ICH E6(R1) Guideline for Good Clinical Practice PDF

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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 th...

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. ADDENDUM (e) Reports of on-site and/or centralized monitoring should be provided to the sponsor (including appropriate management and staff responsible for trial and site oversight) in a timely manner for review and follow up. Results of monitoring activities should be documented in sufficient detail to allow verification of compliance with the monitoring plan. Reporting of centralized monitoring activities should be regular and may be independent from site visits. ADDENDUM 5.18.7 Monitoring Plan The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention should be given to those aspects that are not routine clinical practice and that require additional training. The monitoring plan should reference the applicable policies and procedures. 5.19 Audit 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. 32  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. ADDENDUM If noncompliance that significantly affects or has the potential to significantly affect human subject protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. 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 investiga- tor's/institution’s participation in the trial. When an investigator's/institution’s parti- cipation is terminated because of noncompliance, the sponsor should notify promptly the regulatory authority(ies). 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 33 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 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). 34  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 35 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 36  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 6.9 Statistics 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.) 37 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 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 38  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 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 39 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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)). (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: 40  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice  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 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 41 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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. 42  Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 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: 43 Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice 7.5 APPENDIX 2: TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example) - Confidentiality Statement (optional)................................................................................ - Signature Page (optional)................................................................................................. 1 Table of Contents............................................................................................................. 2 Summary.......................................................................................................................... 3 Introduction...................................................................................................................... 4 Physical, Chemical, and Pharmaceutical Properties and Formulation............................ 5 Nonclinical Studies.......................................................................................................... 5.1 Nonclinical Pharmacology............................................................................................... 5.2 Pharmacokinetics and Product Metabolism in Animals.................................................. 5.3 Toxicology....................................................................................................................... 6 Effects in Humans............................................................................................................ 6.1 Pharmacokinetics and Product Metabolism in Humans.................................................. 6.2 Safety and Efficacy.......................................................................................................... 6.3 Marketing Experience...................................................................................................... 7 Summary of Data and Guidance for the Investigator...................................................... NB: References on 1. Publications 2. Reports These references should be found at the end of each chapter Appendices (if any) 44 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 8.1 Introduction Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements. Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the process to confirm the validity of the trial conduct and the integrity of data collected. The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the individual elements are readily identifiable. Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate files. Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies). ADDENDUM The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval. Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation) based on the importance and relevance of the specific documents to the trial. 45 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not have exclusive control of those data. When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial. 8.2 Before the Clinical Phase of the Trial Commences During this planning stage the following documents should be generated and should be on file before the trial formally starts Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.1 INVESTIGATOR’S BROCHURE To document that relevant and current scientific X X information about the investigational product has been provided to the investigator 8.2.2 SIGNED PROTOCOL AND AMENDMENTS, To document investigator and sponsor agreement X X IF ANY, AND SAMPLE CASE REPORT to the protocol/amendment(s) and CRF FORM (CRF) 8.2.3 INFORMATION GIVEN TO TRIAL X X SUBJECT - INFORMED CONSENT FORM To document the informed consent (including all applicable translations) - ANY OTHER WRITTEN INFORMATION To document that subjects will be given X X appropriate written information (content and wording) to support their ability to give fully informed consent 46 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution - ADVERTISEMENT FOR SUBJECT To document that recruitment measures are X RECRUITMENT (if used) appropriate and not coercive 8.2.4 FINANCIAL ASPECTS OF THE TRIAL To document the financial agreement between the X X investigator/institution and the sponsor for the trial 8.2.5 INSURANCE STATEMENT To document that compensation to subject(s) for X X (where required) trial-related injury will be available 8.2.6 SIGNED AGREEMENT BETWEEN To document agreements INVOLVED PARTIES, e.g.: - investigator/institution and sponsor X X - investigator/institution and CRO X X (where required) - sponsor and CRO X - investigator/institution and authority(ies) X X (where required) 47 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.7 DATED, DOCUMENTED To document that the trial has been subject to X X APPROVAL/FAVOURABLE OPINION OF IRB/IEC review and given approval/favourable INSTITUTIONAL REVIEW BOARD (IRB) opinion. To identify the version number and date /INDEPENDENT ETHICS COMMITTEE of the document(s) (IEC) OF THE FOLLOWING: - protocol and any amendments - CRF (if applicable) - informed consent form(s) - any other written information to be provided to the subject(s) - advertisement for subject recruitment (if used) - subject compensation (if any) - any other documents given approval/ favourable opinion 48 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.8 INSTITUTIONAL REVIEW To document that the IRB/IEC is constituted in X X BOARD/INDEPENDENT ETHICS agreement with GCP (where COMMITTEE COMPOSITION required) 8.2.9 REGULATORY AUTHORITY(IES) To document appropriate X X AUTHORISATION/APPROVAL/ authorisation/approval/notification by the (where (where NOTIFICATION OF PROTOCOL regulatory authority(ies) has been obtained prior to required) required) (where required) initiation of the trial in compliance with the applicable regulatory requirement(s) 8.2.10 CURRICULUM VITAE AND/OR OTHER To document qualifications and eligibility to X X RELEVANT DOCUMENTS EVIDENCING conduct trial and/or provide medical supervision of QUALIFICATIONS OF INVESTIGATOR(S) subjects AND SUB-INVESTIGATOR(S) X X 8.2.11 NORMAL VALUE(S)/RANGE(S) FOR To document normal values and/or ranges of the MEDICAL/ LABORATORY/TECHNICAL tests PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL 49 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.12 MEDICAL/LABORATORY/TECHNICAL To document competence of facility to perform X X PROCEDURES /TESTS required test(s), and support reliability of results (where - certification or required) - accreditation or - established quality control and/or external quality assessment or - other validation (where required) 8.2.13 SAMPLE OF LABEL(S) ATTACHED TO To document compliance with applicable labelling X INVESTIGATIONAL PRODUCT regulations and appropriateness of instructions CONTAINER(S) provided to the subjects 8.2.14 INSTRUCTIONS FOR HANDLING OF To document instructions needed to ensure proper X X INVESTIGATIONAL PRODUCT(S) AND storage, packaging, dispensing and disposition of TRIAL-RELATED MATERIALS investigational products and trial-related materials (if not included in protocol or Investigator’s Brochure) 8.2.15 SHIPPING RECORDS FOR To document shipment dates, batch numbers and X X INVESTIGATIONAL PRODUCT(S) AND method of shipment of investigational product(s) TRIAL-RELATED MATERIALS and trial-related materials. Allows tracking of product batch, review of shipping conditions, and accountability 50 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.16 CERTIFICATE(S) OF ANALYSIS OF To document identity, purity, and strength of X INVESTIGATIONAL PRODUCT(S) SHIPPED investigational product(s) to be used in the trial 8.2.17 DECODING PROCEDURES FOR BLINDED To document how, in case of an emergency, X X TRIALS identity of blinded investigational product can be (third party if revealed without breaking the blind for the applicable) remaining subjects' treatment 51 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.2.18 MASTER RANDOMISATION LIST To document method for randomisation of trial X population (third party if applicable) 8.2.19 PRE-TRIAL MONITORING REPORT To document that the site is suitable for the trial X (may be combined with 8.2.20) 8.2.20 TRIAL INITIATION MONITORING To document that trial procedures were reviewed X X REPORT with the investigator and the investigator’s trial staff ( may be combined with 8.2.19) 52 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice 8.3 During the Clinical Conduct of the Trial In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is documented as it becomes available Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.1 INVESTIGATOR’S BROCHURE UPDATES To document that investigator is informed in a X X timely manner of relevant information as it becomes available 8.3.2 ANY REVISION TO: To document revisions of these trial related X X - protocol/amendment(s) and CRF documents that take effect during trial - informed consent form - any other written information provided to subjects - advertisement for subject recruitment (if used) 53 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.3 DATED, DOCUMENTED To document that the amendment(s) and/or X X APPROVAL/FAVOURABLE OPINION OF revision(s) have been subject to IRB/IEC review INSTITUTIONAL REVIEW BOARD (IRB) and were given approval/favourable opinion. To /INDEPENDENT ETHICS COMMITTEE identify the version number and date of the (IEC) OF THE FOLLOWING: document(s). - protocol amendment(s) - revision(s) of: - informed consent form - any other written information to be provided to the subject - advertisement for subject recruitment (if used) - any other documents given approval/favourable opinion - continuing review of trial (where required) 8.3.4 REGULATORY AUTHORITY(IES) To document compliance with applicable X X AUTHORISATIONS/APPROVALS/NOTIFIC regulatory requirements (where ATIONS WHERE REQUIRED FOR: required) - protocol amendment(s) and other documents 8.3.5 CURRICULUM VITAE FOR NEW (see 8.2.10) X X INVESTIGATOR(S) AND/OR SUB- INVESTIGATOR(S) 54 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.6 UPDATES TO NORMAL To document normal values and ranges that are X X VALUE(S)/RANGE(S) FOR MEDICAL/ revised during the trial (see 8.2.11) LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL 8.3.7 UPDATES OF MEDICAL/LABORATORY/ To document that tests remain adequate throughout X X TECHNICAL PROCEDURES/TESTS the trial period (see 8.2.12) (where required) - certification or - accreditation or - established quality control and/or external quality assessment or - other validation (where required) 8.3.8 DOCUMENTATION OF (see 8.2.15.) X X INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT 8.3.9 CERTIFICATE(S) OF ANALYSIS FOR NEW (see 8.2.16) X BATCHES OF INVESTIGATIONAL PRODUCTS 8.3.10 MONITORING VISIT REPORTS To document site visits by, and findings of, the X monitor 55 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.11 RELEVANT COMMUNICATIONS OTHER To document any agreements or significant X X THAN SITE VISITS discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) - letters reporting - meeting notes - notes of telephone calls 8.3.12 SIGNED INFORMED CONSENT FORMS To document that consent is obtained in X accordance with GCP and protocol and dated prior to participation of each subject in trial. Also to document direct access permission (see 8.2.3) 8.3.13 SOURCE DOCUMENTS To document the existence of the subject and X substantiate integrity of trial data collected. To include original documents related to the trial, to medical treatment, and history of subject 8.3.14 SIGNED, DATED AND COMPLETED To document that the investigator or authorised X X CASE REPORT FORMS (CRF) member of the investigator’s staff confirms the (copy) (original) observations recorded 8.3.15 DOCUMENTATION OF CRF To document all changes/additions or corrections X X CORRECTIONS made to CRF after initial data were recorded (copy) (original) 8.3.16 NOTIFICATION BY ORIGINATING Notification by originating investigator to sponsor X X INVESTIGATOR TO SPONSOR OF of serious adverse events and related reports in SERIOUS ADVERSE EVENTS AND accordance with 4.11 RELATED REPORTS 56 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.17 NOTIFICATION BY SPONSOR AND/OR Notification by sponsor and/or investigator, where X X INVESTIGATOR, WHERE APPLICABLE, applicable, to regulatory authorities and (where TO REGULATORY AUTHORITY(IES) AND IRB(s)/IEC(s) of unexpected serious adverse drug required) IRB(S)/IEC(S) OF UNEXPECTED SERIOUS reactions in accordance with 5.17 and 4.11.1 and ADVERSE DRUG REACTIONS AND OF of other safety information in accordance with OTHER SAFETY INFORMATION 5.16.2 and 4.11.2 8.3.18 NOTIFICATION BY SPONSOR TO Notification by sponsor to investigators of safety X X INVESTIGATORS OF SAFETY information in accordance with 5.16.2 INFORMATION 8.3.19 INTERIM OR ANNUAL REPORTS TO Interim or annual reports provided to IRB/IEC in X X IRB/IEC AND AUTHORITY(IES) accordance with 4.10 and to authority(ies) in (where accordance with 5.17.3 required) 8.3.20 SUBJECT SCREENING LOG To document identification of subjects who X X entered pre-trial screening (where required) 8.3.21 SUBJECT IDENTIFICATION CODE LIST To document that investigator/institution keeps a X confidential list of names of all subjects allocated to trial numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject 57 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.3.22 SUBJECT ENROLMENT LOG To document chronological enrolment of subjects X by trial number 8.3.23 INVESTIGATIONAL PRODUCTS To document that investigational product(s) have X X ACCOUNTABILITY AT THE SITE been used according to the protocol 8.3.24 SIGNATURE SHEET To document signatures and initials of all persons X X authorised to make entries and/or corrections on CRFs 8.3.25 RECORD OF RETAINED BODY FLUIDS/ To document location and identification of X X TISSUE SAMPLES (IF ANY) retained samples if assays need to be repeated 58 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice 8.4 After Completion or Termination of the Trial After completion or termination of the trial, all of the documents identified in Sections 8.2 and 8.3 should be in the file together with the following Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.4.1 INVESTIGATIONAL PRODUCT(S) To document that the investigational product(s) X X ACCOUNTABILITY AT SITE have been used according to the protocol. To documents the final accounting of investigational product(s) received at the site, dispensed to subjects, returned by the subjects, and returned to sponsor 8.4.2 DOCUMENTATION OF To document destruction of unused investigational X X INVESTIGATIONAL PRODUCT products by sponsor or at site (if destroyed at DESTRUCTION site) 8.4.3 COMPLETED SUBJECT IDENTIFICATION To permit identification of all subjects enrolled in X CODE LIST the trial in case follow-up is required. List should be kept in a confidential manner and for agreed upon time 8.4.4 AUDIT CERTIFICATE (if available) To document that audit was performed X 8.4.5 FINAL TRIAL CLOSE-OUT MONITORING To document that all activities required for trial X REPORT close-out are completed, and copies of essential documents are held in the appropriate files 59 Integrated Addendum to E6(R1): Guideline for Good Clinical Practice Title of Document Purpose Located in Files of Investigator/ Sponsor Institution 8.4.6 TREATMENT ALLOCATION AND Returned to sponsor to document any decoding X DECODING DOCUMENTATION that may have occurred 8.4.7 FINAL REPORT BY INVESTIGATOR TO To document completion of the trial X IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES) 8.4.8 CLINICAL STUDY REPORT To document results and interpretation of trial X X (if applicable) 60