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Introduction to Clinical Trials
Chapter 1
Introduction to Clinical Trials Brenda Wright
Chapter Outline What Is a Clinical Trial? Why Do We Do Clinical Trials? Clinical Team Study Participant Medicines Regulatory Authorities
1 1 3 3 3
IRB/IEC Ethics Committees Sponsor Contract Research Organizations Managing the Trial Further Reading
4 4 5 5 9
The purpose of this book is to illustrate and provide guidelines and information for planning and conducting a successful Clinical Trial from the Project Management perspective. Project Management is the application of planning, knowledge, skills, and technique to execute projects effectively and efficiently. It will also describe the processes from beginning to end, and link these processes to key stakeholders and Good Clinical Practice (GCP), all of which are critical to the success of a trial (Table 1.1 and Fig. 1.1).
WHAT IS A CLINICAL TRIAL? A Clinical Trial is a prospective biomedical or behavioral research project that involves human volunteers (participants) and/or uses materials of human origin, for example, observed behavior, answers to questions, and/or obtaining tissue or specimen samples.
WHY DO WE DO CLINICAL TRIALS? Clinical trials are designed to answer a specific research question. They are used to determine if a new biomedical or behavioral intervention is safe, efficacious, and effective.
A Comprehensive and Practical Guide to Clinical Trials. DOI: http://dx.doi.org/10.1016/B978-0-12-804729-3.00001-8 © 2017 Elsevier Inc. All rights reserved.
1
2
A Comprehensive and Practical Guide to Clinical Trials
TABLE 1.1 What Is Good Clinical Practice? GCP provides guidelines as defined by the ICH, an international body which defines standards that governments can transpose into regulations for clinical trials involving humans. These standards are referred to as ICH-GCP or ISO-GCP. It is a standard for clinical trials, which includes the design, conduct, performance, monitoring, termination, auditing, recording, analysis, reporting, and documentation of clinical trials. These standards ensure that the trials are scientifically and ethically sound and that the clinical properties of the pharmaceutical product under investigation are properly documented and the data and reported results are credible and accurate. It also ensures that the rights, integrity, and confidentiality of trial participants are protected. GCP guidelines therefore protect the human rights of participants in a clinical trial and provide assurance of the safety and efficacy of the newly developed compound. These guidelines also require detailed documentation for the clinical protocol, record keeping, training, and facilities, including computers and software. It defines the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors. Quality assurance and inspections ensure that these standards are met. The aim of GCP is to provide Investigators and their study teams with the tools to protect human subjects and collect quality data.
Clinical team/site
Contract research organization
Study participant
Key stakeholders Regulatory authorities
Sponsor
IRB/IEC ethics committees
FIGURE 1.1 Key stakeholders.
Introduction to Clinical Trials Chapter | 1
3
Good Research Questions are: G G
G
G
G
Clear. They are easy to understand and unambiguous. Specific. They are specific enough to understand what constitutes an answer. Answerable. It is clear what data we need, to answer the questions, and how the data will be collected. Interconnected. All the questions are related in some meaningful way, forming a coherent whole. Substantively relevant. They are nontrivial questions that are fundamentally worthy of the research effort and cost. Some approaches are:
G
G
G
G
To evaluate interventions (drugs, medical devices, etc.) for treating a disease, syndrome, or condition. To evaluate interventions that will identify or diagnose a particular disease or condition. To find methods to prevent the onset or recurrence of a disease or condition (medicine, vaccines, lifestyle changes, etc.). To investigate and identify methods to improve quality of life and comfort for patients with chronic illnesses.
These approaches have to follow GCP guidelines as defined by the International Council for Harmonization (ICH) and subsequently adapted in many countries (Table 1.1).
CLINICAL TEAM The Sponsor or its contracted research organization (CRO) will appoint an Investigator Site consisting of the Principal Investigator and his/her Clinical Team who will conduct the clinical trial. In many countries the research team will be provided by a Clinical Trials Unit (CTU), which is based within the institution. On others, a CRO may provide all the research staff.
STUDY PARTICIPANT A voluntary, informed person who has read and signed the Informed Consent Document, agreeing to the procedures, etc. he/she will be involved in during a Clinical Trial.
MEDICINES REGULATORY AUTHORITIES In the case of trials involving an investigative medicinal product, regulatory requirements include approval by a medicines regulatory
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A Comprehensive and Practical Guide to Clinical Trials
authority (MRA). The MRA is responsible for ensuring that all clinical trials of both nonregistered medicines, and new indications of registered medicines, comply with the necessary requirements for safety, quality, and efficacy. Applications for clinical trials and for registration of medicines and medical devices are reviewed by a MRA expert committee, which considers among other issues the scientific, medical, and ethical issues of the applications. Reports on the progress of the study are sent to the MRA on a regular basis. Proof of safety, quality, and efficacy must be submitted when applying to the Medicines Control Council (MCC) for approval and registration of a medicine for use in South Africa. In the United States the regulatory body is the FDA (Food and Drug Administration) and in Europe it is the EMEA (European Agency for the Evaluation of Medicinal Products). In South Africa the MCC is the statutory body that regulates the performance of clinical trials and registration of medicines and medical devices for use in specific diseases. See Chapter 4, Regulatory Requirements, for more detailed information regarding International Regulatory submissions.
IRB/IEC ETHICS COMMITTEES Approval by an institutional review board (IRB), or ethics board, is necessary prior to the conduct of a clinical trial. The IRB should consist of clinicians, researchers, and members from the community. They play an important role in ensuring that the trial is ethical, and that the welfare and human rights of the participants are protected according to GCP guidelines and the protection of personal information. The IRB inspects the trial for medical safety and protection of the participants involved in the trial, prior to approval.
SPONSOR The Sponsor can be an individual, company, institution, or organization that has the responsibility to initiate and manage the clinical trial. The sponsor may or may not provide the funding. It may be a governmental organization, a pharmaceutical, and biotechnology or medical device company. The clinical trial may also be managed by an outsourced partner, i.e., a contract research organization (CRO) or an academic clinical trial unit. National health agencies and academic institutions may offer grants to Investigators who design clinical trials that attempt to answer
Introduction to Clinical Trials Chapter | 1
5
research questions of interest to the agency or institution. A study initiated by an investigator from academia is known as an Investigator Lead Trial (ILT) and usually the academic institution acts as the regulatory sponsor.
CONTRACT RESEARCH ORGANIZATIONS A CRO provides support to the pharmaceutical, biotechnology, and medical device industries in performing one or more of the trial-related duties and functions, i.e., to conduct clinical research trials on behalf of the Sponsor. The CRO is contracted by a pharmaceutical, medical device, or biotechnology company (Sponsor). CROs employ various clinical research associates, biostatisticians, medical writers, project managers, and similar clinical research professionals to support the conduct of clinical trials on behalf of their pharmaceutical, biotech, and medical device company sponsors. A CRO will also review and validate (monitor) the trial data during the clinical trial. Other CRO services may include medical writing, regulatory support, investigator/site selection and qualification, clinical trial management, and data analysis (biostatistics). CROs are not routinely used in ILTs.
MANAGING THE TRIAL Management of the trial process requires a fluidity of steps summarized in Figs. 1.2 1.4 and illustrates the systematic approach to be followed in order to successfully conduct a clinical trial. During this time, the stakeholders each has their specific roles to play and certain steps must be in place before continuing with the next. There are three stages to the process, each of which is described below: Section 1 illustrates the first stage and discusses the development of the study drug, the research question, and the regulatory requirements. Some of these processes may happen simultaneously and not necessarily in the exact order as illustrated below, but they all have to be in place before the conduct of a clinical trial can commence.
6
A Comprehensive and Practical Guide to Clinical Trials
Establish need for project and the research question to be answered Stakeholder: Researcher/Sponsor
Find source of funding and/or Sponsor for Project Stakeholder: Researcher/Sponsor
Drug is developed in laboratories Stakeholder: Researcher
Animal testing Stakeholder: Researcher/CRO appointed by Sponsor
Write synopsis Stakeholder: Sponsor/medical writer, investigator appointed by Sponsor
Site assessment and site selection for phase 1–4 Stakeholder: Sponsor/CRO appointed by Sponsor
Protocol, investigator brochure, informed consent document design Stakeholder: Medical writer and/or investigator appointed by Sponsor
Contracts and insurance Stakeholder—insurance: Sponsor. Stakeholder—contracts: Sponsor, CRO, CRA, suppliers, laboratories, etc.
Regulatory submissions Stakeholder: Sponsor/CRO/CRA
Investigator meeting (start up meeting) Stakeholder: Sponsor/CRO/Clinical Team/analytical laboratories
FIGURE 1.2 Section 1—Flowchart.
Introduction to Clinical Trials Chapter | 1
7
Section 2 illustrates the planning and training stage. During this time, the clinical team will plan the conduct and make sure that all documents, contracts, supplies are in place. Training of staff is done and specific duties are allocated by the principal investigator. This stage of a clinical trial sometimes may take longer than conducting the actual trial. However, meticulous planning is essential for success.
Recruitment strategy Stakeholder: PI and Clinical Team
Review CRF and design source document templates Stakeholder: Clinical Team
CRO supplies site and trial master files, clinical team maintains Stakeholder: CRO and/or Clinical Team
Obtain regulatory, MRA, & HREC approvals Stakeholder: CRO and/or Clinical Team
Site initiation meeting Stakeholder: CRO and/or Clinical Team
Staff training Stakeholder: Prinicipal investigator and study coodinator
Receipt of IP Stakeholder: Clinical pharmacist or investigator with dispensing licence (the regulations vary from country to country) FIGURE 1.3 Section 2—Flowchart.
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A Comprehensive and Practical Guide to Clinical Trials
Section 3 illustrates the conduct of the clinical trial and what happens when a trial closes.
Clinical conduct Stakeholder: Clinical Team for conduct and Sponsor/CRO for monitoring and evaluating
Database lock Stakeholder: Clinical Team for entering data and answering queries, Sponsor/CRO for monitoring, and data management for evaluating and locking of CRF
Closeout meeting Stakeholder: CRO and Clinical Team
Archiving Stakeholder: Sponsor, Clinical Team
Investigational product destruction/return Stakeholder: Clinical Team destructs or return to Sponsor for destruction
Results published Stakeholder: Sponsor
Submission to regulatory body to register drug Stakeholder: Submission to regulatory body to register drug
FIGURE 1.4 Section 3—Flowchart.
Introduction to Clinical Trials Chapter | 1
Keypoints G
G
G G
Research Question—Clinical trials are designed to answer a specific Research question. It defines the study design and outcomes to be met. GCP—Good clinical practice should be followed throughout the research project. Key Stakeholders—Know who they are and where they fit into the trial. Process Flow—Strategic planning will ensure the systematic flow of your project from beginning to end.
FURTHER READING ICH Harmonised Tripartite Guideline E6 (R1), Current step 4 version dated 10 June 1996. https://clinicaltrials.gov/ct2/about-studies/learn. https://grants.nih.gov/grants/funding/phs398/instructions2/p2_human_subjects_definitions.htm. U.S. Department of Health and Human Services/Clinical Research Definitions and Procedures. SNM Clinical Trials Network.
9
Introduction to Clinical Trials Brenda Wright
Chapter Outline What Is a Clinical Trial? Why Do We Do Clinical Trials? Clinical Team Study Participant Medicines Regulatory Authorities
1 1 3 3 3
IRB/IEC Ethics Committees Sponsor Contract Research Organizations Managing the Trial Further Reading
4 4 5 5 9
The purpose of this book is to illustrate and provide guidelines and information for planning and conducting a successful Clinical Trial from the Project Management perspective. Project Management is the application of planning, knowledge, skills, and technique to execute projects effectively and efficiently. It will also describe the processes from beginning to end, and link these processes to key stakeholders and Good Clinical Practice (GCP), all of which are critical to the success of a trial (Table 1.1 and Fig. 1.1).
WHAT IS A CLINICAL TRIAL? A Clinical Trial is a prospective biomedical or behavioral research project that involves human volunteers (participants) and/or uses materials of human origin, for example, observed behavior, answers to questions, and/or obtaining tissue or specimen samples.
WHY DO WE DO CLINICAL TRIALS? Clinical trials are designed to answer a specific research question. They are used to determine if a new biomedical or behavioral intervention is safe, efficacious, and effective.
A Comprehensive and Practical Guide to Clinical Trials. DOI: http://dx.doi.org/10.1016/B978-0-12-804729-3.00001-8 © 2017 Elsevier Inc. All rights reserved.
1
2
A Comprehensive and Practical Guide to Clinical Trials
TABLE 1.1 What Is Good Clinical Practice? GCP provides guidelines as defined by the ICH, an international body which defines standards that governments can transpose into regulations for clinical trials involving humans. These standards are referred to as ICH-GCP or ISO-GCP. It is a standard for clinical trials, which includes the design, conduct, performance, monitoring, termination, auditing, recording, analysis, reporting, and documentation of clinical trials. These standards ensure that the trials are scientifically and ethically sound and that the clinical properties of the pharmaceutical product under investigation are properly documented and the data and reported results are credible and accurate. It also ensures that the rights, integrity, and confidentiality of trial participants are protected. GCP guidelines therefore protect the human rights of participants in a clinical trial and provide assurance of the safety and efficacy of the newly developed compound. These guidelines also require detailed documentation for the clinical protocol, record keeping, training, and facilities, including computers and software. It defines the roles and responsibilities of clinical trial sponsors, clinical research investigators, and monitors. Quality assurance and inspections ensure that these standards are met. The aim of GCP is to provide Investigators and their study teams with the tools to protect human subjects and collect quality data.
Clinical team/site
Contract research organization
Study participant
Key stakeholders Regulatory authorities
Sponsor
IRB/IEC ethics committees
FIGURE 1.1 Key stakeholders.
Introduction to Clinical Trials Chapter | 1
3
Good Research Questions are: G G
G
G
G
Clear. They are easy to understand and unambiguous. Specific. They are specific enough to understand what constitutes an answer. Answerable. It is clear what data we need, to answer the questions, and how the data will be collected. Interconnected. All the questions are related in some meaningful way, forming a coherent whole. Substantively relevant. They are nontrivial questions that are fundamentally worthy of the research effort and cost. Some approaches are:
G
G
G
G
To evaluate interventions (drugs, medical devices, etc.) for treating a disease, syndrome, or condition. To evaluate interventions that will identify or diagnose a particular disease or condition. To find methods to prevent the onset or recurrence of a disease or condition (medicine, vaccines, lifestyle changes, etc.). To investigate and identify methods to improve quality of life and comfort for patients with chronic illnesses.
These approaches have to follow GCP guidelines as defined by the International Council for Harmonization (ICH) and subsequently adapted in many countries (Table 1.1).
CLINICAL TEAM The Sponsor or its contracted research organization (CRO) will appoint an Investigator Site consisting of the Principal Investigator and his/her Clinical Team who will conduct the clinical trial. In many countries the research team will be provided by a Clinical Trials Unit (CTU), which is based within the institution. On others, a CRO may provide all the research staff.
STUDY PARTICIPANT A voluntary, informed person who has read and signed the Informed Consent Document, agreeing to the procedures, etc. he/she will be involved in during a Clinical Trial.
MEDICINES REGULATORY AUTHORITIES In the case of trials involving an investigative medicinal product, regulatory requirements include approval by a medicines regulatory
4
A Comprehensive and Practical Guide to Clinical Trials
authority (MRA). The MRA is responsible for ensuring that all clinical trials of both nonregistered medicines, and new indications of registered medicines, comply with the necessary requirements for safety, quality, and efficacy. Applications for clinical trials and for registration of medicines and medical devices are reviewed by a MRA expert committee, which considers among other issues the scientific, medical, and ethical issues of the applications. Reports on the progress of the study are sent to the MRA on a regular basis. Proof of safety, quality, and efficacy must be submitted when applying to the Medicines Control Council (MCC) for approval and registration of a medicine for use in South Africa. In the United States the regulatory body is the FDA (Food and Drug Administration) and in Europe it is the EMEA (European Agency for the Evaluation of Medicinal Products). In South Africa the MCC is the statutory body that regulates the performance of clinical trials and registration of medicines and medical devices for use in specific diseases. See Chapter 4, Regulatory Requirements, for more detailed information regarding International Regulatory submissions.
IRB/IEC ETHICS COMMITTEES Approval by an institutional review board (IRB), or ethics board, is necessary prior to the conduct of a clinical trial. The IRB should consist of clinicians, researchers, and members from the community. They play an important role in ensuring that the trial is ethical, and that the welfare and human rights of the participants are protected according to GCP guidelines and the protection of personal information. The IRB inspects the trial for medical safety and protection of the participants involved in the trial, prior to approval.
SPONSOR The Sponsor can be an individual, company, institution, or organization that has the responsibility to initiate and manage the clinical trial. The sponsor may or may not provide the funding. It may be a governmental organization, a pharmaceutical, and biotechnology or medical device company. The clinical trial may also be managed by an outsourced partner, i.e., a contract research organization (CRO) or an academic clinical trial unit. National health agencies and academic institutions may offer grants to Investigators who design clinical trials that attempt to answer
Introduction to Clinical Trials Chapter | 1
5
research questions of interest to the agency or institution. A study initiated by an investigator from academia is known as an Investigator Lead Trial (ILT) and usually the academic institution acts as the regulatory sponsor.
CONTRACT RESEARCH ORGANIZATIONS A CRO provides support to the pharmaceutical, biotechnology, and medical device industries in performing one or more of the trial-related duties and functions, i.e., to conduct clinical research trials on behalf of the Sponsor. The CRO is contracted by a pharmaceutical, medical device, or biotechnology company (Sponsor). CROs employ various clinical research associates, biostatisticians, medical writers, project managers, and similar clinical research professionals to support the conduct of clinical trials on behalf of their pharmaceutical, biotech, and medical device company sponsors. A CRO will also review and validate (monitor) the trial data during the clinical trial. Other CRO services may include medical writing, regulatory support, investigator/site selection and qualification, clinical trial management, and data analysis (biostatistics). CROs are not routinely used in ILTs.
MANAGING THE TRIAL Management of the trial process requires a fluidity of steps summarized in Figs. 1.2 1.4 and illustrates the systematic approach to be followed in order to successfully conduct a clinical trial. During this time, the stakeholders each has their specific roles to play and certain steps must be in place before continuing with the next. There are three stages to the process, each of which is described below: Section 1 illustrates the first stage and discusses the development of the study drug, the research question, and the regulatory requirements. Some of these processes may happen simultaneously and not necessarily in the exact order as illustrated below, but they all have to be in place before the conduct of a clinical trial can commence.
6
A Comprehensive and Practical Guide to Clinical Trials
Establish need for project and the research question to be answered Stakeholder: Researcher/Sponsor
Find source of funding and/or Sponsor for Project Stakeholder: Researcher/Sponsor
Drug is developed in laboratories Stakeholder: Researcher
Animal testing Stakeholder: Researcher/CRO appointed by Sponsor
Write synopsis Stakeholder: Sponsor/medical writer, investigator appointed by Sponsor
Site assessment and site selection for phase 1–4 Stakeholder: Sponsor/CRO appointed by Sponsor
Protocol, investigator brochure, informed consent document design Stakeholder: Medical writer and/or investigator appointed by Sponsor
Contracts and insurance Stakeholder—insurance: Sponsor. Stakeholder—contracts: Sponsor, CRO, CRA, suppliers, laboratories, etc.
Regulatory submissions Stakeholder: Sponsor/CRO/CRA
Investigator meeting (start up meeting) Stakeholder: Sponsor/CRO/Clinical Team/analytical laboratories
FIGURE 1.2 Section 1—Flowchart.
Introduction to Clinical Trials Chapter | 1
7
Section 2 illustrates the planning and training stage. During this time, the clinical team will plan the conduct and make sure that all documents, contracts, supplies are in place. Training of staff is done and specific duties are allocated by the principal investigator. This stage of a clinical trial sometimes may take longer than conducting the actual trial. However, meticulous planning is essential for success.
Recruitment strategy Stakeholder: PI and Clinical Team
Review CRF and design source document templates Stakeholder: Clinical Team
CRO supplies site and trial master files, clinical team maintains Stakeholder: CRO and/or Clinical Team
Obtain regulatory, MRA, & HREC approvals Stakeholder: CRO and/or Clinical Team
Site initiation meeting Stakeholder: CRO and/or Clinical Team
Staff training Stakeholder: Prinicipal investigator and study coodinator
Receipt of IP Stakeholder: Clinical pharmacist or investigator with dispensing licence (the regulations vary from country to country) FIGURE 1.3 Section 2—Flowchart.
8
A Comprehensive and Practical Guide to Clinical Trials
Section 3 illustrates the conduct of the clinical trial and what happens when a trial closes.
Clinical conduct Stakeholder: Clinical Team for conduct and Sponsor/CRO for monitoring and evaluating
Database lock Stakeholder: Clinical Team for entering data and answering queries, Sponsor/CRO for monitoring, and data management for evaluating and locking of CRF
Closeout meeting Stakeholder: CRO and Clinical Team
Archiving Stakeholder: Sponsor, Clinical Team
Investigational product destruction/return Stakeholder: Clinical Team destructs or return to Sponsor for destruction
Results published Stakeholder: Sponsor
Submission to regulatory body to register drug Stakeholder: Submission to regulatory body to register drug
FIGURE 1.4 Section 3—Flowchart.
Introduction to Clinical Trials Chapter | 1
Keypoints G
G
G G
Research Question—Clinical trials are designed to answer a specific Research question. It defines the study design and outcomes to be met. GCP—Good clinical practice should be followed throughout the research project. Key Stakeholders—Know who they are and where they fit into the trial. Process Flow—Strategic planning will ensure the systematic flow of your project from beginning to end.
FURTHER READING ICH Harmonised Tripartite Guideline E6 (R1), Current step 4 version dated 10 June 1996. https://clinicaltrials.gov/ct2/about-studies/learn. https://grants.nih.gov/grants/funding/phs398/instructions2/p2_human_subjects_definitions.htm. U.S. Department of Health and Human Services/Clinical Research Definitions and Procedures. SNM Clinical Trials Network.
9