ICH GCP Obligations of Investigators Conducting Clinical Trials

Chapter 1: Overview

This chapter discusses the obligations of investigators when conducting clinical trials.

Chapter 1: Overview

ICH GCP Guideline

Good Clinical Practice (GCP) is defined by International Conference of Harmonisation (ICH) as 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.

Individuals conducting clinical trials are obligated to consider the rights, safety, and well-being of clinical trial subjects. These considerations should “prevail over interests of science and society.”

Although ICH allows for some flexibility in the application of GCP, the standard requires adherence to all applicable regulatory requirements (i.e., local, national and regional laws and regulations).

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The ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R2) is the primary source for this course. Throughout the course, this guideline and its contents will typically be referred to as ICH GCP. Citations for information taken from this guideline are indicated by the section number enclosed in brackets (e.g., [4.8.10]).

About this course…

After completing this course, you will be able to recognize how to comply with ICH GCP. You will also be able to identify principal investigator obligations with respect to:

qualifications and agreements.
resources.
medical care of research participants.
Institutional Review Board/Independent Ethics Committee (IRB/IEC) communications
protocol compliance.
control and use of investigational products, including randomization and unblinding.
informed consent.
documentation requirements, including reports addressing progress, safety, premature termination, and final trial status.

If you work for a sponsor company overseeing clinical research, you will also be able to recognize ICH GCP requirements applicable to investigators.

If your organization has purchased the option for continuing education credits directly through UL EduNeering, then click <a class="jobaid" data-forced="no" href="Assets/lang_1/jobaids/continuing_education_credits_directly_through_ul_eduneering.pdf" target="_blank">here</a> to learn more.

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This course addresses the following: <ul> <li>ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R2)</li> <li>World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects; amended by the 64th WMA General Assembly, Fortaleza, Brazil, October 2013.</li> </ul>

Principles of GCP

This chapter discusses the core principles of GCP.

Chapter 2: Principles of GCP

Section 2 of ICH GCP is a framework of principles that also contains specific obligations for maintaining safety and data integrity.

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2.1

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, which you can view in full by clicking <a class="jobaid" data-forced="no" href="Assets/lang_1/jobaids/declaration_helsinki.pdf" target="_blank">here</a>. Initially issued by the World Medical Association in 1964, this declaration states, “Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.” Clinical trials should also be conducted so that they are consistent with ICH GCP and the applicable regulatory requirement(s).

2.2

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.

2.3

The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

2.4

The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

2.5

Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

2.6

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.

2.7

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.

2.8

Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

The investigator’s qualifications are nearly universally documented by means of a current curriculum vitae (CV). Sponsors and regulatory agencies may also require documentation of specialized training/certifications. These qualifications also include knowledge of the investigational product and its use, which is typically provided by the sponsor in an Investigator’s Brochure and protocol.

2.9

Freely given informed consent should be obtained from every subject prior to clinical trial participation.

2.10

All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. This applies to all records (paper and electronic).

2.11

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).

2.12

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.

2.13

Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Terms

Definitions within ICH GCP will help you understand and differentiate between the obligations of various parties involved in clinical trials. The books on this page contain those definitions.

Investigator

<h1> Investigator </h1> 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. See also Subinvestigator. It is ESSENTIAL that investigators comply with applicable regulatory requirements as well as adhere to GCP principles taken from the Declaration of Helsinki. Knowledge of and agreement to follow GCP and all applicable regulatory requirements is a prerequisite for serving as an investigator. This includes allowing monitoring and auditing by sponsor representatives as well as inspection by regulatory authorities. Many sponsors and some regulatory agencies require documentation of formal GCP training. Other “pre-trial” documentation normally includes a formal contract/agreement with the sponsor, the so-called clinical trial agreement, and approval/favorable opinion from the IRB/IEC regarding the protocol and informed consent documents.

Subinvestigator

<h1> Subinvestigator </h1> "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." Please note: Sponsors and CROs require the subinvestigator be qualified by training and expertise to conduct trial-related procedures and/or make trial related decisions.

Sponsor

<h1> Sponsor </h1> A sponsor is an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.

Sponsor-Investigator

<h1> Sponsor-Investigator </h1> A sponsor-investigator is 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 (i.e., 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. The trials conducted by a sponsor-investigator are commonly known as “investigator-initiated trials.”

Institutional Review Board (IRB)

<h1> Institutional Review Board (IRB) </h1> An IRB is an independent body constituted of medical, scientific, and non-scientific 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.

Independent Ethics Committee (IEC)

<h1> Independent Ethics Committee (IEC) </h1> An IEC is an independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical 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. Note: Section 3.1.4 of ICH E6 (R2) states that both IRB/IEC should conduct continuing reviews of ongoing clinical trials at least once per year, at intervals appropriate to the degree of risk to clinical trial participants.

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Who is responsible for the conduct of the clinical trial at a trial site?

investigator

subinvestigator

sponsor

Institutional Review Board (IRB)

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.

An investigator is responsible for the conduct of the clinical trial at a trial site.

What is the term used to identify an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial?

sponsor

investigator

subinvestigator

Institutional Review Board (IRB)

A sponsor is an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.

TRUE OR FALSE: A subinvestigator is an 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.

A subinvestigator is an 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).

TRUE OR FALSE: 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.

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.

Which of the following provides continuing reviews of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects?

Institutional Review Board (IRB)/Independent Ethics Committee (IEC)

sponsor

investigator

The IRB/IEC is also responsible for ensuring the protection of the rights, safety, and well-being of human subjects.

The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) provides continuing reviews of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Clinical Research

This chapter discusses the phases of clinical research conducted prior to marketing approval.

Chapter 3: Clinical Research

Clinical research is conducted to identify the clinical, pharmacological, and/or pharmacodynamics 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 determining its safety and/or efficacy. Before beginning a review of specific investigator responsibilities, a high-level review of the “phases” of clinical research provides a useful context describing the sequence in which clinical trials are conducted.

Phases

The clinical investigation of investigational products not previously approved for marketing is generally divided into three phases based on both the sequence and typical objectives. These phases involve evaluations of both safety and efficacy.

Phase 1 – Human pharmacology and pharmacodynamics
Phase 2 — Therapeutic exploratory
Phase 3/4 — Therapeutic confirmatory

Safety and Effectiveness

The information derived from clinical research, combined with information obtained in non-clinical investigations, will be used by regulatory agencies to evaluate the safety and effectiveness of an investigational product prior to approval.

Primary Objectives

ICH has classified clinical trials by their primary objectives which are human pharmacology, therapeutic exploratory, and therapeutic confirmatory. Although these terms are often seen as equivalent to Phase 1, 2, and 3, they are not synonymous. For example, Phase 2 or 3 trials may contain human pharmacology components.

Click on each button to learn more about each phase of clinical research.

Phase 1 — Human pharmacology and pharmacodynamics

Phase 1 trials are conducted to assess the tolerability and pharmacologic properties of a new product; they are often called human pharmacology studies. Beginning with a single dose in a small number of subjects, additional trials will be conducted if the compound is judged to be adequately safe. Phase 1 is normally completed in 6-12 months and typically involves less than 100 participants, normally healthy volunteers. As Phase 1 progresses, more individuals are included and doses are increased to define the maximum tolerated dose. Researchers must pay special attention to the pharmacokinetic properties of the compound (e.g., its absorption, distribution, metabolism, and excretion). Except when toxic compounds are being tested in patients with the indication under study (e.g., anti-cancer agents). Phase 1 trials do not attempt to assess the efficacy of the investigational product.

Phase 2 — Therapeutic exploratory

Phase 2 is conducted in patients with the condition being treated. It is used to assess the therapeutic benefit of the compound and to establish dose and trial design that will be used during Phase 3; it is often called the therapeutic exploratory phase. Generally, 100-200 participants will be included in multiple trials during a 1-2 year period. The number of participants studied during Phase 2 is not large enough to statistically verify the compound’s efficacy.

Phases 3 and 4 — Therapeutic confirmatory

Phases 3 and 4 are the longest phases to conduct. They are primarily interested in statistically confirming the efficacy of the treatment while continuing to assess its safety and tolerability. Phase 3 often compares current treatments to the new compound and is called the therapeutic confirmatory phase. Hundreds to thousands of subjects will be enrolled over a 2-3 year period. A marketing application is submitted at the end of Phase 3.

Phase IV clinical trials are conducted to identify and evaluate the long-term efficacy and safety of new drugs and treatments over a long period of time for a greater number of patients. Phase IV research takes place after regulatory agency approval of a drug or device.

Terms

You should be familiar with the terms used in clinical research. Click <a class="jobaid" data-forced="no" href="Assets/lang_1/jobaids/page_12_terms.pdf" target="_blank">here</a> to view a printable job aid of these terms and definitions.

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The purpose of a Phase 3 trial is to _____.

statistically confirm the safety and efficacy of the treatment

evaluate the maximum safe dose that is well-tolerated in healthy, normal subjects

begin assessing therapeutic benefit

establish the dose

The purpose of a Phase 3 trial is to confirm the safety and efficacy of the final dose to be prescribed to the target population.

One of the primary purposes of a Phase 2 trial is to _____.

establish the dose and trial design that will be used during Phase 3

define the maximum tolerated dose

compare current treatment to the new compound

The purpose of a Phase 2 trial is to balance the safety profile with the most effective dose in a target population. The results of this trial will determine the final dose to be tested in Phase 3 safety and efficacy trials.

The purpose of a Phase 2 trial is to balance the safety profile with the most effective dose in a target population.

TRUE OR FALSE: The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product.

The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product. The dose from this trial will give the basis for the dose range tested in Phase 2 trials.

The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product.

TRUE OR FALSE: Phase 1 trials do not attempt to assess the efficacy of the investigational product.

Phase 1 trials do not attempt to assess the efficacy of the investigational product except when toxic compounds are being tested in patients with the indication under study (e.g., anti-cancer agents).

Phase 1 trials do not attempt to assess the efficacy of the investigational product.

Informed Consent

This chapter discusses the obligations regarding informed consent of research subjects.

Chapter 4: Informed Consent

Written Informed Consent

IRB/IEC approval or favorable opinion is required for the written informed consent form and any other written material including advertisements, study brochures, and diaries provided to subjects.

The written informed consent form and any other written information to be provided to subjects should be revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised written informed consent form and other written information should receive IRB/IEC approval or favorable opinion prior to use.

New Information

When new information becomes available that may influence subjects’ willingness to continue participation in the trial, it must be expeditiously communicated to subjects or their legally acceptable representative (LAR) and documented in writing as part of the trial records. An IRB/IEC must approve or provide a favorable opinion of any revised informed consent forms and other written information prior to use.

The investigator and trial staff should not coerce or unduly influence a subject to participate or to continue to participate in a trial.

Consent Discussion

The consent discussion may be conducted by the investigator or a person designated by the investigator.

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Criteria

The consenting process must meet the following criteria:

<ul> <li>It must not cause any actual or apparent waiver of legal rights.</li> <li>It must not release or appear to release the investigator, institution, sponsor, or their agents from liability for negligence.</li> <li>The language used in the written information should be understandable to the subject or LAR and, when required, an impartial witness. It is recommended that consent documents be written in lay language and be as non-technical as practical.</li> <li>The subject (or LAR) should have adequate time and opportunity to have all questions answered to their satisfaction before deciding whether or not to participate in the trial. All questions about the trial should be answered to the satisfaction of the subject/subject’s LAR.</li> </ul>

Signature

Prior to a subject’s participation in the trial, the written informed consent form must be signed and personally dated by the subject or subject’s legally accepted representative (LAR), and by the person conducting the informed consent discussion. In instances where the subject or subject’s LAR are unable to read the form, an impartial witness must be present during the entire consent discussion. After the written informed consent and any other written information has been read and explained to the subject or subject’s LAR, and after the subject or subjects’ LAR has orally consented to the subject’s participation in the trial (and, if capable to do so, has signed and personally dated the informed consent form, their oral consent, and, when possible, signatures as explained above are obtained), the witness should sign and personally date the consent form.

This signature serves as an attestation by the witness that the information was accurately explained to and apparently understood by the subject/LAR, and that the informed consent was freely given by the subject or the subject’s LAR.

<ul> <li>A copy of the signed and dated consent form, and any other written information, including revisions, should be provided to the subject or subject’s LAR.</li> <li>In some instances, the IRB/IEC many require additional signatures and/or consent procedures.</li> </ul>

Special circumstances

In instances where subjects can only be enrolled with consent provided by an LAR (e.g., children, mental incapacity), the subjects should be informed about the trial to the greatest extent compatible with their capacity for understanding. In such circumstances, if capable, the subject should indicate their assent by signing and personally dating the informed consent form.

Nontherapeutic trials

Nontherapeutic trials (those with no anticipated direct benefit to the subject) should normally be conducted in subjects who are capable of personal consent. However, these trials may be conducted with the consent of an LAR if:

<ul> <li>the objectives of the trial cannot be met by means of a trial in subjects who can give informed consent personally.</li> <li>the foreseeable risks to the subjects are low.</li> <li>the negative impact on the subject’s well-being is minimized and low.</li> <li>the trial is not prohibited by law.</li> <li>the approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/favorable opinion covers this aspect. </li> </ul>

Such trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

Emergency situations

In emergency situations, when prior consent by the subject is not possible, it should be sought from the subject’s LAR. However, enrollment in situations when subject consent is not possible and the subject’s LAR is unavailable, enrollment should require measures as described in the protocol (or other documentation) that has received approval/favorable opinion of the IRB/IEC.

Other specific regulatory requirements may exist and must be complied with. Following such an enrollment, the subject or subject’s LAR should be informed as soon as possible and consented to continue in the clinical trial as appropriate (section 4.8.10).

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Informed consent Click <a class="jobaid" data-forced="no" href="Assets/lang_1/jobaids/page_17_jobaid.pdf" target="_blank" data-forced="no">here</a> to view a printable checklist of information to be included in the informed consent.

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TRUE OR FALSE: The consenting process includes a release for the investigator, institution, sponsor, or their agents from liability for negligence.

The consenting process must not release or appear to release the investigator, institution, sponsor, or their agents from liability for negligence.

TRUE OR FALSE: When new information becomes available that may influence subjects’ willingness to continue participation in the trial, it must be expeditiously communicated to subjects or their legally acceptable representative (LAR).

In instances where the subject or subject’s LAR are unable to read, _____ must be present during the entire consent discussion.

an impartial witness

an attorney

a doctor

a nurse

In instances where the subject or subject’s LAR are unable to read, an impartial witness must be present during the entire consent discussion.

TRUE OR FALSE: Nontherapeutic trials should be conducted in patients having a disease or condition for which the investigational product is intended, unless an exception is justified.

Nontherapeutic trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended. Subjects in these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly distressed.

Nontherapeutic trials, unless an exception is justified, should be conducted in patients having a disease or condition for which the investigational product is intended.

IRB/IEC approval or favorable opinion is _____ for the written informed consent form and any other written material provided to subjects.

required

recommended

This includes advertisements, when used.

IRB/IEC approval or favorable opinion is required for the written informed consent form and any other written material provided to subjects.

Protocol Compliance

This chapter discusses obligations regarding protocol compliance.

Chapter 5: Protocol Compliance

Investigators must conduct the trial in strict compliance with the approved protocol agreed to by the sponsor, IRB/IEC, and if required, by the applicable regulatory authorities. Prior to enrolling the first subject, agreement with the sponsor and in some instances with regulatory authorities is required. Approval by or favorable opinion from a properly constituted IRB/IEC is also required.

Agreements, made by the sponsor with the investigator/institution and/or with any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate contract.

IRB/IEC Approval/Favorable Opinion

The investigator must have written and dated approval/favorable opinion from the IRB/IEC for the following before beginning the trial or initiating changes to the protocol or consent documents:

protocol.
informed consent form, including updates.
any other written information provided to subjects.
recruitment procedures, including advertisements, if any.

A copy of this documentation is routinely requested by and provided to the sponsor. Although the complete list of documents that must be submitted to the IRB/IEC as part of an initial or ongoing application may vary, it includes those items listed above, a copy of the current Investigator’s Brochure (IB), and any other requested or required documents. Copies of revised/updated documents should also be provided to the IRB/IEC.

Protocol Adherence

The investigator should not implement any exception to, or changes to, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC. The only exception is where the change is purely administrative or logistical (e.g., changes in names or telephone numbers) or in instances where such a change is needed to eliminate an immediate risk to subjects.

This latter type of deviation may be undertaken without prior agreement, but the sponsor, IRB/IEC, and (where required) the regulatory authorities must be notified as soon as possible. All protocol deviations must be documented and explained by the investigator or a designee.

Medical Care of Trial Subjects

Medical oversight, including provision of adequate medical care for adverse events arising during and following the trial, is also required. Ensuring such care, including referral to other healthcare providers when appropriate, and all trial-related medical or dental decisions, is the responsibility of the investigator or a subinvestigator. Documentation of appropriate licensure is typically required, and in many cases, a copy of the individual’s medical/dental licensure will be requested by the sponsor. Individual sponsors may require additional licensure or certification (e.g., certification by a professional association).

A qualified physician (or dentist, when appropriate), who is an investigator or a subinvestigator for the trial, should be responsible for all trial-related medical (or dental) decisions. During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory values, related to the trial. The investigator/institution should inform a subject when medical care is needed for illness(es) of which the investigator becomes aware.

Withdrawal Reasons

Although there is no obligation on the part of a subject who chooses to withdraw before the end of the trial to provide justification, the investigator should, while respecting the subject’s rights, attempt to determine the reason for the premature withdrawal.

Risk

Failure to strictly adhere to the protocol creates many problems. Foremost among these is the potential to place research subjects at risk. Additionally, the methods by which the data will be analyzed are determined prior to enrolling subjects. Deviations from the protocol increase variability and can invalidate the statistical inferences drawn.

For example, if a safety parameter based on the known pharmacokinetic profile of a compound is scheduled for assessment 24 hours after the initial dose, but is collected at another time, the true impact of the compound may not be known.

Resources

Adequate resources (e.g., time, qualified staff, facilities, and access to suitable subjects) are expected and will be assessed by the sponsor both before and during the trial. As part of this obligation, the investigator must ensure that anyone assisting with the trial is, like the investigator, adequately qualified by training, education, and experience to carry out their assigned duties. Specific information/training in the protocol, including the investigational product, should be provided and documented.

Delegated Tasks

The investigator may delegate study tasks conducted at the trial site, however, the investigator is responsible for supervising any individual or party to whom study tasks were delegated. If the investigator/institution retains the services of any party to perform study tasks they should ensure this party is qualified to perform those study tasks and should implement procedures to ensure the integrity of the study tasks performed and any data generated.

A list of individuals to whom the investigator has delegated duties is maintained as part of the trial’s permanent documentation. This list is often combined with a log recording individual signatures and initials.

Questions or Comments

Investigators and their staff should direct questions or comments about the protocol or any aspect of the clinical investigation to the sponsor’s designated personnel, including the medical lead or medical monitor at any time, but should not expect them to authorize exceptions (i.e., allow deviations) from the protocol. Failure to follow the protocol is one of the most frequent findings by both auditors and regulatory inspectors.

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TRUE OR FALSE: Investigators must conduct the trial in strict compliance with the approved protocol agreed to by the sponsor, IRB/IEC, and if required, by the applicable regulatory authorities.

Prior to enrolling the first subject, agreement with the sponsor and in some instances with regulatory authorities is required.

Investigators must conduct the trial in strict compliance with the approved protocol agreed to by the sponsor, IRB/IEC, and if required, by the applicable regulatory authority(ies).

The investigator _____ implement any deviations/exceptions from, or changes to, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment unless there are instances where such a change is needed to eliminate an immediate risk to a subject.

should not

should

Protocol deviations/exceptions can only be implemented with prior review and documented agreement from the sponsor and IRB/IEC except where the change is purely administrative or logistical (i.e., changes in names or telephone numbers) or in instances where such a change is needed to eliminate an immediate risk to a subject.

The investigator should not implement any deviation/exception from, or changes of, the protocol without agreement by the sponsor and prior review and documented approval/favorable opinion from the IRB/IEC of an amendment unless there are instances where such a change is needed to eliminate an immediate risk to a subject.

The methods by which the data will be analyzed during a trial are determined _____ to enrolling subjects.

prior

after

during

Deviations from the protocol increase the trial’s variability and can invalidate the statistical inferences drawn.

The methods by which the data will be analyzed during a trial are determined prior to enrolling subjects.

TRUE OR FALSE: Failure to follow the protocol is one of the most frequent findings by both auditors and regulatory inspectors.

Failure to follow the protocol is one of the most frequent findings by both auditors and regulatory inspectors.

TRUE OR FALSE: A list of individuals to whom the investigator has delegated duties is maintained for 90 days after the trial is finished.

A list of individuals to whom the investigator has delegated duties is maintained as part of the trial’s essential documents, which are retained for at least two years.

Ensuring medical care of trial subjects, including referral to other health care providers and all trial-related medical or dental decisions, is the responsibility of _____.

either a qualified physician (or dentist, when appropriate), who is an investigator or a subinvestigator

the investigator

the subinvestigator

neither the investigator or a subinvestigator

Ensuring medical care of trial subjects, including referral to other health care providers and all trial-related medical or dental decisions, is the responsibility of either a qualified physician (or dentist, when appropriate), who is an investigator or a subinvestigator.

TRUE OR FALSE: Although protocol and consent forms require IRB/IEC approval, recruitment procedures, including advertisements, do not.

The investigator must have written and dated approval/favorable opinion from the IRB/IEC for protocol, informed consent, and recruitment procedures.

The investigator must have written and dated approval/favorable opinion from the IRB/IEC for recruitment procedures.

Investigational Product

This chapter discusses the investigator’s obligations related to the investigational product.

Chapter 6: Investigational Product

Control of investigational product (i.e., receipt, storage, dispensing, and accountability) at the trial site is the responsibility of the investigator/institution. Depending on local and institutional policies, the investigator may delegate some or all of these responsibilities to an appropriately qualified individual (e.g., pharmacist) who is under the supervision of the investigator/institution.

Investigational Product Records

Regardless of the individual who performs these tasks, the investigator must maintain records (i.e., an ongoing accountability) showing the following:

delivery and receipt by the site.
inventory at the site.
amount currently available.
used by individual subjects, including amounts and date of dispensation to and return by subjects.
final disposition (i.e., a detailed inventory of the amounts returned to the sponsor or destroyed). Destruction of investigational product by the site normally requires written authorization by the sponsor.

Record Contents

Records regarding investigational product should include:

dates.
quantities.
batch/serial numbers.
expiration dates, if applicable.
unique code numbers assigned to the product and individual subjects.

Storage and Use

Investigational product must be stored and used as required by the protocol and any regulatory requirements. The protocol or other documentation will contain instructions regarding storage requirements. Additionally, investigators, or someone designated by the investigator or institution, should explain the use of the investigational product to each subject and periodically check that each subject is following these instructions.

Appropriate Doses and Inventory

Investigators should maintain records that document adequately that the subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor. Investigational products may never be used by individuals who are not enrolled in the specific clinical trial for which they are supplied.

Procedures

The investigator should always be able to verify that the product was dispensed and used as required by the approved protocol and be able to account for all product received.

Randomization procedures must be followed precisely, and treatment codes only broken as described in the protocol. All unblinding by the investigational site must be documented, explained, and promptly reported to the sponsor.

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TRUE OR FALSE: Control of investigational product (i.e., receipt, storage, dispensing, and accountability) at the trial site is the responsibility of the IRB.

Control of investigational product (i.e., receipt, storage, dispensing, and accountability) at the trial site is the responsibility of the investigator/institution.

TRUE OR FALSE: Destruction of an investigational product by the site normally requires written authorization by the sponsor.

Destruction of an investigational product by the site normally requires written authorization by the sponsor.

TRUE OR FALSE: Investigators, or someone designated by the investigator or institution, should explain the use of the investigational product to each subject and periodically check that each subject is following dosing instructions and frequency of intake.

The protocol or other documentation will contain instructions regarding environmental conditions (e.g., temperature) and other dosing instructions and frequency of intake.

Investigators, or someone designated by the investigator or institution, should explain the use of the investigational product to each subject and periodically check that each subject is following instructions.

Who should maintain records that document adequately that subjects were provided the doses specified by the protocol and reconcile all investigational product(s) received from the sponsor?

Investigators

Records and Reports

This chapter discusses the investigator’s reporting and documentation requirements.

Chapter 7: Records and Reports

The investigator must maintain adequate and accurate source documents and trial records that include all pertinent observations on each subject. This is based on the ALCOA-C principles, which indicate that “source data should be attributable, legible, contemporaneous, original, accurate, and complete (ALCOA-C).” Changes to source data should be traceable, should not obscure the original entry, and should be explainable if necessary (e.g., via an audit trail). In addition, the investigator should ensure the accuracy, completeness, legibility, and timelines of the data reported in the CRF and all required reports.

Data reported on the CRF, derived from source documents, should be consistent with the source documents or the discrepancies should be explained. Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic changes or corrections. Sponsors should provide guidance to investigators (and/or the investigators' designated representatives) on making these corrections. Sponsors should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated representatives are documented, necessary, and are endorsed by the investigator.

Maintenance of Documents

The investigator/institution should prevent accidental or premature destruction of these documents. The financial aspects of the trial should be documented in an agreement between the sponsor and the investigator/institution. Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should make available for direct access all requested trial-related records.

Trial Documentation

The investigator institution must maintain detailed trial documentation as specified in Section 8 of ICH GCP and as required by the applicable institutional, sponsor, and regulatory requirements. Many institutions and sponsors require additional items. These records, referred to as essential documents, “… are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.”

Essential documents facilitate management of the trial by the investigator, sponsor, and monitors, and provide a record for audits and/or inspections.

Section 8

Section 8 of ICH GCP provides three tables detailing the documentation that should be present in the trial master file for each clinical trial. It identifies the location of the files (e.g., sponsor, investigator, or both), and provides a brief description of the purpose each document serves. Click <a class="jobaid" data-forced="no" href="http://ichgcp.net/8-essential-documents-for-the-conduct-of-a-clinical-trial" target="_blank" data-forced="no">here</a> to review the list of essential documents that should be generated and kept on file for the following stages:

Before the Clinical Phase of the Trial Commences
During the Clinical Conduct of the Trial
After Completion or Termination of the Trial

Subject Records

Each subject’s progress throughout a clinical trial is recorded in source documents and subsequently transcribed to Case Report Forms (CRFs)/eCRFs. Any inconsistencies between CRF/eCRF data and data found in the source documents must be explained. Regardless of whether documents, including CRFs, are electronic or paper, any changes must be accompanied by information on who made the change and when it was made. When paper documents are used, changes or corrections should be initialed, dated, and explained (if necessary) by the person making the change.

Audit Trail

In order to maintain an “audit trail” the original data should not be obscured. In a paper copy, corrections are accomplished by drawing a single line through the original entry and entering the new data nearby. Erasures, use of “white out,” or other permanent changes that hide or eliminate the original entry are not allowed. Electronic CRFs have automated methods for recording the time and date of data entry while maintaining the original entry and the identity of the person entering the change.

Electronic Medical Records (EMR)/Electronic Health Records (HER) systems are designed to store data accurately and to capture the state of a patient across time. It eliminates the need to track down a patient's previous paper medical records and assists in ensuring data is accurate and legible. It can reduce risk of data replication as there is only one modifiable file, which means the file is more likely up to date, and decreases risk of lost paperwork. Due to the digital information being searchable and in a single file, EMRs are more effective when extracting medical data for the examination of possible trends and long-term changes in a patient.

Record Retention and Access

Essential documents need to “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.”

Investigators must, however, also be aware that agreements with the sponsor and/or regulatory requirements may require longer retention periods. In practice, records should not be disposed of without permission of the sponsor who also has an obligation to inform the investigator when records are no longer needed.

Direct access to trial documents should be made available to authorized sponsor representatives (e.g., monitors, auditors), IRB/IEC personnel, and/or inspectors from regulatory authorities, when requested.

Reporting Requirements

Click on each button to learn about the investigator’s additional reporting requirements.

Safety reports

Prompt and accurate safety reports are essential in fulfilling the fundamental GCP obligation of protecting the research subject. The protocol will identify the procedures and time requirements for reporting of adverse events, laboratory abnormalities, and other critical safety evaluations.

Several definitions are important to the understanding of safety reporting requirements.

<ul> <li>Adverse Event (AE)</li> <li>Adverse Drug Reaction (ADR)</li> <li>Serious Adverse Event (SAE)</li> <li>Unexpected ADR</li> </ul>

Procedures

Unless specifically identified in the protocol or other trial documentation (e.g., Investigator Brochure), all SAEs must be immediately reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. These reports should be followed by detailed, written reports. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the IRB/IEC. Follow-up reports may be necessary as new information becomes available (e.g., pathology reports, final medical reports, autopsy reports). Additionally, the investigator should comply with all requirements for the reporting of these events to the IRB/IEC and regulatory authorities.

Subject-related reports should identify subjects with a unique code number and not by name, personal identification number, and/or address. It is important that investigators and their staffs are familiar with applicable confidentiality-related regulatory requirements.

A detailed discussion of safety reporting may be found in the ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.

Progress reports

Investigators are responsible for submitting progress reports to their IRB/IEC and to the sponsor. Although more frequent reports may be requested, these reports are typically submitted annually. When required by local regulation, investigators are also responsible for providing progress reports to their institution. Written reports should be provided to the sponsor and IRB/IEC on any changes significantly affecting the conduct of the trial and/or increasing the risk to the trial subjects.

Final report

Upon completion of the clinical trial, investigators should inform the institution and the IRB/IEC, and provide the sponsor all required reports. They should provide the IRB/IEC with a summary of the trial’s outcome. Where required, requests by the regulatory authorities for reports must be fulfilled. Final reports are usually submitted after the statistical analysis of safety and efficacy has been completed.

Premature termination or suspension of a trial

If a trial is terminated prematurely or suspended for any reason, investigators should promptly inform trial subjects and should ensure and arrange for appropriate therapy and follow-up.

In each of the following instances, the investigator should provide the appropriate entities (e.g., institution, IRB/IEC, sponsor and/or regulatory authorities) with a detailed, written explanation of the termination or suspension.

Case 1: Investigator terminates or suspends trial without prior agreement of the sponsor

The investigator should inform the institution, sponsor, and the IRB/IEC.

Case 2: Sponsor terminates or suspends trial

The investigator should inform the institution and IRB/IEC and provide the IRB/IEC with a detailed written explanation. (Also see section 5.2.1) The sponsor should notify regulatory authorities.

Case 3: IRB/IEC terminates or suspends the trial

The investigator should inform the institution and the sponsor. (Also see sections 3.1.2 and 3.3.9)

How much have you learned?

Practice your knowledge by completing the learning activity.

TRUE OR FALSE: Essential documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.

The investigator institution must maintain detailed trial documentation as specified in section 8 and as required by the applicable institutional, sponsor, and regulatory requirements. A minimum list is found in Section 8 of ICH GCP. These records are referred to as essential documents, which individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced.

Essential documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical Practice and with all applicable regulatory requirements.

Which of the following correctly demonstrates how a date should be modified on a paper Case Report Form (CRF)?

incorrect date has a single line through it, new date entered, and initials of the person making the change are adjacent

incorrect date is deleted, new date entered, and initials of the person making the change are adjacent

When making changes, a single line should be drawn through the original data and the new data entered near it. Original data must not be obscured. Revisions should be initialed and dated by the person making the change.

Original data must not be obscured. Revisions should be initialed and dated by the person making the change.

TRUE OR FALSE: Data missing from Case Report Forms (CRFs) and other documentation can invalidate evaluations and jeopardize subject safety.

Investigators must ensure the accuracy, completeness, legibility, and timelines of the data reported.

Missing data can invalidate product evaluations and jeopardize subject safety.

Subjects should be identified with a _____.

unique code number

name

personal identification number

address

As in all subject-related reports, subjects should be identified with a unique code number and not by name, personal identification number, and/or addresses. It is important that investigators and their staffs are familiar with applicable confidentiality-related regulatory requirements.

Subjects should be identified with a unique code number and not by name, personal identification number, and/or addresses.

TRUE OR FALSE: Final reports are usually submitted before the statistical analysis of safety and efficacy has been completed.

Final reports are usually submitted after the statistical analysis of safety and efficacy has been completed.

Oversight

This chapter discusses the type of visits an investigator should prepare for.

Chapter 8: Oversight

The purpose of monitoring visits is to oversee the progress of a trial, and ensuring that the trial is conducted, recorded and reported in accordance with the protocol, standard operating procedures (SOPs), GCP, and applicable regulatory requirements. Investigators must allow a qualified representative from the sponsor to examine and review CRFs at agreed upon times. During these visits, authorized sponsor personnel must be afforded access to source documents. Time will be required during these monitoring visits to explain deviations from the protocol and to make corrections to entries on CRFs.

Investigators must also allow sponsor representatives to review investigational product storage and inventory. Sponsor representatives must also be allowed to communicate with staff members involved in the clinical research program.

How much have you learned?

Practice your knowledge by completing the learning activity.

TRUE OR FALSE: Investigators must allow qualified representatives from the sponsor and regulatory authorities to examine records.

Investigators must allow sponsor audits and regulatory authority inspections.

Investigators must allow the inspection of records.

TRUE OR FALSE: The purpose of monitoring visits is for the monitor to communicate only with the investigator.

TRUE OR FALSE: Regulatory authority representatives may inspect all records pertaining to an inspection, but may not copy them without the written authorization of the sponsor.

Regulatory authority representatives may have access to, inspect, and copy any de-identified documents relating to the clinical trial.

Regulatory authority representatives are permitted to copy records.

Who must permit regulatory authorities to inspect documents related to the clinical trial?

Investigator

Independent Ethics Committee (IEC)

Institutional Review Board (IRB)

Subinvestigator

The investigator should notify the sponsor of the inspections by regulatory authorities as soon a possible. Sponsors may help organize the trial records in order to expedite the inspection.

Investigators must permit regulatory authorities to inspect documents related to the clinical trial.

Conclusion

We’ll consider some final thoughts on ICH GCP obligations of investigators conducting clinical trials.

Chapter 9: Conclusion

This course introduced the obligations of investigators as described by the ICH. You were presented with phases and procedures used protect the rights and welfare of human subjects and data integrity.

You should now have a better understanding of how to plan, conduct, record, and report clinical trials. Your role as a clinical investigator in the conduct of clinical trials is critical to ensuring patient safety and the quality and integrity of the data as well as supporting the advancement of clinical research.

Challenge

Complete the following activity to receive credit for this course.

How much have you learned?

Complete the following activity to receive credit for this course.

The purpose of a Phase 3 trial is to _____.

statistically confirm the safety and efficacy of the treatment

evaluate the maximum safe dose that is well-tolerated in healthy, normal subjects

begin assessing therapeutic benefit

establish the dose

The purpose of a Phase 3 trial is to confirm the safety and efficacy of the final dose to be prescribed to the target population.

One of the primary purposes of a Phase 2 trial is to _____.

establish the dose and trial design that will be used during Phase 3

define the maximum tolerated dose

compare current treatment to the new compound

The purpose of a Phase 2 trial is to balance the safety profile with the most effective dose in a target population.

TRUE OR FALSE: The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product.

The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product. The dose from this trial will give the basis for the dose range tested in Phase 2 trials.

The purpose of a Phase 1 trial is to assess the tolerability and pharmacologic properties of a new product.

TRUE OR FALSE: The consenting process includes a release for the investigator, institution, sponsor, or their agents from liability for negligence.

The consenting process must not release or appear to release the investigator, institution, sponsor, or their agents from liability for negligence.

In instances where the subject or subject’s LAR is unable to read, a _____ must be present during the entire consent discussion.

an impartial witness

an attorney

a doctor

a nurse

In instances where the subject or subject’s LAR is unable to read, an impartial witness must be present during the entire consent discussion.