98,99 €
Mehr erfahren.
- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
A must-have guide for any professional in the drug manufacturing industry
The Good Clinical Practice (GCP) audit is a tedious but necessary exercise that assures that all parties do their job properly and in compliance with the applicable FDA code. Clinical Trials Audit Preparation demystifies the audit process for all parties involved, including clinical research sponsors, clinical investigators, and institutional review boards.
This book provides a step-by-step explanation of the FDA audit procedures for clinical trials and of how pharmaceutical companies, clinical investigators, and institutional review boards should prepare for regulatory audits. The book emphasizes the processes and procedures that should be implemented before a clinical audit occurs, making this an imperative guide to any professional in the drug manufacturing industry, including drug manufacturing companies, regulatory affairs personnel, clinical investigators, and quality assurance professionals.
Among the topics discussed:
-
Good Clinical Practices and therapeutic product development in clinical research
-
The roles of the sponsor of a clinical investigation, the IRB, or independent ethics committee
-
The roles and responsibilities of the clinical trial investigator
-
The inspection preparation
-
The Audit Report and the Form 483
-
Warning letters issued to clinical investigators and clinical trial sponsors and their impact on product development
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 501
Veröffentlichungsjahr: 2010
Ähnliche
Clinical Trials Audit Preparation
Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey. Published simultaneously in Canada.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission.
Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com.
Library of Congress Cataloging-in-Publication Data:
Mihajlovic-Madzarevic, Vera. Clinical trials audit preparation : a guide for good clinical practice (GCP) inspections / Vera Mihajlovic-Madzarevic. p. ; cm. Includes index. ISBN 978-0-470-24885-0 (cloth) 1. Drugs--Testing--Auditing. 2. Medical audit. I. Title. [DNLM: 1. Clinical Trials as Topic--standards. 2. Guideline Adherence--standards. 3. Management Audit. 4. Quality Control. QV 771 M636c 2010] RM301.27.M54 2010 615.5′80724--dc22 2009027971
Contents
Clinical Trials Audit Preparation
Preface
Introduction
Background History on Clinical Research Standards
Glossary
Chapter 1 Good Clinical Practice and Therapeutic Product Development
1.1 Good Clinical Practice in Clinical Research
1.2 Role of the Sponsor of a Clinical Investigation
1.3 Role of the Institutional Review Board/Independent Ethics Committee (IRB/IEC)
1.4 Roles and Responsibilities of the Clinical Trial Investigator
1.5 Clinical Trial Protocol and Protocol Amendments
Chapter 2 Therapeutic Products Clinical Development in the United States
2.1 Drug Discovery
2.2 Preclinical Development
2.3 Clinical Development
2.4 FDA Considerations for Drug Development
2.5 Phase IV, Postmarketing Surveillance and GCP
2.6 Quality Assurance in Clinical Research
2.7 FDA Inspectional Background and Data
2.8 FDA Bioresearch Monitoring Program
Chapter 3 The Inspection Preparation
3.1 Conduct of an Internal GCP Inspection: Quality Assurance Inspection
3.2 Steps to Prepare for the Internal QA Inspection
3.3 The GCP Quality Assurance Unit
3.4 Steps to Prepare for the Regulatory Inspection
3.5 Clinical Investigator Inspections Preparation
3.6 What to Do When an Investigator Site FDA Inspection is Announced
3.7 Sponsor's Inspection Preparation
3.8 What to Do When Sponsors FDA Inspector Arrive Unannounced
3.9 The Institutional Review Board Inspections Preparation
3.10 What to Do When an IRB FDA Inspection is Announced
3.11 The Investigator Site Inspection
3.12 Investigator's Responsibilities
3.13 Types of Clinical Investigator Site Inspections
3.14 Inspectional Procedures
3.15 FDA Audit Procedures for Investigative Sites
3.16 FDA Inspections of International Clinical Trial Sites
3.17 The Audit Report and Form 483
Chapter 4 Analysis of Warning Letters
4.1 Analysis of Warning Letters Issued to Clinical Investigators
4.2 An Analysis of Warning Letters Issued to Clinical Trial Sponsors
4.3 Analysis of Warning Letters Issued to Institutional Review Boards
Chapter 5 Fraud and Misconduct in Clinical Research
5.1 What Type of Data is Falsified?
5.2 How is Data Falsified?
5.3 Why is Data Falsified?
5.4 Who Falsified the Data?
5.5 What Can be Done to Detect Fraud?
5.6 How Do We Prevent Fraud?
Appendix A Some Answers to the Most Problematic Questions in Compliance
How Can an Investigator Site Demonstrate That the Proper Consent Process Was Followed?
How Does One Demonstrate that a Subject Understood the Consent Information?
How Does One Demonstrate that all the Clinical Trial Procedures were Followed?
How Does One Demonstrate Principal Investigator Personal Involvement in the Supervision of Clinical Trial Activities?
Why Follow Standard Operating Procedures in Clinical Trials?
Appendix B Guidance for Industry---E6 Good Clinical Practice: Consolidated Guidance
Introduction
Appendix C World Medical Association Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects
A. Introduction
B. Basic Principles for all Medical Research
C. Additional Principles for Medical Research Combined with Medical Care
Appendix D Nuremberg Code
Appendix E The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research
Part A: Boundaries Between Practice and Research
Part B: Basic Ethical Principles
Part C: Applications
Index
Preface
GCP inspections of clinical trial sites are the challenges that clinical research faces in demonstrating data credibility and patient safety. However, I found in my clinical research experience that audits are a tedious but nevertheless necessary activity to assure that all parties do their job right.
Being a clinical scientist and third party auditor allowed me to understand the struggles in clinical research (CR) and quality assurance (QA). Although CR and QA are independent activities (we do not talk to each other unless necessary) they have interdependent tasks. The auditor should know the challenges of the clinical research associate/monitor, and vice versa. Understanding the objectives of each other’s tasks will allow the clinical work to proceed smoothly.
In the last 15 years since ICH GCP was issued as an International Guidance for clinical research, the pharmaceutical research-based industry as well as academic research institutions had to realign all their activities to remain “compliant” to regulations. The setting of clear and uniform standards raised the bar for clinical research and development (R&D); however, it also increased the cost to staggering levels.
During my preregulatory inspections of clinical trial sites and sponsors as well as GLP labs, a constant issue was always present—the dread of the inspected facility of the possible findings and their consequences.
Many times while performing inspections I was asked “Are we in compliance?” or “Do you see something serious?” My logical thought was “Will I be able to find all possible sources of noncompliance before the FDA inspector comes?” Could I provide assurance to my client that everything was OK?
Obviously, some of my clients are happy to see me and eager to walk though the inspection, learning and uncovering all possible issues. However, others dislike my presence, thinking that I will point a finger at people who did things wrong and who thus may lose their jobs. At that point I feel isolated and unwanted, but badly needed.
The best part is at the end of the inspection, when we all sit down to dissect the results and the clinical teams start to understand the meaning of the findings and accept suggestions to achieve compliance. Finally, we all shake hands and, with a smile, we go home after long days of document hunting and endless reading.
The writing of the report is another story. When I write my inspection report, it does not look like a Form 483; it is a “catharsis” for my client. I summarize hundreds of findings in a tabulated manner where the last column is “Suggested Remedial Action.” I point out the noncompliance and how to get back on track. That is a relief to my clients, since action can be taken immediately to ensure future compliance.
Of course, it would be childish to suggest that all noncompliance can be remediated: some noncompliance issues are based on the complete misunderstanding of the requirement or regulation, and on strong opinions based on old school medicine.
With this book I was given the task of putting together the world of the regulator, the sponsor of clinical research, and the investigators. As a professional development instructor and former university teacher, I understand that we cannot start speaking of a particular topic without first seeing the big picture, and where that topic fits in and the implications and future consequences of the issue discussed. I do not take anything for granted until it is explained and understood. Therefore, it was very important that with the first chapters I review compliance to what, and then compliance by whom, and finally how to achieve compliance. Understanding the drug development process is also a must, since the reader needs to be on the same page to understand the inspection process. The processes described in this book are part of the FDA BIMO compliance programs 7348.810 and 7348.811 that are publicly available.
The challenge in writing this book was to present the subjects objectively to avoid the boredom inherent in a dry topic as GCP compliance. Therefore, I covered the responsibilities of the parties in clinical research according to GCP and 21 CFR 312, and other applicable requirements and utilized examples as much as possible. The biggest challenge was that every time I thought I had finished, new things happened in the clinical research world that I had to include, and every review was an update until I said this is it, for now. I am already thinking of the next edition and how things will change in the coming years.
We have to move forward in clinical research and in how therapeutic products are developed. Ten to twelve years for development and billions of dollars is too much for a failure rate of more than 75%, and changes are coming soon. Read the FDAAA (http://www.fda.gov/oc/initiatives/advance/fdaaa/accomplishments.html) for current insight.
Having the privilege to work in basic scientific research, medicine, clinical research and development and being a scientist, I was able to present clearly issues from product discovery to market and write about them from the compliance point of view.
Another topic that I consider extremely informative is the analysis of warning letters. As we go through the regulatory findings we can easily see where the failures in compliance are and what may be missing. I do suggest that all clinical research professionals read the FDA warning letters to clinical investigators, sponsors, and institutional review boards as they appear in the FDA website, since they point out issues that arose after detailed review of data and documents; this will increase the reader’s pool of regulatory knowledge.
Lastly, I formulated several key questions in understanding GCP compliance to clarify topics that may pop up when reading the guidance.
The footnote references are a pivotal part of this book; the reader has been provided some of the documents referred to in the footnotes in the appendixes.
My last bit of advice is that before implementing processes or procedures (SOPs), read the code of federal regulations applicable to your activity or product. Also, go to the source, and never rely on interpretations or guidance that may be only the opinion of one party. See the whole picture, and then you will understand why.
VERA MIHAJLOVIC-MADZAREVIC
Thornhill, Ontario, Canada
January 2010
Introduction
Clinical trials are conducted in humans to determine safety, tolerability, and efficacy of potential therapeutic products. Those trials have to be conducted in compliance with specific regulatory requirements and Good Clinical Practice to demonstrate that patient’s rights, safety, and well-being, as well as data credibility are ensured.
Internal sponsor audits together with FDA regulatory inspections of clinical trial activities are essential to assure compliance with SOPs, GCPs, and established regulatory requirements.
This book intends to summarize specific aspects of drug development as well as present in a clear and concise manner the principles of drug development and Good Clinical Practices.
It is very important that the clinical research stakeholder (sponsor, investigator, or member of an Institutional Review Board) understands the basic principles of the GCP guideline, since it highlights the spirit of the requirements for clinical trials. The FDA, although it did not implement ICH/GCP into its regulations, is fully observant.
Following the principles of GCP will allow stakeholders to focus their activities in a compliant fashion. Understanding the regulatory requirements established in the FDA code of federal regulations, particularly 21 CFR 11, 50, 54, 56, 312, 314, 320, 601, 812, and 814, will allow the research professional to establish proper processes and procedures to ensure compliance for FDA regulated trials.
This book will guide the reader through the extensive foundation of knowledge that is necessary to understand and be prepared for the task of conducting clinical investigations in human subjects.
Since its implementation, the FDA Bioresearch Monitoring Program has been in charge of GCP inspections of clinical trial investigative sites, sponsors, Institutional Review Boards, and Contract Research Organizations. The processes and procedures that the inspector follows are publicly available in the FDA Compliance Program Guidance Manual. However, this book assists readers to understand how the process works, who is inspected and why, and what are the consequences of an inspection. An in-depth analysis of warning letters gives the reader an insight of what is essentially going wrong, and where stakeholders have to improve.
Background History on Clinical Research Standards
Clinical research and development has undergone extensive changes in the last decades, adapting to a continuously changing regulatory framework. With the need to expand the applicability of clinical trial data gathered internationally, it was recognized that common grounds should be established for global research and development of therapeutic products.
Large R&D-oriented pharmaceutical companies initially implemented their own R&D standards and internal processes aimed at local regulatory requirements for submission purposes. In the last few decades, before new guidelines were set into place, clinical trials were mostly conducted at a local level, and the industry had to spend additional resources and time to satisfy every country-specific requirement. There was no unified standard for the conduct of clinical trials; therefore, standards were set up independently by regulatory bodies to be consistent with the Declaration of Helsinki.1
The Declaration of Helsinki was adopted by the 18th World Medical Association Assembly in 1964 and outlined the basis for the ethical principles for medical research involving human subjects, serving as the main document for the conduct of medical research. The fundamentals of the declaration were set in the Nuremberg Code2 after the Nuremberg tribunal exposed medical research crimes committed during the Second World War.
In the United States, on April 18, 1979, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research issued the Belmont Report3, which identified the basic ethical principles that underlined the conduct of biomedical and behavioral research involving human subjects and developed guidelines that should be followed to assure that such research is conducted in accordance with those principles.
Both documents focused on subjects’ rights and safety as the main concern; however, they were inadequate on setting a standard for data quality, accuracy, and integrity. It is reasonable to understand that data quality was not the objective of those documents since they are mostly an extension of the Nuremberg Code, which focused purposely on subjects’ rights and safety.
Therefore, after observing a great procedural and implemental disparity in clinical research, the need was identified for a process that will be internationally accepted to set the guidelines for the conduct of human research, taking into account both aspects of clinical research: subject’s rights and safety, and data quality, accuracy, and validity.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use issued the ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1)4 on June 10, 1996. In this document the industry and stakeholders, for the first time, have an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. This document addresses both aspects of clinical research: patients’ rights and safety and data quality, accuracy, and integrity.
1 World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. See Appendix C at the end of this book.
2 See Appendix D at the end of this book for a copy of the Nuremberg Code.
3 See Appendix E for a copy of this report.
4 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH Harmonised Tripartite Guideline for Good Clinical Practice E6(R1), June 10, 1996.
Glossary
The glossary in this book is aligned with the definitions provided in the ICH/GCP document.5
Adverse Drug Reaction (ADR):
In the preapproval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility; that is, the relationship cannot be ruled out.
Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis, or therapy of diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
Adverse Event (AE):
Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).
Applicable Regulatory Requirement(s):
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
Approval (in relation to Institutional Review Boards): The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.
Audit:
A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the protocol, sponsor’s standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Audit Certificate:
A declaration of confirmation by the auditor that an audit has taken place.
Audit Report:
A written evaluation by the sponsor’s auditor of the results of the audit.
Audit Trail:
Documentation that allows reconstruction of the course of events.
Blinding/Masking:
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). Single-blinding usually refers to the subject(s) being unaware, and double-blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).
Case Report Form (CRF):
A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.
Clinical Trial/Study:
Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
Clinical Trial/Study Report:
A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
Comparator (Product):
An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
Compliance (in relation to trials):
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.
Confidentiality:
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary information or of a subject’s identity.
Contract:
A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.
Coordinating Committee:
A committee that a sponsor may organize to coordinate the conduct of a multicenter trial.
Coordinating Investigator:
An investigator assigned the responsibility for the coordination of investigators at different centers participating in a multicenter trial.
Contract Research Organization (CRO):
A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor’s trial-related duties and functions.
Direct Access:
Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor’s monitors and auditors) with direct access should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary information.
Documentation:
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, X rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.
Essential Documents:
Documents that individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see point 8 in Essential Documents for the Conduct of a Clinical Trial).
Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee):
An independent data monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.
Impartial Witness:
A person who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.
Independent Ethics Committee (IEC):
An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and nonmedical members, whose responsibility it is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial and to provide public assurance of that protection by, among other things, reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to Independent Ethics Committees may differ among countries but should allow the Independent Ethics Committee to act in agreement with GCP as described in this guideline.
Informed Consent:
A process by which a subject voluntarily confirms his/her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject’s decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.
Inspection:
The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor’s and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).
Institution (medical):
Any public or private entity or agency or medical or dental facility where clinical trials are conducted.
Institutional Review Board (IRB):
An independent body constituted of medical, scientific, and nonscientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.
Interim Clinical Trial/Study Report:
A report of intermediate results and their evaluation based on analyses performed during the course of a trial.
Investigational Product:
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.
Investigator:
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator.
Investigator/Institution:
An expression meaning “the investigator and/or institution, where required by the applicable regulatory requirements.”
Investigator’s Brochure:
A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects.
Legally Acceptable Representative:
An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject’s participation in the clinical trial.
Monitoring:
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
Monitoring Report:
A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.
Multicentre Trial:
A clinical trial conducted according to a single protocol but at more than one site and therefore carried out by more than one investigator.
Nonclinical Study:
Biomedical studies not performed on human subjects.
Opinion (in relation to Independent Ethics Committee):
The judgment and/or the advice provided by an Independent Ethics Committee (IEC).
Original Medical Record:
See Source Documents.
Protocol:
A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP guideline the term protocol refers to protocol and protocol amendments.
Protocol Amendment:
A written description of a change(s) to or formal clarification of a protocol.
Quality Assurance (QA):
All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).
Quality Control (QC):
The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.
Randomization:
The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.
Regulatory Authorities:
Bodies having the power to regulate. In the ICH GCP guideline the expression “regulatory authorities” includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities.
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR):
Any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.
Source Data:
All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).
Source Documents:
Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, X rays, subject files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical trial).
Sponsor:
An individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.
Sponsor–Investigator:
An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor–investigator include both those of a sponsor and those of an investigator.
Standard Operating Procedures (SOPs):
Detailed, written instructions to achieve uniformity of the performance of a specific function.
Subinvestigator:
Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.
Subject/Trial Subject:
An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.
Subject Identification Code:
A unique identifier assigned by the investigator to each trial subject to protect the subject’s identity and used in lieu of the subject’s name when the investigator reports adverse events and/or other trial-related data.
Trial Site:
The location(s) where trial-related activities are actually conducted.
Unexpected Adverse Drug Reaction:
An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator’s Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product).
Vulnerable Subjects:
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
Well-being (of the trial subjects):
The physical and mental integrity of the subjects participating in a clinical trial.
5Guidance 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) and Center for Biologics Evaluation and Research (CBER), April 1996 ICH.
Chapter 1: Good Clinical Practice and Therapeutic Product Development
This chapter provides the background information necessary to understand the universal basis of the inspectional strategies for clinical trials. Consequently, to be able to understand the purpose and background of an inspection, it is very important to comprehend Good Clinical Practice (GCP) and its applicability in real situations in clinical trials.
GCP will not teach or direct medical doctors on how to run a clinic, but rather will guide all parties involved in clinical research (the sponsors, the investigator, and the ethics boards) on what practices and procedures will ensure patient safety and data credibility.
It is very important that all personnel involved in clinical trials are properly trained and updated on GCP and understand the end implications of noncompliant activities in clinical research.
Together with GCP the reader should understand the FDA drug development process, where the regulator, observing GCP, outlines country-specific procedures and requirements to ensure compliance.
Also, this book discusses the applicability of GCP in postmarketing studies that have become increasingly necessary for the continuous evaluation of safety and efficacy of a marketed therapeutic product. The new approach of regulators worldwide seeking more postmarketing research took a definite turn with implementation of the FDAAA (FDA Amendment Act) in 2007, where the agency was provided with more enforcement power to direct sponsors holding a market authorization to sell a drug product, to conduct Phase IV clinical trials to further support safety and efficacy.
Initially, to ensure compliance to standards and regulatory requirements, all parties in clinical research have to implement quality assurance (QA) processes as needed. This book discusses, in a concise manner, what QA means for all clinical research parties involved and how to implement an efficient QA program to act preemptively on a regulatory inspection.
The main topics discussed in this chapter are:
Good Clinical Practice in clinical researchClinical development of therapeutic products in the United StatesPhase IV studies and GCPQuality assurance in clinical research1.1 Good Clinical Practice in Clinical Research
1.1.1 Definition
Good Clinical Practice is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
The main elements of GCP are (1) the subject’s rights, welfare, and confidentiality and (2) data validity, integrity, and credibility.
1.1.2 GCP Compliance
Compliance with GCP provides public assurance that the rights, safety, and well-being of trial subjects are protected in consistency with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.
Patient safety and data credibility are the main objectives not only to GCP as a guideline, but to the FDA and other regulatory authorities as their requirements for clinical investigations on human therapeutic products.
1.1.3 GCP Objectives
The objective of GCP is stated by the document as follows:
“To provide a unified standard for the European Union (EU), Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions.”
This definition applies also to all other countries that adhere to these guidelines.
These standards were adopted by most countries worldwide that have regulatory bodies that want to be integrated into the global mutual clinical data flow for submission purposes.
The FDA is observant of ICH/GCP guidelines (meaning that the FDA CFR precedes the guideline, but does not disagree with the principle).
It must be noted that although these guidelines should be followed by any party when generating clinical trial data that are intended to be submitted to regulatory authorities for market approval purposes, it also should be applicable to any investigation where human subjects are participants.
GCP should be considered applicable to any investigation where human subjects are participants.
1.1.4 Principles of ICH GCP
Clinical Trial Conduct
Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).
Risk Assessment
Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.
Subject’s Rights and Safety
The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
Background Information
All available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.
Clinical Trial Protocol
Clinical trials should be scientifically sound and described in a clear, detailed protocol.
Note that the content structure of the protocol should be consistent to a standard format to allow easy search reading and understanding.
Ethics Review and Approval
A trial should be conducted in compliance with the protocol that has received prior Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approval/favorable opinion. Mainly, all documents reviewed and approved by the IRBs have to be included in the approval letter to identify precisely the study, the protocol, and other related documents.
Ethics review boards have to be duly constituted according to GCP and local requirements and should follow standard operating procedures to demonstrate adherence.
Note that any ethics board that is not constituted and does not function according to regulatory requirements and GCP cannot issue a valid approval. From the investigator’s compliance point of view (see Form 15721) it is like running a clinical trial without approval.
Medical Care of Trial Subject
GCP is very clear that clinical trial personnel have to be qualified to perform the duties required. Therefore, “the medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.” Also if you refer to the Declaration of Helsinki this premise is consistent.
Qualifications of Clinical Trial Personnel
“Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).”
Informed Consent Process
The informed consent process goes far beyond the consent document per se. The process itself is part of the scrutiny during an inspection. It must be demonstrated that the consent was obtained freely, without prejudice or duress: “Freely given informed consent should be obtained from every subject prior to clinical trial participation.”
Data Management
Once a study commences, the clinical trial data has to be collected with extreme care and precision. “All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.” The process of data management has to be described in detail in the sponsor’s standard operating procedures, which also are going to be inspected.
Patient Confidentiality
Patient health records are covered by strict regulations. All data that is collected for clinical trials purposes must be treated as private and confidential. “The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).” The patient information and consent form should be written in accordance with local requirements and GCP to assure the participants that their identity will always be protected. Note that confidentiality of patient records and how the information is handled varies from country to country according to their laws, and the sponsor has to be very much aware of the differences.
Investigational Product Manufacturing, Handling, and Storage
The sponsor is responsible for the investigational product that is being studied. “Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.”
Quality Assurance
Sponsors and Institutional Review Boards should implement standard procedures to ensure that the activities carried out are in compliance with GCP and regulatory requirements. As you can observe, GCP does not establish requirements for the investigator to implement SOPs. The issue of investigators and SOPs will be discussed later.
However, it is not enough to have written procedures of SOPs, since once procedures are written and implemented, a quality assurance process should be put in place to ensure that those activities have been carried out as per procedures and that if deviations have been observed, they are corrected and the activity well documented.
GCP requires that “systems with procedures that assure the quality of every aspect of the trial should be implemented.” Investigators should follow the procedures that are described in the protocol for a clinical investigation.
However, due to the inspectional findings where investigators fail to comply with their own responsibilities as investigators (described in brief in the signed Form 1572), written standard operating procedures are being sought. This issue is also going to be discussed further since written SOPs may not assure that the investigator will not repeat noncompliant activities. Therefore, a robust QA program has to be implemented when procedures are written and adopted.
Other regulatory bodies consider SOPs for investigators a requirement (Health Canada).
1.1.5 GCP Applicability
Good Clinical Practice applies to the three main parties involved in a clinical trial: (1) the sponsor of the clinical investigation, (2) the principal investigator (PI), and (3) the Institutional Review Board (IRB) or Ethic Review Board or Committee (see Figure 1.1)
Figure 1.1 Parties in a clinical trial.
In the case where the principal investigator initiates the clinical trial (academic clinical trials not sponsored by industry), he/she also bears the responsibilities of the sponsor. This is procedurally defined as a dual role sponsor – investigator. The dual role is discussed in-depth later to allow institutions that foster this type of human research to understand the scope of FDA regulatory applicability.
The role and responsibilities of the clinical research sponsor are discussed first since the sponsor is the initiator of a clinical study.
1.2 Role of the Sponsor of a Clinical Investigation
The sponsor of a clinical trial is an individual, corporation, manufacturer, agency, or scientific institution that assumes the sponsor’s responsibilities as described in Good Clinical Practice and the applicable regulatory requirements. For FDA purposes, the sponsor is the individual or company that identifies himself or itself as such in Form 15712.
1.2.1 GCP: Responsibilities of a Sponsor of a Clinical Trial
When a sponsor initiates the development of an investigational product in humans, he/she assumes the following responsibilities:
1.Provide for Quality Assurance (QA) and Quality Control (QC). The clinical trial sponsor has to confirm and demonstrate that all clinical trial activities are conducted in accordance with GCP and regulatory requirements. The sponsor should:
(a) Implement QA and QC. The sponsor is responsible for implementing and maintaining quality assurance (audit capabilities) and quality control (monitoring clinical trials) systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
(b) Secure Agreements with Parties. The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial-related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities. Agreements, made by the sponsor with the investigator/institution and any other parties involved with the clinical trial, should be in writing as part of the protocol or in a separate agreement. The potential agreements within parties in clinical trials are between:
Sponsor – investigatorSponsor–contract research organization/third party contractorsSponsor– clinical trial laboratory testing facilityInvestigator – institutionInvestigator– site management organization (SMO—not directly included in GCP or regulations)Site management organizations are identified as new players in the clinical research industry, providing services to the investigator site as coordinators and other clinical trial site-specific services. Note that these organizations, new in the clinical research setting, are not mentioned yet in GCP or regulatory requirements, and therefore are not subject to regulatory inspections. It is very important to address that, although SMOs are necessarily not inspected by the regulator, the sponsor should inspect the SMO that provides services for the investigator’s site and determine that it is fully compliant with GCP and regulations. Also, the sponsor has to know in detail the agreement between the investigator site and the SMO to guarantee accessibility to records and quality of the activity contracted.
(c) Provide for Monitoring. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.
2.Hire a Contract Research Organization (CRO). In the last two decades, the industry faced an increased number of clinical trials and locations of investigational sites. Also, with the adoption of GCP and the increase in regulatory demands, sponsors had to seek out third party service providers for clinical research activities to remain compliant and to complete projects in a timely manner. GCP is very clear on the relationship between a sponsor and a sponsor’s service provider.
(a) Transfer Trial-Related Duties. A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in writing. The transfer should be done in writing in the format of a contract agreement where the transferred duties must be detailed. Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. Transfer of duties does not mean in any case transfer of responsibilities. Note that the sponsor is always ultimately responsible for the quality and integrity of the trial data.
(b) Ensure QA and QC of CRO. The CRO should implement quality assurance and quality control. CRO compliance to GCP and regulatory requirements is the same as for the sponsor; therefore, it has to implement QA and QC.
(c) CRO Shares Sponsor’s Responsibilities. All references to a sponsor in GCP also apply to a CRO to the extent that a CRO has assumed the trial-related duties and functions of a sponsor, and therefore assumes responsibility for the activities contracted.
3.Provide for Medical Expertise. Clinical trials, although not a replacement for medical treatment, have to always consider the health, safety, and well-being of the subjects involved. Medical decisions on efficacy and/or safety have to be done in an ongoing manner from the part of a sponsor of a clinical study. Therefore, the sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial-related medical questions or problems. Since it may become impractical for a company/sponsor to keep on staff full-time medical experts, then, if necessary, outside consultant(s) may be appointed for this purpose.
4.Develop Trial Design. The design of the clinical trial is the sponsor’s responsibility. 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 Case Report Forms and planning the analyses to analyzing and preparing interim and final clinical trial reports.
5.Provide for Trial Management, Data Handling, and Recordkeeping.
(a) Clinical Trial Management Personnel Qualifications. Adequately qualified personnel are the key to a successful study. 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.
(b) Independent Data Monitoring Committee. Due to the complexity and size of clinical trials, continuous safety surveillance of the subjects has to be provided to ensure that the sponsor reacts to safety concerns appropriately. The sponsor should 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 should maintain written records of all its meetings.
(c) Electronic Data. GCP established the grounds for many aspects of data management when electronic systems are utilized; nevertheless, regulators defined specific requirements that are to be implemented strictly to assure compliance. When using electronic trial data handling and/or remote electronic trial data systems, the sponsor should:
(i) Perform System Validation. 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).
(ii) Use Standard Operating Procedures. Maintain SOPs for using these systems.
(iii) Institute an Audit Trail. 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).
(iv) Provide System Security. Maintain a security system that prevents unauthorized access to the data.
(v) Determine Access Privileges. Maintain a list of the individuals who are authorized to make data changes.
(vi) Provide for Data Backup. Maintain adequate backup of the data.
(d) Blinding. Maintaining the blinding in a clinical trial is essential to reduce bias on the observations on the part of the blinded parties. The sponsor should safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing).
(e) Source Data. Source data should exist for all information collected in a clinical trial CRF. If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data. The sponsor should ensure access to the source at any time.
(f) Unique Subject Code. The sponsor should use an unambiguous subject identification code that allows identification of all the data reported for each subject. Also, since we should have one code for a subject, we should have one subject for a code. In other words, we cannot re-enroll subjects who previously participated in the study(ies) without particular exemptions (extensions, open label phases, etc.) since they are not going to contribute with new data, and long or repeated exposure to the investigational product may be of a higher unknown risk.
1.2.2 Essential Documents for the Clinical Trial
GCP states that “the sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial.” The sponsor should have an organized system, the Trial Master File (TMF) for filing, searching, and retrieving those essential documents. The sponsor also should maintain an electronic Trial Master File that contains all the essential documents for the clinical trial either electronically generated or scanned from the original paper documents. Accessibility privileges and all other assurances for the integrity of the filing system should follow the criteria for electronic systems in clinical trials. Also, the sponsor must keep the original paper documents as a source.
Retention of the Essential Documents for the Clinical Trial
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).
Archiving of the Essential Documents for the Clinical Trial After Discontinuation of Development
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) (in Canada the record retention is for 25 years).
Notification
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.
Transfer of Data Ownership
In these times when mergers and acquisitions of pharmaceutical and biotech companies occur frequently, it is important that there is evidence of ownership of (and responsibility for) the data for the investigational products that continue development. Transferring data ownership also entitles the transfer of sponsors’ responsibilities before the eyes of the regulator. GCP states that “any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the applicable regulatory requirement(s).”
Records Retention
Access to records by the parties of a clinical study will allow the regulator through compliance inspections, to confirm the adherence to requirements. A comparison with original records at the investigator site and at the sponsor’s site will only be possible if the records are retained for a minimum established period. 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 (in Canada the record retention is for 25 years).
Also, the sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention (e.g., in the clinical trial agreement) and should notify the investigator(s)/institution(s) in writing when the trial-related records are no longer needed. The sponsor is responsible for ensuring access to source documents and other clinical trial documents at the investigator site to auditors and regulatory inspectors for the stipulated period of time.
1.2.3 Investigator Selection
Clinical trial success depends on selecting the right investigator with the right resources and facilities. The selection process should be detailed in procedures that are very explicit on the sponsor’s selection criteria.
GCP establishes that the sponsor is responsible for selecting the investigator(s)/institution(s).
Investigator’s Qualifications
GCP states that “each investigator should be qualified by training and experience.” It is very important to note that the investigator is responsible for the medical care of subjects; therefore, when selecting an investigator, he/she should be qualified and able to provide that medical care (licensed to practice in the province, state, or region), and at the same time be able to conduct the study at the site.
Resources at the Investigator’s Site
The investigator should have personnel to assist him/her in the undertaking of a clinical trial since it entails various activities that are time consuming and extensive. The investigator must comply with GCP, regulatory requirements, and specific study requirements at all times, and a person who acts as a coordinator for those activities may be required. Also, the investigator site should have, if required by the protocol, a study nurse and co/subinvestigators who will have certain responsibilities delegated to them in order to achieve the study’s objectives in a timely and compliant manner. GCP states that “the investigator should have adequate resources to properly conduct the trial for which he/she is selected.” If organization of a coordinating committee is to be achieved and/or selection of coordinating investigator(s) is to be done in multicenter trials, their organization and/or selection are the sponsor’s responsibilities.
Protocol and Investigator’s Brochure
The sponsor has the responsibility to write and have the protocol and Investigator’s Brochure available for the investigator to peruse before committing to the study.
GCP states that “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.”
Agreement with the Investigator/Institution
It is essential that the sponsor secure a written agreement with the investigator/institution before the clinical trial is initiated.
The sponsor should obtain the investigator’s/institution’s agreement for the following: (1) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the IRB/IEC; (2) to comply with procedures for data recording/reporting; (3) to permit monitoring, auditing, and inspection; and (4) to retain the trial-related essential documents until the sponsor informs the investigator/institution that these documents are no longer needed.
The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.
Although GCP states the four essential elements of compliance in the agreement between an investigator and sponsor (compliance to regulatory requirements and GCP and IRB approved protocol; compliance to protocol procedures for data recording/reporting; permitting monitoring and audit; and document retention), it is important to emphasize that the sponsor should include specific conditions for the implementation of the clinical trial at the site and consequences for violations, deviations, or noncompliant activities.
1.2.4 Allocation of Responsibilities
GCP states that, prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions. This activity is usually performed by the assigned project manager/project leader, who, with the guide of the protocol and the Investigator’s Brochure, will estimate and allocate clinical trial functions to ensure compliance and project control.
1.2.5 Compensation to Subjects and Investigators
Compensation to Subjects for Trial-Related Injuries
A subject compensation clause is applicable when regulatory authorities establish that requirement and when the patient is financially responsible for his/her medical care. It is essential that this issue is discussed properly in the patient information and consent form. GCP establishes that “if required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial — compensation for trial related injuries — except for claims that arise from malpractice and/or negligence.”
It is important to note that any claims that arise from malpractice and/or negligence against the site are the investigator’s responsibility and he/she should have knowledge of that to make sure his/her professional insurance covers clinical trial situations. In the same way, the sponsors are responsible for their part in any claim.
GCP states that “the sponsor’s policies and procedures (SOPs) should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).”
Other Types of Compensation to Trial Subjects
It is generally accepted that healthy volunteers who participate in Phase I studies be compensated for their participation in the study. However, depending on the regulatory body, patients in Phase II or III trials might not be entitled to monetary compensation. It is important to note that the compensation should not be construed as a benefit. The GCP guidance states that “when trial subjects receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).”
1.2.6 Financing
Previously, we discussed the GCP guideline where there should be a written agreement between the sponsor and the investigator on the compliance terms of the clinical study — the Clinical Trial Agreement (CTA). Also, the sponsor and the investigator must agree on the financial terms of the study. Those financial terms can be part of the CTA, but not necessarily. The parties may have an independent financial agreement that also has to be available for inspection. GCP states in this matter that “the financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution.”
It is important to note that investigations of a site within an institution may be subject to institutional overhead. Financial agreements between the sponsor and investigator will set the basis for the amount of overhead charged.
1.2.7 Notification/Submission to Regulatory Authorities
Drugs, biologicals, and medical devices intended to be tested in humans are regulated products. Sponsors must ensure that they request and obtain regulatory authorization to start the development of an investigational product in humans. The scope of the regulated product may vary from country to country, but the applicability of the principle is the same.
The GCP principle states that “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.”
1.2.8 Confirmation of Review by IRB/IEC
The sponsor does not communicate with the IRB/IEC directly. However, in a January 2010 draft guidance, the FDA suggested that the sponsor should submit annual safety reports directly to IRBs since they have access to a broader base of information. All communications and interactions within the IRB/IEC are done through the investigator.
According to GCP regarding IRB/IEC, it is the sponsor’s responsibility to obtain the following from the investigator/institution:
