INSTITUTIONAL REVIEW BOARDS

Structure

An Institutional Review Board (IRB) is an independent body established to protect the

rights and welfare of human research participants. Under Title 45 Part 46 of the Code of
Federal Regulations (45 CFR 46), any research that is federally funded must be reviewed
and approved by an IRB.

Any clinical investigation involving a product regulated by the U.S. Food and Drug
Administration (FDA) must also be reviewed and approved by an IRB (21 CFR 56).
Individual institutions or sponsors may require that all research, no matter how it is funded,
be reviewed and approved by an IRB.

An IRB has specific authority over the conduct of research under its jurisdiction. No
clinical study may begin enrolling participants until it has received IRB approval. The IRB
has the authority to:

 Approve, disapprove, or terminate all research activities that fall within its local
jurisdiction according to relevant federal regulations and institutional policy.
 Require modifications in protocols, including protocols of previously approved
research.
 Require that participants be given any additional information that will assist them in
making an informed decision to take part in research. (Requirements for informed
consent are covered in the Informed Consent module.)
 Require documentation of informed consent or allow a waiver of documentation.
(Documentation of informed consent is covered in the Informed Consent module.)
Every institution that participates in research studies must identify an IRB to review and
approve those studies. The IRB must follow the requirements of 45 CFR 46 (described in
this module) and of the Office for Human Research Protections. Some research sites are
under the jurisdiction of two or more IRBs. In these cases, the IRBs may perform joint
review, separate review or agree to abide by the review of one of the involved IRBs.

This module provides an overview of the regulations governing IRBs. Many of the topics
covered here are also addressed in other modules of this training program. Links to those
topics are provided where relevant.

The purpose of an IRB is to safeguard the rights, safety, and well–being of all human
research participants. The IRB fulfills this purpose by:

 Reviewing the full study plan (see section IRB responsibilities for the documents
which comprise a full protocol) for a research study to ensure that the research
 meets the criteria specified in 45 CFR 46.111. (See summarized Criteria for IRB
approval of research.)
 Confirming that the research plans do not expose participants to unreasonable risks.
 Reviewing and approving proposed payments or other compensation to study
participants.
 Ensuring that human participant protections remain in force throughout the research
by conducting continuing review of approved research. This continuing review is
conducted at intervals appropriate to the degree of risk posed by each study, but not
less frequently than once a year.
 Considering adverse events, interim findings, and any recent literature that may be
relevant to the research.
 Assessing suspected or alleged protocol violations, complaints expressed by
research participants, or violations of institutional policies.
 Reviewing proposed changes to previously approved studies.
The IRB may suspend or terminate ongoing research that:

 Is not being conducted in accordance with IRB requirements, or

 Is associated with unexpected or serious harm to participants.
The IRB may also suspend or terminate research when additional information results in a
change to the study's likely risks or benefits.

An IRB must have a diverse membership that includes both scientists and non-scientists.
Scientific members may include researchers, physicians, psychologists, nurses, and other
mental health professionals. Non-scientific members of an IRB may have special
knowledge of a certain population (pregnant women, children, or prisoners).

Collectively, IRB members must have the qualifications and experience to review and
evaluate the scientific, medical, behavioral, social, legal, and ethical aspects of a proposed
study. An IRB must have at least five members. However, it may have as many members as
necessary to perform a complete and adequate review of research activities. The following
table lists the minimum criteria for IRBs based on ICH guidelines as well as FDA
guidelines for research in the U.S.
Diversity of Membership
IRB membership must be diverse in terms of race, gender, and cultural heritage. Members
must be sensitive to issues such as community attitudes.

Every effort must be made to ensure that no IRB consists entirely of men or entirely of
women. However, no one can be appointed to an IRB solely on the basis of gender.

No IRB may consist entirely of members of one profession.

Each IRB should include at least one member whose primary concerns are in scientific
areas and one member whose primary concerns are in non-scientific areas.

Each IRB should include at least one member who is not affiliated with the institution or
study site.

Knowledge of Vulnerable Populations

If the IRB reviews research that involves vulnerable populations — such as children,
prisoners, pregnant women, or disabled or cognitively impaired persons — its membership
should include one or more persons who are knowledgeable about and/or experienced in
working with these populations. The individuals specializing in vulnerable populations may
be fulltime voting members or alternates to fulltime voting members.
Conflicts of Interest
No IRB member may participate in the review of any project in which he or she has a
conflicting interest, except to provide information requested by the IRB.

An investigator may be a member of an IRB. However, the investigator (or any other IRB
member) cannot participate in the review or approval of any research in which he or she has
a current or potential conflict of interest. The investigator should be absent from the
meeting room while the IRB discusses and votes on the research in which he or she has an
interest.

Non-Voting Members
The IRB may invite individuals with competence in special areas to assist in the review of
issues that require expertise beyond or in addition to that of the IRB members. These
consultants are not voting members of the IRB. However, when research involves
vulnerable populations, individuals specializing in these areas must be voting members of
an IRB and maintained on the IRB roster accordingly.

Provision of an Infrastructure to Support the Ethical Review of Proposed and

Ongoing Research
This infrastructure includes the following IRB processes:
 Perform its functions according to written operating procedures.
 Maintain written records of its activities and minutes of its meetings.
  Comply with all applicable federal and state regulatory requirement(s).
 Should review a proposed clinical trial within a reasonable timeframe.
 Make its decisions at announced meetings at which a quorum is present.
 Retain all relevant records (e.g., written procedures, membership lists, lists of
occupations/affiliations of members, submitted documents, minutes of meetings,
and correspondence) for a period of at least 3 years after completion of a study and
make them available upon request from any regulatory authority.
 Notify investigators promptly in writing of its decisions, stating the reasons for
those decisions and noting the procedures for appeal.
Reviewing and Understanding the Full Plan of Study
To provide a full review, the IRB should obtain the following documents (examples of
information included in a full plan of study):
 Study protocol(s) and protocol amendment(s).
 Written Informed Consent Form(s) and consent form updates that the investigator
proposes to use.
 Documents and other media relating to participant recruitment procedures (e.g.,
advertisements).
 Written information to be provided to participants including questionnaires and
explanatory materials.
 Information about payments and compensation available to participants.
 Investigator's Brochure.
 Available safety information, including references to relevant literature.
 Investigator's current curriculum vitae and/or other documentation that provides
evidence of the investigator's qualifications.
 Any other documents needed to fulfill the IRB's responsibilities.
Keeping a Written Record of IRB Decisions
The following written records should be kept pertaining to an IRB's review of a proposed
study:
 Identification of the study.
 List of documents reviewed.
 Decision reached:
 Approval.
 Disapproval.
 Rationale for disapproval.
 Termination or suspension of prior approval.
 Date decision was reached.
 Correspondence with the investigator.
Considering the Investigator's Qualifications
The IRB should consider the qualifications of the investigator for the proposed study, as
documented by a current curriculum vitae or other relevant documentation.

Conducting Continuing Review of Ongoing Studies

The IRB conducts continuing review of each ongoing study at intervals appropriate to the
degree of risk to human participants. By regulation, this interval must be at least once per
year.

Requesting More Information When Necessary

The IRB may request more information to assist in their review. One of the reasons for
such a request would be when the IRB judges that the additional information would add
meaningfully to the protection of the rights, safety, or well-being of participants.

Reviewing Incentives for Participation

Payment to participants for their participation in a research study must never be coercive in
either amount or method of distribution. (This issue is also discussed in the Informed
Consent module.)
The IRB should review both the amount and method of payment to participants to assure
that neither exerts undue influence on study participants. Payments to participants should
be prorated (divided in a proportional manner) and not entirely contingent on a participant's
completion of the study (no large, consolidated payment at the end).
The IRB should confirm that information regarding payment to participants, including the
methods, amounts, and schedule of payments to study participants, is justified by the
protocol and set forth in the written Informed Consent Form and any other written
information provided to participants. The way payment will be prorated should be
specified.
Some IRBs have written requirements concerning what is adequate compensation for study
participants. Investigators should be familiar with these requirements before submitting a
protocol to the IRB for approval.

Criteria: Risks to Participants are Minimized

The IRB should ensure that procedures used in the proposed research are consistent with
sound research design, that they do not expose participants to risk unnecessarily, and, when
appropriate, involve diagnostic or treatment procedures that pose no further risk
The Belmont Report, the report of the National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research established three key principles that
underlie the current system of human research protections: respect for persons, beneficence
(do no harm/maximize possible benefits and minimize possible harms), and justice. These
principles are the basis for the criteria for Institutional Review Board (IRB) approval of
research (Reference: The Belmont Report).
Criteria: Informed Consent is Properly Obtained and Documented
The IRB must review the informed consent form and ensure that Informed Consent is
sought from each prospective participant or from the participant's legally authorized
representative. The IRB must also ensure that the process of obtaining informed consent is
properly documented. (This topic is discussed in detail in the Informed Consent module.)
Adequate provision is made for monitoring the data collected to ensure the safety of
participants. The IRB must review the plans for data collection, storage and analysis and for
ensuring participant safety. This includes the plan for capturing and reporting information
about adverse events. (Adverse events are covered in the Participant Safety and Adverse
Events module.)
Complex or high-risk studies may be required to have a data and safety monitoring plan.
Some sponsors may require all studies to have a data safety monitoring plan. For example,
in the Clinical Trials Network, all studies must have a data and safety monitoring plan and
be monitored by a Data and Safety Monitoring Board.
Criteria: Adequate Provision is Made to Protect Participants' Privacy and Maintain
the Confidentiality of Data
Protection of participants' privacy. The IRB must consider whether the research involves
an invasion of privacy. Factors to be considered include:
 The private or sensitive nature of the information sought.
 The likelihood that participants will regard the study as an invasion of privacy.
 The importance of the research.
 The availability of alternative ways to conduct the study.
Confidentiality of data. IRBs must evaluate whether adequate provisions exist to safeguard
the confidentiality of information that is collected. (See Confidentiality module.)

Criteria: Additional Safeguards are Included for Vulnerable Populations

Some individuals' willingness to volunteer in a clinical trial may be unduly influenced by
the expectation, whether justified or not, of benefits associated with participation, or by
actual or perceived coercion by persons in positions of authority. Examples of such
vulnerable populations include:
 Children.
 Prisoners.
 Pregnant women.
 Mentally disabled persons.
 Economically or educationally disadvantaged persons.
 Patients with incurable diseases.
 Patients in emergency situations.
 Medical, nursing, dental, and pharmacy students.
 Subordinate hospital personnel.
 Members of the armed forces.
When some or all of a study's participants are likely to be drawn from a vulnerable
population, the IRB must ensure that appropriate additional safeguards are included in the
study to protect the rights and welfare of these participants. Such additional safeguards may
include:
 Heightened monitoring of the informed consent process. In some cases, the IRB
may wish to approve the enrollment of each participant in the study.
 Changes to the composition of the IRB. For example, when research involving
prisoners is being reviewed, at least one voting member (or Alternate) of the IRB
must be a prisoner or a prisoners' representative with appropriate background and
experience to serve in that capacity. If a particular research project is under the
jurisdiction of more than one IRB, each IRB of record needs to satisfy this
requirement.
An IRB may use an expedited review procedure for research that:
 Involves no more than minimal risk and
 Falls into a category that appears on an approved list of categories of research
eligible for expedited review.
An IRB may also use expedited review to approve minor changes in previously approved
research that are made during the period (1 year or less) for which the approval is
authorized. The IRB must have written procedures that specify how an expedited review
will be conducted.
An expedited review (which may involve less waiting time for IRB approval) may be
carried out by the IRB chairperson or by one or more experienced IRB members designated
by the chairperson. The reviewers may exercise all of the authorities of the IRB except that
of disapproving the research. A proposal submitted for expedited review may be
disapproved only by the full IRB.
Research Eligible for Expedited Review
The Department of Health and Human Services has determined that certain types of
research involve no more than minimal risk and are therefore eligible for expedited
review.
The following are examples of research that may be eligible for expedited review:
 Collection of hair or baby teeth.
 Collection of external secretions, including sweat and saliva.
 Recording of data from adults using noninvasive procedures that are routinely
employed in clinical practice (not including exposure to electromagnetic radiation
outside the visible range, for example, x-rays or microwaves.)
 Collection of blood samples by venipuncture.
 Voice recordings made for research purposes, such as investigations of speech
defects.
 Moderate exercise by healthy volunteers.
 Study of existing data, documents, records, pathological specimens, or diagnostic
specimens.
Further information about the types of research that may be eligible for expedited review
may be found on the Office of Human Research Protections website.

The investigator must:

 Ensure that the IRB receives all the documents it requires to review the proposed
research.
 Admit no participant to a study before the IRB has issued its written approval of the
study.
 Make no changes to or deviations from the study protocol without prior written
approval from the IRB, except when necessary to eliminate immediate hazards to
participants.
 Report promptly to the IRB:
 o Changes to or deviations from the protocol, including changes made to
eliminate immediate hazards to study participants.
o Changes that increase the risk to participants or significantly affect the
conduct of the study.
o All adverse drug reactions that are both serious and unexpected.
o New information that may adversely affect the safety of participants or the
conduct of the study.
Reporting requirements may vary, and it is the investigator's responsibility to know the
individual reporting requirements of each IRB involved with the research study. For
example, an IRB may require that every serious adverse drug reaction be promptly
reported, whether it was unexpected or not.
 Respond in a timely fashion to all requests from the IRB for additional information
about a research study.
 Submit progress reports to the IRB annually, or more frequently, if requested by the
IRB, and submit a final report to the IRB when the study is completed or
terminated.
Multi-site trials funded by NIH are characterized by the involvement of multiple
institutions and study sites engaged in a single research study. CTN studies are an example
of multi-site trials funded by the National Institute on Drug Abuse (NIDA).

When a research study involves more than one institution, each institution is responsible for
safeguarding the rights and well-being of research participants at that institution.

With the implementation of the NIH policy on Use of a Single Institutional Review Board
for Multi-Site Research (effective May 25, 2017), multi-institutional research in the U.S.
involving non-exempt human participants will use a single IRB. Based on 45 CFR 46.114,
the use of a single IRB allows for a more streamlined IRB review and increases efficiencies
while maintaining the protection of human study participants (NIH Office of Extramural
Research, 2016).

For more information, including the scope and applicability of the Use of a Single
Institutional Review Board for Multi-Site Research, reference the NIH policy.

Additional resources are available on the NIH Office of Science Policy’s website for single
IRB (sIRB).
Summary of key points
 The purpose of an Institutional Review Board (IRB) is to safeguard the rights,
safety, and well-being of all human research participants.
 Any federally funded research involving human participants must be reviewed and
approved by an IRB.
 Any clinical investigation involving a product regulated by the FDA must be
reviewed and approved by an IRB.
 An IRB has the authority to approve or disapprove all research activities that fall
within its jurisdiction. It may disapprove a research project with a request for
modification. It also has the authority to suspend a research study that it previously
approved.
 All previously approved ongoing research must be reviewed by an IRB at least once
a year to determine whether approval should be continued.
 Every institution, including in the NIDA Clinical Trials Network (CTN), that
participates in a clinical study must identify all IRBs that have jurisdiction to review
and approve the protocol.
 To approve a research protocol, the IRB must ensure that:
o Risks to participants are minimized.
o Risks to participants are reasonable in relation to anticipated benefits.
o Selection of participants is equitable.
o Informed consent is properly obtained and documented.
o Adequate provision is made for monitoring the data collected to ensure the
safety of participants.
o Adequate provision is made to protect participants and maintain
confidentiality of data.
o Additional safeguards are included for vulnerable populations.
INFORMED CONSENT
When most people hear the phrase “informed consent,” they think of the legal document
that explains the study and contains the required dated signatures. However, informed
consent is first and foremost a continuing process. This includes a person voluntarily
agreeing to participate in a research study after being fully informed about it via verbal
discussion with study staff, followed by documentation in a written, signed, and dated
informed consent form. A participant’s consent will be continually sought during the course
of the study, and the participant will be notified of any changes to the study, along with any
other pertinent information that may influence their decision to remain in the study.
While documentation of informed consent is required in most clinical studies, there are
occasions when a waiver or alteration of written informed consent is obtained from the
Institutional Review Board (IRB) for some or all study participants. The fundamental
criteria for waivers and alterations of informed consent are located in 45 CFR 46.116(c)
and 45 CFR 46.116(d). Please consult the local IRB for determining when it is appropriate
to waive the requirement for written consent.
The informed consent document should contain all of the information that the person needs
to make an informed decision about taking part in the study. Many research teams use the
consent document to guide the verbal explanation of the study to potential participants.
The participant must sign and date the informed consent document before taking part in any
study procedures. Signing the consent form is NOT the final step in the informed consent
process. The participant may withdraw consent and decline to participate in the study at any
time before or after signing the consent document until their participation in the study is
completed.
The general requirements for informed consent in federally funded research are spelled out
in 45 CFR 46.116 and 21 CFR 50.20. Some states have enacted requirements for informed
consent that go beyond federal regulations. This module reviews the requirements for
informed consent that are set out in federal regulations and in the Good Clinical Practice
guidelines of the International Council for Harmonization (ICH GCP 4.8.10). It is the
principal investigator’s responsibility to know and abide by any additional state
requirements.
All researchers must ensure that the process of obtaining informed consent from study
participants not only conforms to federal, state, and local regulations but also respects each
individual’s right to make a voluntary, informed decision.

The Informed Consent Document

1. Study purpose
The consent document must state (ICH GCP 4.8.10):
 That the trial involves research.
 The purpose of the trial.
2. Study treatment and Randomization
The consent document must state (ICH GCP 4.8.10):
  The trial treatment(s) and the probability for random assignment to each treatment
(if a randomized clinical trial).
3. Study Procedures
The consent document must state (ICH GCP 4.8.10):
 The trial procedures to be followed, including all invasive procedures.
 The participant’s responsibilities.
 Those aspects of the trial that are experimental.
 The expected duration of the participant’s involvement in the trial.
4. Risks of Taking Part in the Study
The consent document must state (ICH GCP 4.8.10):

 The reasonably foreseeable risks or inconveniences to the participant and, when

applicable, to an embryo, fetus, or nursing infant.
5. Benefits of Taking Part in the Study
The consent document must state (ICH GCP 4.8.10):

 The reasonably expected benefits. When there is no intended clinical benefit to the
participant, the participant should be made aware of this.
6. Alternatives to Taking Part in the Study
The consent document must state (ICH GCP 4.8.10):
 The alternative procedure(s) or course(s) of treatment that may be available to the
participant, and their important potential benefits and risks.
Points to note: IRBs often want the informed consent document to list other therapies
available for the condition under treatment in addition to other treatment options at the
facility where the study is being conducted.

7. Costs of Participation and Compensation in the Event of Injury

The consent document must state (ICH GCP 4.8.10):

 The compensation and/or treatment available to the participant in the event of trial-
related injury.
 The anticipated expenses, if any, to the participant for participating in the trial.
Points to note: When research involves more than minimal risk to the participant, the
consent document must describe the treatment and compensation that will be provided in
the event that a participant sustains a research-related injury. The language in the consent
cannot appear to limit the participant’s rights in seeking damages related to injury in a trial.
Federal regulations do not limit the definition of “injury” to a physical injury. An injury
may be psychological, social, financial, or of another nature.
8. Payment for taking Part in the Study
The consent document must state (ICH GCP 4.8.10):
 The anticipated prorated payment, if any, to the participant for participating in the
trial.
Points to note: Payment to participants for their participation in a research study must never
be coercive in either amount or method of distribution.
9. Voluntary Nature of Study
The consent document must state (ICH GCP 4.8.10):
 That the participant’s participation in the trial is voluntary and that the participant
may refuse to participate or withdraw from the trial, at any time, without penalty or
loss of benefits to which the participant is otherwise entitled.
 The foreseeable circumstances and/or reasons under which the participant’s
participation in the trial may be terminated.

10. Confidentiality of Personal Information

The consent document must state (ICH GCP 4.8.10):
 That the monitor(s), the auditor(s), the IRB, and the regulatory authority(ies) will be
granted direct access to the participant’s original medical records for verification of
clinical trial procedures and/or data, without violating the confidentiality of the
participant, to the extent permitted by the applicable laws and regulations and that,
by signing a written informed consent form, the participant or the participant’s legal
representative is authorizing such access.
 That records identifying the participant will be kept confidential and, to the extent
permitted by the applicable laws and/or regulations, will not be made publicly
available. If the results of the trial are published, the participant’s identity will
remain confidential.
Points to note: Certificates of Confidentiality are issued by the National Institutes of
Health (NIH) to prevent investigators from having to release (e.g., via a subpoena) names
or other identifying information about research participants.
Certificates of Confidentiality provide additional protection for participants who are
enrolled in studies in which information is being collected that, if disclosed, could have
adverse consequences for participants or could damage their financial standing,
employability, insurability, or reputation.

11. New Information that may Affect Study Participation

The consent document must state (ICH GCP 4.8.10):

 That the participant or the participant’s legally acceptable representative will be

informed in a timely manner if information becomes available that may be relevant
to the participant’s willingness to continue participation in the trial.
12. Study Contacts
The consent document must state (ICH GCP 4.8.10):
 The person(s) to contact for further information regarding the trial and the rights of
trial participants in the event of trial-related injury.
13. Duration of Participation and Number of People Taking Part in
the Study

The consent document must state (ICH GCP 4.8.10):

 The expected duration of the participant's participation in the trial.

 The approximate number of participants involved in the trial.
Points to note: A consent form should be written in non-technical language that
participants would understand. Also, it should be written in language consistent with the
participants educational level, cultural views, and familiarity with research.

SPECIAL REQUIREMENTS CONCERNING CONSENT

The information that must be provided in an informed consent document is specified in 45
CFR 46.116, 21 CFR 50.20, and ICH E6 GCP 4.8.10. In the following sections, we will
take a closer look at how this information is presented in a sample informed consent
document.

The consent document should include the following:

 State that the study involves research.

 Briefly explain the purpose of the research, the reason(s) why the person is being
invited to participate, and the expected duration of the person’s participation in the
study.
  Describe the procedures or interventions to be carried out, identifying which
procedures are investigational and which might be provided as standard care in
another setting.
 Explain the use of research methods such as randomization and placebo controls.
 Describe any foreseeable risks or discomforts to the participant. Estimate how likely
it is that these risks and discomforts will occur.
 Describe the steps that will be taken to prevent or minimize risks or discomforts to
the participant.
 Acknowledge that participation in the study may pose unknown and unforeseeable
risks.
 Describe any benefits to the participant or to others that the research may
reasonably be expected to produce. Estimate how likely it is that these benefits will
occur.
 Disclose any appropriate alternative procedures or courses of treatment that may
benefit the participant.
 Describe the extent to which records will be kept confidential and provide examples
of people or organizations that may have access to research records (e.g., hospital
personnel, study sponsors, staff of the U.S. Food and Drug Administration).
 For research that involves more than minimal risk, explain and describe any
compensation and any medical treatments that are available if participants are
injured as a result of participation in the study, where further information can be
obtained, and who should be contacted in the event of a research-related injury.
 Explain who should be contacted for answers to questions about the research and
the participant’s rights (including the name and phone number of the principal
investigator).
 State that participation in the study is voluntary and that declining to participate or
deciding to withdraw at any time will involve no penalty or loss of benefits to which
the participant is otherwise entitled.
 State that the participant’s signature will indicate that he or she has decided to
participate in the study, having read and discussed the information presented to him
or her about the research.
 Provide any other information that prospective participants might need to make an
informed decision about whether or not to participate in the research study, such as
any recently obtained information about the investigational drug’s toxicity in
animals.

Informed Consent of Trial Participants (ICH GCP 4.8.10)

Both the informed consent discussion and the written informed consent form and any other
written information to be provided to participants should include explanations of the
following:

1. That the trial involves research.

2. The purpose of the trial.
3. The trial treatment(s) and the probability for random assignment to each treatment.
4. The trial procedures to be followed, including all invasive procedures.
5. The participant’s responsibilities.
6. Those aspects of the trial that are experimental.
7. The reasonably foreseeable risks or inconveniences to the participant and, when
applicable, to an embryo, fetus, or nursing infant.
8. The reasonably expected benefits. When there is no intended clinical benefit to the
participant, the participant should be made aware of this.
9. The alternative procedure(s) or course(s) of treatment that may be available to the
participant, and their important potential benefits and risks.
10. The compensation and/or treatment available to the participant in the event of trial-
related injury.
11. The anticipated prorated payment, if any, to the participant for participating in the
trial.
12. The anticipated expenses, if any, to the participant for participating in the trial.
13. That the participant’s participation in the trial is voluntary and that the participant
may refuse to participate or withdraw from the trial, at any time, without penalty or
loss of benefits to which the participant is otherwise entitled.
14. That the monitor(s), the auditor(s), the IRB, and the regulatory authorities will be
granted direct access to the participant’s original medical records for verification of
clinical trial procedures and/or data, without violating the confidentiality of the
participant, to the extent permitted by the applicable laws and regulations and that,
by signing a written informed consent form, the participant or the participant’s
legally acceptable representative is authorizing such access.
15. That records identifying the participant will be kept confidential and, to the extent
permitted by the applicable laws and/or regulations, will not be made publicly
available. If the results of the trial are published, the participant’s identity will
remain confidential.
16. That the participant or the participant’s legally acceptable representative will be
informed in a timely manner if information becomes available that may be relevant
to the participant’s willingness to continue participation in the trial.
17. The person(s) to contact for further information regarding the trial and the rights of
trial participants, and whom to contact in the event of trial-related injury.
18. The foreseeable circumstances and/or reasons under which the participant’s
participation in the trial may be terminated.
19. The expected duration of the participant’s participation in the trial.
20. The approximate number of participants involved in the trial.
Special Requirements Concerning the Consent of
Pregnant Women
When a research activity involves pregnant women as participants:

 Both mother and father must be informed about any potential

impact of the research on the fetus.
 Both mother and father must consent to the woman’s participation
in the research. However, the father’s consent is not required in the
following circumstances:
o The purpose of the research is to meet the health needs of
the mother.
o The father’s identity or whereabouts cannot be determined.
o The father is not reasonably available.
o The pregnancy resulted from rape.
 If either parent is unable to consent because of availability,
incompetence, or temporary incapacity, the informed consent of
one parent will suffice provided the criteria in the previous bullet
points are not met.
 Consent of a legally acceptable representative of either or both
parents does not suffice for informed consent.
Additional protections for pregnant women involved as participants in
research are set forth in 45 CFR 46 Subpart B.

Special Requirements Concerning the Consent of Children

The CFR defines children as:

“...persons who have not attained the legal age for consent to treatments or procedures
involved in the research, under the applicable law of the jurisdiction in which the research
will be conducted.” (45 CFR 46.402)
The legal age for consent in most states is 18; persons under age 18 are considered minors.
However, in some jurisdictions, persons under age 18 can consent to treatment for
substance abuse or dependence.

Additional protections for children and minors involved as participants in research are set
forth in 45 CFR 46 Subpart D.
When children or minors are involved in research, both the assent of the child or minor and
the permission of his or her parent(s) are usually required.

Permission means the agreement of parent(s) or a legal guardian to the participation of

their child or ward in research.

Assent means a child’s agreement to participate in research. Failure to object is not assent.

In most cases, both parents must give their permission for their child or minor’s
participation in research. However, exceptions to this requirement are permitted in certain
circumstances. An exception is also permitted in the case of an emancipated minor.

Although children may be legally incapable of giving informed consent, they may
nevertheless be able to assent to or dissent from participation in research.

Out of respect for children as developing persons, children should be asked whether or not
they wish to participate in the research, particularly if:

 The research does not involve interventions that are likely to benefit the
participants, and
 The child can understand what it means to be a volunteer for the benefit of others.
A child’s assent should be sought when the child is capable of providing such assent, taking
into account his or her age, maturity, and psychological state. The age that a child needs to
attain to give assent varies from state to state. In certain circumstances, the IRB may
determine that research can proceed without the assent of the children involved.

Special Requirements Concerning the Consent of Children

The CFR defines children as:

“...persons who have not attained the legal age for consent to treatments or procedures
involved in the research, under the applicable law of the jurisdiction in which the research
will be conducted.” (45 CFR 46.402)
The legal age for consent in most states is 18; persons under age 18 are considered minors.
However, in some jurisdictions, persons under age 18 can consent to treatment for
substance abuse or dependence.

Additional protections for children and minors involved as participants in research are set
forth in 45 CFR 46 Subpart D.

When children or minors are involved in research, both the assent of the child or minor and
the permission of his or her parent(s) are usually required.
Permission means the agreement of parent(s) or a legal guardian to the participation of
their child or ward in research.

Assent means a child’s agreement to participate in research. Failure to object is not assent.

In most cases, both parents must give their permission for their child or minor’s
participation in research. However, exceptions to this requirement are permitted in certain
circumstances. An exception is also permitted in the case of an emancipated minor.

Although children may be legally incapable of giving informed consent, they may
nevertheless be able to assent to or dissent from participation in research.

Out of respect for children as developing persons, children should be asked whether or not
they wish to participate in the research, particularly if:

 The research does not involve interventions that are likely to benefit the
participants, and
 The child can understand what it means to be a volunteer for the benefit of others.
A child’s assent should be sought when the child is capable of providing such assent, taking
into account his or her age, maturity, and psychological state. The age that a child needs to
attain to give assent varies from state to state. In certain circumstances, the IRB may
determine that research can proceed without the assent of the children involved.

Special Requirements Concerning the Consent of Prisoners

Because of their incarceration, prisoners may be under constraints that potentially affect
their ability to make a truly voluntary decision about whether or not to participate in a
study.

45 CFR 46.303 defines a prisoner as:

“Any individual involuntarily confined or detained in a penal institution. The term is

intended to encompass individuals sentenced to such an institution under a criminal or civil
statute, individuals detained in other facilities by virtue of statutes or commitment
procedures which provide alternatives to criminal prosecution or incarceration in a penal
institution, and individuals detained pending arraignment, trial, or sentencing.”
Additional safeguards for the protection of prisoners involved in research (set forth in 45
CFR 46 Subpart C) include the following:

 The IRB must approve the study as prisoner research.

 The IRB that reviews and approves the study must include a prisoner or prisoner
advocate in its membership.
  A majority of the IRB members (exclusive of prisoner members) must have no
association with the prison(s) involved in the research, apart from their membership
on the IRB.
 The study must present no more than minimal risk to the participants.
 The proposed research must involve the study of:
o The possible causes, effects, and processes of incarceration and criminal
behavior.
o Prisons as institutional structures or prisoners as incarcerated persons.
o Conditions that particularly affect prisoners (e.g., vaccine trials; research on
hepatitis, which is more prevalent in prisons than elsewhere; research on
social and psychological problems such as alcoholism, drug addiction and
sexual assault).
o Practices intended to improve the health or well-being of the participants.

Elements of the Informed Consent Process

Part 1 of this module examined the informed consent document in detail. Part 4 will
examine the process of obtaining informed consent from potential study participants.

To be valid, informed consent must be based on the following:

Capacity to Give Informed Consent

Before the informed consent process can begin, the potential participant must be deemed
capable of understanding his or her actions and making a reasoned decision. If the person
lacks capacity because he or she is a minor, is ill, or for any other reason, special provisions
must apply (such as a life-threatening emergency), or the person may not be included in the
study.

A person who has a court-appointed legal guardian or who has been determined by a court
to be legally incompetent cannot sign an Informed Consent Form even if he or she has the
capacity to make a decision. This determination is made by the legal system and not by
clinicians.

Disclosure of all Relevant Information

The research team must disclose all relevant information about the study to the potential
participant. The information disclosed must be sufficient to enable the potential participant
to make an informed reasoned decision about whether to participate. This information
generally includes:

 The purpose of the study.

  The nature of the procedure or intervention that is being studied.
 Reasonable alternatives to participation in the study.
 The potential risks and benefits as well as the uncertainties of study participation.
 The participants obligations for the duration of the study.

Comprehension by the Participant

The potential participant must understand the information disclosed to him or her about the
research study. The participant is free to ask questions to the study team as well as take
additional time to make a decision regarding participation. The research team must be able
to evaluate the potential participant’s ability to understand what his or her participation in
the study would involve. The informed consent document might include a quiz or other
documented assessment to assess whether the participant truly understands the study.

Voluntary Agreement by the Participant

The participant must agree to participate in the research study and his or her agreement
must be voluntary and free from coercion or undue influence.

Right to Withdraw

The participant must be informed that he or she has a right to withdraw from the study at
any time and for any reason, without penalty or loss of benefits that he or she would
otherwise be entitled to receive.

If a participant wishes to withdraw from a study in which an experimental drug is being

tested, he or she must be informed of any procedures that are recommended to ensure safe
withdrawal from the study drug. The participant must also be advised of any consequences
of withdrawal, such as the inability to continue taking the study medication. No further data
will be collected on the participant, but the participant will be informed that data already
collected can be used for study analysis.

The research team or principal investigator may terminate participation in a study if it is in

the best interest of the participant.

Written documentation of Institutional Review Board approval of the study, consent

document(s) and recruitment materials (where appropriate) must be obtained and provided
to the sponsor. NIDA and the CTN Lead Investigator must give their approval before
recruitment can begin at a study site.
Members of the research team may find it helpful to keep the following questions in mind
as they go through the process of recruiting participants for a study:
Protection of human research participants is the primary goal of the IRB and the informed
consent process. Failure to comply with general requirements for informed consent (45
CFR 46.116) and documentation of informed consent (45 CFR 46.117) may result in
suspension of a study. Errors in the informed consent process are considered protocol
violations and, as such, must be reported to the relevant IRBs, along with a description of
the action taken to correct the error and prevent it from occurring again.
If violations of the informed consent process are severe or continuing, penalties may be
imposed and the IRB may report the problem to the regulatory authorities. It is therefore
important to ensure that the process of obtaining informed consent from participants is
carried out carefully and with due attention to every detail. This section describes common
errors that can occur in the informed consent process and discusses how they can be
prevented.
Remember, mistakes will happen. The most important thing to remember is to deal with
them openly and honestly and report them immediately upon identification. The study staff
will help you identify methods to prevent them from happening again.
The following are examples of some of the most common errors that can occur in the
informed consent process.

The Participant Signs the Informed Consent Form After Study

Procedures Have Begun
How did this happen?
Some studies may involve clients as they come into the clinic. An eager staff member sees
that the person who usually conducts consent interviews is busy and tries to help by having
the client “just fill out some forms” while waiting.

Another staff member later assumes, without checking and without seeing the completed
forms, that the participant has already completed the informed consent documentation and
proceeds to enroll the person into the study.

How can this error be prevented?

 Never assume anything. Always check that a participant’s informed consent
documentation is complete before beginning a study procedure.
 Never perform any study assessments on potential participants before informed
consent has been obtained.
Corrective Action: Review the study and the consent form with the participant as soon as
the failure is identified. Document all steps to correct the situation, attach them to the
signed Informed Consent Form and notify your supervisor as soon as possible.

The Consent Form is Signed by the Participant But is Missing the Initials or Signature of
the Investigator or Witness (if Applicable), or is Not Dated
How did this happen?
The investigator may have become distracted. Perhaps the phone rang or another client
needed attention. Perhaps the participant asked a question about another aspect of the study
and the investigator turned the page, forgetting to sign or initial the form as required or to
check that the participant has written the date on the form next to his or her signature.
It is important to remember that the principal investigator (PI) is accountable for the
informed consent process. While the PI may delegate the task of reviewing or discussing
informed consent to another research staff member, such as the research coordinator or
clinician, the PI must provide oversight of the process and ensure that the participant is
comfortable with the discussion.
How can this error be prevented?
 Conduct consent interviews in a quiet, separate room.
 When reviewing a consent form with a participant, focus on that task. Don’t answer
the phone or respond to distractions unless there is a genuine emergency.
  The person obtaining the participant’s consent must be present when the consent
form is signed. Having the investigator sign the consent form later is unacceptable.
Never backdate a consent form.
 Create and use a checklist to ensure that every detail in the informed consent
process is completed.

Whiteout is Used to Correct an Error on the Consent Form

How did this happen?

Failure to follow Good Clinical Practice or Good Medical Record correction techniques is
the only reason for this error. Whiteout should never be used on any research or medical
record document.

How can this error be prevented?

By following good documentation practices. If an error occurs while the consent form is
being completed, use Good Clinical Practice or Good Medical Record correction
techniques to correct it: Cross out the error without obscuring the original entry, initial and
date the crossing-out, and enter the correct information. (See also Good Medical Record
practices to observe when writing progress notes in the Documentation and Record-
Keeping module.)

An Out-of-Date Version of the Consent Form is Used

How did this happen?

Several versions of an Informed Consent Form may be developed before IRB approval is
received. Or, if the study has been in progress for more than 1 year, a new version of the
consent form (most likely with a different date stamp) will have been prepared. In either
case, a staff member may mistakenly pull out and use an out-of-date version of the form.

How can this error be prevented?

 Ensure that the current version of the consent form is readily identifiable (e.g., color
coded, marked with a prominent date stamp).
 Keep copies of the current version of the consent form in a different place than
older, archived versions. Destroy copies of old, unused consent forms and mark the
old original as obsolete in the regulatory binder.
Corrective Action: When the issue is identified reconsent the participant using the
appropriate Informed Consent Form. Attach a memo identifying the issue and the
corrective action to the new consent form.
A New Consent Form is Required, But Not All Participants Signed
It

How did this happen?

 Some participants were absent from the clinic during the week when most
participants signed new consent forms. When the absent participants returned the
following week, the need for them to sign new consent forms was overlooked.
 A staff member assumes that a colleague already had the participant sign a new
consent form.

How can this error be prevented?

 Again, never assume anything. When a new consent form is required, check on each
participant’s next clinic visit to ensure that he or she has signed the new form.
 Devise a system for flagging the files of participants who have not yet signed new
consent forms.
 Use a tracking spreadsheet.
 Ensure documentation of consent form is in the source notes.
Corrective Action: When the issue is identified have the participant review, sign and date
the new consent form. Document the reason for the delay and attach it to the new consent
form.

The Original Consent Form Has Been Lost

How did this happen?

 A staff member may mislay a participant’s consent form among other papers on his
or her desk.
 The form may have been filed incorrectly.
 The original of the consent form may have been given to the participant by mistake.

How can this error be prevented?

 Devise written procedures for the handling of informed consent documentation and
train all staff in the use of these procedures.
Corrective Action: Report the loss of a consent form immediately to the IRB and/or the
sponsor and get another signed as soon as possible. To avoid the appearance of fraud,
carefully document the sequence of events that led to the loss of the first consent form.
Part 7: Requirements for the Documentation of Informed Consent  >>
1 of 1
Requirements for the documentation of informed consent are set forth in 45 CFR
46.117, 21 CFR 50.27, and ICH GCP 4.8. In brief, these requirements are as follows.

Informed Consent Shall be Documented by the Use of a Written

Consent Form
 The IRB must approve the consent form.
 The participant or the participant’s legally authorized representative must sign the
current version of the IRB approved consent form.
 ICH GCP requires that the consent form should also be signed by the person
conducting the informed consent discussion.
 A copy of the form must be given to the person who signs it. The study site must
keep the original on file.

The Consent Form May Take One of Two Organizational Structures

 A written document that embodies the elements of informed consent required by 45
CFR 46.116. This form may be read to the participant or the participant’s
representative. The investigator should give the participant or representative ample
time to absorb the content of the form before signing it.
 A short-form written document stating that the elements of informed consent were
presented orally to the participant or the participant’s representative. When the short
form document is used:
o A witness must be present at the oral presentation.
o The IRB must approve a written summary of what is to be said to the
participant or representative.
o The participant or representative must sign only the short form itself.
o The witness must sign both the short form and a copy of the summary.
o The person obtaining the participant’s consent must also sign a copy of the
summary.
o A copy of the summary, in addition to a copy of the short form, must be
given to the participant or the participant’s representative.

Researchers Must Not Waive or Appear to Waive Any Legal Rights

of Participants
For example, care must be taken when describing what compensation (beyond the
provision of immediate or therapeutic intervention) the institution is voluntarily willing to
provide in an event such as a research-related injury.

Participants should understand that, regardless of what the institution may agree to provide
as compensation for a research-related injury, they retain the right to take legal action
against the institution and/or those responsible for the injury.

The Consent Form Must be Revised When New Information

Becomes Available that May Be Relevant to the Participant’s
Consent
If a new adverse event appears to be related to the study medication (e.g., a severe allergic
reaction that occurs shortly after a medication is given), this risk should be added to a
revised consent form.

 The revised consent form must be approved by the IRB.

 The participant must be informed of the new information in a timely manner.
 The communication of the new information to the participant must be documented.

Other considerations for the Informed Consent Process

The investigator must document the informed consent process in the participants’ source
notes. When new information becomes available which results in a revised informed
consent form, the participant must be informed in a timely manner and the communication
of this information must be documented in the source notes.

In obtaining and documenting the informed consent, the investigator should comply with
ethical principles that have their origin in the Declaration of Helsinki, ICH GCP, CFR and
applicable regulatory requirements.

Non-therapeutic trials should be conducted in subjects who are capable of personally giving
consent and signing and dating the consent form.(ICH GCP 4.8.13)

Non-therapeutic trials may be conducted with consent from a legal representative if the
following conditions are met:

 The objectives of the trial cannot be met by a participant that can personally give
consent.
 The foreseeable risks to the participants are low.
 Any negative impact on the participants’ well-being is minimized.
 The trial is not prohibited by law.
  The approval of the IRB is expressly sought on the inclusion of such participants
and is documented in a written approval letter.
These type of non-therapeutic trials should be conducted in patients having a disease or
condition for which the investigational product is intended and they should be closely
monitored.

Further Information
 45 CFR 46.116
 21 CFR 50.20
 ICH E6 GCP 4.8 — ICH GCP Guidelines
 45 CFR 46 Subpart B — Research Involving Pregnant Women
 45 CFR 46.408 — Research Involving Children
 45 CFR 46.303 — Research Involving Prisoners

Summary of Key Points >> 1 of 1

 Informed consent is a process by which a person voluntarily agrees to participate in
a research study after being fully informed about it.
 The informed consent document should contain all of the information that the
participant needs to make an informed decision about participating in the study.
 The participant’s signature on the informed consent document confirms his or her
voluntary agreement to take part in the study.
 The general requirements for informed consent in federally funded research are
spelled out in 45 CFR 46.116 and 21 CFR 50.20. Some states have enacted
requirements for informed consent that go beyond federal regulations.
 All researchers have a responsibility to ensure that the process of obtaining
informed consent or assent from study participants not only conforms to federal,
state, and local regulations but also respects each individual’s right to make an
informed decision voluntarily.
 The first step in the process of informed consent is preparing the consent document
and supporting documents for presentation to the Institutional Review Board that
must review and approve the study and consent document. The IRB must review
and approve the consent document before the study can begin.
 Consent documents should be written in nontechnical language that the proposed
participants would understand. The language should be consistent with the proposed
participants’ educational level, cultural views, and familiarity with research.
  The information that must be provided in an informed consent document is
specified in 45 CFR 46.116, 21 CFR 50.20, and ICH GCP 4.8.10.
 The legal age for consent in most states is 18; persons under age 18 are considered
minors. Additional protections for children involved as participants in research are
set forth in 45 CFR 46 Subpart D. In most cases, both parents must provide
permission and the child himself or herself must assent to the child’s participation in
research.
 If a person is unable to provide informed consent, a legal representative may give
permission for the individual to participate in research in some circumstances. Only
one person gives consent. If the participant is capable and is not court ordered
legally incompetent, then he or she should sign. If the participant is not capable or is
legally incompetent, then the legal representative or guardian should sign. A child
and the parents sign, but minor children assent, parents provide permission, and
legal guardians consent.
 Participants must not be coerced or unduly influenced. Coercion occurs if an
individual perceives that he or she could be harmed or punished for refusing to take
part in a study. In some cases, coercion may occur subtly and unintentionally.
 The value of an incentive for participation in a study should not be so high that it
could be considered an undue influence on an individual’s decision to participate.
 It is important to ensure that the process of obtaining informed consent from human
participants is carried out carefully and with vigilant attention to every detail.
Failure to comply with general requirements for informed consent (45 CFR 46.116)
and documentation of informed consent (45 CFR 46.117) may result in suspension
of a study as well as fines and penalties.
CONFIDENTIALITY & PRIVACY
Federal regulations require that research records identifying the participant be kept
confidential to the extent permitted by applicable laws and regulations. For example, if the
results of a clinical study are published, participants’ identities must remain confidential
( 45 CFR 46 ; ICH GCP 4.8.10(o)).
Federal law also protects the confidentiality of individually identifiable health information
for all research participants. Other federal laws and regulations protect the records and
identity of vulnerable populations as well as study participants receiving alcohol and drug
abuse treatment.
This module summarizes federal laws and regulations that protect the confidentiality and
privacy of study participants.
In addition to federal laws and regulations, many states have enacted their own laws and
regulations to protect the confidentiality and privacy of individuals receiving health care.
Researchers must be familiar with the confidentiality and privacy provisions that apply in
the state where their studies are conducted.
What records must be kept confidential?
45 CFR 46 provides protections for the confidentiality of research participants as follows:
 Subpart A – Basic protections of human research participants
 Subpart B – Additional protections for research participants that are pregnant
women, fetuses, neonates
 Subpart C – Additional protections for participants that are prisoners involved
biomedical and behavioral research
 Subpart D – Additional protections for research participants that are children
In addition to 45 CFR 46, the Health Insurance Portability and Accountability Act
(HIPAA) mandates privacy protections for individually identifiable health information
under 45 CFR 160 and 164. In general, whether research related or not, all records of the
identity, diagnosis, prognosis, or treatment of any person in a clinical trial must be
maintained. This includes any record in connection with alcohol or drug abuse prevention,
education, training, treatment, rehabilitation, or research must be kept confidential.
“Identity” includes not only the participant’s name but also any other information that
could be readily linked to the participant. Additionally, applicable information may be in
any form (e.g., paper, electronic, verbal). The HIPAA Security Rule, also under 45 CFR
160 and 164, establishes standards to protect individuals’ electronic personal health
information.
For example, clinical research staff may not disclose that a participant is enrolled in an HIV
study. This type of disclosure would be in violation of the participant’s confidentiality and
can make things difficult for the participant given the stigma associated with the disease in
certain communities.
With certain exceptions, an alcohol or drug abuse treatment program may not disclose to
anyone outside the program that a particular person attends the program, or disclose any
information that identifies a person as an alcohol or drug abuser, unless:
 the person consents to the disclosure in writing, or
 the disclosure is allowed by a court order and the study or research site is not
operating under a Certificate of Confidentiality (see Part 5 of this module for the
provisions and exceptions of Certificates of Confidentiality).
A breach of confidentiality is usually defined as any disclosure of protected information
about a participant to a third party without either a court order or consent of the participant.
The breach of confidentiality may be oral or written and may occur by telephone, fax, or
electronic means (e.g., electronic mail or other internet-based method of communication)
Federal regulations identify certain exceptions to the confidentiality requirements for
alcohol and drug abuse participant records. Consider the following circumstances for
disclosure:

“Need to Know” (42 CFR 2.12(c)(3))

Information in a participant's medical record can be disclosed to people within a health

program, or between a health program and an entity having direct administrative control
over that health program, as they may need this information to perform duties related to the
participant's diagnosis and treatment. For example, a physician at the research site may
provide participant information for the purpose of referral for treatment of alcohol or drug
abuse to another health entity within the site or program.

Criminal Activity (42 CFR 2.12(c)(5))

Information in a participant's medical record can be disclosed to law enforcement officers

when the participant has committed or threatened to commit a crime on program premises
or against program staff.

The information disclosed must be limited to the circumstances of the incident, including
the participant's:

 Participant status.
 Name and address.
 Last known whereabouts.

Suspected Child Abuse or Neglect (42 CFR 2.12(c)(6))

Information in a participant's medical record can be disclosed when it is necessary to report

suspected child abuse or neglect to state or local authorities. However, original participant
records may not be used in civil or criminal proceedings that arise from the report.

Armed Forces and Veterans Administration (42 CFR 2.2(e))

The confidentiality regulations do not apply to the exchange of information regarding

suspected child abuse and neglect within the Armed Forces or between the Armed Forces
health care facilities operated by the U.S. Veterans Administration (VA). The regulations
do not apply to the reporting of child abuse or neglect under State law.

In addition, disclosure of confidential information without a participant's consent is

permitted in the situations described below ( 42 CFR 2.51 ).

Medical Emergencies (42 CFR 2.51(a))

Confidential information about a participant may be given to medical personnel in a
medical emergency for the purpose of treating a condition that poses an immediate threat to
the health of any person and requires immediate medical intervention.

Research Activities (42 CFR 2.52)

Confidential information about a participant may be disclosed for research purposes,

provided that the recipient of the information:

 Is qualified to conduct the research.

 Has a research protocol that ensures the information will be kept secure and will not
be re-disclosed except to the source from which it was obtained.
 Will not identify any individual participant in any report of the research.
In addition, a group of at least three independent persons must review the protocol to ensure
that:

 The rights and welfare of participants will be adequately protected.

 The risks of disclosing information about participants are outweighed by the
potential benefits of the research.

Audit and Evaluation Activities (42 CFR 2.53)

Confidential information about a participant may be disclosed for management audits,

financial audits, or program evaluation activities provided that the information:

 Is not re-disclosed except to the source from which it was obtained.

 Is used only to carry out an audit or evaluation purpose or to investigate or
prosecute criminal or other activity as authorized by a court order.

Danger to Self (42 CFR 2.51; 45 CFR 164.512(j)(4))

If a participant speaks of an intention to kill himself or herself, the participant must be

evaluated by a qualified mental health professional. If the participant is found to be at risk
for suicide, confidential information may be disclosed to ensure his or her safety.
Specifically, it may be necessary to admit the participant to a hospital or to notify an
emergency response team.

A member of the research team who suspects a participant is in danger of harming himself
or herself should notify a supervisor, qualified counselor, or physician.

Danger to Others (42 CFR 2.51; 45 CFR 164.512(j)(4))

If a participant speaks of an intention to harm another person, he or she must be evaluated
by a qualified mental health professional. If the threat is considered credible, a report must
be made both to the police (42 CFR 2.12(c)(5)) and to the identified target. A member of
the research team who suspects a participant is in danger of harming another person should
notify a supervisor, qualified counselor, or physician.

Communicable Diseases

Confidential information about a participant may be disclosed when the participant has a
disease that poses a risk to public health. All states require that cases of selected
communicable diseases be reported to local health authorities. Since 1999, certain
infectious diseases have also been designated as notifiable to the National Notifiable
Diseases Surveillance System (NNDSS) of the U.S. Centers for Disease Control and
Prevention. However, state reporting to the NNDSS is voluntary. All states generally report
the internationally quarantinable diseases (e.g., cholera, plague, yellow fever) in
compliance with the World Health Organization's International Health Regulations.

State, local, or institutional policies may also require that communicable diseases be
reported to other agencies. Researchers should contact their state health departments to
obtain current and complete information about communicable disease reporting
requirements in individual states.

Court Order

Disclosure of confidential information about a participant may be authorized by a court

order if the disclosure is:

 Necessary to protect against a threat to life or a threat of serious bodily injury (e.g.,
child abuse, neglect, and threats against third parties) (42 CFR 2.63(a)(1)).
 Necessary to the investigation or prosecution of a serious crime (e.g., homicide,
rape, kidnapping, armed robbery, and assault with a deadly weapon) (42 CFR
2.63(a)(2)).
 Relevant to a legal or administrative proceeding in which the participant offers
evidence that pertains to the confidential disclosure (42 CFR 2.63(a)(3)).
A court order alone does not compel disclosure of confidential information. A subpoena or
other legal mandate must be issued to compel disclosure.

Requirements of State Law

States may determine additional exceptions to the requirements for confidentiality of

alcohol and drug abuse participant records. In some states, health care providers must
report suspected domestic violence to authorities. Members of the research team should be
familiar with their state's laws and regulations. Copies of relevant state laws should be on
file at each study site.
When the research is protected by a Certificate of Confidentiality (CoC), research
participants must be informed of the conditions that the certificate does not prevent
disclosure. The CoC conditions for disclosure are not all inclusive of the circumstances
mentioned above. (See Part 5 of this module for more information on Certificates of
Confidentiality.

Maintaining the Security of Written Records

When not in use, written records covered by the confidentiality regulations must be kept in
a secure room, a locked file cabinet, a safe, or other secure place. Each program must adopt
written procedures to control access to and use of these records.

What happens to participant records when a program is discontinued?

If a research site discontinues operation or is acquired by another program, there are certain
medical record responsibilities that must be followed regarding the clinical records. Each
site Principal Investigator must be aware of the procedures and retention period
requirements for medical and study related records established by the sponsor and
regulatory entities with oversight authority. For example, in the Clinical Trials Network,
when a program is discontinued, the sponsor requires the program director to notify NIDA
immediately to discuss the retention of any essential source documents created during the
clinical study from which study data were obtained. Additionally, these documents must be
kept at the study site, at the site, or by the sponsor, for a period defined by the sponsor.

Medical Record Responsibilities

The program must purge participant-identifying information from its records or destroy the
records unless:

 The subject of the records gives written consent to transfer of the records to the
acquiring program or to any other designated program.
 The law requires that the records be kept for a specified period.
Retained records must be sealed in envelopes or other containers and:

 Sealed in envelopes or other containers.

 In accordance with 42 CFR 2.19(b)(1), labeled as follows:
“Records of [insert name of program] required to be maintained under [insert
citation to statute, regulation, court order, or other legal authority requiring that
records be kept] until a date not later than [insert appropriate date].”
 Held by a responsible person who must destroy the records as soon as is practicable
at the end of the specified retention period.
Recommended Routine Practices for Maintaining the Confidentiality of Research
Participants

Researchers ordinarily use information that study participants have disclosed or provided
voluntarily (i.e., with their informed consent) for research purposes. Because the
relationship between researcher and study participant is based on trust, it is most important
to ensure that the confidentiality of this information is maintained.

The following routine practices are recommended to ensure the confidentiality of research
participants:

 Substitute codes for information that identifies the participant (e.g., use numbers
instead of names to identify participants).
 Remove face sheets that contain identifiers, such as names and addresses.
 Properly dispose of all paper documents that contain identifiers.
 Limit access to all data that identifies participants.
 Educate research staff on the importance of maintaining confidentiality.
 Store paper records in locked cabinets.
 Assign security codes to computerized record

What is a Certificate of Confidentiality?

A Certificate of Confidentiality provides an additional level of protection for the privacy

of participants in biomedical, behavioral, and clinical research studies.

Certificates of Confidentiality may be granted for studies collecting information that, if

disclosed, could have adverse consequences for study participants or damage their financial
standing, employability, insurability, or reputation. By protecting researchers and
institutions from being compelled to disclose information that would identify research
subjects, Certificates of Confidentiality help achieve the research objectives and promote
participation in studies by assuring confidentiality and privacy to participants. For more
information review the NIH Certificate of Confidentiality Kiosk.

Key Points about Certificates of Confidentiality

 A Certificate of Confidentiality is not transferable from one researcher to another.

 Every Certificate of Confidentiality has an expiration date. If the research project
covered by the certificate will not be completed by the expiration date, the
researcher must submit a written request for an extension well in advance of the
expiration date.
  The Certificate of Confidentiality must be amended if significant changes occur in
the research project (e.g., changes in key personnel, major changes in the scope or
direction of the research protocol, changes in the drugs administered or the persons
administering them). Amendment of the certificate must be requested in writing,
giving details of the changes, before the changes are implemented.
 For a multi-site trial, one Certificate of Confidentiality (CoC) may be required for
all sites. However, each study investigator may contact the CoC coordinator with
the agency issuing the certificate.

Applying for a Certificate of Confidentiality

Certificates of Confidentiality are granted by the Department of Health and Human

Services (DHHS). (Click here for more information and instructions about applying to
NIDA for a Certificate of Confidentiality.)

Additional Information Required

The following additional information is required in the application for a Certificate of

Confidentiality for any research project involving the administration of investigational
product:

 Identification of the drugs to be administered; description of the methods of

administration, including dosages.
 Evidence that the persons administering the drugs are authorized to do so.
 For controlled drugs, a copy of the research project's Drug Enforcement
Administration (DEA) registration form.

What Participants Should Know About a Certificate of Confidentiality

Participants must be told that a research project has been granted a Certificate of
Confidentiality. They must be informed that:

 Except under certain conditions, researchers may not be compelled to identify

research participants in any civil, criminal, administrative, legislative, or other
proceeding.
 The certificate is not transferable.
 The certificate has an expiration date.
 The certificate must be amended if major changes occur in the research project.
Covered entities may use or disclose the “minimum necessary” amount of protected health
information (PHI) to or among themselves, without the individual's authorization, for
purposes of treatment, payment, and health care operations.
The only exceptions to the “minimum necessary” requirement are for the use and disclosure
of PHI:

 To or by health care providers for treatment purposes.

 To the individual who is the subject of the protected health information.
 To the Secretary of Health and Human Services, who has authority for the Privacy
Rule.
 Use or disclosure that is required by the law.
Additionally, covered entities may disclose PHI for certain “public policy” purposes
without the individual's authorization. However, they are required to track these disclosures
for accounting purposes.

Public Policy Purposes

The HIPAA Privacy Rule permits covered entities to use or disclose protected health
information (PHI) without the individual's authorization for the following public policy
purposes:

 When the disclosure is required by law.

 For public health activities (e.g., prevention or control of disease, notification of
adverse drug events).
 In cases of abuse, neglect, or domestic violence.
 For health care oversight activities authorized by law or regulations.
 For judicial and administrative purposes (e.g., a court order, subpoena, or warrant).
 To a law enforcement official for law enforcement purposes.
 To a coroner, medical examiner, or funeral director when the information concerns
a deceased person.
 For cadaveric organ, eye, and tissue donation.
 For research purposes.
 To avert a serious threat to health or safety.
 For national security or intelligence activities.
 For workers' compensation purposes.

Permitted Disclosures of Protected Health Information for Research Purposes

Research is defined as “any systematic investigation designed to develop or contribute to

generalizable knowledge.” Covered entities can disclose protected health information (PHI)
when:
Authorization is Obtained from the Participant
Under the HIPAA Privacy Rule, a research participant may authorize a covered entity to
use and disclose his or her protected health information (PHI) for research purposes. The
authorization form must be approved by the relevant Institutional Review Board or a
Privacy Board.

IRBs and Confidentiality

In accordance with the Belmont Report, IRBs must ensure adequate provision is made to
protect subjects’ privacy and maintain the confidentiality of data.

Protection of Subjects’ Privacy.

The IRB must consider whether the research involves an invasion of privacy. Factors to be
considered include:

 The private or sensitive nature of the information sought,

 The likelihood that subjects will regard the study as an invasion of privacy,
 The importance of the research, and
 The availability of alternative ways to conduct the study.
Confidentiality of Data
IRBs must evaluate whether adequate provisions exist to safeguard the confidentiality of
information that is collected.

Authorization for disclosures is obtained routinely from participants during the informed

consent process. The authorization may be combined with the Informed Consent Form that
a research participant signs when agreeing to participate in a study, or the participant may
sign a separate authorization form. In either case, the authorization must include the
following:

All members of the NIDA Clinical Trials Network (CTN) must ensure that the process of
obtaining informed consent from research subjects not only conforms to federal, state, and
local regulations but also respects each individual’s right to make a voluntary, informed
decision.

 Description of the information to be disclosed.

 Identity of the person who may use or disclose the information.
 Identity of the person to whom the information will be disclosed or by whom it will
be used.
 Purpose of the use or disclosure.
 Length of time the data will be retained with identifiers.
  Expiration date of the authorization.
 A statement of the participant's right to revoke authorization.
 A statement that information disclosed in accordance with an authorization may no
longer be protected by the Privacy Rule.
 Participant's signature and date of signature.
Treatment programs do not need to keep track of disclosures that are authorized by the
participant. In other words, once a program obtains a participant's permission to disclose his
or her PHI, there is no need to document each occasion that a disclosure is made.

Rights of Research Participants Under the HIPAA Privacy Rule

The Privacy Rule defines two new rights for research participants.

Right to an Accounting

Participants have a right to ask researchers for an accounting of their protected health
information (PHI) that has been obtained under a waiver of or exception to the HIPAA
Privacy Rule. An accounting of such disclosures may be requested for the previous six
years.

A researcher is not required to account for disclosures that were:

  Authorized by the participant;
 Contained in a limited data set; or
 Released as de-identified data.
Other instances where accounting is not required include for national security or
intelligence purposes, and disclosure to correctional institutions or law enforcement
officials.

Right to Revoke Authorization

Participants have the right to revoke their authorization of the use or disclosure of their
protected health information (PHI). However, the revocation has no effect if the researcher
has already made a disclosure in accordance with the participant's original authorization.

Enforcement and Oversight of the HIPAA Privacy Rule

The DHHS Office of Civil Rights is responsible for enforcing compliance with the HIPAA
Privacy Rule and for investigating complaints about lack of compliance. Failure to comply
with the Privacy Rule may result in the levying of civil or criminal penalties. For more
information about enforcement of the Privacy Rule, go to http://www.hhs.gov/ocr/hipaa/.

SUMMARY OF KEY PONTS

 Federal law and regulations protect the confidentiality of participant records. In

addition, Federal law protects the confidentiality of identifiable health information
for all research participants.
 In general, all records of the identity, diagnosis, prognosis, or treatment of any
person that are maintained in connection with alcohol or drug abuse prevention,
education, training, treatment, rehabilitation, or research must be kept confidential.
 The regulations identify certain exceptions to the confidentiality requirements.
Information in a participant's medical record can be disclosed:
o To people performing duties related to the participant's diagnosis, treatment,
or referral for treatment of alcohol or drug abuse.
o To law enforcement officers when the participant has committed, or
threatened to commit, a crime on program premises or against program staff.
o When reporting suspected child abuse or neglect to state or local authorities.
o To medical personnel in a medical emergency.
o For research purposes, with certain conditions.
o For management audits, financial audits, or program evaluation.
 o If a participant is found to be at risk for suicide or if he or she makes a
credible threat to harm another person.
o When the participant has a communicable disease that poses a risk to public
health.
o When authorized by a court order.
o When required by state law.
 If a program discontinues operation or is acquired by another program, there are
certain medical record responsibilities that must be followed regarding the clinical
records. Each site Principal Investigator must be aware of the procedures and
retention period requirements for medical and study related records established by
the sponsor and regulatory entities with oversight authority.
 A Certificate of Confidentiality provides an additional level of protection for the
privacy of participants involved in research studies.
 Except under certain conditions, a researcher who has obtained a Certificate of
Confidentiality cannot be compelled to identify research participants in any federal,
state, or local civil, criminal, administrative, legislative, or other proceeding.
 Participants must be told that a research project has been granted a Certificate of
Confidentiality.
 The HIPAA Privacy Rule protects all individually identifiable health information
that is held or transmitted by covered entities and their business associates. The
information may be in any form (e.g., paper, electronic, oral). The Privacy Rule
calls this information protected health information (PHI). A covered entity may not
use or disclose PHI except as permitted or required by the Privacy Rule.
 Covered entities may use or disclose the “minimum necessary” amount of PHI to or
among themselves, without the individual's authorization, for purposes of treatment,
payment, and health care operations.
 PHI may be disclosed for research purposes when the disclosure is authorized by
the research participant. Authorization for disclosures is obtained routinely from
participants during the informed consent process. Treatment programs do not need
to keep track of disclosures that are authorized by the participant.
 Health information that has been de-identified by the removal of all elements that
could identify an individual is no longer considered PHI and is not subject to the
Privacy Rule.
PARTICIPANT SAFETY & ADVERSE EVENTS

Inherent Complexities of Client Safety and Adverse Events

Participant safety is a broad topic that cuts across all aspects of Good Clinical Practice
(GCP) as is discussed in the document the ICH Guideline for Industry: Clinical Safety
Data Management. Among other issues, ensuring participant safety encompasses protocol
design, quality-assurance monitoring, government regulations, and ethical issues. It may
also involve the use of clinical judgment, and entail situations/decisions on which no two
clinicians may be in complete agreement. As a result, new researchers may feel frustrated
when questions arise about participant safety.
This module focuses on ways of protecting participants’ safety and well-being as well as
how adverse events should be recorded and reported for clinical studies.
Because of the complexity of the topic, this module cannot cover every participant safety
issue that might arise in a clinical trial. Researchers are advised to seek further guidance as
needed from the study investigator or other knowledgeable team members. The role of
investigators in protecting the safety and well-being of research participants is discussed
further in this module.

Key Points About the Protection of Participant Safety

 The obligation to protect the well-being of study participants does not end when a
study receives Institutional Review Board (IRB) or Data and Safety Monitoring
Board (DSMB) approval, or when a participant signs the informed consent form.
The interests of study participants must be safeguarded at all times—and by many
entities—throughout a clinical research study.
 Ultimately, no single individual or institution can provide complete protection for
trial participants. A systematic plan must be followed for each trial to ensure that
everyone involved understands and fulfils his or her responsibilities.
 Research team members with adequate knowledge of clinical trials, statistics, and
the clinical disorder and the Investigational Product being studied must review the
study data regularly to ensure that events are properly interpreted and reported.
 Ongoing communication among all study staff is an essential part of ensuring
participant safety.
In studies conducted under the Investigational New Drug (IND) regulations, responsibility
for ensuring compliance with FDA regulations on participant safety rests with the sponsor
of the IND under which the study is conducted.

The investigator is responsible for:

"protecting the rights, safety, and welfare of study participants under the investigator’s
care."
The U.S. Food and Drug Administration (FDA) requires the investigator to:
"promptly report to the IRB (Institutional Review Board) all unanticipated problems
involving risk to human subjects or others"
and to report to both the sponsor and the IRB:
"any serious adverse event, whether or not considered drug related and must include an
assessment of whether there is a reasonable possibility that the drug caused the event" .

Ongoing Informed Consent

As discussed in the Informed Consent module, informed consent is a process as well as a
legally required document. Throughout any study, researchers must continue to keep study
participants informed about any new information with regard to the safety of the product
and, in particular, about any new developments or findings that may affect participants’
willingness to remain in the study.
Researchers must:
 Inform participants, in a language that they understand, about emerging
developments in the study, related studies utilizing the same Investigational
Product(s), or pertinent pre-clinical studies that are significant to participant safety.
 Offer participants the opportunity to ask questions about the information they have
been given.
 Ensure that participants understand they may withdraw from the study at any time
and cannot be penalized for doing so.
 Be satisfied that each participant understands what he or she has been told and is
making a voluntary, informed decision to remain in the study.
The Good Clinical Practice (GCP) guidelines of the International Council for
Harmonization (ICH) define an adverse event (AE) as: “any untoward medical occurrence
in a patient or clinical investigation subject administered a pharmaceutical product and that
does not necessarily have a causal relationship with this treatment” (ICH GCP, E6(R2) 1.2).

The term adverse event is defined in the U.S. Code of Federal Regulations (CFR) Title 21
Section 312.32(a) as follows: "any untoward medical occurrence associated with the use of
a drug in humans, whether or not considered drug related."

ICH guidelines for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting uses the ICH GCP definition.

An AE may be “any unfavorable or unintended" sign, symptom, or disease that occurs in a

person who has taken a medication. The occurrence does not need to be related to the drug
treatment.
An adverse event (AE) may be:

 A physical event (e.g., a rash).

 A psychological event (e.g., depressed mood).
 A laboratory event (e.g., elevated blood sugar).
 An increase in the severity or frequency of a pre-existing symptom or condition
(e.g., increased pain in a painful tooth)
An adverse event may also be referred to as an “adverse experience.”

Situations involving the use of a drug in humans in which an adverse event may occur
An adverse event (AE) may occur as a result of:
 A drug overdose, whether accidental (e.g., the patient is of a small size or has poor
metabolism of the drug) or intentional (e.g., suicide attempt).
 An interaction with food or with another medication.
 Drug abuse (e.g., the patient faints when taking a nonprescribed drug to “get high”).
 Drug withdrawal (e.g., the patient stops taking a prescribed medication and has a
seizure).
 Any failure of expected pharmacological action (e.g., a drug given to slow a
patient’s heart rate instead increases the heart rate).
 The use of a drug in professional practice (e.g., when an approved [marketed] drug
is given to a patient and he or she develops a rash). The patient does not need to be
enrolled in a clinical trial.
Examples of events that should or should not be reported as adverse events
An adverse event (AE) may occur as a result of:

 Worsening of a withdrawal symptom—even if it is a symptom noted in the patient’s

medical history form—should be recorded as an AE if it occurs during the course of
a study. Withdrawal symptoms can be coded as such to differentiate them from
similar AEs that are not withdrawal related.
 Stable chronic conditions (e.g., arthritis that is present before the participant enters a
clinical trial and does not worsen) are not considered AEs. These conditions should
be accounted for in the participant’s medical history.
 Reports of unintentional overdose of any medication (including the study
medication) that result in no associated adverse reaction should not be reported as
AEs. They should be routinely followed up to ensure that information is as complete
as possible with regard to symptoms, treatment, and outcome.
  Drug abuse during a study should not be recorded as an AE unless it worsens during
treatment (e.g., the participant is hospitalized for detoxification).
As defined in the previous section, an AE is commonly understood to be an event that
occurs during treatment with a drug or device. However, the definition can also be applied
to any “untoward occurrence” that occurs in any clinical trial, including behavioral studies.

For trials that are not regulated by the FDA, the Investigators and protocol teams may
define the term adverse event to reflect what is clinically and scientifically relevant to their
study.

Thus, for a behavioral trial that does not involve treatment with a drug, an AE may be
defined as:

“Any unfavorable, unintended diagnosis, symptom, sign (including an abnormal laboratory

finding), syndrome, or disease that occurs during the study, having been absent at baseline,
or—if present at baseline—appears to worsen.” (Interim Guidelines for NIH Intramural
Principal Investigators and for NIH Institutional Review Boards on Reporting Adverse
Events)

In certain studies, including some behavioral studies, it may be important to capture the
occurrence of nonmedical events such as arrest, imprisonment, and violence to others,
which may be contributing factors to an AE or may indicate that an AE has occurred. As an
example of the latter, a participant’s increased drug abuse—an AE—could result in an
arrest.

Investigators may elect to capture nonmedical events that may be behavioral (e.g.,

violence) or social (e.g., arrest, imprisonment) on the AE Case Report Form (CRF), or such
events may be captured elsewhere.

The terms adverse event and adverse drug reaction are easily confused, but they have
distinctly different meanings. As discussed in earlier sections, an adverse event (AE) is any
“untoward occurrence” in a patient or clinical study participant that need not be related to
treatment.
By contrast, an adverse drug reaction (ADR) implies an adverse event that results from a
medicine or treatment (i.e., there is a degree of relatedness between the adverse reaction
and the treatment).
FDA regulations define an ADR as
“an undesirable effect, reasonably associated with the use of a drug, that may occur as part
of the pharmacological action of the drug or may be unpredictable in its occurrence” (21
CFR 201.57(c)).
Remember: Although every ADR is also an AE, only some AEs will also be ADRs.
Therefore, it is very important to collect clear and complete information about every AE.
An AE is considered serious if it poses a threat to the patient’s life or functioning. The FDA
defines a serious adverse event (SAE) as any untoward medical occurrence that:
 Results in death, or
 Is life-threatening (places the patient at risk of death), or
 Requires hospitalization or prolongs an existing hospitalization, or
 Causes persistent or significant disability or incapacity, or
 Is a birth defect, or
 Requires medical intervention to prevent one of the above outcomes (e.g., an
asthma attack that requires intensive treatment in an emergency room, a seizure that
does not result in hospitalization but requires medical treatment).
An AE needs to meet only one of the above criteria to be considered serious. A change in
vital signs, diagnostic tests (e.g., an electrocardiogram), or laboratory test results may be an
SAE if the change is of sufficient magnitude to meet one of the above criteria.
An adverse event is judged “serious” on the basis of the threat it poses to a patient’s life or
functioning. For example, a patient could be diagnosed with pneumonia in his or her
doctor’s office and given antibiotics to take at home. The pneumonia is an AE, but not an
SAE
However, if the patient is hospitalized for the pneumonia, that is considered an SAE. (The
SAE is pneumonia resulting in hospitalization.)
It is also imperative to clarify between severe and serious. While the intensity of an event
may be severe, it may not meet the criteria for serious (e.g. Severe Migraine). Severity is
discussed in this module.
Elective surgery (i.e. surgery that is planned prior to entry into the study) is not a Serious
Adverse Event. For example, removal of bunions on feet, nose reconstruction, planned
hysterectomy, etc.

The definition of an SAE in the previous section is commonly understood to relate to

clinical studies of drug treatments. However, the definition can be applied to any kind of
clinical study, including behavioral studies.
The Investigator of a study may, for the purposes of the study, limit or expand the FDA
criteria for an SAE to reflect the specific risks of the study intervention and the
characteristics of the study population.
The Investigator may describe in the research protocol other AEs that in that particular
study are to be considered serious, although the AE may not meet the FDA criteria. For
example, all suicide attempts may be considered SAEs in a specific research protocol,
whether or not they require hospitalization or place the patient at immediate risk of death.
On the other hand, certain occurrences that would be considered SAEs under the standard
definition, such as hospitalizations for normal childbirth or voluntary admissions for
detoxification, may be explicitly defined not to be reportable as AEs and/or SAEs, if the
Investigator so chooses. Any such modifications to the definition of an SAE must be
approved during the protocol review process and by the appropriate IRBs.

For clinical studies that involve the use of marketed drugs (as opposed to investigational
new drugs), FDA defines an unexpected AE as:
 An AE that is not listed in the drug’s current labeling, or
 An AE that is more severe or more specific than indicated in the labeling.
For clinical studies in which investigational new drugs are used, the FDA defines an
unexpected AE as:
 An AE that is not consistent with the information about the drug’s risks that appears
in the relevant source document(s) (e.g., protocol, Investigator's Brochure, and
consent documents), or
 An AE that is not consistent with the risk information, or
 An AE that has occurred within the class of drugs, but not specifically with the
Investigational Product.

In studies conducted under the Investigational New Drug regulations, the known risks and
expected benefits of an investigational new drug are described in the Investigator's
Brochure.
However, an Investigator’s Brochure is often not prepared for behavioral studies. For this
reason, researchers who conduct behavioral studies are expected to describe in the research
protocol any adverse events that might be expected to occur in the study population as a
result of the experimental behavioral intervention. They must also briefly describe these
events in the consent documents.
In a behavioral study, therefore, an unexpected adverse event would be an AE that is not
mentioned in the protocol or consent documents or an AE that has not been seen before.
Aditionally, unexpected AEs in a behavioral study can be considered as unanticipated
problems (discussed further below) and are thereby regulated under 45 CFR46.
The Office of Human Research Protections (OHRP) defines unanticipated problems
involving risks to study participants and others as an event that meets all of the following
criteria:
1. unexpected (in terms of nature, severity, or frequency) given (a) the research
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the
characteristics of the subject population being studied;
2. related or possibly related to participation in the research (in this guidance
document, possibly related means there is a reasonable possibility that the incident,
experience, or outcome may have been caused by the procedures involved in the
research); and
Suspected unanticipated problems must be promptly reported to the IRB, who will make
the subsequent determination to report it to the proper regulatory authority.
Although unanticipated problems are found but not defined in 45 CFR 46, all NIH funded
studies are required to comply with 45 CFR 46. For OHRP’s current guidance on
unanticipated problems, follow the link here.

Every protocol should list specific AEs that are to be addressed at every visit. Generally,
this will be a very short list of lab values and clinical signs and symptoms. The protocol
should also specify the duration that information on AEs will be collected.
All AEs that occur in any clinical study participant should be assessed for:
Severity
The severity of an AE is not the same as its seriousness. Severity refers to the intensity of a
specific event (e.g., mild, moderate, or severe pain). However, the event itself may be of
minor medical significance (e.g., a severe toothache). (Click here to see sample definitions
of the grades of severity of an AE.)
By contrast, the seriousness of an AE is assessed by the extent to which it poses a threat to
the patient’s life or functioning. Thus, an AE may be severe (e.g., severe pain from a
toothache) without being serious (threatening the patient’s life or functioning).
Determining the severity of an AE is largely a matter of individual clinical judgment. No
universally accepted scale exists for describing or measuring the severity of AEs. The
severity of an AE should be determined with input from a qualified physician or licensed
medical staff.
Relatedness
An AE may or may not be causally related to the study intervention. A causal relationship
means that the intervention caused (or is reasonably likely to have caused) the AE. This
usually implies a relationship in time between the intervention and the AE (e.g., the AE
occurred shortly after the participant received the intervention).
For all AEs, it is the responsibility of the clinician who examines and evaluates the patient
to determine the relatedness of the event to the study intervention. Data managers who have
no role in patient clinical assessment must not perform this important task.
Acceptance that an AE is related to the intervention usually requires a plausible mechanism
of action—that is, a believable sequence of events by which the intervention brought about
the AE. It may be helpful to seek the opinion of the Study Medical Monitor on this point. It
can also be helpful to ask the participant whether he or she thinks the intervention could
have brought about the AE. (Click here to see terminology utilized in protocols to assist
clinicians in their assessment of the relatedness of an event.)

If an AE is thought to have a causal relationship with the intervention, and the AE raises
concern about the safety of the participant, serious consideration must be given to
temporarily halting or permanently discontinuing the intervention. Additionally,
rechallenging the participant (that is, giving the intervention again to test the causal
relationship to see if the AE occurs again) is not often done because of safety concerns. For
this reason, it is often impossible to say with certainty that an experimental intervention
caused an AE.
The causal relationship between an intervention and an AE may be tested by discontinuing
the intervention and then rechallenging the participant (giving the intervention again) to see
if the AE occurs again. However, this is rarely done because of safety concerns. For this
reason, it is often impossible to say with certainty that an experimental intervention caused
an AE.
When an AE is labeled “associated with the use of the intervention,” therefore, this means
there is a reasonable possibility that the AE may have been caused by the intervention and
is meant to convey in general that there are facts (evidence) or arguments to suggest a
causal relationship.
Early in the development of a drug or other intervention, when little is known of its safety
profile, it is especially important to maintain a high level of suspicion for AEs and to report
all AEs that may in any way be causally related to an experimental drug or intervention.
Any AE reported by a participant should be followed up at each subsequent study visit until
the AE has resolved. It is important to document both the duration (e.g., minutes, hours,
days) and severity of an AE. An AE that persists from one study visit to the next should be
documented as one event. For AEs that are sustained past the study duration, follow-up
may occur until resolution or for a reasonable period of time defined by the protocol.
The initial report of an AE is usually made by the participant; however, an AE may also be
reported by a family member, friend, nurse or other caregiver, or someone else. For
example, a family member or friend may call to report that a participant has been
hospitalized. Or another participant may report hearing from a third party that a participant
is seriously ill.
Regardless of who reports an AE, the event should always be documented in the
participant’s source documents including progress notes. When an AE is reported by a
third party, the Research Assistant should make every effort to contact the participant
directly to verify the report. In some cases, a report of an AE may turn out to be false. As
more information about the event is gathered and assessed, the Research Assistant must
ensure that source documents and reports are updated with accurate information about the
AE

AE reporting is an essential part of participant safety protection during a clinical study.

Determining whether an incident is a reportable AE—and if so, what should be reported
about it, to whom, and when—depends on many factors, including:
 Previous experience and knowledge of the drug or intervention,
 The disease being treated, and
 Regulatory requirements.
In addition to the factors listed above, investigators must consider incident reporting
requirements for NIH-funded studies, including reportable AEs and unanticipated problems
(UPs). All NIH-funded studies are required to comply with 45 CFR 46 for safety event
reporting. For OHRP’s current guidance on UPs involving participant safety risks, follow
the link here.
Not all AEs require reporting, as they might not directly impact participant risk or present
significant new findings. Inundating the study IRB with individual, unanalyzed UPs is an
uninformative process, and UPs that don’t impact participant risk can be covered during the
IRB’s continuing review. Requirements for the reporting of AEs are defined in each
protocol.
The investigator and research team must consider these factors when writing the sections of
the protocol and the operations manual that discuss adverse event reporting. The
investigators and the study sponsor jointly determine the extent and type of AE data that
will be collected for a specific trial.
They may decide that minor complaints of daily living will not be considered AEs. An
event such as the worsening of symptoms of a current illness could be captured in the
patient’s progress notes or on a case report form.
ICH GCP requirements for AE reporting
The investigator must report all Serious Adverse Events to the sponsor immediately. The
immediate reports should be followed promptly by detailed, written reports.
In the event of a death, the investigator should supply the sponsor and the IRB with any
additional requested information.
In addition, the investigator must comply with the applicable regulatory requirements as
well as protocol specific requirements related to the reporting of safety issues. In some
instances, the local laws or network requirements may request more stringent reporting of
emergent or safety
FDA Requirements
For IND studies FDA guidelines (21 CFR 312.32) require expedited reporting by the
sponsor of all AEs that are associated with the use of the drug, serious, unexpected and
reasonably related to the investigational product.
 Related and unexpected fatal or life–threatening AEs (severity grade 4 or 5) that are
associated with the use of the drug must be reported to FDA by telephone or fax no
later than 7 calendar days after the sponsor first learns of the event. This initial
report must be followed within 8 additional calendar days by a written safety report
that is as complete as possible.
 FDA must be notified of serious, related and unexpected AEs associated with the
use of the drug that are not fatal or life-threatening in a written safety report no later
than 15 calendar days after the sponsor first learns of the event.
 The sponsor should report pertinent follow-up information for previously submitted
reports to the FDA as soon as it is available, including for AEs that were not
initially deemed reportable if the follow-up information causes a change in
assessment.
Aggregate analyses of adverse events observed from a clinical trial, or from other studies
outside the sponsor’s scope, that detail new information regarding the investigational
product (i.e. new side effects, or increasing frequency of side effects) should be reported to
the FDA. Significant non-clinical findings are also reportable if they’re suggestive of
increased risk for human studies. The FDA also accepts voluntary reporting for marketed
drugs in studies exempt from FDA reporting requirements with their MedWatch system.
Under these guidelines, expedited reporting to the FDA is generally not necessary for AEs
that are:
 Serious but expected.
 Serious but not related to the study drug, whether expected or not (e.g., a patient
who dies of a cancer that was present prior to entry into a study of an
antidepressant).
  Non-serious, whether expected or not.
For studies of investigational new drugs, FDA requires the sponsor to notify all
participating investigators in a written safety report of any serious and unexpected AE that
is associated with the use of the study drug. The sponsor may add additional requirements
to this notification. Consider how NIDA fufills this obligation. NIDA has directed Lead
Investigators to distribute such reports within 24 hours of learning of an AE that:
 Is considered serious, related and unexpected, or
 Requires revision of the protocol or the informed consent form, or
 Requires termination of the study or suspension of enrolment.
If a serious related and unexpected AE represents an increased risk to study participants,
investigators must inform participants of this increased risk as soon as possible.

CTN Requirements
ICH GCP guidelines (E6) state that all serious adverse events (SAEs) should be reported
immediately to the sponsor. An exception is made for SAEs that are identified in the
protocol or other document (e.g., Investigator's Brochure as not requiring immediate
reporting).
For CTN studies (whether conducted under an Investigational New Drug application or
not), any AE that meets FDA’s criteria for a serious adverse event (SAE) must be reported
within 24 hours to the NIDA Study Medical Officer and all parties specified in the protocol.
The FDA’s definition of an SAE is to be used unless the protocol specifically limits or
expands the FDA definition.
Following the initial report of the SAE by phone, fax, or e-mail all efforts will be made to
gather additional information available on the SAE. Once received, this information will be
sent to NIDA within the time frame specified in the research study protocol.
For studies conducted under an IND, it is then NIDA’s responsibility (as sponsor of most
investigational new drug studies conducted within the CTN) to send an IND
(Investigational New Drug) Safety Report to the FDA within the required timeframe.
SAEs that are exempt from expedited reporting must be documented and reported in a
timely fashion (e.g., monthly, quarterly) in accordance with local IRB requirements. For all
CTN studies, any serious adverse event (SAE) must be reported to NIDA within 24 hours
after CTN protocol staff learn of the event. This deadline applies:
 Whether or not the investigator considers the SAE to be related to the study
intervention.
 Regardless of the severity or outcome of the SAE.
  For SAEs that occur in both drug studies and behavioral studies.
 For studies conducted under the Investigational New Drug regulations and those
that are not.
 For all SAEs that occur during a study, including those that occur during a post–
treatment observation period as defined by the study protocol.
The National Institutes of Health (NIH) has issued guidance to NIH-supported investigators
on reporting to IRBs about AEs that occur in multi-center clinical trials. Investigators must
know the policies of the local IRB, adhere to them, and keep a copy of them in the study
file. Investigators are also responsible for accurately documenting, investigating, and
following up all possible study-related adverse events.
Site PIs should follow the policies of their Institutional Review Board on timeframes for
reporting AEs. Additionally, investigators must ensure that NIDA is informed of any
actions taken by the IRB as a result of its continuing review of participant safety.

Adverse Event Reporting in CTN Studies

Multiple parties need to be notified of AEs that occur in CTN studies. This can lead to
confusion.
Study investigators must report AEs to:
 The study sponsor (NIDA for most CTN trials).
 Relevant IRBs.
If NIDA is the study sponsor, and the study is conducted under an IND, NIDA must inform
FDA and any other relevant regulatory agencies of findings that could adversely affect
participant safety, affect the conduct of the trial, or alter IRB approval to continue the trial.
The research protocol may, if appropriate, establish additional reporting requirements
based on the severity of an AE. For example, the protocol and consent forms could state
that trial-related hospitalizations will be reported to the participant’s treating physician.
In CTN trials, any AE that occurs between the times a participant signs the informed
consent form and the time he or she leaves the study after the final follow-up visit must be
captured and recorded, unless the protocol states differently. The investigators and NIDA
(as the study sponsor) may jointly determine an alternative period (e.g., beginning with the
first trial-related procedure or the first time a participant takes the study drug) during which
AEs must be reported.
How quickly an AE must be reported and to whom depends, in part, on the nature of the
event. Reporting requirements encompass both routine reporting and expedited (rapid)
reporting.
For studies conducted under an IND, FDA regulations require investigators to “promptly”
report to the study sponsor any AE that is reasonably likely to have been caused by the
study drug. If the AE is “alarming”, the investigator must report it immediately. The
sponsor, in turn, is responsible for expedited (rapid) reporting to the FDA of certain serious
adverse events (SAEs) that are both reasonably related and unexpected. All other AEs must
be reported to the FDA in protocol amendments or in annual reports (21 CFR 312.32).

Adverse Event Reporting in CTN Behavioral Studies

For NIH-funded studies that do not involve the use of investigational new drugs,
requirements for AE reporting vary depending on the nature of the study. Federal
regulations (45 CFR Part 46, Subpart A) require written procedures and policies for
ensuring that “unanticipated problems” involving risks to participants are reported to the
IRB, appropriate institutional officials, and the relevant department or agency head.
Most AEs that occur in CTN behavioral studies are found to be unrelated to the study
treatments received. For this reason, unlike FDA requirements for drug trials, non-serious
AEs are sometimes not tracked in CTN studies. The Lead Investigator should specify in
the protocol of a behavioral study which untoward occurrences should be captured and
reported as adverse events, and which should not. Furthermore, the protocol should specify
the types of events that will or will not qualify as SAEs and be reported as such.
For NIH-funded studies in which investigational drugs or devices are used, i.e. studies
conducted under IND or IDE, investigators must comply with both NIH and FDA
requirements for the reporting of AEs.
Additionally, OHRP provides the definition of unanticipated problems that affect the safety
risks to study participants and others. As NIH-funded studies are regulated by 45 CFR 46,
OHRP provides the criteria for determining unanticipated problems and the review and
reporting of these incidents and AEs
Expedited Reporting of Adverse Events
Participants in clinical studies may experience AEs which, if they are thought to be
probably or possibly caused by an experimental intervention, might be significant enough
to lead to important changes in the way a drug or other intervention is developed or used
(e.g., changes in dose, treatment population, required monitoring, consent forms). This is
particularly true for AEs that, in their most severe forms, threaten life or function.
Such AEs must be reported promptly to investigators, sponsors, regulators, and IRBs. This
is referred to as expedited or rapid reporting. The purpose of expedited reporting is to
ensure that the appropriate parties are quickly made aware of important new information
about the potential adverse effects of a drug or other experimental intervention.
Medical Follow-Up of Participants with an Adverse Event
Unless otherwise specified in the protocol, in some networks it is common practice that all
AEs and non-study–related SAEs should be followed-up until they have resolved or
stabilized or until 30 days after the participant’s involvement in the study has ended,
whichever occurs sooner.
All SAEs should be followed until resolution, or until the condition has stabilized with no
further change expected. According to FDA guidance, participants should receive
appropriate medical evaluation and treatment until resolution of any emergent condition
related to the study intervention that develops during or after the course of their
participation in a study, even if the follow-up period extends beyond the end of the study.
When a participant discontinues participation in a study because of an SAE, investigators
should:
 Continue to follow up the SAE as noted above.
 Document the SAE and its follow-up in the participant’s record.
 Attempt to complete any final evaluations required by the study protocol.
 Attempt to perform other medical evaluations to try to determine the cause of the
SAE and its possible relationship to the study intervention. These evaluations would
include obtaining an autopsy report, if available, in the event of a participant’s
death.
For a woman who is discontinued from a study because of pregnancy, attempt to follow up
the outcome of the pregnancy to term. If the woman was enrolled in a trial of an
investigational drug that is known to present a risk of birth defects, any information
regarding birth or congenital abnormality should be obtained.
Loss to follow-up of participants with ongoing SAEs is a serious problem that can affect
the validity of a study’s results. For this reason, every effort should be made to contact
participants who leave a study after experiencing an SAE. Documentation of that effort
should be maintained by the PI.

Part 6: Summary of Key Points >> 1 of 1

 The safety and well-being of study participants must be safeguarded at all times
during the conduct of a clinical research study.
 An adverse event (AE) is defined in the Good Clinical Practice guidelines as any
“untoward medical occurrence” in a person who receives a drug while participating
 in a clinical study. The occurrence need not be causally related to the drug
treatment.
 For behavioral studies, an AE may be defined as “any unfavorable, unintended
diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome, or
disease that occurs during the study, having been absent at baseline, or—if present
at baseline—appears to worsen.”
 An AE is considered serious if it poses a threat to the patient’s life or functioning.
The U.S. Food and Drug Administration (FDA) defines a serious adverse event
(SAE) as any untoward medical occurrence that:
o Results in death, or
o Life threatening (places the patient at risk of death), or
o Requires hospitalization or prolongs an existing hospitalization, or
o Causes persistent or significant disability or incapacity, or
o Is a congenital anomaly/birth defect, or
o Requires medical intervention to prevent one of the above outcomes.
 The Investigator in a behavioral trial may modify or expand the FDA criteria for an
SAE to reflect the specific risks of the intervention and the characteristics of the
study population.
 The severity of an AE is not the same as its seriousness. An adverse event may be
severe (e.g., severe pain from a toothache) without being serious (threatening the
patient’s life or functioning).
 SAEs must be reported by phone or fax immediately to all parties notified as
specified in the protocol.
 The purpose of expedited reporting to the FDA or other regulatory authority is to
ensure that the appropriate parties—including investigators, sponsors, regulators,
and IRBs—are quickly made aware of new, important information about the
potential adverse effects of a drug or other experimental intervention.
 In addition to reporting AEs and SAEs, NIH-funded studies are required to report
unanticipated problems that affect the safety of study participants and others. While
unanticipated problems are found in and regulated by 45 CFR 46, OHRP provides
the criteria for determining unanticipated problems and the reporting and review of
these incidents (see OHRP, 2007).
 Generally, all AEs and SAEs should be followed up until they have resolved or
stabilized.
  Data and safety monitoring must occur periodically throughout every study to
protect participant safety and ensure the integrity of study data, for example, by the
Data and Safety Monitoring Board for a clinical trial.

QUALITY ASSURANCE
What is quality assurance?
Quality Assurance (QA) in clinical trials consists of planned, systematic activities that are
conducted to ensure that a trial is performed―and that trial data are generated,
documented, and reported―in compliance with the protocol, Good Clinical
Practice (GCP) guidelines, and all other applicable regulatory requirement(s).
Why is QA important?
Research that is not conducted according to high standards of quality yields invalid data. It
is also unethical because it may put research participants at risk. (Protection of the safety,
rights, and well-being of research participants is discussed in
the Introduction, Institutional Review Boards, Informed Consent, and Participant
Safety and Adverse Events modules.)
Audits conducted by the U.S. Food and Drug Administration (FDA) find that
several problems commonly occur in research studies.
Quality data are critical to ensure that the results of studies are interpreted correctly. Sloppy
or incorrect data can lead to misleading conclusions. Careful attention to standards of
quality also ensures that studies are completed in a timely fashion. Timely completion of
high quality studies bridges the gap between research and practice by bringing effective
new treatments to clients more quickly.
Who is responsible for QA?
All members of the protocol team are responsible for QA.
While it is common for QA and monitoring-related duties and functions to be transferred to
a CRO, the sponsor has ultimate responsibility for implementing and maintaining QA
systems. (ICH GCP 5.1.1) This responsibility includes oversight of all QA systems as well
as any trial-related functions performed or managed by other parties (i.e. the CRO, or a
subcontractor to the CRO) on behalf of the Sponsor (ICH GCP 5.2.2)
Investigators and every member of the protocol team are expected to perform his or her
duties diligently and thoroughly, thus ensuring that the trial is conducted according to the
highest possible standards of quality.
The sponsor is responsible for ensuring the trial’s integrity and for developing a risk-based
monitoring plan. As the sponsor of all studies conducted by the network, NIDA CTN has
transferred the regulatory responsibility of all monitoring to the Clinical Coordinating
Center (CCC).
The CCC develops systematic, prioritized, and risk-based (ICH GCP E6(R2) 5.18.3)
monitoring plans to be utilized for each CTN study. This plan is customized for each trial
and describes the strategy, methods, responsibilities, and requirements for monitoring the
trial (ICH GCP E6(R2) 1.64). Additionally, the plan provides operational guidelines to
ensure the quality and integrity of data collected in accordance with CTN protocols. This
document also ensures consistency in the conduct of CTN studies across multiple sites and
protocols. This monitoring plan:
 Emphasizes the monitoring of critical data and processes.
 Ensures the quality and integrity of CTN clinical studies.
 Ensures the protection of human participants.
 Advances collaboration between treatment and research staff at CTN sites.
Roles and responsibilities of the Lead Investigator
The Lead Investigator (LI) is a CTN-specific role for the investigator that has overall
responsibility for the entire study. The LI convenes a Protocol Team that assists with all
aspects of the development and operation of the study. In other studies outside of the CTN,
this role may be considered the Principal Investigator.
The Project Director (or Protocol Coordinator) is the LI’s “right hand.” He or she is
responsible for coordinating and carrying out day–to–day study operations. The Project
Director is a member of the Protocol Team and is the primary contact for questions about
the overall study. Other roles and responsibilities represented on the Protocol Team usually
include, but may not be limited to, the following:
 Data Management
 Quality Assurance
 Training
 Regulatory Affairs
Roles and Responsibilities of the Node Principal Investigator
The Node PI (or grantee) is another CTN-specific role that is responsible to NIDA for study
performance at his or her Node. He or she works with Node staff, the Site Principal
Investigator(s), and the Lead Investigator to implement the study at that Node. 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 Site PI(s) and the Lead Investigator. Other
responsibilities of the Node PI include:
  Appointing the Site PI and Study Coordinator.
 Managing the Node budget and staff.
 Appointing a monitor to conduct Quality Assurance visits at research sites within
the Node.
 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.
 Knowing the policies of his or her institution/university and ensuring compliance at
the Node with these policies.
The Monitoring Plan
The monitoring plan sets out monitoring strategies, the monitoring responsibilities of all
parties involved, the various monitoring methods to be used, and the rationale for their use.
It also describes monitoring procedures, types of visits, what is involved in the conduct of
those visits, and the quantity or percentage of each type of document to be monitored.
These procedures can be further defined on a protocol basis depending on the purpose,
design, size, complexity, and primary outcome measures of the trial (ICH GCP E6(R2)
5.18.3).

According to GCP guidelines, “the Sponsor may choose on-site monitoring, a combination
of on-site and centralized (remote) monitoring, or, where justified, centralized monitoring
alone…Centralized monitoring processes provide additional monitoring capabilities that
can complement or reduce the extent and/or frequency of on-site monitoring and help
distinguish between reliable data and potentially unreliable data without the need for total
source data verification” (ICH GCP 5.18.3). The rationale for the chosen monitoring
strategy is documented in the monitoring plan.

In general, on-site monitoring is required and remote monitoring may occur at any given
research site before a trial begins, while it is in progress, and after it concludes or is
terminated. In many instances, study monitors may visit each site after the first one to two
participants are enrolled and then schedule subsequent visits based on multivariate criteria,
such as the rate of enrollment, volume of data to review, site performance, and other
considerations.

Study monitors conduct site visits according to the procedures describes in the monitoring
plan and in accordance with Good Clinical Practice (GCP) guidelines.
Monitoring Role for Sponsors
The Good Clinical Practice guidelines state that the sponsor is responsible for selecting
monitors and for ensuring that the following criteria are met (see ICH GCP 5.18.2).
 Monitors are appropriately trained and have the scientific or clinical knowledge
needed to monitor the trial adequately. Monitors qualifications should be
documented.
 Monitors are thoroughly familiar with the investigational product(s), protocol,
written informed consent form, and any other written information about the trial to
be provided to study participants, the Sponsor’s SOPs, GCP, and the applicable
regulatory requirement(s).
Quality Assurance (QA)/Study Monitor Role
QA/study monitors perform the following study activities:

 Conduct initiation, interim, and closeout visits.

 Conduct centralized monitoring, as applicable.
 Provide training on protocol-specific issues and Good Clinical Practice, when
needed or appropriate.
 Follow-up on issues identified during earlier monitoring visits.
 File reports with the sponsor and other applicable parties, as required.

Monitors ensure that the trial is conducted properly by:

 Verifying that:
o Only eligible participants are being enrolled in the study.
o Written informed consent was obtained before each participant's enrollment.
o The investigator has adequate qualifications, resources, and facilities
(including laboratories, equipment, and staff) to conduct the study.
o The investigator is following the approved protocol and any approved
amendment(s).
o The investigator and trial staff are performing specified trial functions in
accordance with the protocol and have not delegated these functions to
unauthorized individuals.
 For investigational product(s), verifying that:
 o Storage times and conditions are acceptable and supplies adequate.
o Product(s) are supplied only to eligible participants and only at protocol-
specified dose(s).
o Participants receive necessary instructions on the proper use, handling,
storage, and return of the product(s).
o Receipt, use, and return of the product(s) at study sites are adequately
controlled and documented.
o Disposition of unused product(s) at study sites complies with the applicable
regulatory requirement(s)
o The Investigator receives the current Investigator’s Brochure.
 Checking the accuracy, consistency, and completeness of entries on case report
forms (CRFs), source documents, and other trial-related records; specifically,
verifying that:
o Modifications in dose or therapy are properly documented for each trial
participant.
o Adverse events, concomitant medications, and intercurrent illnesses are
reported in accordance with the protocol on the CRFs.
o Missed visits, tests not conducted, and examinations not performed are
clearly reported on the CRFs.
o All withdrawals and dropouts of enrolled participants are reported and
explained on the CRFs
 Ensuring that corrections, additions, or deletions needed in the CRFs are made,
dated, explained (if necessary), and initialed by the investigator or by an authorized
designee.
 Determining whether all adverse events are appropriately reported within the
required time periods.
 Determining whether the investigator is maintaining essential documents for the
conduct of a clinical trial. (See the Record Keeping module for more information on
essential documents.)
 Notifying the investigator of deviations from the protocol, SOPs, GCP, and
applicable regulatory requirements and taking appropriate action to prevent their
recurrence.
 Notifying the investigator and sponsor of any noncompliance that significantly
affects or has the potential to significantly affect human subject protection or
reliability of trial results.
  Participating in root cause analyses and ensuring that appropriate corrective and
preventative actions are implemented to correct each identified incidence of
noncompliance.

Initiation visits occur before a research site begins participant recruitment for protocol
participation and after the necessary IRB approvals are obtained. During a site initiation
visit, study monitors review trial documents to ensure that they are complete and in order.
A listing of documents to be retained by sites before, during, and after a trial can be found
in ICH GCP Section 8. They will also inspect sites to ensure that the facilities are
appropriate, that the work and storage space necessary to conduct the trial are available, and
that equipment, medication, and supplies needed to start the trial are available. They ensure
that adequate staff is available and properly trained.

Study monitors will document action items that need to be performed by the site prior to
site activation. Research sites cannot begin participant recruitment until the Investigator(s)
and sponsor have provided their approval.
Additionally, sponsor organizations can help to assure quality by:
 Providing all research team members with adequate training before the trial begins.
 Monitoring progress early in the trial to assess the quality of screening, recruitment,
randomization, and documentation practices (for example, after the first few
participants have been randomly assigned to a treatment group). This helps to
ensure that any deficiencies are detected early and at the source (i.e., at the site
where the research is performed), that inefficiencies and wasteful procedures are
eliminated, and that any necessary retraining is performed in a timely fashion. Early
monitoring also helps to reduce the likelihood that errors will occur later in the trial,
by providing additional information to help troubleshoot for future risk mitigation
strategies and risk-based monitoring of the study.
 Increasing the frequency of monitoring when necessary to correct any deficiencies
in the conduct of the trial or to provide technical support

 Quality Assurance (QA) consists of planned, systematic activities conducted to

ensure that a trial is performed―and that trial data are generated, documented, and
reported―in compliance with the protocol and with Good Clinical Practice (GCP)
and all other applicable regulatory requirement(s).
 QA is the responsibility of every member of the research team. The role of QA staff
is to support and assist members of the research team in adhering to high quality
standards.
 The purposes of monitoring are to verify that:
o The rights and well-being of human participants are protected.
o Reported trial data are attributable, legible, contemporaneous, original,
accurate, and complete.
o The trial is conducted in compliance with the currently approved protocol
(including any amendments), as well as with GCP and all other applicable
regulatory requirement(s).
 Monitoring can occur on-site and/or remotely (via centralized monitoring), and it is
required before, during, and after completion of a trial.