Quick guide to good clinical practice

Cemal Cingi Nuray Bayar Muluk Quick Guide to Good Clinical Practice How to Meet International Quality Standard in Clinical Research 123 Quick Guide to Good Clinical Practice Cemal Cingi • Nuray Bayar Muluk Quick Guide to Good Clinical Practice How to Meet International Quality Standard in Clinical Research Cemal Cingi Medical Faculty, ENT Department Eskisehir Osmangazi University Medical Faculty, ENT Department Eskisehir Turkey Nuray Bayar Muluk ENT Department Kırıkkale University Kırıkkale Turkey ISBN 978-3-319-44343-0 ISBN 978-3-319-44344-7 DOI 10.1007/978-3-319-44344-7 (eBook) Library of Congress Control Number: 2016957158 © Springer International Publishing Switzerland 2017 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is Gewerbestrasse 11, 6330 Cham, Switzerland We wish to dedicate this book to our lovely children ‘Can Cemal Cingi’, ‘Alp Cingi’ and ‘Hakan Muluk’ hoping them to be highly ethical and scientific all through their life Preface Clinical trials are needed to develop new molecules or to set new treatment modalities as well as to improve present ones in medicine On the other hand, we had the oath of Hippocrates, and we promised not to harm our patients As clinicians, we need to trials without any harm to anybody Good Clinical Practice (GCP) rules which cover international ethical and scientific quality standard for designing, conducting, recording and reporting trials came out to combine these two needs in order to standardise research protocols without any harm to patients or to healthy volunteers who will take part in clinical research plans The International Conference on Harmonization (ICH) provided GCP guidelines Compliance with these standards and consistence with the principles that have their origin in the Declaration of Helsinki should be the aim of all clinical researchers In order to help the clinical researchers, we reviewed all related publications and rules and quoted the most important parts to set a practical guideline for clinicians We hope this practical review will be a useful source and help all researchers Eskisehir, Turkey Kırıkkale, Turkey Cemal Cingi, MD Nuray Bayar Muluk, MD Contents Clinical Trials: Historical Aspects and Importance and New Drug Developments 1.1 Introduction 1.2 Clinical Trials 1.2.1 Why Are Clinical Studies Conducted? 1.2.2 Participating in Clinical Studies 1.2.3 How Are Participants Protected? 1.3 Historical Aspects of Clinical Trials 1.3.1 562 BC–1537: Pre-James Lind Era 1.3.2 1747: James Lind and Scurvy Trial 1.3.3 1800: Arrival of Placebo 1.3.4 1943: The First Double-Blind Controlled Trial (Patulin for Common Cold) 1.3.5 1946: The First Randomised Curative Trial (The Randomised Controlled Trial of Streptomycin) 1.3.6 Evolution of Ethical and Regulatory Framework 1.3.7 The Food and Drug Administration (FDA) in the USA 1.3.8 European Medicines Agency (EMEA) 1.3.9 Japanese Pharmaceuticals and Medical Devices Agency (PMDA) 1.4 Evolution of the Drugs References 1 3 7 11 13 14 15 15 x Contents The Definition of GCP 2.1 Introduction 2.2 Definitions References 17 17 18 27 The Principles of GCP 3.1 The Principles of ICH GCP 3.2 WHO Principles of GCP References 29 29 30 32 The Drug Development Process and Evolution of Regulations 4.1 Introduction 4.2 Drug Development 4.3 Recent Developments in Drug Approval 4.4 Emergence of a New Drug System References 33 33 35 39 40 42 Planning Clinical Research 5.1 Introduction 5.2 Methodology 5.2.1 Considerations for the Plan 5.2.2 Planning a Study References 45 45 45 45 49 55 Preparation of Ethics Committee (IRB) Proposal 6.1 ICH GCP Requirements for the Composition of the Ethics Committee (IRB) 6.2 What Documents Must Be Submitted to the Ethics Committee (IRB)? 6.3 Communication with an IRB/IEC 6.4 Compliance with Protocol References 57 57 58 59 60 61 Contents 10 Preparation of Informed Consent 7.1 The Steps for Preparation of Informed Consent 7.2 Obtaining Informed Consent 7.3 Delegation of Consent Process 7.4 Checklist for Obtaining Informed Consent References Preparation of Findings Tables 8.1 Planning Your Paper: When to Use Tables and Figures 8.2 When to Choose Tables 8.3 Best Practices for Presentation of Tables and Figures 8.4 Completion of Record Forms in Research Facilities References Setting the Ideal Statistical Methods 9.1 Introduction 9.2 Randomisation Plan 9.3 Blinding 9.4 Sample Selection/Allocation Procedures 9.5 Statistical Analysis Methodology 9.5.1 Statistical Analysis Example for a Randomised Study 9.5.2 Statistical Analysis Example for a Longitudinal Cohort Study References xi 63 63 68 69 70 72 73 73 74 74 75 77 79 79 79 80 81 83 84 84 85 The Duties of a Clinical Research Coordinator 87 10.1 Introduction 87 10.2 Job Duties and Tasks of a Clinical Research Coordinator 88 xii Contents 10.3 Job Activities Associated with Being a Clinical Research Coordinator 10.4 Skills Needed for a Clinical Research Coordinator 10.5 Abilities Needed to Be a Clinical Research Coordinator 10.6 Knowledge, Experience and Education Required to Be a Clinical Research Coordinator References 11 90 93 94 96 96 The Duties of Clinical Researchers 11.1 Conducting Ethical Research 11.2 Informed Consent Process 11.3 Statement of Investigator 11.4 Reporting Adverse Events 11.5 Maintaining Accurate Records 11.6 Steps to Becoming a Clinical Trial Investigator References 97 98 98 99 100 100 101 103 12 The Phases of Clinical Studies 12.1 Introduction 12.2 Preclinical Studies 12.3 Phase 12.4 Phase I 12.5 Phase II 12.6 Phase III 12.7 Phase IV 12.8 Summary of Clinical Trial Phases References 105 105 106 106 107 108 109 111 112 114 13 Safety in Clinical Trials 115 13.1 Introduction 115 13.2 Safety Monitoring 116 23.18 Monitoring 23.18.2 223 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 ICF and any other written information that is to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirement(s) [1–3]’ 23.18.3 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 [1–3]’ 23.18.4 Monitor’s Responsibilities ‘The monitor(s), in accordance with the sponsor’s requirements, should ensure that the trial is conducted and documented 224 23 Responsibilities of the Sponsor 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 (and these remain adequate throughout the trial period), and that the staff and facilities, including laboratories and equipment, are adequate to safely and properly conduct the trial (and that these 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’s authorised procedures’ (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 IB, all documents, and all trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s)’ 23.18 Monitoring 225 (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 unauthorised individuals’ (i) ‘Verifying that the investigator is enrolling only eligible subjects’ (j) ‘Reporting the subject recruitment rate’ (k) ‘Verifying that source data/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’ (m) ‘Checking the accuracy and completeness of the CRF entries, source data/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 data/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’ 226 23 Responsibilities of the Sponsor (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 authorised to initial CRF changes for the investigator This authorisation should be documented’ (o) ‘Determining whether all AEs are appropriately reported within the time periods required by GCP, and the ICH Guidance for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s)’ (p) ‘Determining whether the investigator is maintaining the essential documents’ (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 [1–3]’ 23.18.5 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 [1–3]’ 23.18.6 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’ 23.19 Audit 227 (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 by the sponsor should be documented by the sponsor’s designated representative [1–3]’ 23.19 Audit ‘If or when sponsors perform audits, as part of implementing quality assurance, they should consider [1–3]’ 23.19.1 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’ 23.19.2 Selection and Qualifications of Auditors (a) ‘The sponsor should appoint individuals who are independent of the clinical trial/data collection system(s) 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 [1–3]’ 23 Responsibilities of the Sponsor 228 23.19.3 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 noncompliance exists, or in the course of legal proceedings’ (e) ‘Where required by applicable law or regulation, the sponsor should provide an audit certificate [1–3]’ 23.20 Noncompliance ‘Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution, or by any member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance’ ‘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 23.22 Clinical Trial/Study Reports 229 participation in the trial When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should promptly notify the regulatory authority(ies) [1–3]’ 23.21 Premature Termination or Suspension of a Trial ‘If a trial is terminated prematurely 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 with the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s) [1–3]’ 23.22 Clinical Trial/Study Reports ‘Regardless of whether a trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial/study 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/study reports in marketing applications meet the standards of the ICH Guidance for Structure and Content of Clinical Study Reports (The ICH Guidance for Structure and Content of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain cases.) [1–3]’ 23 Responsibilities of the Sponsor 230 23.23 Multicentre Trials For multicentre trials, the sponsor should ensure that: ‘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 an approval/favourable opinion by the IRB/IEC’ ‘The CRFs are designed to collect the required data at all multicenter trial sites For those investigators who are collecting additional data, supplemental CRFs should also be provided that are designed to collect the additional data’ ‘The responsibilities of the coordinating investigator(s) and the other participating investigators are documented before the start of the trial’ ‘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’ ‘Communication between investigators is facilitated [1–3]’ References Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance U.S Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) ICH, April 1996 Hutchinson D The Trial Investigator’s GCP handbook: a practical guide to ICH requirements Brookwood Medical Publications Ltd.; Surrey, UK, 1997 Committee: ICHS: ICH Harmonised Tripartite Guideline for Good Clinical Practice Second publication, Brookwood Medical Publications Ltd.; Richmond, Surrey, UK, 1997 Chapter 24 Clinical Trial Protocols ‘The contents of a trial protocol should generally include the following topics However, site-specific information may be provided on a 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 IB’ 24.1 General Information ‘Protocol title, protocol identifying number, and date Any amendment(s) should also bear the amendment number(s) and date(s)’ ‘Name and address of the sponsor and monitor (if other than the sponsor)’ ‘Name and title of the person(s) authorised to sign the protocol and the protocol amendment(s) for the sponsor’ The English in this document has been checked by at least two professional editors, both native speakers of English For a certificate, please see http://www.textcheck.com/certificate/6YXd9a C Cingi, N Bayar Muluk, Quick Guide to Good Clinical Practice, DOI 10.1007/978-3-319-44344-7_24, © Springer International Publishing Switzerland 2017 231 232 24 Clinical Trial Protocols ‘Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate) for the trial’ ‘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)’ ‘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)’ ‘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 [1–3]’ 24.2 Background Information ‘Name and description of the investigational product(s)’ ‘A summary of findings from nonclinical studies that potentially have clinical significance and from clinical trials that are relevant to the trial’ ‘Summary of the known and potential risks and benefits, if any, to human subjects’ ‘Description of and justification for the route of administration, dosage, dosage regimen, and treatment period(s)’ ‘A statement that the trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s)’ ‘Description of the population to be studied’ ‘References to literature and data that are relevant to the trial, and that provide background for the trial [1–3]’ 24.3 Trial Objectives and Purpose ‘A detailed description of the objectives and the purpose of the trial [1–3]’ 24.4 Trial Design 24.4 233 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’: ‘A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the trial’ ‘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’ ‘A description of the measures taken to minimise/avoid bias, including (for example)’: (a) ‘Randomisation’ (b) ‘Blinding’ ‘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 labeling of the investigational product(s)’ ‘The expected duration of subject participation, and a description of the sequence and duration of all trial periods, including follow-up, if any’ ‘A description of the ‘stopping rules’ or ‘discontinuation criteria’ for individual subjects, parts of trial, and entire trial’ ‘Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if any’ ‘Maintenance of trial treatment randomisation codes and procedures for breaking codes’ ‘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 [1–3]’ 24 Clinical Trial Protocols 234 24.5 Selection and Withdrawal of Subjects ‘Subject inclusion criteria’ ‘Subject exclusion criteria’ ‘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 [1–3]’ 24.6 Treatment of Subjects ‘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’ ‘Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or during the trial’ ‘Procedures for monitoring subject compliance [1–3]’ 24.7 Assessment of Efficacy ‘Specification of the efficacy parameters’ ‘Methods and timing for assessing, recording, and analysing efficacy parameters [1–3]’ 24.9 Statistics 24.8 235 Assessment of Safety ‘Specification of safety parameters’ ‘The methods and timing for assessing, recording, and analysing safety parameters’ ‘Procedures for eliciting reports of, and for recording and reporting, AEs and intercurrent illnesses’ ‘The type and duration of the follow-up of subjects after AEs [1–3]’ 24.9 Statistics ‘A description of the statistical methods to be employed, including timing of any planned interim analysis(ses)’ ‘The number of subjects planned to be enrolled In multicenter trials, the number of enrolled subjects projected for each trial site should be specified Reasons for choice of sample size, including reflections on (or calculations of) the power of the trial and clinical justification’ ‘The level of significance to be used’ ‘Criteria for the termination of the trial’ ‘Procedure for accounting for missing, unused, and spurious data’ ‘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 the protocol and/or in the final report, as appropriate)’ ‘The selection of subjects to be included in the analyses (e.g all randomised subjects, all dosed subjects, all eligible subjects, subjects suitable for evaluation) [1–3]’ 24 Clinical Trial Protocols 236 24.10 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) by providing direct access to source data/documents [1–3]’ 24.11 Quality Control and Quality Assurance Quality Control and Quality Assurance should be performed [1–3] 24.12 Ethics Description of ethical considerations relating to the trial [1–3] 24.13 Data Handling and Record-Keeping Data Handling and Record-Keeping should be performed and maintained [1–3] 24.14 Financing and Insurance ‘Financing and insurance if not addressed in a separate agreement [1–3]’ References 24.15 237 Publication Policy ‘Publication policy, if not addressed in a separate agreement [1–3]’ 24.16 Supplements ‘Since the protocol and the clinical trial/study report are closely related, further relevant information can be found in the ICH Guidance for Structure and Content of Clinical Study Reports [1–3]’ References Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance U.S Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) ICH, April 1996 Hutchinson D The Trial Investigator’s GCP handbook: a practical guide to ICH requirements Brookwood Medical Publications Ltd.; Surrey, UK, 1997 Committee: ICHS: ICH Harmonised Tripartite Guideline for Good Clinical Practice Second publication, Brookwood Medical Publications Ltd.; Richmond, Surrey, UK, 1997 .. .Quick Guide to Good Clinical Practice Cemal Cingi • Nuray Bayar Muluk Quick Guide to Good Clinical Practice How to Meet International Quality Standard in Clinical Research Cemal... April 1996 Good clinical practice Wikipedia https://en.wikipedia.org/wiki/ Good_ clinical_ practice Accessed online at 13 Oct 2015 Verma K Base of a research: good clinical practice in clinical trials... published Good Clinical Practice, which has 1.3 Historical Aspects of Clinical Trials 11 become the universal standard for ethical conduct of clinical trials [2]’ ‘In parallel to ethical guidelines, clinical