-8 21:56 | 显示全部楼层
(m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against each other. The monitor specifically should verify that:
(i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
(ii) Any dose and/or therapy modifications are well documented for each of the trial subjects.
(iii) Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are reported and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained (if necessary), and initialled by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential documents (see 8. Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.
5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.
5.18.6 Monitoring Report
(a) The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.
(b) Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
(c) 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.
(d) The review and follow-up of the monitoring report with the sponsor should be documented by the sponsor’s designated representative.
5.19 Audit
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 楼主| 发表于 2009-3-8 21:56 | 显示全部楼层
If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
5.19.1 Purpose
The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
(b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be documented.
(d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
(e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
5.20 Noncompliance
5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance.
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial. When an investigator's/institution’s participation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies).
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 楼主| 发表于 2009-3-8 21:57 | 显示全部楼层
5.21 Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.)
5.23 Multicentre Trials
For multicentre trials, the sponsor should ensure that:
5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data.
5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial.
5.23.4 All investigators are given instructions on following the protocol, on complying with a uniform set of standards for the assessment of clinical and laboratory findings, and on completing the CRFs.
5.23.5 Communication between investigators is facilitated.
6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
The contents of a trial protocol should generally include the following topics. However, site specific information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the information listed below may be contained in other protocol referenced documents, such as an Investigator’s Brochure.
6.1 General Information
6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment number(s) and date(s).
6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
6.1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for the sponsor.
6.1.4 Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial.
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6.1.5 Name and title of the investigator(s) who is (are) responsible for conducting the trial, and the address and telephone number(s) of the trial site(s).
6.1.6 Name, title, address, and telephone number(s) of the qualified physician (or dentist, if applicable), who is responsible for all trial-site related medical (or dental) decisions (if other than investigator).
6.1.7 Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technical department(s) and/or institutions involved in the trial.
6.2 Background Information
6.2.1 Name and description of the investigational product(s).
6.2.2 A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial.
6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
6.2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s).
6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable regulatory requirement(s).
6.2.6 Description of the population to be studied.
6.2.7 References to literature and data that are relevant to the trial, and that provide background for the trial.
6.3 Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the trial.
6.4 Trial Design
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:
6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial.
6.4.2 A description of the type/design of trial to be conducted (e.g. double-blind, placebo-controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
6.4.3 A description of the measures taken to minimize/avoid bias, including:
(a) Randomization.
(b) Blinding.
6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the investigational product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
6.4.5 The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any.
6.4.6 A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial and entire trial.
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6.4.7 Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any.
6.4.8 Maintenance of trial treatment randomization codes and procedures for breaking codes.
6.4.9 The identification of any data to be recorded directly on the CRFs (i.e. no prior written or electronic record of data), and to be considered to be source data.
6.5 Selection and Withdrawal of Subjects
6.5.1 Subject inclusion criteria.
6.5.2 Subject exclusion criteria.
6.5.3 Subject withdrawal criteria (i.e. terminating investigational product treatment/trial treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/ investigational product treatment.
(b) The type and timing of the data to be collected for withdrawn subjects.
(c) Whether and how subjects are to be replaced.
(d) The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
6.6 Treatment of Subjects
6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s), the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
6.6.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial.
6.6.3 Procedures for monitoring subject compliance.
6.7 Assessment of Efficacy
6.7.1 Specification of the efficacy parameters.
6.7.2 Methods and timing for assessing, recording, and analysing of efficacy parameters.
6.8 Assessment of Safety
6.8.1 Specification of safety parameters.
6.8.2 The methods and timing for assessing, recording, and analysing safety parameters.
6.8.3 Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent illnesses.
6.8.4 The type and duration of the follow-up of subjects after adverse events.
6.9 Statistics
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6.9.1 A description of the statistical methods to be employed, including timing of any planned interim analysis(ses).
6.9.2 The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification.
6.9.3 The level of significance to be used.
6.9.4 Criteria for the termination of the trial.
6.9.5 Procedure for accounting for missing, unused, and spurious data.
6.9.6 Procedures for reporting any deviation(s) from the original statistical plan (any deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final report, as appropriate).
6.9.7 The selection of subjects to be included in the analyses (e.g. all randomized subjects, all dosed subjects, all eligible subjects, evaluable subjects).
6.10 Direct Access to Source Data/Documents
The sponsor should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory inspection(s), providing direct access to source data/documents.
6.11 Quality Control and Quality Assurance
6.12 Ethics
Description of ethical considerations relating to the trial.
6.13 Data Handling and Record Keeping
6.14 Financing and Insurance
Financing and insurance if not addressed in a separate agreement.
6.15 Publication Policy
Publication policy, if not addressed in a separate agreement.
6.16 Supplements
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
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7. INVESTIGATOR’S BROCHURE
7.1 Introduction
The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the 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/interval, methods of administration: and safety monitoring procedures. The IB 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. For this reason, a medically qualified person should generally participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated the described data.
This guideline delineates the minimum information that should be included in an IB and provides suggestions for its layout. It is expected that the type and extent of information available will vary with the stage of development of the investigational product. If the investigational product is marketed and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may be an appropriate alternative, provided that it includes current, comprehensive, and detailed information on all aspects of the investigational product that might be of importance to the investigator. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB 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, in accordance with Good Clinical Practice, relevant new information may be so important that it should be communicated to the investigators, and possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is included in a revised IB.
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is available from the commercial manufacturer. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel. In cases where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an expanded background information section in the trial protocol that contains the minimum current information described in this guideline.
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7.2 General Considerations
The IB should include:
7.2.1 Title Page
This should provide the sponsor's name, the identity of each investigational product (i.e., research number, chemical or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release date. It is also suggested that an edition number, and a reference to the number and date of the edition it supersedes, be provided. An example is given in Appendix 1.
7.2.2 Confidentiality Statement
The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a confidential document for the sole information and use of the investigator's team and the IRB/IEC.
7.3 Contents of the Investigator’s Brochure
The IB should contain the following sections, each with literature references where appropriate:
7.3.1 Table of Contents
An example of the Table of Contents is given in Appendix 2
7.3.2 Summary
A brief 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.
7.3.3 Introduction
A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s) when approved) of the investigational product(s), all active ingredients, the investigational product (s ) pharmacological class and its expected position within this class (e.g. advantages), the rationale for performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the investigational product.
7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation
A description should be provided of the investigational product substance(s) (including the chemical and/or structural formula(e)), 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 formulation(s) to be used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and handling of the dosage form(s) should also be given.
Any structural similarities to other known compounds should be mentioned.
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7.3.5 Nonclinical Studies
Introduction:
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 unfavourable and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
• Species tested
• Number and sex of animals in each group
• Unit dose (e.g., milligram/kilogram (mg/kg))
• Dose interval
• Route of administration
• Duration of dosing
• Information on systemic distribution
• Duration of post-exposure follow-up
• Results, including the following aspects:
− Nature and frequency of pharmacological or toxic effects
− Severity or intensity of pharmacological or toxic effects
− Time to onset of effects
− Reversibility of effects
− Duration of effects
− Dose response
Tabular format/listings should be used whenever possible to enhance 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 effect(s)).
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(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 the following headings where appropriate:
− Single dose
− Repeated dose
− Carcinogenicity
− Special studies (e.g. irritancy and sensitisation)
− Reproductive toxicity
− Genotoxicity (mutagenicity)
7.3.6 Effects in Humans
Introduction:
A thorough discussion of the known effects of the investigational product(s) 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 product(s) other than from in clinical trials, such as from experience during marketing.
(a) Pharmacokinetics and Product Metabolism in Humans
− A summary of information on the pharmacokinetics of the investigational product(s) should be presented, including the following, if available:
− Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and elimination).
− Bioavailability of the investigational product (absolute, where possible, and/or relative) using a reference dosage form.
− Population subgroups (e.g., gender, age, and impaired organ function).
− Interactions (e.g., product-product interactions and effects of food).
− Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
(b) Safety and Efficacy
A summary of information should be provided about the investigational product's/products' (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be discussed. In cases where a number of 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) would be useful. Important differences in adverse drug
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reaction patterns/incidences across indications or subgroups should be discussed.
The IB 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 related products. A description should also be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
(c) Marketing Experience
The IB should identify countries where the investigational product has been marketed or approved. Any significant information arising from the marketed use should be summarised (e.g., formulations, dosages, routes of administration, and adverse product reactions). The IB should also identify all the countries where the investigational product did not receive approval/registration for marketing or was withdrawn from marketing/registration.
7.3.7 Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical and clinical data, and should summarise the information from various sources on different aspects of the investigational product(s), wherever possible. In this way, the 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 investigator 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 product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product.
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7.4 APPENDIX 1:
TITLE PAGE (Example)
SPONSOR'S NAME
Product:
Research Number:
Name(s): Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR'S BROCHURE
Edition Number:
Release Date:
Replaces Previous Edition Number:
Date:
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