THE CLINICAL ENDPOINT ADJUDICATION HANDBOOK V2.0 © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com BY ETHICAL EADJUDICATION®, THE PROVIDERS OF THE ENDPOINT ADJUDICATION MANAGED SOFTWARE SERVICE 1 MORE INFO AND TOOLS AT HTTPS://WWW.ENDPOINTADJUDICATION.COM FOREWORD Traditionally, handbooks are written by experts with decades of experience and mostly used by young professional (or amateurs) who wish to have all the basic knowledge concentrated in a single publication. But can one really speak of tradition in innovation? And what if no one has decades of experience simply because the specific subject matter is brand new? It then comes to some of us to take the challenge and try to group all the available knowledge under one title. And this is what we did. We hope that this handbook will be useful to all and beg for everyone’s leniency if we have omitted or misrepresented any of the content. © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com 2 1. TABLE OF CONTENTS 2. INTRODUCTION 7 3. CLINICAL OUTCOMES AND CLINICAL ENDPOINTS 7 3.1. CLINICAL OUTCOMES 7 3.2. CLINICAL ENDPOINTS 7 PRIMARY, SECONDARY, EXPLORATORY ENDPOINTS 7 DIRECT AND SURROGATE ENDPOINTS 8 SIMPLE AND COMPOSITE ENDPOINTS 8 WHY SHOULD WE ADJUDICATE ENDPOINTS? 8 4. ENDPOINT ADJUDICATION COMMITTEES (EAC) 9 4.1. COMPOSITION OF AN ENDPOINT ADJUDICATION COMMITTEE 9 SELECTION AND RECRUITMENT 9 EXPERTISE 9 NUMBER OF MEMBERS 9 ROLES 9 4.2. REVIEWERS TRAINING AND EDUCATION 10 BEFORE ADJUDICATION STARTS 10 DURING THE ADJUDICATION PERIOD 10 4.3. REVIEWERS VALIDATION 10 BEFORE ADJUDICATION STARTS 10 DURING THE ADJUDICATION PERIOD (INTER- AND INTRA-VARIABILITY) 10 4.4. REVIEWERS SUBSTITUTION 11 FOLLOWING A LEAVE 11 FOLLOWING EXCLUSION FOR LOSS OF QUALIFICATION 11 4.5. REVIEWERS MANAGEMENT 11 CURRICULA 11 CONFLICT OF INTEREST 11 CONTRACTS 12 PAYMENTS 12 4.6. REVIEWERS QUALIFICATION QUALITY CONTROL (METRICS) 12 REVIEWER TRAINING 12 REVIEWER QUALIFICATION BEFORE THE STUDY START 12 REVIEWER INTER-VARIABILITY (SAME EVENT ASSESSMENT AT DIFFERENT TIME POINTS) 12 REVIEWER CONSENSUS ATTITUDE 12 5.THE ADJUDICATION CHARTER 13 6. SOFTWARE & DATA MANAGEMENT 13 6.1. DATABASE & DATA MANAGEMENT 13 SOFTWARE SELECTION 13 USER REQUIREMENTS SPECIFICATIONS (URS) 14 SOFTWARE VALIDATION (ACCEPTANCE TESTS) 14 © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com 3 SOFTWARE TRAINING 14 SOFTWARE INTEGRATION 14 6.2. EVENTS MANAGEMENT 14 EVENT DEFINITION 14 EVENT DETECTION AND TRIGGERING OF ADJUDICATION PROCESS 14 MEDDRA STANDARD QUERIES 15 ESTIMATE OF % OF EVENTS TO BE ADJUDICATED 15 EVENTS DETECTED BY CENTRAL ADMINISTRATOR OR REVIEWERS 15 RELATED EVENTS 15 7. ENDPOINT ADJUDICATION PROCESSES 15 7.1. EVENT MEDICAL RECORDS IDENTIFICATION 15 SOURCE DOCUMENTS, VARIABLES, IMAGES, MULTI-MEDIA FILES 15 OWNERSHIP OF MEDICAL RECORDS 16 SOURCE OF MEDICAL RECORDS 16 FORMATS OF MEDICAL RECORDS 16 TIME OF CREATION OF MEDICAL RECORDS 16 RECURRENCE OF MEDICAL RECORDS 16 EXPIRATION OF MEDICAL RECORDS 16 7.2. EVENT MEDICAL RECORDS COLLECTION 16 INTERACTIVE LOAD, AUTOMATED LOAD, LINKING CENTRALIZED LOAD, SITE 16 LOAD 7.3. EVENT MEDICAL RECORDS ANONYMIZATION 17 OFFLINE / ONLINE 17 CENTRALIZED / DECENTRALIZED (BY SITE) 17 7.4. EVENT MEDICAL RECORDS TRANSLATION 17 OFFLINE / ONLINE 17 CENTRALIZED / DECENTRALIZED (BY SITE) 17 7.5. EVENT MEDICAL RECORDS LABELLING 18 OFFLINE / ONLINE 18 CENTRALIZED / DECENTRALIZED (BY SITE) 18 7.6. EVENT MEDICAL RECORDS FORMAT CONVERSION 18 FOR READABILITY / MEASURABILITY 18 FOR SUMMARIZING (PATIENT PROFILES) 18 FOR COMPARISON IN TIME / VERSIONING 18 FOR LEVELLING OUT SITE DIFFERENCES 18 7.7. EVENT MEDICAL RECORDS PACKAGE VALIDATION 19 COMPLETENESS 19 VALIDITY (TIME) 19 ACCURACY 19 BLINDING 19 7.8. EVENT MEDICAL RECORDS QUERYING FOR MORE INFO 19 BEFORE SUBMISSION / AFTER SUBMISSION 19 OFFLINE // ONLINE 19 MISSING DATA MANAGEMENT 20 © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com 4 7.9. EVENT MEDICAL RECORDS UPDATE 20 DUE TO CHANGES DURING TIME 20 DUE TO NEW RELATED EVENTS 20 DUE TO QUERIES 20 7.10. EVENT MEDICAL RECORDS VERSIONING 20 DUE TO MEDICAL RECORDS UPDATES 20 7.11. EVENT MEDICAL RECORDS DISPLAYING 21 VISUALIZATION TOOLS FOR TEXT, VARIABLES, DOCUMENTS, IMAGES, ETC 21 FOR MEASUREMENT 21 FOR TRENDING GRAPHIC REPRESENTATION 21 TOOLS CONFIGURATIONS 21 TOOLS VALIDATION / RE-VALIDATION 21 7.12. EVENT ASSEMBLING ONGOING MANAGEMENT 21 PACKAGES BY STATUS (COMPLETE, INCOMPLETE, TO BE LABELLED, TO BE TRANSLATED, TO BE QUERIED, WAITING QUERY RESULTS, MEDICAL REVIEW, ETC) 21 PACKAGES ASSIGNMENT TO STAFF 21 7.13. EVENT MEDICAL RECORDS COLLECTION QUALITY CONTROL (METRICS) 22 DELIVERY TIMING 22 PACKAGE COMPLETENESS 22 MEDICAL RECORDS ACCURACY 22 QUERY RESOLUTION TIMING 22 SEGMENTATION: 22 7.14. EVENTS SUBMISSION / RE-SUBMISSION 22 ASSIGNMENT TO REVIEWERS, RULES DEFINITION 22 INTERACTIVE / AUTOMATED 23 FIXED / VARIABLE (BY CHARGE) 23 REVIEWERS’ ALTERNATION FOR RESUBMISSION 23 7.15. REVIEWERS ALERTING TO EVENTS 23 EMAIL / SMS / PHONE 23 INTERACTIVE / AUTOMATED 23 PER EVENT / PER CHARGE / INTERACTIVE 23 7.16. ADJUDICATION FORMS 23 EVENT TO FORM DEFINITION 23 FORM FIELDS DEFINITIONS 24 FORM FIELD FORMAT DEFINITION 24 FORM FIELD VALIDATION RULES / ERROR MESSAGES 24 FORMS GENERAL DESIGN 24 FORMS WORKFLOWS (HIERARCHY AMONG FIELDS) 24 FORM TO EVENT ASSIGNMENT RULES (INTERACTIVE / AUTOMATED) 24 7.17. REVIEW ASSESSMENT WORKFLOW 24 ROLES DEFINITION 24 ASSESSMENT WORKFLOW DEFINITION 24 7.18. DISAGREEMENT MANAGEMENT 25 MAJOR DISAGREEMENT 25 © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com 5 MINOR DISAGREEMENT 25 DISAGREEMENTS MANAGEMENT FLOW 25 CONSENSUS WORKFLOW / ROLES 25 CONSENSUS TOOLS (PREVIOUS ASSESSMENT COMPARISON) 25 CONSENSUS ADJUDICATION FORMS 25 7.19. ADJUDICATION PROCESS ONGOING MANAGEMENT 25 7.20. AUTOMATED ASSESSMENT(S) 26 PER IMAGING MEASUREMENT 26 ARTIFICIAL INTELLIGENCE 26 7.21. REVIEW PROCESS QUALITY CONTROL (METRICS) 26 7.22. ADJUDICATION STUDY CLOSURE 26 SOP DEFINITION 26 7.23. ADJUDICATION AUDIT TRAIL 27 CONTENT DEFINITION 27 FORMATS DEFINITION 27 7.24. ADJUDICATION DATA / METADATA EXPORT TO SUBMISSION 27 CONTENT DEFINITION 27 FORMATS DEFINITION 27 7.25. ADJUDICATION MEDICAL RECORDS EXPORT TO SUBMISSION 27 CONTENT DEFINITION 27 FORMATS DEFINITION 27 7.26. ADJUDICATION DATA / METADATA / MEDICAL RECORDS ARCHIVING 28 SOP 28 VALIDATION 28 LIFETIME 28 8. GLOSSARY 29 9. BIBLIOGRAPHY 35 © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.com 6 2. INTRODUCTION The present handbook is dedicated to all Clinical Research professionals who are or are likely to become involved in Clinical Endpoint Adjudication operations. We hope that you will find it helpful, easy to use, complete and accurate. With this publication we hope to bring a small contribution to the common effort for a world without disease. The FDA1,2,3 and the EMA4,5,6,7 have published several guidelines directly or indirectly describing the use of clinical endpoint adjudication and providing recommendations to strengthen the quality and validity of clinical data 3. CLINICAL OUTCOMES AND CLINICAL ENDPOINTS In clinical trial we often use the terms of “Outcome” and “Endpoint”, sometimes interchangeably. For clarity, in this manual we will define the exact meaning of each of these terms. 3.1. CLINICAL OUTCOMES Clinical outcomes are measurable changes in health, bodily function or quality of life that result from giving care to patients. Clinical outcomes can be measured by activity data such as hospital re-admission rates, or by agreed scales and other forms of measurement . The term “outcome” in clinical trials refers to a measured variable (e.g., peak volume of oxygen or PROMIS Fatigue score). 3.2. CLINICAL ENDPOINTS A clinical endpoint generally refers to one of the target outcomes of the trial that can be measured objectively to determine whether the intervention being studied is beneficial but may also refer to any disease or sign that strongly motivates the withdrawal of the patient from the trial, then often termed humane (clinical) endpoint. PRIMARY, SECONDARY, EXPLORATORY ENDPOINTS The primary endpoint of a clinical trial is the basis for making any therapeutic claims about the drug under study. All drugs have safety risks. The only reason that a patient would want to take a drug is if the drug 1) improves survival, 2) results in a benefit that was detectable by the patient (improvement in symptoms, improvement in functional capacity) or 3) decreases the chances of developing a condition or disease complication that is itself apparent to the patient and is undesirable (e.g. stroke). Therefore, a primary endpoint should be a direct measure of one of these and serve to claim an effect beneficial to the patient. Secondary endpoints investigate additional effects of the drug and are not used to support the principle claim. Secondary endpoints are endpoints for which the trial may not be powered nor randomized. However, it sometimes happens that a secondary endpoint result indicates an important effect of the drug that later becomes its primary purpose of use. Secondary endpoints align with secondary questions and need to be clearly defined up front. These allow to explore information obtained in the trial that may or may not provide definitive conclusions, but might guide the direction of future studies . © 2019 Ethical GmbH - All Rights Reserved - more info at: https://www.endpointadjudication.comhttps://www.endpointadjudication.com