Contents

Part 1: Introduction
Part 2: Contents of the Research Protocol (ICH E3 GCP 6)
Part 3: What is a Protocol Amendment?
Part 4: What is a Protocol Violation?
Part 5: Summary of Key Points

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Part 1: Introduction

Documents to Ensure Standardization

Standardization — everyone doing the same things in the same way — is critical in a clinical research study
and particularly critical for multisite trials. Research that is not conducted in a standardized manner is
unethical because it may put research participants at risk while yielding invalid data. (Protection of the
safety, rights, and well-being of research participants is discussed in the Introduction, Institutional Review
Boards, and Informed Consent module.)

Several documents are key to ensuring that a research study is conducted in a standardized manner (see the
module on Documentation & Record-Keeping for a full list of essential study documents). All research staff
that participates in a clinical study must be familiar with, and must strictly adhere to, the procedures
described in these documents.

Investigator's Brochure
The Investigator's Brochure is a document containing nonclinical and clinical data to describe previous
experience with the experimental intervention, often a medication.

Operations Manual
The operations manual “operationalizes” the protocol, providing more detail on the actual procedures
needed to perform the research.

For example, the protocol might specify that a urine sample is to be collected at each study visit, whereas
the operations manual would describe details of the collection, labeling, storage, and shipping of the
samples. For another example, the operations manual might state that each study site is to maintain a site
contact log containing the names, addresses, and phone numbers of all individuals involved in the study at
that site. Additionally, even more detailed information, such as a list of staff responsible for maintaining the
contact log and the detailed procedures involved, would be appropriate for an Operations Manual; however,
such detail would be inappropriate in the research protocol.

Standard Operating Procedures

Standard operating procedures (SOPs) describe in detail how specific procedures (e.g., taking vital signs,
performing urine tests, and assessing adverse events) are to be carried out in the research study. Most SOPs
will be identical for all study sites. However, in some cases site-specific variations are needed. For example,
if procedures for handling a medical emergency vary slightly from one research site to another, the SOP for
these procedures at a specific site will reflect those variations. Additionally, site staff will need to be trained
appropriately for the site-specific procedures.

Other Study Documents

This module focuses on the research protocol. Some information may be provided in other documents that
accompany the protocol, such as the Investigator's Brochure. Additional site-specific information that may
change during the trial (such as the names and addresses of research sites and the sponsor's medical expert
information) may be provided in a separate document, such as the operations manual. This is acceptable as

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long as the protocol contains language that refers to the operations manual for this information.

Research Protocol
The research protocol provides a plan for the essential aspects of the proposed research. (See summarized
research protocol contents.) It must be approved by the designated Institutional Review Board (IRB) before
the research can begin. Any changes to the protocol must also be approved by the IRB.

Why is the research protocol so important?

The research protocol is one of the main documents that must be approved by the designated Institutional
Review Board before any research study can begin.

The Good Clinical Practice (GCP) guidelines of the International Council for Harmonization require a research
protocol for any study that involves human participants. In addition, Title 21 Part 312 of the Code of Federal
Regulations (21 CFR 312) describes both a research protocol and protocol amendments for studies
conducted under an Investigational New Drug application.

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Part 2: Contents of the Research Protocol (ICH E3 GCP 6)

The research protocol must clearly and succinctly describe the following aspects of the research study:

Why the study is being done.

What will be done in the study.
Where the study will be done (for multi-site trials, site-specific information may be incorporated into
local protocol versions).
Who is involved in the research study.
When study interventions will take place.

The protocol should contain enough information to provide a clear and complete, but not overly detailed,
description of the study. Further details should appear, as discussed earlier, in other documents such as the
operations manual, standard operating procedures, quality assurance plan, training plan, and data
management plan.

To ensure that research protocols include the appropriate sections and content, a sponsor may develop a
standardized template for investigators to use for each type of study. For example, a research network has
developed such templates to assist investigators in preparing research protocol documents for network
specific trials. For NIH-funded studies under an Investigational New Drug (IND), there is a protocol template
available at the following NIH website.

The protocol generally covers the following topics (see ICH GCP E6 6).

General Information

Protocol title, identifying number, version number, and date.

Name and address of the sponsor and monitor (if other than the sponsor).
Name and title of the person authorized to sign the protocol and the protocol amendments for the
sponsor.
Names and titles of the investigators responsible for conducting the study, and the address and
telephone number of the trial sites.
Name, title, address, and telephone number of the sponsor’s medical expert.
Name, title, address, and telephone number of the qualified physician who is responsible for all study–
related medical decisions.
Names and addresses of all institutions involved in the study (including clinical laboratories and other
medical or technical departments).
Addresses and telephone numbers of all clinical laboratories and/or institutions involved in the trial.

Background Information

A description of the issue the study is addressing as well as its public health significance.
Findings from clinical or nonclinical studies that may be significant to the proposed study.
Summary of the known potential risks and benefits to human participants.
A statement that the trial will be conducted in compliance with the protocol, GCP, and the applicable
regulatory requirement(s).
Description of the study population.
References to relevant literature and data (this will often be compiled in a separate section in the
protocol).
If the study involves the use of an investigational product or therapy:
Name and description of the investigational product or therapy.
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 Description of and justification for the route of administration, dosage, dosage regimen, and
treatment period(s).

Study Objectives and Purposes

A detailed description of the major (primary) and minor (secondary and exploratory) objectives and the
purpose of the trial.

Study Design

The scientific integrity of the study and the credibility of the data obtained from the study largely depend on
the study design. This section of the protocol should describe:

Primary and secondary endpoints to be measured and how they will be measured.
Study type (e.g., double-blind), with a schematic diagram of the study design, procedures, and stages.
Measures that will be taken to avoid or minimize bias (e.g. randomization, blinding).
Dosage and dosage regimen, dosage form, packaging, and labeling of investigational products.
Expected duration of participant participation, sequence and duration of all study periods, including
follow–up.
"Stopping rules" or "discontinuation criteria" for individual participants, parts of the study, and the
entire study.
Accountability procedures for the investigational product, including the placebo and comparator.
Maintenance of study treatment randomization codes and procedures for breaking codes.
Identification of any data to be recorded directly on the CRFs and considered to be source data.

Selection and Withdrawal of Participants

Criteria for inclusion and exclusion of participants.

Procedures for withdrawal of participants (participant or investigator-initiated):
When and how to withdraw participants from the study/investigational product treatment.
Type and timing of data to be collected for participants who withdraw from the study.
Whether and how participants are to be replaced.
Follow–up for participants withdrawn from trial treatment.

Treatment of Participants

Pharmacological treatment:
Names of all products to be administered.
Doses.
Dosing schedules.
Method(s) of administration (i.e., oral, intramuscular).
Other medications or treatments permitted (including rescue medication) and not permitted before
and/or during the study.
Other interventions (i.e., chiropractic, physical therapy, social therapy, behavioral therapy, counseling):
Name of intervention (i.e., Motivational Interviewing, Cognitive Behavioral Therapy).
Frequency of sessions.
Duration of each session.
Method of each intervention (i.e. individual, group).
Treatment adherence.
All interventions:
Period(s) of intervention, including follow–up periods for participants in each group.
Procedures for monitoring participant compliance.
Identification of who will administer an intervention.

Assessment of Efficacy

This section describes the methods that will be used to determine the success of the treatment, including:

Criteria for determining the treatment’s effectiveness.

Methods and timing for assessing, recording, and analyzing the effectiveness criteria.

Assessment of Safety

This section describes how the study will be monitored and how adverse events will be dealt with. (See
Participant Safety and Adverse Events module.)

Specification of safety criteria.

Methods and timing for assessing, recording, and analyzing the safety criteria.
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 Procedures for obtaining reports of adverse events and illnesses experienced by participants during the
study period and for recording and reporting these events, including expedited reporting procedures.
Type and duration of follow–up of participants who experience adverse events.

Statistics

This section describes the strategy for analyzing the data collected during the study, including:

Statistical methods to be employed, including the timing of any planned interim analyses.
Total number of participants to be enrolled. (In multi–center studies, the minimum and maximum
number of participants to be enrolled at each study site should be specified.)
Reason for the choice of sample size, including reflections on (or calculations of) the power of the study
and clinical justification.
Level of significance to be used.
Criteria for termination of the study.
Procedure for accounting for missing, unused, and false data.
Procedures for reporting deviations from the statistical plan (any deviations from the statistical plan
should be described and justified in the protocol and/or in the final report, as appropriate).
Selection of participants to be included in analyses (e.g. all randomized participants, all dosed or treated
participants, all eligible participants, all evaluable participants, per a stated definition of “evaluable”).

Direct Access to Source Data or Documents

The sponsor should ensure that the protocol or other written agreement specifies that study investigators or
institutions will permit study–related monitoring, audits, IRB review, and regulatory inspections by providing
direct access to source data or documents.

Quality Control and Quality Assurance

A detailed quality assurance plan describing the set standards and controls that are in place to confirm that
the execution of each step follows the agreed–upon plan is usually submitted as a separate document. The
protocol should, however, provide a general description of the quality assurance methods. (See Quality
Assurance module.)

Ethics

This section should describe ethical considerations relating to the study and measures taken to protect
human participants and maintain confidentiality of study data. (See Informed Consent, Institutional Review
Boards, and Confidentiality modules.)

Data Management

A detailed data management plan describing the way study data will be gathered, documented, submitted,
verified, and archived is usually submitted as a separate document. The protocol should, however, provide a
general description of the data management activities associated with the protocol.

The data management plan describes the procedures that will ensure data integrity throughout the study
and at all study sites, including:

A description of the data system design and development.

Data collection methods and activities.
Methods of data entry and editing.
Procedures for data monitoring (including query resolution), reporting, and transfer.
Data recipients and procedures for data dissemination.

Financing and Insurance

This section describes how the study will be financed and insured. In some research networks, these issues
are addressed in a separate agreement and need not be included in the protocol.

Publication Policy

This section describes the policies and procedures relating to publication of findings from the study. In some
research networks, policies and guidelines are established for researchers for the publications planning
process. For example, it is a common requirement for the publication on primary outcome data to precede
other publications on the study findings. Researchers should be familiar with and adhere to institutional and
sponsor policies and requirements for publications.

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In accordance with the Food and Drug Administration Amendments Act (42 CFR Part 11), trial results will also
be published on a public website, [Link]. This website will not identify participants, but will provide
a resource for clinical trial participants, and those seeking clinical trial involvement, to inform themselves.

Supplements

This section supplies any additional information that may be required, depending on the nature of the
research. For example, the informed consent template, the therapy manual, a patient information handbook,
etc., may be included as attachments.

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Part 2: What is a protocol violation?

Interactive: Developing the Research Protocol

Users are instructed as follows:

Of the 10 items listed below, which sections are relevant to the development of the research protocol
document for a trial investigating the effectiveness of motivational counselling sessions in reducing Body
Mass Index (BMI) in individuals with a BMI of 30 or more? After choosing your response, consider the
feedback.

SECTION: Assessment of Efficacy

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Assessment of Safety

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Background

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Drug Accountability

Feedback: Is this section necessary for this research protocol: Yes or No? Investigational product (drug or
device) is not used in this study. Therefore, Investigational Product and Drug Accountability sections should
not be included in the research protocol document. The correct response is No.

SECTION: Investigational Product and Dosage

Feedback: Is this section necessary for this research protocol: Yes or No? Investigational product (drug or
device) is not used in this study. Therefore, Investigational Product and Dosage and Drug Accountability
sections should not be included in the research protocol document. The correct response is No.

SECTION: Quality Assurance and Monitoring

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Statistical Analysis

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Study Intervention

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Study Objectives and Design

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Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

SECTION: Study Population and Eligibility Criteria

Feedback: Is this section necessary for this research protocol: Yes or No? The correct response is Yes.

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Part 3: What is a protocol amendment?

A protocol amendment is a written description of a change to some aspect(s) of the study as described in the
research protocol.

Protocol amendments must be submitted in writing to the designated Institutional Review Board (IRB) and
must be approved by the IRB before they can be implemented, except when necessary to eliminate
immediate hazards to the participants or when the change(s) involves only logistical or administrative
aspects of the trial (e.g., change of monitor(s), telephone number(s)). If the study involves a product that is
regulated by the U.S. Food and Drug Administration (FDA), the amendment must be submitted to FDA as well
as to the IRB, prior to enacting the amendment (21 CFR 312.30).

Protocol Amendments and Informed Consent

Study participants must be informed of protocol amendments. Depending on the nature and extent of the
amendment, the Informed Consent Form may be revised, and participants will need to complete and sign a
new Informed Consent Form.

A protocol amendment is not to be confused with a “protocol clarification.” A protocol clarification aids in the
implementation or conduct of the study and provides internal guidance. It does not change the protocol or
alter the risk-benefit ratio of the study. A protocol clarification generally does not need to be submitted to the
IRB. A clarification should be provided in writing to all investigators.

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Part 4: What is a protocol violation?

A protocol violation occurs whenever a study staff person performs any action that does not adhere to the
research protocol. Protocol violations are sometimes referred to as protocol "deviations." Although
"deviations" may sound less serious than “violation,” the two terms are identical.

Protocol Violations Policy

A protocol violation may be the result of a problem with study oversight, training of study personnel, or site
study procedures.

A protocol violation may be:

An omission (i.e., failure to do something required in the protocol)

An addition (i.e., any action that is not required in the protocol).
A change in any procedure described in the protocol.

Protocol violations may occur due to human error. However, every attempt should be made to keep them at
a minimum. Each violation and the action taken to correct the situation that led to the violation must be
documented and submitted to the IRB.

Repeated protocol violations may indicate the need for additional training of research staff or the need for a
protocol amendment (e.g. to allow more flexibility in a follow-up plan that participants are having a difficult
time adhering to).

What to Do When a Protocol Violation Occurs

When a protocol violation occurs:

Any concerns regarding participant safety must be addressed immediately by staff at the study site.
The violation and a plan for corrective action must be documented.
The violation must be reported to the principal investigator at the site, the study investigator, project
management (if applicable), and the sponsor, and the FDA if the study is under an IND, in accordance
with established procedures.
The local IRB must be notified in a manner that conforms to the IRB's documented procedures.

(For a more detailed discussion of the roles of the principal investigator and lead investigator, see the Roles
and Responsibilities module.)

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Part 4: What is a protocol violation?

Interactive: IS THIS A PROTOCOL VIOLATION OR NOT?

Users are instructed as follows:

Consider each of the five scenarios described below. Then, classify the occurrence as a protocol violation by
choosing Violation or not by choosing No Violation .

Scenario 1

The clinic is approaching the end of the day. The Research Coordinator has a patient there that is eligible for
the study, and he wants to quickly get through screening procedures. He decides to streamline procedures
and collect the screening urine specimen before the patient has an opportunity to discuss, review, and sign
the Informed Consent.

Feedback: Is this a Violation or No Violation? This is a Violation. The informed consent process communicates
all of the information that the individual needs to make an informed decision about taking part in the study,
before any study procedures are performed.

Scenario 2

The study protocol indicates that cash incentives are awarded based on a payment schedule, which will
occur over the 12 months of the study. At each of the six study visits, the participant will receive 15 dollars in
cash at the end of the visit. If the participant missed a visit or withdrew participation before the end of the
study, they would not receive the reward for the missed visit(s).

The study staff at the ABC Research Clinic enrolled two participants at their site in the first week of study
launch. At the first study visit, the PI determined that each participant and all future participants enrolled
would receive the entire incentive ($90) at the last visit at the end of the study if the participants completed
all six study visits. When the protocol monitor arrived weeks later for an interim monitoring visit, the site
staff described these site procedures for applying incentives for the enrolled participants.

Feedback: Is this a Violation or No Violation? This is a Violation. Site staff did not follow the incentive
payment schedule outlined in the protocol. Also, incentive payments should not be conditional on the
participant’s completion of the study.

Scenario 3

The protocol indicates that at the third and sixth study visits, the participant will have urine collected for drug
testing. If the urine was not collected on the scheduled visit, study staff should collect at the following study
visit.

At the Mercy Hospital, the clinician forgot to collect the urine specimen for drug testing on Visit 3. She
collected the urine and performed the drug testing at Visit 4.

Feedback: Is this a Violation or No Violation? This is No Violation. The site staff completed the urine drug
testing according to the procedures outlined in the protocol.

Scenario 4

A participant receives the wrong dose of the study medication.

Feedback: Is this a Violation or No Violation? This is a Violation. Research that is not conducted in a
standardized manner is unethical because it may put research participants at risk unnecessarily while
yielding invalid data.

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Scenario 5

Participants are enrolled in the study although they do not meet the inclusion or exclusion criteria.

Feedback: Is this a Violation or No Violation? This is a Violation. Enrolling participants into a study that they
are not eligible to participate in may put research participants at risk unnecessarily while yielding invalid
data.

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Part 4: What is a protocol violation?

How to Avoid Protocol Violations

Care should be taken when writing a protocol to avoid unnecessary rigidity in schedules and procedures and
to allow for flexibility whenever it does not compromise the integrity of the study or the safety of
participants. This is the first step in avoiding protocol violations.

Then, every member of the research team must be familiar with the protocol and aware of the importance of
following it at all times. The following steps can help to ensure that protocol violations are minimized.

Provision of thorough protocol training as well as periodic refresher training for all members of the study
team.
Notification to all members of the study team of a protocol amendment.
Updating research materials when changes occur such as the Informed Consent Form or Operations
Manual reflecting the changes to the protocol or procedures.
Reminders about protocol requirements during regular study team meetings.

Again, protocol violations will occur in spite of the best intentions of research staff. Violations must be
documented and corrective actions taken to prevent re-occurrences.

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Part 5: Summary of Key Points

Summary of Key Points

Standardization of procedures is critical in a clinical research study. Research that is not conducted in a
standardized manner is unethical because it may put research participants at risk while yielding invalid
data.
All research staff involved in a clinical study must be familiar with, and must strictly adhere to, the
procedures described in the research protocol.
The research protocol is one of the main documents that must be approved by a designated
Institutional Review Board before a research study can begin. The research protocol provides a plan for
the essential aspects of the proposed research.
The Good Clinical Practice guidelines of the International Council for Harmonization require a research
protocol for any study that involves human participants. In addition, Title 21 Part 312 of the Code of
Federal Regulations requires a research protocol for studies conducted under an Investigational New
Drug application.
A protocol amendment is a change to some aspect of the study. Amendments must be approved by the
IRB before they can be implemented, unless there is an immediate safety concern for participants. If the
study is to be submitted to the FDA, such as being under an IND, the amendment must be submitted to
the FDA as well as to the IRB.
A protocol violation occurs whenever any study staff member performs any action that does not adhere
to the study description in the research protocol. Each violation must be documented and action must
be taken to correct the situation that led to the violation. Repeated protocol violations may indicate the
need for additional staff training or a protocol amendment.

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Contents

Part 1: Introduction
Part 2: Documentation Requirements in GCP and Federal Regulations
Part 3: Examples of Other Sponsor-Required Documents
Part 4: Documenting the Use of Investigational Drugs
Part 5: Summary of Key Points

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Part 1: Introduction

Proper documentation is critical to the success of a clinical study. Every aspect of the study must be
documented in order to obtain useful data and demonstrate compliance with Good Clinical Practice (GCP)
guidelines and with all applicable regulations.

This module provides an overview of GCP documentation requirements, requirements in federal regulations,
and sponsor required documentation.

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Part 2: Documentation Requirements in GCP and Federal Regulations

Documentation Requirements in Good Clinical Practice

Guidelines
Essential documents for the conduct of a clinical study are defined in ICH GCP 8.1 as follows:

"… those documents that 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 may be audited or inspected by quality assurance monitors or by regulatory authorities
to confirm the validity of the study and the integrity of the data collected.

GCP guidelines list the essential documents (ICH GCP E6 Section 8) that, at a minimum, must be maintained
for every clinical study. These documents are to be maintained by the site and the sponsor, and are
classified according to the stage of a study at which they are normally created. These documents may be
maintained in multiple locations, depending on whether they are stored with regulatory files or as participant
documents. The sponsor and the investigator/institution should maintain a record of the location(s) of their
respective essential documents, including source documents. Additional documents may be developed and
maintained by the sponsor or the sponsor(s) representatives.

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Part 2: Documentation Requirements in GCP and Federal Regulations

BEFORE

Before a Study Begins

The following essential documents must be created and kept on file at study sites before a study begins:

Signed protocol and amendments, if any.

IRB-approved Informed Consent Form and any other written information that will be given to
prospective study participants to enable them to make an informed decision about enrolling in the trial.
Sample case report forms, either electronic or paper.
Participant recruitment advertisements, if any.
Documentation that the Institutional Review Board (IRB) is set up in accordance with GCP and that all
necessary IRB approvals have been obtained.
Decoding procedures for blinded trials to document how, in case of an emergency, identity of blinded
investigational product can be revealed without breaking the blind for the remaining subjects'
treatment, if applicable.
Documentation of study personnel's qualifications (e.g., curriculum vitae, professional licenses).
Documentation of financial agreements and any other arrangements between the parties involved in
conducting the study (e.g., investigator(s), institution(s), sponsor, contract research organization).
Insurance statement, where required, to document that compensation to subject(s) for trial-related
injury will be available.
If the study involves the use of an investigational drug, instructions for handling, dispensing, and
tracking the investigational product, as well as shipping records, and a sample of the label to be
attached to the investigational product container.
Investigator's Brochure, when applicable.
Evidence of notification, approval, or authorization of the protocol and its supporting documentation by
regulatory authorities (if required)
Evidence of approval or certification of facilities that are performing medical or laboratory tests required
by the study protocol.
Normal value(s)/ range(s) for medical, laboratory, and/or technical procedures and tests included in the
protocol.
Reports of site initiation visits and qualification visits by quality assurance monitors.

IN PROGRESS

While a Study is in Progress

The following are essential documents that should be added to the file while a study is in progress:

Amendments to the Protocol and changes to the case report forms (CRFs), recruitment materials,
Informed Consent Form, and Investigator's Brochure.
Documentation of approval of amendments by the Institutional Review Board (IRB) and regulatory
authorities (if required).
Copies of all reports, including interim and annual reports, sent to the IRB and other regulatory
authorities.
Informed consent forms signed by study participants.
Signed, dated, and completed CRFs and documentation of any CRF corrections with the signature sheet.
Documentation of investigational products and trial-related materials shipment.
Relevant communications, such as letters and meeting notes, that document agreements or discussions
about issues including protocol violations, adverse events, the conduct and administration of the study,
and all safety information notifications and communications.
Relevant communications other than site visits, such as letters and meeting notes.
Reports of interim visits by quality assurance monitors.
Curriculum vitae for new investigators and sub-investigators.
Source documents.
Participant screening log, enrollment log, and identification code list.
Documentation that investigational drugs, if used in the study, have been handled and accounted for as
required in the protocol.
Records of location and identification of retained tissue samples, if any.
Staff signature log, documenting signatures and initials of all persons authorized to make entries and/or
corrections to CRFs.
Updates to CVs, license etc.
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AFTER

After a Study is Completed or Terminated

The following are essential documents that should be added to the file after a study is completed or
terminated:

Documentation that investigational drugs, if used, were handled, accounted for, and returned or
destroyed as required in the protocol.
List of all participants enrolled in the study at the site (completed subject identification code list).
Reports of closeout visits by quality assurance monitors.
Final reports to Institutional Review Boards and regulatory authorities.
Clinical study report, which documents the study’s results, if applicable.

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Part 2: Documentation Requirements in GCP and Federal Regulations

Documentation Requirements in Federal Regulations

21 CFR 312.62 requires investigators to:

Maintain adequate records of the disposition of investigational drugs.

Maintain adequate case histories for all participants in studies that involve the use of investigational
products.
Retain records for 2 years after the date a marketing application is approved for the drug for the
indication for which is it has been investigated by the U.S. Food and Drug Administration (FDA) or for 2
years after the study is discontinued and the FDA is notified.
Records of all NIH–sponsored studies must be maintained for at least 3 years after the study ends per
NIH policy and for a longer time if required by regulations or local institutional policies. This requirement
applies to all research projects, including studies of investigational drugs, behavioral studies, and
survey–based studies.

Click to view Clinical Trial Network related content

CTN

Records of all CTN–sponsored studies must be maintained for at least 3 years after the study ends per NIH
policy and for a longer time if required by regulations or local institutional policies. This requirement applies
to all research projects, including studies of investigational drugs, behavioral studies, and survey–based
studies.

Of note, most facilities where CTN research is conducted are covered entities that must comply with the
HIPAA Privacy Rule. Covered entities are required to account for disclosures (must retain documentation) 6
years from the date of creation on which the accounting is requested. (Reference the Clinical Research and
the HIPAA Privacy Rule.)

Read more...

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Part 3: Examples of Other Sponsor-Required Documents

In addition to the essential documents included in the GCP guideline, the sponsor may require other
documentation. The following lists examples of other documentation that may apply to clinical trials.

Certificate of Confidentiality
A Certificate of Confidentiality provides an additional level of protection for the privacy of participants in
alcohol and drug use research studies. (For more detailed information on Certificates of Confidentiality, go to
the Confidentiality and Privacy module.)

Quality Assurance Documents

Quality assurance documents may include the following:

Research site Initiation Activation Form, which indicates that a site is ready to start study enrollment.
Site visit logs, to record visits to the research site by quality assurance monitors and other personnel.

Training Documents
A training plan and verification of compliance with the training plan, including:

A training documentation form for each staff person

Documentation of required assessments training per the study training plan.
Documentation of study–specific training.
Pertinent certifications for clinical staff implementing a study intervention.

Behavioral Therapy Documents

Many CTN studies involve behavioral interventions. Behavioral studies may require essential documents
different from, or in addition to, those required by GCP guidelines. These documents may include therapy
manuals and materials, audio and videotapes of treatment sessions, and other documents specific to the
behavioral intervention that is being studied.

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Source Documents
Source documents are original documents, data, or records that are created during a clinical study, that
relates to the medical treatment and the history of the participant, and from which study data are obtained.
Source documents are one type of essential document that is required by GCP guidelines.

The purpose of source documents (GCP 8.3.13) is to:

Document the existence of study participants.

Substantiate the integrity of the study data collected.

Any document in which information, an observation, or data generated relevant to a study is recorded for
the first time is a source document. Thus, a scrap of paper, a Post–It ® note, or an electronic mail message
may be a source document if it is the original form on which information relevant to a study is recorded.

Examples of Source Documents

The following are examples of source documents:

Adverse event and concomitant medication logs

Reports of diagnostic test results
Signed and dated Informed Consent Forms
Participant diaries
Appointment calendars
Progress notes
Paper case report forms (CRFs) on which data are entered directly onto the CRF, rather than extracted
from another source document.

Progress Notes
These source materials must be readily available and retrievable for quality assurance monitoring and for
auditing, for example, by the study sponsor (NIDA) or for inspection by the U.S. Food and Drug Administration
(FDA).

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The purpose of progress notes is to document participants’ involvement in the study and the study–related
care they receive. Both research and clinical staff may complete progress notes.

Progress notes are source documents; and may not be recorded in the study database or sent to the sponsor.
Often, progress notes are used on–site to monitor the progress of the study. Another important purpose of
progress notes is to substantiate the data recorded in the case report forms (CRFs).

Progress notes should be concise but should provide enough information that the participant’s study–related
activities, and the order in which events occurred, can be easily understood.

Progress notes are of two types, both considered to be essential study documents:

Clinical notes record information related to the experimental treatment that the participant received
during the clinical phases of the study.
Research notes record information related to the participant's involvement in the research phases (e.g.,
follow-up assessment visits) of the clinical study.

Click here for a list of information that should be documented in both clinical and research progress notes.

Click here for a summary of Good Medical Record practices that should always be observed when writing
progress notes.

Case Report Forms

GCP defines a Case Report Form (CRF) as follows:

“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” (ICH GCP 1.11)

Thus, a CRF may be a printed document that a study team member completes in the clinic or an electronic
document that is sent directly from a laboratory to the data management center.

The purpose of CRFs is to gather study data in a standardized format so that the data can be entered into a
computerized database and analyzed. The CRFs record all of the information needed to complete the data
analyses used to assess the outcomes of the study.

A CRF is a source document only when study data are entered directly onto the CRF, rather than extracted
from another source document (e.g., progress notes).

Click to view Clinical Trial Network related content

CTN

CTN–Specific Essential Documents

CTN investigators are required to maintain a Certificate of Confidentiality, QA, Training, Behavioral Therapy,
Source, Progress Note, and CRF documents for CTN studies. Additionally, contact information should be
maintained for the following CTN study personnel:

Key personnel at the Lead Node.

Key personnel at the Participating Node.
Key personnel at the NIDA Center for the Clinical Trials Network (CCTN).
The NIDA Study Medical Officer and other parties who must be contacted when expedited reporting of
an adverse event is necessary.

Read more...

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Part 4: Documenting the Use of Investigational Drugs

21 CFR 312.62 requires investigators to maintain adequate records of the disposition of investigational
drugs, including dates, quantities, and use by participants. The investigator must also maintain records of
receipt.

The following equation may help in understanding the process of accountability for drug disposition:

Although this equation may look simple, in practice accounting accurately for the disposition of an
investigational drug can be quite complicated. The investigator must account for every unit of the
investigational product (e.g., tablet, capsule, inhaler).

Let’s take a closer look at what is involved in accounting for every unit of an investigational product.

Documentation of the "Amount of Drug Received"

Documentation of the "amount of drug received" must account for:

The total number of capsules, tablets, etc. in every dosage (e.g., 5 mg, 10 mg).
Multiple lot numbers.
The type of packaging in which the medication is delivered (e.g., bulk supply, individual kits).

Documentation of the "Amount of Drug Used"

Documentation of the "amount of drug used" must account for:

The amount of medication that each study participant is individually exposed to.
The total amount of medication consumed by all study participants.
The amount of medication that is returned by participants (i.e. unused).
The amount of medication that is wasted (e.g., lost, dropped down the kitchen sink).

Verification of the "Amount of Drug on Hand"

Inventory must be taken at regular intervals to verify the "amount of drug on hand." Any discrepancies must
be documented.

To ensure proper accountability, a carefully designed plan (or standard operating procedure) must be in
place at the beginning of the study to document the disposition of the investigational product at each site.
This plan must be adhered to throughout the study and, if necessary, modified to ensure 100%
accountability. The investigator’s records of drug disposition must agree with the data submitted to the
sponsor.

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Summary of Key Points

Every aspect of a clinical study must be documented in order to obtain useful data and demonstrate
compliance with Good Clinical Practice (GCP) standards and with all applicable regulations.
GCP guidelines specify the essential documents that must be maintained for every clinical study. These
documents are classified according to whether they are normally created before a study begins, while a
study is in progress, or after a study is completed or terminated.
Federal regulations require investigators to retain records for 2 years after approval of the
investigational drug by the U.S. Food and Drug Administration (FDA) or for 2 years after the study is
discontinued and FDA is notified.
Sponsors may require specific documentation in addition to the list of essential documents specified by
GCP.
Source documents are original documents created during a clinical study, from which study data are
obtained. The purpose of source documents is to document the existence of study participants and
substantiate the integrity of the study data collected.
Progress notes document participants’ involvement in the study and the study–related care they
receive. Progress notes are used to monitor the progress of the study and substantiate the data
recorded in the case report forms (CRFs).
The purpose of CRFs is to gather study data in a standardized format so that the data can be entered
into a computerized database and analyzed. All of the information needed to complete the data
analyses used to assess the outcomes of the study is recorded in the CRFs.

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Contents

Part 1: Introduction
Part 2: Identifying Research Misconduct
Part 3: Investigating Allegations of Research Misconduct
Part 4: Responding to Allegations of Research Misconduct
Part 5: Safeguards for Informants and Accused Persons
Part 6: Possible Penalties for Research Misconduct
Part 7: Summary of Key Points

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Part 1: Introduction

Public concern about misconduct in research arose in the early 1980s after reports of serious misbehavior by
researchers. In one case, a researcher republished dozens of articles under his name that had previously
been published by others. In other cases, researchers falsified or made up research results. Instead of
looking into these problems, research institutions sometimes ignored them or covered them up.

Eventually, Congress required federal agencies and research institutions to develop policies on research
misconduct. The U.S. Public Health Service created regulations for dealing with research misconduct (42 CFR
50 Subpart A). These policies generally have three goals:

To define research misconduct.

To establish procedures for reporting and investigating research misconduct.
To protect both those who report alleged research misconduct and those accused of research
misconduct.

This module discusses how federal policy defines research misconduct and provides a brief overview of the
processes established by the U.S. Public Health Service (PHS) for responding to allegations of misconduct in
PHS-supported research.

Defining Research Misconduct

Federal regulations define research misconduct as:

"...fabrication, falsification, plagiarism, or other practices that seriously deviate from those that are
commonly accepted within the scientific community for proposing, conducting, or reporting research."

Fabrication is making up data or results and recording or reporting them.

Falsification is changing research materials, equipment, or processes or altering or omitting data or
results so that the research record does not accurately reflect the research findings.
Plagiarism is using another person’s ideas, processes, results, or words without giving appropriate
credit.

Research misconduct does not include honest error or differences of opinion. In addition, the federal policy
on research misconduct does not apply to authorship disputes unless they involve plagiarism.

Research misconduct has a very specific meaning in federal regulations. Noncompliance with policies and
procedures for the protection of human research subjects, although reportable to an Institutional Review
Board (IRB), is not considered to be research misconduct under the federal definition.

To whom does federal policy on research misconduct apply?

Federal policy on research misconduct applies to all federally funded research and all proposals submitted to
federal agencies for research funding.

Many research institutions and universities apply the federal policy on research misconduct to all research,
whether or not it is federally funded. In addition, many institutions have broadened the federal definition of
research misconduct to include other improper practices. Researchers must be familiar with their
institutional policies on research misconduct as well as with the federal policy.

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Part 2: Identifying Research Misconduct

What federal agency oversees investigations of alleged research

misconduct?
The Office of Research Integrity (ORI) in the Department of Health and Human Services is responsible for
promoting research integrity within the U.S. Public Health Service. ORI oversees investigations of research
misconduct allegations and makes final decisions on findings of research misconduct.

Through its Rapid Response Technical Assistance Program, ORI provides technical assistance to any
institution that is responding to an allegation of research misconduct. In addition, researchers may hold
informal discussions with ORI about allegations of research misconduct or the handling of research
misconduct cases.

Records maintained by ORI during the investigation of an allegation of research misconduct are exempt from
disclosure under the Freedom of Information Act to the extent permitted by law and regulation.

Research Misconduct and Other Types of Misconduct

Research misconduct destroys the integrity or honesty of the research record. This sets it apart from other
improper activities that may occur in research settings (e.g., financial conflicts of interest, misuse of grant
funds, violation of human subject protections, sexual harassment, and discrimination). Although these
improper activities are taken very seriously, they are not considered research misconduct because they do
not alter the integrity of the research record.

The term fraud has often been used to describe dishonesty in research. However, this term is more aptly
used to describe illegal, deceptive financial practices. Behavior that destroys the integrity of the research
record through fabrication, falsification, or plagiarism is most aptly termed research misconduct .

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Part 2: Identifying Research Misconduct

Interactive: Identifying Research Misconduct - TRUE OR FALSE

Instructions: Based on the description below, choose whether the information is True or False.

All three of the elements below must be present for a finding of research misconduct to be made. Under
federal policy, a finding of research misconduct requires that:

There be a significant departure from accepted practices of the relevant research community; and
The misconduct be committed intentionally, or knowingly, or recklessly; and
The allegation be proven by a preponderance of the evidence.

Feedback: Is this information True or False? All three of the elements must be present for a finding of
research misconduct to be made. Therefore, the correct response is True.

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Part 3: Investigating Allegations of Research Misconduct

Who is responsible for investigating allegations of research

misconduct?
Federal policy on research misconduct places the primary responsibility for reporting and investigating
allegations of research misconduct with researchers and research institutions. This is consistent with the
position, supported by most researchers, that research is a profession that should regulate its own conduct.

Research Institutions
Individual Researchers

Research institutions that receive federal funding are expected to:

Foster an environment that discourages all research misconduct.

Use procedures for receiving and investigating reports of research misconduct.
Inform scientific and administrative staff of the procedures for responding to allegations of research
misconduct and of the importance of complying with these procedures.
Take immediate, appropriate action when research misconduct is suspected or alleged to have occurred
at the institution.
Investigate and rule on suspicions or allegations of research misconduct.
Report both the start of and the results of a formal investigation (not the initial inquiry) into an
allegation of research misconduct to the Office of Office of Research Integrity.
File an Annual Report on Possible Research Misconduct with the designated federal agency.

Federal policy on research misconduct assumes that research is a self-regulating profession. To be

successful, professional self-regulation relies on conscientious participation by all members of the profession.
Individual researchers are expected to:

Maintain a high standard of integrity at all times in all of their research activities.
Assume responsibility for their actions.
Take misconduct or alleged misconduct seriously.
Report apparent misconduct by other researchers.
Keep confidential at all times information that is relevant to an investigation of alleged misconduct.

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Part 4: Responding to Allegations of Research Misconduct

Requirements for the Response to an Allegation of Research

Misconduct
Federal policy makes researchers and research institutions primarily responsible for reporting and
investigating alleged research misconduct. Research institutions’ expected tasks in dealing with such
allegations are spelled out in 42 CFR Part 50 Subpart A.

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Part 4: Responding to Allegations of Research Misconduct

Generally, the response to an allegation of research misconduct has three stages.

INQUIRY

The inquiry assesses the facts of the allegation and the need for an investigation. An inquiry must be
completed within 60 calendar days of its start, unless circumstances clearly require a longer time.

Those accused of misconduct must be informed of the allegation and of the inquiry. A written report of the
inquiry must be prepared, summarizing the evidence reviewed and conclusions reached. The accused
person(s) must be given a copy of the inquiry report.

INVESTIGATION

If the inquiry provides an adequate basis for an investigation, that investigation should begin within 30 days
of completion of the inquiry. The decision to begin an investigation must be reported in writing to the
Director, Office of Research Integrity (ORI), on or before the date the investigation begins.

The investigation normally will include:

Examining all documents, including relevant research data, proposals, publications, correspondence,
and records of telephone calls.
Interviewing all informants and all those accused of misconduct as well as others who may have
information about key aspects of the allegation.
Preparing a report of the investigation’s findings and making the report available for comment by all
informants and all those accused of misconduct.
Submitting a final report to ORI, the PI, the sponsor, and NIH for NIH-funded or supported research.

In most cases, the investigation should be completed within 120 days of its start. If the institution decides it
cannot complete the investigation within this time, it must submit to ORI a written request for an extension.
This request must explain the reason for the delay, report on the investigation’s progress so far, and
estimate when the investigation will be completed and the final report submitted.

ADJUDICATION

If the investigation concludes that the allegation has merit, the institution may impose suitable penalties. In
addition, the ORI may impose penalties of its own on investigators or institutions.

Institutions must notify the Office of Research Integrity (ORI) immediately if certain circumstances are found
during an inquiry or investigation into an allegation of research misconduct.

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Part 4: Responding to Allegations of Research Misconduct

Click to view Clinical Trial Network related content

CTN

Responding to Allegations of Research Misconduct in CTN Trials

Every CTN member institution is expected to have an official responsible for investigating complaints of
research misconduct, also referred to as the Research Integrity Officer (RIO). When an allegation of scientific
misconduct is made in a CTN trial, the Research Integrity Officer of the research institution should be
contacted immediately.

The Research Integrity Officer should promptly assess whether the allegation falls under the federal
definition of research misconduct and whether sufficient evidence exists to warrant an inquiry. He or she
should alert the NIDA Center for the Clinical Trials Network office that an allegation of research misconduct
has been made at one or more CTN sites. Within NIDA, responsibility for oversight of inquiries and
investigations into research misconduct rests with the Office of Extramural Affairs.

In addition, if NIDA is the sponsor of a study under an Investigational New Drug (IND), NIDA must promptly
report to the FDA any information that any person involved in human subject trials committed research
misconduct. If the FDA receives a complaint of alleged trial misconduct, the FDA will independently
investigate, separate from the ORI investigation, and proceed with any necessary regulatory actions.

Read more...

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Part 5: Safeguards for Informants and Accused Persons

Ensuring Fairness and Timeliness in Responding to Allegations

of Research Misconduct
An allegation of research misconduct can have a significant impact on the informant, the accused person(s),
and the institution where the alleged misconduct took place. Procedures must be in place to ensure the
security of original documents, computers, biological specimens, laboratory notebooks, research and
financial records, and other relevant items that might be altered, lost, or destroyed.

In addition, specific safeguards are necessary to assure the protection of all persons concerned with an
allegation of research misconduct.

Safeguards for Informants

A whistleblower (informant) is any member of a research institution, including a non-employee, who alleges
that the institution or one of its members has engaged in, or has failed to respond adequately to an
allegation of, research misconduct.

The role of the whistleblower is essential to the effort to protect the integrity of research. People who in good
faith report apparent research misconduct must be able to do so in confidence and without fear of retaliation
or payback.

Federal policy requires institutions to offer informants the following safeguards:

Protection of privacy to the extent possible. However, informants cannot remain anonymous.
Protection against retaliation.
Fair and objective procedures for examining and resolving research misconduct allegations.
Diligence in protecting the positions and reputations of informants.

Neither research institutions nor individual researchers may penalize persons who, in good faith, report
alleged research misconduct. Even if the allegations are not sustained, as long as they are made in good
faith, informants must be protected because they play a vital role in professional self-regulation.

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Safeguards for Accused Persons
Most allegations of research misconduct are not substantiated. Persons accused of research misconduct
must be assured that the mere filing of allegations will not bring their research to a halt or be the basis for
other disciplinary action without compelling reasons. Other safeguards for accused persons include:

Timely written notification of allegations made against them.

A description of all allegations.
Reasonable access to the data and other evidence supporting the allegations.
The opportunity to respond to allegations, supporting evidence, and any proposed findings of research
misconduct.
Confidential treatment to the maximum extent possible.

Objectivity and Expertise of Investigators

The persons selected to investigate allegations of research misconduct must have appropriate expertise and
no unresolved conflicts of interest.

Timeliness
Reasonable time limits must be set for the response to an allegation of research misconduct. Extensions of
time may be allowed when necessary.

Confidentiality
To the extent possible, knowledge of the identities of both subjects and informants involved in research
misconduct investigations should be closely held. However, the accused person is entitled to know the
identity of the informant.

Alleged misconduct in a clinical trial that could threaten the health or safety of trial participants must be
reported immediately to the trial principal investigator, the federal agency sponsoring the trial (NIDA in the
case of CTN studies), and the Office of Research Integrity (ORI). The name(s) of the accused person(s) should
remain confidential, but steps must be taken to ensure the safety of trial participants.

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Part 6: Possible Penalties for Research Misconduct

Research institutions may penalize researchers who are found to have committed research misconduct by
terminating their employment or by requiring supervision of future research activities.

When a grantee institution upholds a finding of research misconduct by anyone working on a NIH-funded
research project, the grantee must assess the effect of the finding on that person’s ability to continue
working on the research project. In addition, the grantee must promptly obtain approval from the sponsor
and NIH for any intended change of principal investigator or other key personnel involved in the research
project.

The Office of Research Integrity (ORI) may also impose penalties for research misconduct. Penalties are
determined by the severity of the misconduct. Factors that ORI may consider in choosing a penalty may
include the degree to which the misconduct:

Was committed in a knowing, intentional, or reckless manner.

Was an isolated event or part of a pattern.
Had a significant impact on the research record, research subjects, other researchers, institutions, or
the public welfare.

The Office of Research Integrity (ORI) may impose a variety of penalties when a finding of research
misconduct is upheld. These penalties may include:

Correction of the research record.

Letters of reprimand.
Suspension or termination of a research grant.
Suspension or debarment from receiving federal funds.

When administrative actions are imposed by ORI (or the FDA, who has their own bulletin boards for debarred
and disqualified investigators), the names of the individuals will be made public.

If the ORI believes that research misconduct may have involved criminal or civil fraud, it will refer the matter
promptly to an investigative body such as the Department of Justice or the Office of the Inspector General,
Department of Health and Human Services.

ICH GCP and Research Misconduct

ICH GCP was put together and became operational after public outcry of research misconduct that had
occurred over the years. Following the ICH GCP guideline assists in preventing fraud and misconduct. So
research misconduct is also a form of non-compliance to ICH GCP

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Summary of Key Points

Federal policy defines research misconduct as “fabrication, falsification, or plagiarism in proposing,

performing, or reviewing research, or in reporting research results.” This definition does not include
honest error or differences of opinion or authorship disputes unless they involve plagiarism.
Federal policy on research misconduct applies to all federally funded research and all proposals
submitted to federal agencies for research funding.
The Office of Research Integrity (ORI) in the Department of Health and Human Services oversees
investigations of research misconduct allegations and makes final determinations on findings of
research misconduct within the U.S. Public Health Service.
Federal policy places the primary responsibility for reporting and investigating allegations of research
misconduct with researchers and research institutions.
Generally, the response to an allegation of research misconduct has three stages:
Inquiry (to assess the facts of the allegation).
Investigation (if the inquiry provides adequate basis for one).
Adjudication (imposing of suitable penalties if the allegation is found to have merit).
Penalties for research misconduct may include termination of employment, suspension or termination of
a research grant, and suspension or debarment from receiving federal funds.

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Contents

Part 1: Introduction
Part 2: Responsibilities by Role
Part 3: Summary of Key Points

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Part 1: Introduction

Many individuals and groups are involved in conducting a clinical study. The central roles are those of the
Sponsor and Principal Investigator, as defined by Good Clinical Practice (GCP) guidelines.

There are additional roles and responsibilities defined for other individuals and groups whose work is
essential to the proper conduct of a clinical study. How these roles are referenced, may vary from one
research network to another.

This module will:

Discuss the roles and responsibilities of the Sponsor, and Principal Investigator as outlined in the GCP
guidelines.
Briefly describe how these roles and responsibilities are fulfilled in clinical studies.
Discuss the roles and responsibilities of other individuals and groups involved in studies.

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Part 2: Responsibilities by Role

The following is a summary of responsibilities, as outlined in the GCP guidelines according to role.

Central Roles:

Sponsor
Principal Investigator
Other Roles
Research Site Staff

Sponsor:

MONITORING

Data and Safety Monitoring

All NIH–supported multicenter Phase III clinical trials must have an independent Data and Safety Monitoring
Board (DSMB). This requirement applies to both studies of drug therapies and to behavioral studies.

Members of each DSMB include experts in the disease area, treatment, clinical trial design, biostatistics, and
research ethics. The DSMBs are appointed by and report to the sponsor. Their role is to:

Protect participant safety by being familiar with the study, proposing appropriate analyses, and
reviewing outcome and safety data as they become available.
Ensure study integrity by reviewing data on issues such as participant enrollment, site visits, study
procedures, completion of forms, data quality, losses to follow-up, and other measures of adherence to
the study protocol.
Monitor adverse events and recommend changes in the protocol or operation of the study if necessary.
This monitoring function is over and above the oversight traditionally provided by the IRB and is
particularly important for multicenter research studies.

Click here to see the NIH policy document on data and safety monitoring.

QA & QC

Quality Assurance and Quality Control (ICH GCP 5.1)

The Sponsor is responsible for implementing and maintaining quality assurance and quality control systems
to ensure that studies are conducted and documented in compliance with the protocol, GCP, and regulatory
requirements.

EXPERTISE

Medical Expertise (ICH GCP 5.3)

The Sponsor is responsible for designating appropriately qualified medical personnel to advise on trial-
related medical questions or problems.

STUDY DESIGN & MANAGEMENT

Study Design and Management (ICH GCP 5.4, 5.5))

The Sponsor is responsible for designating qualified individuals to carry out all stages of the study process,
including:

Designing the protocol.

Supervising the overall conduct of the study.
Managing and verifying the study data.
Ensuring the safety and rights of human participants.
Monitoring study performance.
Planning and conducting the statistical analyses.
Preparing study reports.

TRANSFER OF OBLIGATIONS

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Transfer of Trial-Related Obligations

The Sponsor may transfer any or all of the Sponsor’s trial-related duties and functions to a Contract Research
Organization (CRO). However, the ultimate responsibility for the quality and integrity of the trial data always
resides with the Sponsor. Any trial-related duties and functions that are transferred to and assumed by a
CRO are specified in writing.

Principal Investigator:

OVERVIEW

Overview

While studies have a Lead Investigator with primary responsibility over the entire trial, this individual is often
the Principal Investigator (PI) at the lead research site and has responsibility over the conduct of a clinical
study at that site. For multicenter trials, there are a number of research sites, each with its own Principal
Investigator with oversight responsibility and staff involved in the conduct of a study.

The PI retains ultimate oversight responsibility even when specific tasks are delegated to other site research
staff. Additionally, PI responsibilities include:

Documenting the delegation of study responsibilities to qualified and adequately trained research staff.
Supervising study performance and overseeing the performance of study staff at the research sites.
Ensuring that:
Participants’ well-being and safety are protected.
All study procedures are conducted at the research sites in accordance with the protocol and GCP.
Preparing a communication plan for all staff involved in the study.
Overseeing Investigational product accountability.

Of note, the PI must sign the protocol signature page in that capacity. If the study is being conducted under
an Investigational New Drug (IND) application, the PI must also sign Form FDA 1572.

QUALIFICATIONS & EXPERIENCE

Qualifications and Experience (ICH GCP 4.1)

The PI must:

Be qualified by education, training, and experience to assume responsibility for the proper conduct of
the study.
If the study involves the use of an investigational product, be thoroughly familiar with the appropriate
use of that product as described in the study protocol.
Be aware of and remain in compliance with GCP and applicable regulatory requirements.
Maintain a list of qualified persons to whom he or she delegates significant study-related duties.

CARE FOR PARTICIPANTS

Medical Care of Study Participants (ICH GCP 4.3)

All study participants should receive appropriate medical care both for study-related adverse events and for
all medical conditions unrelated to study participation.

A qualified physician affiliated with the study should be responsible for all study-related medical
decisions.
The participant’s primary care physician should be informed about the participant’s involvement in the
study, provided that the participant:
Has a primary care physician.
Agrees that the primary care physician may be informed.

COMMUNICATION

Communication with Institutional Review Board (ICH GCP 4.4)

The PI is identified to the designated IRB. Before and during a study, the PI must comply with all
requirements of the designated Institutional Review Boards (IRBs). A study may not begin prior to obtaining
IRB approval. (See material regarding the Investigators’ responsibilities to the IRB from the Institutional
Review Boards module.)

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COMPLIANCE

Compliance with the Protocol (ICH GCP 4.5)

The PI is responsible for ensuring that the study is conducted in compliance with the research protocol. He or
she should ensure that all protocol violations are identified, documented, and reported in accordance with
sponsor and IRB requirements. Repeated protocol violations may indicate that protocol amendments,
procedural changes, or additional training are needed.

USE OF PRODUCTS

Use of Investigational Products (ICH GCP 4.6)

If the study involves the use of an investigational product, the PI is responsible for ensuring that the
investigational product is used only in accordance with the study protocol and federal regulations; and that
accountability of the investigational product is maintained. (See related material from the Investigational
New Drugs module.)

For clinical investigations that use controlled study drug, the PI may be required to have a medical license.
When the PI is not required to have a medical license, responsibility for receiving or administering certain
drugs, reviewing safety events, and making independent medical decisions is delegated to qualified medical
personnel, such as a physician, physician’s assistant, nurse practitioner , or other qualified/licensed medical
professional. These delegated responsibilities are documented in the site’s delegation of responsibilities log,
and the staff assigned may serve as a sub-investigator. Consult local regulations and oversight authorities on
medical license requirements for conducting research using controlled drug.

RANDOMIZATION & BLINDING

Randomization and Blinding (ICH GCP 4.7)

The PI is responsible for ensuring that the study’s procedures, if any, for randomization and blinding are
followed.

INFORMED CONSENT

Informed Consent (ICH GCP 4.8)

The PI is responsible for ensuring that procedures for obtaining and documenting informed consent comply
with GCP and with the ethical principles originating in the Declaration of Helsinki.

RECORDS & REPORTS

Records and Reports (ICH GCP 4.9)

The PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of all study data that
are reported to the Sponsor.

The PI should provide written reports on the status of the study to the Sponsor and IRB when and as often as
required to do so at each institution where the study is conducted.

All serious adverse events must be reported immediately to the Sponsor. The PI must also comply with
regulatory requirements to report serious adverse events to the IRB and regulatory authorities.

Final Study Reports (ICH GCP 4.13)

On completion of the study, the PI is responsible for providing:

All required reports to the Sponsor and regulatory authorities.

A summary of the study outcome to the Institutional Review Board.

Records and reports are discussed in greater detail in the Documentation and Record Keeping module.
Serious adverse events are discussed in the Participant Safety and Adverse Events module.

SUSPENSION & TERMINATION

Premature Suspension or Termination of Study (ICH GCP 4.12)

If the study is suspended or stopped early for any reason, the PI is responsible for:

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 Promptly informing all study participants.
Ensuring that all participants receive appropriate therapy and follow-up.
Complying with all requirements to inform regulatory authorities.

Other Roles:

OVERVIEW

Overview

The investigator convenes a Protocol Team to assist with all aspects of the operation of the study. In addition
to the responsibilities listed under Principal Investigator, other responsibilities represented on the Protocol
Team usually include, but are not limited to, Quality Assurance, Training, and Regulatory Affairs.

QA

Quality Assurance

Quality Assurance (QA) staff is responsible for:

Reviewing the protocol to check for inconsistencies and problematic wording that will increase the
likelihood of protocol violations.
Reviewing monitoring reports of site visits to ensure that all identified issues are addressed in an
appropriate and timely fashion and are communicated to the investigative team.
Conducting site visits on the behalf of the Sponsor as needed.

REGULATORY AFFAIRS

Regulatory Affairs

Regulatory Affairs staff is responsible for:

Writing the study informed consent documents.

Submitting the protocol, consent documents, and Institutional Review Board (IRB) documents to the
lead node's IRB and making any changes in those documents required by the IRB.
Distributing the IRB-approved protocol, consent documents, and Institutional Review Board (IRB)
documents to participating research sites to assist them in preparing their IRB submissions.
Preparing and distributing a checklist of items that participating sites must have, and
Providing regulatory guidance to the study sites as necessary.

This responsibility continues throughout the duration of the trial e.g. submission of a Protocol Amendment.

Research Site Staff:

RESEARCH COORDINATOR/ASSISTANT

Research Coordinator/Assistant

Under the supervision of the PI at the site, examples of responsibilities for the Research
Coordinator/Assistant may include:

Ensuring that study data is accurately collected and reported.

Reporting any study or participant problems.
Maintaining regulatory files at the study site.
Working with the Node Quality Assurance Monitor and data management staff to identify and resolve
data and reporting issues.

The Research Assistant’s role frequently also includes interacting with study participants by performing
assessments (e.g., the Addiction Severity Index) and protocol procedures.

OTHER STAFF

Nurses, Pharmacists, Counselors, Supervisors and Other Staff

Nurses, pharmacists, and other staff are responsible for carrying out study procedures as described in the
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protocol (e.g., receiving and dispensing medications, conducting physical examinations, delivering
behavioral interventions) and for assessing and reporting adverse events to appropriate staff.

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Part 2: Responsibilities by Role

Interactive: Study Roles

Users are instructed to read the scenario, and choose the best answer from the multiple choices
provided. Then, consider the feedback.

Scenario: The clinical study team at Midtown Medical Research Park is facing a difficult situation. A
participant has died during the trial, and the team has decided to end the study prematurely. While many
forms and protocols must be followed in this case, who on the team is responsible for ensuring that the site’s
study participants receive appropriate follow-up as outlined in the study protocol?

A. Principal Investigator
B. Sub-Investigator
C. Medical Clinician or Physician
D. Interventionist
E. Quality Assurance Monitor

Feedback: Which did you choose: A, B, C, D, or E? There is study role primarily responsible for the conduct of
a clinical study at a research site, and the individual retains ultimate responsibility even if specific tasks are
delegated to others. If a study is suspended or stopped early for any reason, the PI is responsible for:
promptly informing all study participants; ensuring that all participants receive appropriate therapy and
follow-up; and complying with all requirements to inform regulatory authorities. Therefore, the correct
response is A, the Principal Investigator or PI.

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Part 2: Responsibilities by Role

Click to view Clinical Trial Network related content

CTN

More on Roles and Responsibilities for Clinical Trials in the CTN

The NIDA Clinical Trials Network has established processes to apply GCP, to maximize its node and
multicenter platform, and that adhere to policies for NIH-sponsored research. The following defines the
infrastructure variations and processes established in the CTN that may differ from other research.

Medical Expertise (ICH GCP 5.3)

For CTN studies, the Lead Investigator must designate a study medical monitor, who is responsible for
ensuring the care and safety of study participants. In addition, NIDA appoints a study medical officer, who
has an oversight role and serves as a resource to both the Lead Investigator and the study medical monitor.

Study Design and Management (ICH GCP 5.4, 5.5)

For CTN studies, the Lead Investigator must designate a protocol team that designs the protocol, assists in
protocol implementation and prepares any necessary reports. NIDA fulfills its responsibilities by designating
independent oversight boards to review all protocols and monitor the conduct of the studies. As noted
earlier, NIDA also contracts monitors who perform quality assurance site visits at all research sites where
CTN studies are conducted and requires each Node to perform regular site visits at all research sites
participating in studies within that Node. Findings from these site visits must be reported to NIDA.

Other Roles and Responsibilities in CTN Studies

Everyone working on a study is responsible for:

Protecting the rights and safety of study participants,

Complying with the study protocol, and
Reporting study data accurately and completely.

The following descriptions are intended to clarify roles and responsibilities that must be fulfilled in all CTN
studies, not to define specific positions held by individuals. The position titles used here may differ from
those used at each of the organizations involved in CTN research.

NIDA is typically considered to be the Sponsor for studies conducted within the CTN. This consideration may
vary in special cases. For example, as far as FDA is concerned, the sponsor is the IND Holder in the case that
the study is under IND; and, an agreement for transferring responsibilities is documented with the IND Holder
and the partner organization. While the Sponsor maintains primary responsibility for any clinical
investigations it conducts, the CTN transfers responsibilities wholly or partially to a partner organization.

Roles and Responsibilities at Participating Nodes

Under the terms and conditions of the grant award for each study, NIDA transfers other responsibilities as
Sponsor to the study’s Lead Investigator and the Node Principal Investigator, such as Quality Assurance and
Control, oversight, and training.

For CTN studies, NIDA fulfills the Quality Assurance and Control responsibility by:

Contracting with monitors who perform quality assurance site visits at all research sites where CTN
studies are conducted.
Requiring each Node to perform regular quality assurance site visits at all research sites participating in
studies within that Node. Findings from these site visits must be reported to NIDA.

In the CTN, the network infrastructure includes CTN Nodes that have oversight and training responsibilities
for regionally assigned research sites. Each CTN Node functions independently and creates its own
organizational structure, depending on its needs and resources. As a result, job titles and job descriptions for
research staff are not standardized across Nodes. At one Node, multiple staff members may perform one
role, whereas at another Node, one staff member may perform multiple roles. The CTN Nodes are also
assigned research sites regionally. The following information summarizes the roles of staff at the Node.

Node Principal Investigator

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The Node PI (or grantee) is responsible to NIDA for study performance at his or her Node. He or she works
with Node staff, the study’s Lead Investigator, and the Principal Investigator at the research sites to
implement the study.

The Node PI is responsible for ensuring that the study runs smoothly at his or her Node and for taking
appropriate action when necessary to assist the Lead Investigator and research site PIs and other research
staff. Other responsibilities of the Node PI include:

Appointing staff to direct study operations.

Managing the Node budget and staff.
Appointing a monitor to conduct quality assurance site visits to research sites.
Ensuring that study staff receives appropriate training to conduct the study.
Ensuring that the study receives all necessary IRB approvals and follows all applicable regulations, and
Ensuring compliance of his or her institutional policies at the Node with these policies.

Node Coordinator

The Node Coordinator:

Coordinates all study activities at the Node.

Ensures that day-to-day activities are conducted in accordance with GCP.
Acts as liaison between the Node and the Lead Investigator and the CTN on study matters, and
Serves as the main contact for study information at the Node.

Node Quality Assurance Monitor

The Node QA Monitor is responsible for monitoring the study within the Node and reporting findings to NIDA,
the Node PI, and the Lead Investigator. This individual must be intimately familiar not only with the study
protocol but also with GCP.

Node Regulatory Affairs Staff

The Node Regulatory Affairs Staff are responsible for:

Submitting the study protocol, informed consent form, and any other relevant documents to the
Institutional Review Boards (IRBs) at the Node’s participating sites.
Ensuring that Research sites use the most recently approved informed consent documents.
Assisting with the creation and maintenance of regulatory files for the study.
Submitting data on adverse events, serious adverse events, and protocol violations to the relevant IRBs,
according to their requirements.
Coordinating continuing IRB review of the study protocol and materials to ensure ongoing IRB approval
of the study.

Read more...

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Part 3: Summary of Key Points

Good Clinical Practice (GCP) guidelines specifically define the responsibilities of the Sponsor and
Principal Investigator of a clinical study.
The ultimate responsibility for the quality and integrity of the trial data always resides with the Sponsor
although some obligations of the sponsor maybe delegated to a partner organization or contract
research organization (CRO).
The Principal Investigator (PI) is responsible for the conduct of a clinical study at a research site and
retains ultimate responsibility even if specific tasks are delegated to other site research staff.

Click to view Clinical Trial Network related content

CTN

The NIDA Clinical Trials Network (CTN) has defined roles and responsibilities for other individuals and
groups whose work is essential to the proper conduct of a clinical study.
NIDA is the Sponsor for studies conducted within the CTN. However, under the terms and conditions of
the grant award for each study, NIDA transfers some responsibilities as Sponsor to the study’s Lead
Investigator and to Contract Research Organizations.
Based on the study and parties involved under the CTN structure:
The Lead Investigator has overall responsibility for the entire study.
The Node PI (or grantee) is responsible to NIDA for study performance at his or her Node.
For each study in which the Node is participating, the Node PI designates a PI for each research
site, who maintains oversight of site performance and has responsibility for study integrity, human
participant protection, and staff performance of delegated responsibilities at the assigned research
site(s).
Each CTN Node functions independently and creates its own organizational structure, depending
on its needs and resources. As a result, job titles and job descriptions vary across Nodes.

Read more...

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Contents

Part 1: Introduction
Part 2: Recruitment
Part 3: Recruitment Strategies
Part 4: Advertising for Study Participants
Part 5: Retention
Part 6: Retention Strategies
Part 7: Using Incentives for Study Participation
Part 8: What to Do when a Participant Leaves a Study
Part 9: Summary of Key Points

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Part 1: Introduction

Why are recruitment and retention important?

The purpose of a clinical study is to answer a research question. To do this, researchers must:

Recruit an adequate number of appropriate participants.

Retain as many of those participants as possible for the time period specified in the study protocol.

Overly optimistic recruitment and retention projections are common in clinical studies. If either recruitment
or retention falls short, a study may fail to achieve its objective. The researchers may be unable to answer
the research question they posed and participants who were recruited to the study may have been placed at
risk for no purpose. Thus, recruitment and retention of participants are key to the success of any clinical
study.

A successful recruitment and retention strategy requires informed and detailed planning, commitment of
adequate resources, careful monitoring, and timely identification and resolution of problems.

Recruitment and retention strategies, including the wording, presentation and the mode of communication of
advertising materials, must be approved by the designated Institutional Review Board (IRB) prior to
implementation.

Recruitment and retention are challenges that involve much time and effort on the part of both clinicians and
researchers. This module discusses the issues to be considered in the recruitment and retention of
participants to studies. Part 1 deals with recruitment and Part 2 addresses retention.

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Part 2: Recruitment

What are the major elements of recruitment?

Recruitment to a study has two major elements:

Defining a population of appropriate participants to answer the research question.

Recruiting appropriate participants in an ethical manner.

Issues to Consider in Defining a Population of Participants for a

Study
Defining the participant population for a clinical study involves consideration of various issues, as described
below.

Purpose of the Study

The purpose of a study will often define the appropriate participant population for the study. For example,
the purpose of a study may be to test an intervention that is aimed at pregnant women with gestational
hypertension, runaway teenage girls who are involved in the criminal justice system, military veterans who
use tobacco products, or another defined population subgroup.

Generalizability of Results
It is important that findings from a clinical study be relevant to people who were not in the study but have
the same characteristics as the study participants. This is called generalizability. The number of
participants must be adequate so that the study’s results can be applied to the general population that
might benefit from the research.

Considerations of Fairness
The 1979 Belmont Report established the three key principles on which the current system of human
research protections rests: respect for persons, beneficence, and justice.

The principle of justice requires that participants be selected fairly. Researchers must attempt at all times to
distribute the risks and benefits of participation in a study fairly and without bias across the population.

When deciding to select some people for a study and exclude others, researchers must ensure that
participants are chosen for reasons that are directly related to the problem being studied and not simply
because of their availability, their compromised position, or their vulnerability.

Unless there is a clear justification for doing so, research should not involve persons from groups that are
unlikely to benefit from subsequent applications of the research. For example, it would be unethical to select
as study participants only persons on welfare, institutionalized persons, or members of a specific racial or
ethnic group unless the intervention being studied was intended to directly benefit that group of people.

Adequate Representation of Women and Minorities

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Women and minorities should be adequately represented in the study population so that the research
findings will be meaningful for these groups and so that members of these groups can share in the benefits
of the research. This is particularly important for studies of diseases, disorders, and conditions that
disproportionately affect women or minorities.

Since 1994, the National Institutes of Health has required researchers to provide a clear and compelling
rationale for proposing to conduct a study in a population in which women and minorities are not adequately
represented. (See NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical
Research – Amended October 2001.)

Protection of Vulnerable Participants

Certain groups of participants are considered potentially more vulnerable to coercion to participate in
research. Children, prisoners, economically disadvantaged, or educationally disadvantaged persons are all
considered to be vulnerable populations.

Generally, participants from vulnerable populations should be enrolled only in studies that pertain directly to
their circumstances. For example, pregnant women should be enrolled only in studies in which pregnancy is
pertinent to the research question (e.g., investigating if one treatment strategy is more effective than
another in pregnant substance use disorder).

When participants from vulnerable populations are to be recruited for a study, appropriate additional
safeguards must be included in the protocol to ensure that their rights and welfare are protected. (This issue
is also addressed in the Informed Consent and Institutional Review Boards modules.) However, vulnerable
populations should not be overprotected to the extent that they are excluded from participating in research.

Reasonable Inclusion and Exclusion Criteria

The inclusion and exclusion criteria define precisely who is eligible to participate in the study and who is not.
These criteria must be defined in the study protocol. They must also be carefully reviewed for every potential
participant.

Inclusion criteria are the characteristics that make a potential participant eligible to enroll in a study.
Generally, every potential participant must meet all inclusion criteria in order to be eligible.
Exclusion criteria are the characteristics that prohibit a potential participant from enrolling in a study.
Generally, a potential participant will be ineligible if he or she meets one of the exclusion criteria.

Inclusion and exclusion criteria must be reasonable and appropriate to the study purpose. No individual or
group should be excluded from eligibility to take part in the study without a valid reason. On the other hand,
no individual or group should be included unless they are likely to benefit from applications of the research.

Inclusion and exclusion criteria that are too stringent may make it difficult to recruit an adequate number of
participants into the study. Modification of overly stringent admission criteria for a study can have a
profoundly positive effect on recruitment. On the other hand, inclusion and exclusion criteria that are too
broad may make it more difficult for the study to reach meaningful conclusions and may also result in
increased safety concerns.

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Part 3: Recruitment Strategies

Elements of a Successful Recruitment Strategy

Elements of a successful recruitment strategy include the following:

Avoid specifying unnecessarily restrictive inclusion and exclusion criteria in the protocol.
Develop a compensation strategy that adequately reimburses participants for their time and expenses
without being coercively generous.
Develop a recruitment plan during the protocol planning stage.
Have the necessary recruitment budget for start-up training, advertising, staff time, and other
expenses.
Develop a profile of prospective study participants:
What would motivate prospects to join the study?
From what sources do they obtain information?
What radio and television stations and programs do they listen to and watch?
Where do they live, work, shop, and play?
In what media outlets would it be appropriate to place recruitment advertisements?
Which caregivers and relatives might serve as referral sources?
Review recruitment rates, dropout rates, and screening success rates from previous studies. Identify
and implement strategies that build on previous successes and incorporate lessons learned.
Choose appropriate staff members to conduct recruitment.
Develop a system to track the number of participants enrolled per recruiter per site.
Monitor recruitment carefully and intervene quickly to change recruitment techniques that are proving
unsuccessful.
Identify barriers to recruitment.

In general, recruitment strategies are most effective when they are used together in a coordinated fashion.

Specific Strategies for Recruiting Participants into Clinical

Studies
Contact interested prospects as soon as possible. The longer a prospective participant has to wait
before hearing back from study staff, the less likely it is that he or she will ultimately enroll in the study.
Cultivate potential sources of referrals to the study, network with clinic staff who are not working on the
study, as well as with other local health care providers. Send direct mailings to selected health care
providers.
Give presentations about the study for clinic staff and provide periodic updates on the study’s progress.
Participate in health fairs, speaking engagements, support groups, television and radio interviews, and
other forums.
Ask for public service announcements on radio and television.

Special Considerations in the Recruitment of Individuals with

Substance Use Disorder into Clinical Studies
Researchers wishing to recruit individuals with substance use disorder into clinical studies must ensure that
potential participants are not taken advantage of.

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The National Advisory Council on Alcohol Abuse and Alcoholism has issued guidelines for studies involving
participants with alcohol use disorder. These guidelines apply equally well to studies involving participants
who use drugs other than alcohol. With regard to the recruitment of participants with substance use disorder,
the guidelines state:

People with substance use disorder should not be recruited as participants merely because of their easy
availability, low social or economic status, or limited capacity to understand the nature of the research.
The proposed population for any study must be appropriate in terms of age, sex, familial or genetic
background, prior alcohol use, other drug use, and general medical and psychological condition,
including, if appropriate, alcoholism recovery status.

Ethically Acceptable Strategies for Recruiting Participants into

Clinical Studies
Most study participants are recruited in one of three ways:

Clients already receiving treatment at a research site that are asked to consider enrolling in appropriate
studies.
Other health care providers will refer clients who are potential study participants.
Individuals interested in participating in a study will respond to advertisements placed in newspapers or
flyers as well as advertisements announced on the radio or over the television.

Studies can also use websites to recruit and screen participants. This approach can be especially useful when
recruiting for studies concerned with socially embarrassing diseases or conditions.

All recruitment strategies must be approved by the designated Institutional Review Board (IRB) before
recruitment for a study may begin. In particular, certain rules apply when participants are recruited through
advertising; these rules are discussed in the next section.

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Part 4: Advertising for Study Participants

Advertisements, fliers, and brochures that are prepared to inform potential participants about a study and
recruit them are considered part of the informed consent process. As such, they must be reviewed and
approved by the designated IRB.

Recruitment of participants may not begin until the IRB has approved the protocol, informed consent
documents, and proposed recruitment and advertising materials.

The IRB reviews not only the wording of advertising materials but also the presentation and the intended
mode of communication (e.g., print, radio, television). The purpose of the IRB’s review is to ensure that no
aspect of the advertising materials might be considered coercive or misleading .

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Part 4: Advertising for Study Participants

Interactive: Coercive or Non-Coercive Advertising

Users are instructed to review each of the scenarios given and to answer the question: Would
the IRB consider these scenarios Coercive or Non-Coercive? The consider the feedback.

Scenarios 1: Only clients who agree to enroll in a study will continue to receive treatment.

Feedback: Would the IRB consider this scenario Coercive or Non-Coercive? Making study participation a
condition of continued treatment is not ethical. Therefore, the correct response is Coercive.

Scenarios 2: An employer or counselor says, "I would really appreciate it if you signed up for this study."

Feedback: Would the IRB consider this scenario Coercive or Non-Coercive? Having a person of authority or
influence suggest they would appreciate participation is not ethical. Therefore, the correct response is
Coercive.

Scenarios 3: Study staff handing out fliers about a drug treatment study to passersby on the street.

Feedback: Would the IRB consider this scenario Coercive or Non-Coercive? This is a random and non-invasive
way of recruiting potential study participants. Therefore, the correct response is Non-Coercive.

Scenarios 4: Offer of payment that appears in an advertisement in larger or bolder type than other
information about the study.

Feedback: Would the IRB consider this scenario Coercive or Non-Coercive? Payment cannot be used to
recruit study participants. Therefore, the correct response is Coercive.

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Part 4: Advertising for Study Participants

How might advertising for study participants be misleading?

The following are examples of statements or actions that might be considered misleading:

Saying that a study will involve no invasive procedures when, in fact, participants will be required to
have blood drawn.
Appearing to promise a favorable outcome by:
Using the terms "new treatment," "new medication," or "new drug" without explaining that the
treatment is investigational.
Suggesting that the drug or treatment is equivalent or superior to any other available drug or
treatment.
Offering "free medical treatment" instead of stating that participants will not be charged for
participating in the study.
Making a statement such as "We will cure you in six easy steps."

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Part 5: Retention

Why is retention of study participants important?

Recruitment of an adequate number of participants, although essential, does not in itself assure the success
of a study. Once participants are recruited into a study, they must complete the study to ensure their
information/data can be included in the final analysis.

Unless an adequate number of participants are retained for the duration of the study, investigators may not
obtain enough data to answer the research question they posed, which was the reason for performing the
study in the first place. Also, the cost (in time and resources) of retaining and managing a participant who is
already enrolled is considerably less than the cost of recruiting a new participant.

Retention means assuring that participants:

Undergo study procedures at the required intervals.

Complete questionnaires or responses to interviewers’ questions.
Participate in any other activities required by the study protocol.
Attend follow-up visits as required.

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Part 6: Retention Strategies

Elements of a Successful Retention Strategy

Successful retention involves:

Treating the participant with respect.

Being considerate of the participant’s time.
Identifying and overcoming barriers to retention.
Including retention strategies in the budget.
Identifying and resolving problems in a timely manner.

When devising a retention strategy, the following issues should be considered.

Retention Begins with the Participant’s First Visit

During the first visit, while the participant is going through the informed consent process ensure the
participant understands the time and procedures involved and talk about why it is important to complete all
the required study procedures and visits. Often, study templates or electronic CRFs are created to record a
participant’s contact information, also called locator forms. Using a locator form, the study staff may record
the participant’s address, phone number, and contact information for friends and family members who may
be called, of course, with the consent of the participant. This information will help the clinic to locate the
participant later if he or she misses a visit.

Retention is an Ongoing Process

Do not wait until the last participant is enrolled before starting to think about retention. Devise retention
strategies during the study design phase. Depending on the population being studied, it may be beneficial to
review the participant’s contact information with him or her at every visit. For example, many individuals
with substance use disorder change their home address or job frequently. Ensure that up-to-date contact
information is always on file for every participant.

Retention is Everyone’s Responsibility

All clinic staff should be trained to understand the importance of maintaining up-to-date contact information
for all participants. A participant may casually mention at any time that he or she is about to move, change
jobs, or change his or her marital status. This information should be recorded in the participant’s file and
communicated to all members of the research team.

Specific Strategies for Retaining Participants in a Clinical Study

Stress the importance of compliance during the informed consent interview and throughout the study.
Establish rapport with participants.
If a participant cannot be found and has not withdrawn consent, use the participant's contact
information to try to find him or her. Telephone the participant’s home, telephone his or her contacts, or
(if the participant has given consent for home visits) visit the participant’s home.
Use public information to try to locate the participant. For example, in some states, the motor vehicle
administration and other government agencies will release an individual’s contact information if it is

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considered to be part of the public record.
Consider amending the protocol to ease or eliminate assessments or other procedures that participants
find disagreeable and that may deter retention.
Use regular teleconferences to brainstorm retention strategies with local and national project staff.
Send reminder notes to let the participant know you will be calling shortly to perform or schedule their
next assessment.
Conduct research interviews at a location convenient for the participant.
Offer participants transportation to and from the study site.
Be persistent and document all attempts to contact participants — keep trying.
Ensure that all of these efforts preserve the privacy of the participant.

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Part 7: Using Incentives for Study Participation

Use Incentives for Study Participation

Research participants may be offered rewards such as monetary payments, free medical care, extra vacation
time, food, and lodging. Such rewards are not considered benefits of study participation but rather incentives
for participation.

Receiving a monetary payment, or receiving something for free that would normally have to be paid for, is
an inducement. Any inducement may be coercive or an undue influence on a potential study participant.
People who are poor or needy may be induced to do something, possibly against their better judgment, by
the offer of money or another reward.

Because incentives for participation are potentially coercive, the amount and conditions of such incentives
must be reviewed and approved by the IRB (See related material from the Institutional Review Boards
module).

Is it ethical to offer incentives to people with substance use

disorder to participate in research?
Many potential participants in drug and alcohol research are unemployed or otherwise economically
disadvantaged. Concerns about unduly influencing such participants have led some investigators to decline
to offer any incentives for study participation. It is unfair, however, to assume that any remuneration that is
given to participants with substance use disorders will serve as an undue influence.

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Part 7: Using Incentives for Study Participation

Interactive: Study Recruitment - Criteria for Incentives

Users are instructed to complete the statements below with “should” or “should not” to make
the criteria correct. Then consider the feedback.

1. Incentives offered to any potential research participants, including those with substance use disorders,
_______________ be valuable enough to: induce participants to enter or remain in a study
against their better judgment.

Feedback: Which did you choose: Should or Should Not? The correct response is Should Not. Incentives
should not be valuable enough to: induce participants to enter or remain in a study against their better
judgment.

2. Incentives offered to any potential research participants, including those with substance use disorders,
_______________ be valuable enough to: enable recruitment of an adequate number of
participants.

Feedback: Which did you choose: Should or Should Not? The correct response is Should. Incentives
should be valuable enough to: enable recruitment of an adequate number of participants.

3. Incentives offered to any potential research participants, including those with substance use disorders,
_______________ be valuable enough to: compensate participants for the time and
inconvenience of study participation.

Feedback: Which did you choose: Should or Should Not? The correct response is Should. Incentives
should be valuable enough to: compensate participants for the time and inconvenience of study
participation.

4. Incentives offered to any potential research participants, including those with substance use disorders,
_______________ be given for taking risks.

Feedback: Which did you choose: Should or Should Not? The correct response is Should Not. Incentives
should not be given for taking risks.

5. Incentives offered to any potential research participants, including those with substance use disorders,
_______________ be given for taking medications.

Feedback: Which did you choose: Should or Should Not? The correct response is Should Not. Incentives
should not be given for taking medications.

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Part 7: Using Incentives for Study Participation

Guidelines for Establishing Appropriate Incentives for Study

Participation
Three issues must be considered in determining the appropriateness of incentives for participation in a
study.

Monetary Value
The value of an incentive should reflect the burden posed by participation in the study. The value should not
be so high that the incentive could be considered coercive or an excessive influence on an individual’s
decision to participate in a study.

Method and Timing of Payment

Incentive credits should accrue as the study progresses. Payment should not be conditional on the
participant’s completion of the entire study. However, it may be acceptable to create a payment schedule
that provides some incentive for the participant to complete the study. The completion bonus should not be
large enough to induce participants to remain in the study when they would otherwise have withdrawn.

In some circumstances, participants who withdraw from a study may be paid at the time they would have
completed the study had they not withdrawn. For example, if a study lasts for only a few days, it may be
acceptable to pay all participants on study completion, including those who withdrew.

Forms of Payment
Forms of payment may include cash, store gift cards, money orders, or check cards. Some IRBs are reluctant
to approve cash payments for certain populations, such as substance use disorder populations out of
concern that these individuals might use study payments for drug purchases. On the other hand, avoiding
cash payments can be viewed as paternalistic and disrespectful. Some forms of payments, such as money
orders or check cards, may require the individual to show identification, which can be a potential problem for
some populations, such as those with substance use disorder. Payments over a certain amount may also be
subject to taxes, and the participant should be made aware of this.

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Part 8: What to do when a Participant Leaves a Study

The study protocol should include criteria for withdrawal and procedures for when a participant voluntarily
leaves a study, is withdrawn early from the study for safety concerns, or is discharged after completing a
study. The protocol should specify:

When and how to withdraw participants.

What type of data, if any, will be collected for withdrawn participants.
Whether follow-up of some or all participants that have been withdrawn from the study may occur.

Common end-of-study procedures include, but are not limited to, a closing interview, referral, and follow-up
for a specified period of time.

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Part 8: What to do when a Participant Leaves a Study

CLOSING INTERVIEW

The closing interview is important because it is the final opportunity to obtain study data and likely the last
contact the research team will have with the study participant. This interview also provides an opportunity to
document any adverse events the participant experienced that may need follow-up after the study ends.

REFERRALS

The research team is responsible for ensuring that a participant who leaves the study has any referrals that
he or she needs to obtain services or help elsewhere, if desired.

FOLLOW-UP

Some protocols include a requirement for a follow-up interview to be conducted at a predetermined time
point (e.g., one month) after the participant is discharged from the active treatment phase of the study. It
may be helpful to remind the participant of this requirement during the closing interview and, if possible, to
schedule the day and time of the follow-up interview. Also, review the participant's locator form to ensure
that all contact information is up-to-date.

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Part 8: What to do when a Participant Leaves a Study

Most trial participants view the experience positively and would be open to participating in another trial if
asked. Gaining acceptance to contact a participant for future studies is often part of the informed consent
document and process. In order not to squander this potential resource, keep participants who have
completed a study informed to the extent possible of the study’s status and findings and let them know that
their participation was valuable. Such efforts can also serve as “word-of-mouth” advertising. A thank-you
card or certificate of appreciation can indirectly serve as a recruitment tool for the study, as well as for future
studies.

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Part 9: Summary of Key Points

Recruitment and retention of participants are key to the success of any clinical study.
A successful recruitment and retention strategy requires informed and detailed planning, commitment
of adequate resources, careful monitoring, and timely identification and resolution of problems.
Recruitment of participants may not begin until the Institutional Review Board (IRB) has approved the
protocol, informed consent documents, and proposed recruitment and retention strategies.
Advertisements, fliers, and brochures that are prepared to recruit potential participants and inform
them about a study are considered part of the informed consent process. As such, they must be
reviewed and approved by the IRB (see ICH GCP 3.1.2).
Recruitment for a study has two major elements:
Defining a population of appropriate participants to answer the research question.
Recruiting appropriate participants in an ethical manner.
Recruitment of an adequate number of participants, although essential, does not in itself assure the
success of a study. Unless an adequate number of participants are retained for the duration of the
study, investigators will not obtain enough data to answer the research question they posed, which was
the reason for performing the study in the first place.
Research participants may be offered rewards such as monetary payments or medical care at no cost.
Such rewards are not considered benefits of study participation but rather incentives for participation.
Because incentives for participation are potentially coercive, the amount, form, and conditions of such
incentives must be reviewed and approved by the IRB (see ICH GCP 3.1.8).

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Contents

Part 1: Introduction
Part 2: Phases of Clinical Trials of Investigational New Drugs
Part 3: Investigational New Drugs Requirements
Part 4: Investigational New Drugs Responsibilities
Part 5: Summary of Key Points

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Part 1: Introduction

Definition of an Investigational Product

ICH GCP defines an investigational product as,

“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a

clinical trial” (ICH GCP 1.33).

This may include a marketed product that is being used in a different form than the one it was approved for,
or a marketed product being used for an unapproved or new indication.

Definition of an Investigational New Drug

The Code of Federal Regulations (CFR) defines an investigational new drug as:

"...a new drug or biological drug that is used in a clinical investigation."

In the U.S. Food and Drug Administration (FDA) regulations, an investigational new drug is any substance
(such as a drug, vaccine or other biological product) for which FDA approval is being sought.

A drug may be considered “new” even if it has been in use for years if a change is proposed in its use,
formulation, route of administration, use in patient population where risk would be increased, or packaging.
For example, years ago the FDA approved a drug to treat high blood pressure. The manufacturer of the drug
now wants to test it as a treatment for anxiety in adults. This new use of the drug would be considered
investigational.

In a study protocol and other documents, an investigational new drug may be referred to as the “study
drug,” “experimental product,” “experimental drug,” “new intervention,” or similar term. Investigational new
drugs are regulated under CFR Title 21 Part 312 (21 CFR 312).

Labeling of an Investigational New Drug

The labeling of an investigational new drug:

Must include the following statement: “Caution: New Drug — Limited by Federal (or United States) law
to investigational use.”
Must not be false or misleading and should not imply that the drug is safe or effective for the
investigational purpose.

Control of an Investigational New Drug

An investigational new drug may be given to participants only under supervision by the principal investigator
or by a sub-investigator. (Usually, the person supervising the administration of an investigational new drug is
a physician.) The investigator cannot supply the investigational new drug to any person who is not
authorized to receive it.

Research that involves the use of controlled substances must comply with U.S. Drug Enforcement
Administration regulations (21 CFR 1300-end). When studying an investigational new drug that is considered
a controlled substance, the investigator must take adequate precautions to prevent theft or diversion of the

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drug into illegal channels of distribution. Such precautions include storing the investigational new drug "in a
securely locked, substantially constructed cabinet or other securely locked, substantially constructed
enclosure, access to which is limited."

Promotion of and Charging for Investigational New Drugs

Neither an investigator nor a sponsor may promote (that is, endorse or advertise) an investigational new
drug as safe or effective for the investigational purpose. In addition:

An investigational new drug cannot be distributed commercially or in a test market.

An investigation cannot be prolonged “after finding that the results of the investigation appear to
establish sufficient data to support a marketing application.” In other words, if there is good evidence
that the investigational new drug is safe and effective, the study should be stopped and no other
participants enrolled.
Charging for an investigational new drug in a clinical trial is not permitted without approval from the
FDA unless the drug is being provided for treatment use.

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Part 2: Phases of Clinical Trials of Investigational New Drugs

Clinical trials of an investigational new drug are generally conducted in four phases, Phase 1 to Phase 4.
Phase 0, or “exploratory” trials, also exist as small clinical trials (sometimes only a few participants) that
involve dosing at a sub-therapeutic level. Phase 0 trials are not as prevalent as Phases 1-4. Each phase is
designed to find out different information. Although the phases of a trial are usually conducted sequentially
(one after another), they sometimes overlap.

Individuals may be eligible for studies in different phases, depending on their age, general condition, the
type and stage of their disease, and previous therapy, if any.

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Part 2: Phases of Clinical Trials of Investigational New Drugs

PHASE 1 Trials

Phase 1 trials are the first studies of an investigational new drug in humans. They are usually conducted in
healthy volunteers. In some cases, Phase 1 trials may be conducted in individuals who have the disease the
drug is intended to treat. Phase I trials generally involve between 20 and 80 participants.

Phase 1 trials are designed to:

Make a preliminary determination of the drug's safety in humans.

Identify some of the side effects associated with the drug's use.
Begin to define a safe therapeutic (healing) dose range.

PHASE 2 Trials

Phase 2 trials are usually conducted in individuals who have the disease the drug is intended to treat or are
at high risk for developing the disease. Phase 2 trials are larger than Phase 1 trials but still relatively small,
usually involving no more than several hundred participants.

Phase 2 trials are designed to:

Begin to evaluate the drug's effectiveness in treating or preventing the disease or condition of interest.
Determine the optimal dosing of the drug.
Determine the common short-term side effects and risks associated with the drug.

PHASE 3 Trials

Phase 3 trials are conducted after preliminary evidence from Phase 1 and 2 trials suggests that the
investigational new drug is safe and effective. They usually include between several hundred and several
thousand participants.

Phase 3 trials are designed to:

Gather additional information about the drug's safety and effectiveness to evaluate whether its benefits
outweigh its risks.
Compare it to other commonly used treatments for the same condition (if available) or compared to a
placebo. These studies can be performed in a blinded manner.
Evaluate interactions with other treatments that may be used at the same time as the investigational
new drug.
Provide adequate information to determine the indication for which the drug will be labeled if it is
approved for marketing as well as any limitations on the drug's use that should be stated in the
labeling. For example, if there were insufficient information to show that a drug can safely be given to
children, the labeling would restrict the drug's use to adults.

PHASE 4 Trials
Phase 4 trials are conducted after the drug or treatment has been approved for marketing. They are
designed to:

Continue testing the drug or treatment to collect additional short-term safety information.
Collect information about the effect of the drug or treatment in various populations.
Collect information about side effects associated with long-term use of the drug.

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Part 3: Investigational New Drugs Requirements

The Investigational New Drug Application

A sponsor who wishes to conduct a clinical trial that involves an investigational new drug must submit an
Investigational New Drug application (IND) to the FDA. In IND studies, the IND holder is considered to be the
sponsor.

Information that must be provided in an IND

Information that must be provided in an IND includes the following:

The identity and contact information of the sponsor and the phase (or phases) of the trial.
A commitment that an IRB will be responsible for initial and continuing review of the trial.
The name of the drug, a list of its active ingredients, and its dosage and route of administration.
The objectives and planned duration of the proposed clinical trial(s).
A brief description of the plan for investigating the drug, including:
The reasoning behind the drug or the study,
The indication(s) to be studied,
The kinds of clinical trials to be conducted in the first year after the IND submission,
The estimated number of patients who will be given the drug in the clinical trial(s), and
Any serious risks that are anticipated on the basis of animal studies or previous human studies of
this drug or related drugs.
For most trials, a copy of the investigator's brochure.
A protocol for each planned study. (See related material summarized from The Research Protocol
module.)
The identities and qualifications of all investigators. (As demonstrated in a Curriculum Vitae and Form
FDA 1572. Click here for instructions on completing Form FDA 1572.)
The criteria for patient selection and exclusion and an estimate of the number of patients to be studied.
A summary of previous experience with the drug in both animal and human studies, including (if
relevant):
Previous INDs,
Experience with the drug in other countries,
Known safety issues, chemistry and manufacturing information, and
Dependence and misuse potential.

When an IND Goes Into Effect

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An IND is considered safe to proceed 30 calendar days after the FDA receives it unless:

The FDA notifies the sponsor that the investigation described in the IND is subject to a clinical hold, or
The sponsor receives written permission from the FDA to begin the study before 30 days have elapsed.

At the sponsor's request, the FDA will provide advice on specific matters relating to an IND. Meetings
between a sponsor and the FDA are frequently useful, and the FDA encourages such meetings to the extent
that FDA resources permit.

IND Exemptions for Studies of Lawfully Marketed Drugs

Studies of lawfully marketed drugs are exempt from the IND regulations if they meet all five of the criteria
listed in 21 CFR 312.2(b)(1). The first four of these criteria are straightforward and need no special comment.

The study is not intended to support approval of a new indication or a significant change in the
product's labeling.
The study is not intended to support a significant change in the product's advertising.
The study is conducted in compliance with Institutional Review Board (IRB) and informed consent
regulations.
The study will not be used to promote non-approved indications.

The final criterion, however, requires interpretation.

The investigation does not involve a route of administration, dosage level, use in a patient population,
or other factor that significantly increases the risks (or decreases the acceptability of the risks)
associated with the use of the drug.

It is the investigator's responsibility to determine whether an IND is necessary for a study that involves a
marketed drug. A critical question in determining whether such a study is exempt from IND regulation is
whether the study “significantly increases the risk” associated with use of the drug.

If an investigator is quite sure that a drug study does not require an IND, he or she can simply not submit an
IND application. If the investigator is doubtful about whether an IND is required, or wishes to have proof of
the IND-exempt status of a study, the IND application can be submitted with an exemption from IND
guidelines requested, and FDA staff will review the application to determine whether the study is exempt.
The review is limited to critical safety concerns (dose, schedule, route, and patient population). If, after this
limited review, the FDA determines that a study is exempt from the requirement for an IND, it performs no
further review of the application. The FDA sends a letter to the sponsor giving notice of the exemption. Prior
to submission of the application, the sponsor can also set up a pre-IND meeting with the FDA in order to
discuss any questions or concerns.

IND Protocol Amendments

The sponsor of an IND must submit a protocol amendment to the FDA:

To describe any change in a Phase 1 protocol that significantly affects the safety of participants; or
To describe any change in a Phase 2 or Phase 3 protocol that significantly affects the safety of
participants, the scope of the investigation, or the scientific quality of the study.

The following are examples of changes that would require the submission of a protocol amendment to the
FDA:

An increase in drug dosage or in the duration of participants' exposure to the drug.

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 A significant change in the study design, such as the addition or elimination of a control group.
The addition of a new test or procedure to improve monitoring for, or to reduce the risk of, an adverse
event, or the dropping of a test intended to monitor safety.
The protocol amendment can be implemented at study sites after the amended protocol has been
submitted to and approved by the reviewing IRB, and submitted to the FDA.

A protocol change that is intended to eliminate an apparent immediate hazard to participants may be
implemented immediately, provided that:

The FDA is subsequently notified of the change by a protocol amendment, and

The reviewing IRB is also notified of the change in accordance with the IRB's rules.

IND Safety Reports

Sponsors must promptly review and investigate all information they receive relevant to the safety of an
investigational new drug that is received from any source, foreign or domestic, including information derived
from:

Clinical or epidemiological studies,

Animal studies,
Commercial marketing experience,
Reports in the scientific literature,
Unpublished scientific papers, and
Reports from foreign regulatory authorities.

The sponsor must notify the FDA of any unexpected fatal or life-threatening experience associated with the
use of the drug as soon as possible but not later than 7 calendar days after the sponsor's initial receipt of the
information. Sponsors must provide written notification to the FDA and to all investigators participating in a
trial within 15 calendar days of any adverse event that is:

Both serious and unexpected, and

Reasonably likely to have been caused by the investigational new drug.

Subsequent, appropriate follow-up information must also be submitted, as it becomes available.

The sponsor must also provide written notification of any finding from tests in laboratory animals that
suggests a significant risk for human participants. The written notification must be provided as soon as
possible and no later than 15 calendar days after the sponsor receives the information.

IND Information Amendments and Annual Reports

A sponsor must file an information amendment to report essential information about the IND that is not
within the scope of a protocol amendment, IND safety report, or annual report. The following are examples of
information that requires the filing of an information amendment:

New information about technical features of the drug, such as its toxicology or chemistry.
Discontinuation of a clinical investigation.

Within 60 days of the first anniversary of the date the IND went into effect, and every subsequent year, a
sponsor must submit a brief report of the progress of the investigation. This annual report must include:

A brief summary of the status of each study in progress or completed.

A summary of the most frequent and most serious adverse experiences.
A summary of all IND safety reports submitted.
A list of participants who died during participation in the investigation, with the cause of death for each
participant.
A list of participants who dropped out as a result of any adverse experience, whether or not the adverse
experience is thought to be related to the investigational new drug.
A summary of the general investigational plan for the upcoming year.
An updated Investigator's Brochure, if available.
A summary of any foreign market developments.
A summary of any outstanding business with the FDA regarding the IND (i.e. a response to an FDA
request for information).

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Part 4: Investigational New Drugs Responsibilities

Responsibilities of Sponsors

Both sponsors and investigators who are involved in conducting a clinical trial under an IND filed with the
FDA must accept and fulfill certain responsibilities.

Sponsors' responsibilities include:

Selecting qualified investigators.

Providing investigators with the information they need to conduct the investigation.
Ensuring proper monitoring of the trial.
Ensuring the trial is conducted according to the plan and protocols contained in the IND.
Informing the FDA and all investigators of significant new adverse effects or risks that are reasonably
likely to be caused by the investigational new drug.
Maintaining proper records.
Disposing of unused supplies of the investigational new drug.

Unless the sponsor is a sponsor-investigator, the sponsor does not actually conduct the investigation.

Based on GCP guidelines, other Sponsor responsibilities include (ICH GCP E6, 5.12; 5.13; 5.14):

Ensuring that the Investigational Product is manufactured in accordance with Good Manufacturing
Practices.
Ensuring that Investigational Product is packaged in a way that prevents contamination and
unacceptable deterioration during transport and storage.
Supplying investigators/institutions with the Investigational Product.
Having written procedures that include instructions on the handling and storage of Investigational
product that sites should follow.
Maintaining sufficient quantities of the Investigational Product used in the trial to reconfirm
specifications should the need arise.

The above represent good examples of responsibilities the Sponsor may transfer to a Contract Research
Organization (CRO), such as a clinical coordinating center. However, the ultimate responsibility for
Investigational Product resides with the Sponsor. Any Investigational Product-related duties and functions
that are transferred to and assumed by a CRO are specified in writing.

Responsibilities of Investigators

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Investigators' responsibilities include:

Providing the sponsor with a completed, signed Statement of Investigator. (Form FDA 1572. Click here
for instructions on completing this form.)
Conducting the trial in accordance with the signed investigator statement, protocol, and applicable
regulations.
Protecting the rights, safety, and welfare of trial participants.
Obtaining informed consent from all trial participants.
Maintaining proper records.
Furnishing all required progress reports, safety reports, financial disclosure reports, and a final report.
Complying with Institutional Review Board review. and
Ensuring the proper handling of controlled substances.

This topic is also discussed in the Roles and Responsibilities module.

Based on GCP guidelines, other Investigator responsibilities include (ICH GCP E6, 4.6):

Ensuring Investigational Product accountability

Assigning duties for Investigational Products to a pharmacist or an appropriate individual who has the
necessary license for dispensing
Maintaining records of the Investigational Product from delivery at the site to dispensing to the
participant as well as use by the participant, return by the participant, and reconciling all product prior
to destruction.
Ensuring that the Investigational Product is used in accordance with the approved protocol
Explaining the correct use of the Investigational Product to each participant and checking at intervals
that each participant is following instructions properly.

Click to view Clinical Trial Network related content

CTN

Why is the regulation of investigational new drugs relevant to

the Clinical Trials Network?
Studies performed within the NIDA Clinical Trials Network (CTN) that involve an investigational drug must be
carried out in accordance with the investigational new drug regulations.

The investigational new drug regulations are enacted to:

Protect the safety of research participants,

Ensure that participants are not exposed to experimental drugs or procedures unnecessarily, and
Protect participants' rights.

It is important, however, that all members of the CTN — not only those involved with studies of
investigational new drugs — understand the basics of these important regulations because the reasoning
behind the investigational drug regulations applies to all research involving human participants, including
the International Council for Harmonization Good Clinical Practice guidelines.

These principles are equally applicable to behavioral research, or to medication studies not requiring an IND,
even though these studies do not involve an investigational new drug. Research participants should not be
exposed to any experimental intervention unnecessarily, in an unsafe manner, or in a manner that fails to
protect their rights.

Although behavioral studies and IND-exempt medication studies conducted in the CTN are not subject to the
requirement to submit IND safety reports to the FDA, CTN members who conduct such studies must submit
Adverse Event/Serious Adverse Event information and reports to the DSMB Medical Monitor at NIDA. All CTN
members should be familiar with the similarities and differences in terminology and reporting requirements
between reports required by NIDA and those required by the FDA.

Read more...

Guidance Documents
The FDA has incorporated the concept of Good Clinical Practice (GCP) into agency guidance documents,
which are intended to help researchers comply with GCP regulations. Guidance on Good Clinical Practice may
be found in the following documents:
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 FDA’s Good Clinical Practice: Consolidated Guideline (April 1996)
Clinical Investigation of Medicinal Products in the Pediatric Population
Choice of Control Group and Related Issues in Clinical Trials (May 2001)
Investigational New Drug Applications Prepared and Submitted by Sponsor-Investigators (2015)

Although these guidance documents are not binding, they reflect the FDA’s current thinking about the
interpretation of the regulations. Many guidance documents are available on the FDA’s Website. (Click here
for a list of available guidance documents.) Guidance documents are also published in the Federal Register.

Guidance documents used internationally include both the:

International Conference on Harmonization Good Clinical Practice guidelines E6, and

International Conference on Harmonization Good Clinical Practice guidelines E8.

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Part 4: Investigational New Drugs Responsibilities

Interactive: Investigational New Drugs

Users are instructed as follows:

The three investigators below are planning clinical trials that involve substance use treatment. Read about
each of their trials, and then make a decision: Which Investigator needs to file an Investigational New Drug
Application prior to initiating the study? Then, consider the feedback.

A) Dr. Alvin

Marketed drug with a change in the indication

Dr. Alvin’s trial will see if participants taking a marketed drug, currently used to treat anxiety, will have any
use for relapse prevention in adults with cocaine dependence. Dr. Alvin is planning a small pilot study first,
using the drug at doses currently used clinically, but with a reduction in dosing frequency. If the results are
good, a larger study will be planned.

B) Dr. Bluth

Two marketed drugs in a head to head comparison for the same condition

Dr. Bluth has been approached by a small pharmaceutical company to run a comparison study of two
products, both currently marketed to help adults quit smoking. The company has just gained FDA approval of
their drug and want to use the data from Dr. Bluth's study in advertisements and in a journal article.

C) Dr. Carey

Combination drug treatment for tobacco and stimulant dependence

Dr. Carey is planning a trial to determine if smokers who are currently receiving FDA-approved treatment for
stimulant dependence can benefit from taking an FDA-approved treatment to help them stop smoking. The
goal is to see if stopping a patient from smoking helps with their stimulant dependence. Dr. Carey is drafting
a grant for NIH to hopefully support this study.

Feedback: Which Investigator needs to file an Investigational New Drug Application prior to initiating the
stud: (A) Dr. Alvin, (B) Dr. Bluth, or (C) Dr. Carey?

A) Dr. Alvin

Feedback: Dr. Alvin is exempt from the IND application because the trial involves 1) a product lawfully
marketed in the US 2) not intended to be reported to FDA as a well-controlled study in support of a label
change 3) not intended to support a change in advertising for the drug 4) the study does not increase the
risk associated with the use of the drug. Dr. Alvin will still need approval by the local IRB and ensure patients
are consented. Dr. Bluth’s trial requires an IND application because it is conducting a ‘head to head’
comparison study which, although within the approved labels for both drugs, will be used to make a
significant change to the advertising for the drug. Therefore, A is an incorrect response.

B) Dr. Bluth

Feedback: Dr. Carey is exempt from the IND application because the trial involves 1) two products lawfully
marketed in the US 2) not intended to be reported to FDA as a well-controlled study in support of a label
change 3) not intended to support a change in advertising for the drug 4) the study does not increase the
risk associated with each use of the drug. Dr. Alvin will still need approval by the local IRB and ensure
patients are consented. Dr. Bluth’s trial requires an IND application because it is conducting a ‘head to head’
comparison study which, although within the approved labels for both drugs, will be used to make a
significant change to the advertising for the drug. Therefore, C is an incorrect response.

C) Dr. Carey

Feedback: Dr. Bluth must submit an IND application because, although the trial involves testing two legally
marketed drugs within the approved label, the goal of the study is to make a significant change to the

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advertising materials used from the drug, by, hopefully, saying that drug X is better or safer than drug Y in
helping patients stop smoking. Therefore, the correct response is B.

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Part 5: Summary of Key Points

ICH GCP refers to an Investigational Product as a pharmaceutical form of an active ingredient or placebo
being tested or used as a reference in a clinical trial.
In FDA regulations, an investigational new drug is any substance (such as a drug, vaccine, or biological
product) for which FDA approval is being sought.
A drug may be considered “new” even if it has been in use for years if a change is proposed in its use,
formulation, route of administration, or packaging.
A sponsor who wishes to conduct a clinical trial that involves an investigational new drug must submit
an Investigational New Drug application (IND) to the FDA. Lawfully marketed drugs are exempt from the
IND regulations if they meet certain criteria.
Behavioral studies (like the ones conducted in the CTN) are not subject to investigational new drug
regulations. Moreover, certain medication studies may be IND-exempt. It is important, nonetheless, that
all researchers understand these regulations. The principle that research participants should not be
exposed to experimental interventions unnecessarily, in an unsafe manner, or in a manner that fails to
protect their rights is equally applicable to all studies involving human participants.

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