Human Research Subjects and IRB Process

Human Subject Research and
IRB Process.
Kelvin Qihindas 2018

2
History of Human Subject Research
Regulation
Precursors of Modern Research Ethics
Hippocrates, “Hippocratic Oath:” “…I will do no harm or injustice to [my patients].
Immanuel Kant, Metaphysics of Morals: “Act in such a way that you treat humanity,
whether in your own person or in the person of any other, always at the same time as an
end and never merely as a means to an end.”

3
Regulation
Thomas Percival, Medical Ethics; or, a Code of Institutes and Precepts Adapted to the
Professional Conduct of Physicians and Surgeons(1803)
▪ “[N]ew methods of chirurgical treatment should be devised but … should be
scrupulously and conscientiously governed by sound reason, just analogy, or
well-authenticated facts … [N]o such trials should be instituted without a previous
consultation of the physicians or surgeons according to the nature of the case.”
▪ Experimental treatments permissible when all else fails, and when they can serve the
public good.

4
Regulation
William Beaumont (1833)
▪ There must be recognition of an area in which experimentation in man is needed
▪ Some experimental studies in man are justified when the information cannot
otherwise be obtained
▪ The investigator must be conscientious and responsible…[A] well-considered,
methodological approach is required so that as much information as possible will be
obtained whenever a human subject is used. No random studies are to be made.

5
Regulation
William Beaumont, cont.
▪ The voluntary consent of the subject is necessary
▪ The experiment is to be discontinued when it causes distress to the subject
▪ The project must be abandoned when the subject becomes dissatisfied
American Medical Association Code of Ethics (1847)

6
Regulation
Claude Bernard (“founder of experimental medicine”), Introduction to the Study of
Experimental Medicine (1865)
▪ Permissible to save, cure, or gain personal benefit for the subject
▪ “Those [experiments] that can only harm are forbidden. Those that are innocent are
permissible, and those that may do good are obligatory.”

7
Regulation
Walter Reed (1900)
▪ Conducted a series of experiments on U.S. soldiers and Spanish immigrants to Cuba
to determine whether mosquitoes served as intermediate hosts for yellow fever.
▪ Coded names of participants to shield identities
▪ Used written informed consent for experiment participants. (Oldest extant informed
consent documents)

8
Regulation
Walter Reed (1900)
Informed Consent Elements
▪ Autonomy (respect for persons): “gives his consent…for the reasons and under the
conditions…”
▪ Voluntary Participation : “being in the enjoyment and exercise of his own free will”
▪ Risks : “In case of the development of yellow fever in him, that he endangers his life to a
certain extent.”
▪ Benefits : “He will receive from the said commissioner the greatest care and the most
skillful medical service.”
▪ Compensation: “he will receive the sum of $100 in American gold . . .”
▪ Study withdrawal conditions: “The undersigned binds himself not to leave the bounds
of this camp during the period of the experiments and will forfeit all right to the benefits
named in this contract if he breaks this agreement.”

9
Regulation
The Nuremberg Code (1947)
• Principles enumerated by the Nuremberg Military Tribunals during proceedings against
23 German physicians and administrators for war crimes and crimes against humanity
• Charges arose from medical experimentation on concentration camp prisoners
• First international document to advocate voluntary participation and informed consent

10
Regulation
1939-1944 Nazi Experimentation
Findings of the Tribunal:
▪In every single instance appearing in the record, subjects were used who did not consent
to the experiments;…
▪In no case was the experimental subject at liberty of his own free choice to withdraw from
any experiment.…

11
Regulation
1939-1944 Nazi Experimentation, cont.
▪All of the experiments were conducted with unnecessary suffering and injury and but very
little, if any, precautions were taken to protect or safeguard the human subjects from the
possibilities of injury, disability, or death.
▪In every one of the experiments the subjects experienced extreme pain or torture, and in
most of them they suffered permanent injury, mutilation, or death, either as a direct result of
the experiments or because of lack of adequate follow-up care.

12
Regulation
Nuremburg Code and Voluntary Consent
▪ The duty and responsibility for ascertaining the quality of the consent rests upon each
individual who initiates, directs or engages in the experiment. It is a personal duty and
responsibility which may not be delegated to another with impunity
▪ This means that the person involved should:
▪ Have legal capacity to give consent

13
Regulation
Nuremburg Code and Voluntary Consent
▪ The duty and responsibility for ascertaining the quality of the consent rests upon each
individual who initiates, directs or engages in the experiment. It is a personal duty and
responsibility which may not be delegated to another with impunity
▪ This means that the person involved should:
▪ Have legal capacity to give consent

14
Regulation
▪ Situated as to be able to exercise free power of choice, …; and should have sufficient
knowledge and comprehension of the elements of the subject matter involved as to
enable him to make an understanding and enlightened decision.
▪ This latter element requires that before the acceptance of an affirmative decision
by the experimental subject there should be made known to him the nature,
duration, and purpose of the experiment
▪ The method and means by which it is to be conducted
▪ All inconveniences and hazards reasonably to be expected;
▪ The effects upon his health or person which may possibly come from his
participation in the experiment.

15
Regulation
The Declaration of Helsinki (1964)
• Principles established by the World Medical Association to guide physicians conducting
medical research involving humans subjects
Differentiated between therapeutic and non-therapeutic research:
• Therapeutic research gives patients the opportunity to receive an experimental treatment
that might have beneficial results.
• Non-therapeutic research is conducted to generate knowledge for a discipline, and might
have positive results in future patients.

16
Regulation
1966 NIH Policies for the Protection of Human Subjects
▪ Established the IRB as one mechanism through which human subjects would be
protected.
1974 National Research Act (raised NIH policy to regulation)
▪ Required regulations for protection of human subjects
▪ Informed consent
▪ Institutional Review Boards
▪ Created National Commission for the Protection of Human Subjects of Biomedical
and Behavioral Research

17
Regulation
The Belmont Report (1978)
Established three basic ethical principles:
Principle 1: Respect for persons
• Individuals should be treated as autonomous agents
• Persons with diminished autonomy are entitled to protection.
Application: Informed consent
● Subjects, to the degree that they are capable, must be given the opportunity to choose
what shall or shall not happen to them
● The consent process must include three elements:
• information,
• comprehension, and
• voluntariness.

18
Regulation
The Belmont Report
Principle 2: Beneficence
• Human subjects should not be harmed
• Research should maximize possible benefits and minimize possible harms
Application: Assessment of risks and benefits
• The nature and scope of risks and benefits must be assessed in a systematic manner

19
Regulation
The Belmont Report
Principle 3: Justice
• The benefits and risks of research must be distributed fairly.
Application: Selection of subjects
• There must be fair procedures and outcomes in the selection of research subjects

20
Mission of the IRB
The Institutional Review Board (IRB) a committee charged with providing independent,
objective review of research involving humans subject in order to:
• protect the rights and welfare of human research subjects, and
• ensure compliance of human subject research with established ethical standards and
federal, state, and local regulations and policies.

21
Reporting Requirements &
Compliance Oversight Procedures
Prompt Reporting Requirement - § 46.103(b)(5)
• Unanticipated problems involving risks to subjects or others
▪ Unanticipated problems vs. adverse events
▪ Guidance available at: http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm
• Suspension of termination of IRB approval
• Serious or continuing non-compliance

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Adverse Event/Unanticipated Problems
Policy and Procedures

23
Adverse Events
Any untoward or undesirable experiences associated with research, including
any abnormal sign (for example, abnormal physical exam or laboratory
finding), symptom, or disease, temporally associated with the subject’s
participation in the research, whether or not considered related to the
subject’s participation in the research.

24
Adverse Events
Adverse events may be the result of:
the interventions and interactions used in the research
the collection of identifiable private information in the research
an underlying disease, disorder, or condition of the subject and/or
other circumstances unrelated to the research

25
Adverse Events
Most adverse events are not reportable to the IRB
The majority of adverse events that occur in the context of research are
expected:
the known toxicities and side effects of the research procedures
the expected natural progression of the subjects’ underlying diseases,
disorders, and conditions, and subjects’ predisposing risk factor profiles
for adverse events.

26
Protocol Deviation
A protocol deviation is a divergence or departure from the expected conduct of an IRB-
approved study that is not consistent with the current, approved research protocol, consent
process or document or study addenda. The significance of a protocol deviation, in terms
of subject safety, depends on the nature of the deviation and the study.

27
Protocol Deviation
Those protocol deviations that involve harm or have the potential to impact the
health or welfare of the subject(s) or others must be reported in writing to the IRB by
utilizing the “Unanticipated Problem Potentially Involving Risk to Subjects or Others
Report” form.
Examples of reportable deviations are below:
❑*Medication or Laboratory Errors that involve potential harm;
❑Improper or Unapproved Consent Process or Consent Form;
❑Unintentional change to the protocol without prior IRB approval;
❑Intentional change to the protocol without prior IRB approval to eliminate immediate
hazard to research subject.
*The principal investigator, as the expert in the field, must determine if there is potential for
harm with any medication errors.

28
Protocol Deviation
Those protocol deviations (e.g., missed appointment, labs one day late) that
do not involve harm or have the potential to impact the health or welfare of
the subject(s) or others do not need to be individually reported.
Deviations not affecting risk to subjects or others should be summarized and
reported at time of continuing review.

29
Is the incident UNEXPECTED?
Unexpected (in terms of nature (type of event), severity (extent of
harmfulness), or frequency (number of like events higher than anticipated)
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;

30
Is the incident
UNEXPECTED?....Cont’d
2. related or possibly related to participation in the research (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 In the eyes of the IRB, the PI is in the best position to
make this determination.
3. suggests that the research places subjects or others at a greater risk of
harm (including physical, psychological, economic, or social harm) than
was previously known or recognized

31
Determination of Higher Risk
Reporting
The IRB may, in coordination with other institutional oversight committees,
categorize a protocol as “higher risk” and require the Investigator to report all
local adverse events promptly to the IRB, regardless of whether the event is
related or expected. This determination will be made at time of initial review
or anytime after initial review if the IRB feels it is warranted. This
determination and the form requirements will be clearly communicated back
to the Investigator.
Examples of clinical trials for which the IRB may institute more stringent
reporting are: local, investigator-initiated early phase (Phase I, Phase I/II)
study; local, investigator-initiated trial in extremely vulnerable populations,
e.g., very sick patients, subjects unable to consent for themselves, prisoners.

32
Other Unanticipated Problems
Below are examples of other types of protocol-related problems that must be reported to the
IRB:
• Complaint by a subject;
• Breach of confidentiality/HIPAA violation;
• Enforcement action e.g., unfavorable audit report, suspension or disqualification of
investigator, or Warning Letter;
• Study personnel misconduct;
• Study personnel not on protocol;
• Incarceration of a research subject during participation;
• Other untoward events that present risk to the subject, investigator, research staff or
others.
• These unanticipated problems are to be reported to the IRB utilizing the “Unanticipated
Problem Potentially Involving Risk to Subjects or Others Report” form.
All unanticipated problems are to be reported as soon as possible. If all information is
not available within 7 days, submit an initial report at 7 days and then follow-up with
the IRB as information becomes available.

33
IRB’s role will be…
To determine whether the event or problem is an
Unanticipated Problem Involving Risk To Participants Or Others
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures
that are described in the IRB-approved documents, such as the protocol and informed
consent document, and (b) the characteristics of the subject population being studied
Related or possibly related to participation in the research (possibly related means there is a
reasonable possibility that the event or problem may have been caused by the
procedures involved in the research), and
Suggests that the research places subjects or others at a greater risk of harm (including
physical, psychological, economic, or social harm) than was previously known or
recognized

34
If the IRB determines that the event is an
Unanticipated Problem
The IRB may take any of the following actions:
• Accept the report with no changes
• Accept the report with changes to the risk/benefit profile, the protocol, or the informed consent
documents.
• Require re-consenting of participants
• Increase the frequency of continuing review
• Impose additional monitoring requirements
• Require additional training of the Investigator and research team
• Request an “Administrative Hold” pending further information
• Suspend or Terminate the study

35
Adverse Events vs. Unanticipated Problems
Unanicipat
ed
Problems

36
Adverse Events vs. Unanticipated
Problems
The diagram illustrates three key points:
The vast majority of adverse events (area A) occurring in the context of
research are expected in light of (1) the known toxicities and side effects
of the research procedures; (2) the expected natural progression of
subjects’ underlying diseases; and (3) subjects’ predisposing risk factors.
Thus, most individual adverse events do not meet this criterion for an
unanticipated problem and do not need to be reported.
A small proportion of adverse events are unanticipated problems (area B)
and need to be reported to the IRB.
Unanticipated problems include other incidents, experiences, and
outcomes that are not adverse events (area C) and need to be reported to
the IRB.

37
Compliance Oversight Procedures
• Written complaint/allegation
• Jurisdiction determination
• IRB committee initiates inquiry – asks institution to investigate & provide
report
• IRB committee receives written report, and evaluates report and other
relevant documents
• Additional correspondence/telephone interviews/site visit
• Issue final determination
• Guidance at: http://www.hhs.gov/ohrp/policy/incidreport_ohrp.html

38
Possible Determinations/
Outcomes
In compliance
No recommendations
Recommend improvements
Noncompliance
Need corrective actions
IRB approval restricted or withdrawn, pending corrective actions

39
Informed Consent
Informed consent (minimal risk) requires:
1) Statement that study involves research
2) Explanation of the purpose of the research
3) Expected duration of subject’s participation
4) Identification of procedures that are experimental
5) Descriptions of benefits to subject and/or to others that may reasonably be expected
6) Disclosure of appropriate alternative, beneficial procedures or courses of treatment (if
any)
7) Statement describing the extent, if any, to which confidentiality of records will be
maintained

40
Informed Consent
8) Statement describing the extent, if any, to which confidentiality of records will be
maintained
9) Explanation of whom to contact for pertinent answers to questions about the research,
research subject’s rights, and in the event of a research related to injury to the subject.
10)Statement that participation is voluntary, that refusal to participate involves no penalty
or loss of benefits to which the subject is otherwise entitled, and that the subject may
discontinue participation at any time without penalty

41
Informed Consent – Waiver of
Documentation
An IRB may waive the requirement of a signed consent form for all or some of the subjects,
if:
1) The only record linking the subject and the research would be the consent document
and the principle risk would be potential harm resulting from a breach of confidentiality.
2) The research presents no more than minimal risk of harm to the subjects and involves
no procedures for which written consent is normally required outside the research
context.

42
Informed Consent – Waiver of
Documentation
If the IRB approves waiver of written documentation of consent, it may still require:
• Statement at the beginning of the survey/interview that incorporates the elements of
informed consent
• Written consent statement at the initial screen or cover letter of a survey
(web/mail)
• Consent elements in invitation to participate in survey (e-mail
communication/mailing)
• Oral consent prior to initiating an interview (with subsequent written statement)
• Statement at the conclusion of survey/interview
• Oral consent prior to initiating an interview (with subsequent written statement.

43
Common Research Risks (Non-
Medical)
• Disclosure of private/confidential information
• Psychological risks (insult, trauma)
• Social risks (embarrassment, rejection by peers)
• Economic risks (loss of job, credit, insurance)
• Legal risks (subpoena, fine)
• Inconvenience/intrusiveness (boredom, frustration)

44
Common Application Problems
Anonymity vs. Confidentiality
• Anonymity - Providing anonymity of information collected from research
participants means that either the project does not collect identifying information
of individual subjects (e.g., name, address, Email address, etc.), or the project
cannot link individual responses with participants’ identities. A study should not
collect identifying information of research participants unless it is essential to the
study protocol.
• Confidentiality - Maintaining confidentiality of information collected from research
participants means that only the investigator(s) or individuals of the research
team can identify the responses of individual subjects; however, the researchers
must make every effort to prevent anyone outside of the project from connecting
individual subjects with their responses.

45
Common Application Problems
“Children”
• Anyone under the age of 18 cannot consent to be a participant in research.
• For individuals under 18, a researcher must obtain legal consent from a parent or
guardian and assent from the child or minor (as required by the IRB).
• Assent - a child's affirmative agreement to participate in research.
• Mere failure to object should not, absent affirmative agreement, be construed as
assent. (45 CFR 46.402(b)

46
The Common Rule
The Common Rule (Federal Policy for the Protection of Human Subjects, 56 FR
28003, June 18, 1991) :
• Defines regulated research
• Provides regulatory authority for IRB review
• Establishes requirements for IRB review
• Identifies criteria for IRB approval of research
• Creates additional protections for children

47
Consent and Information forms
A research project may be allowed to use a study information form instead of a consent
form for different conditions like:
1. Research involves no more than minimal risk to the subjects;
2. Waiver or alteration of informed consent will not adversely affect the rights and
welfare of the subjects;
3. Reach could not practicably be carried out without the waiver or alteration; and
4. Whenever appropriate, the subjects will be provided with additional pertinent
information after participation
Study Information Forms Have All Elements Of A Consent Form – Just No Need For
A Signature. Participants Keep A Copy Of The Study Information Form

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Oral Consents
• Oral Consent Script
• Must include all elements of a traditional informed consent
• Purpose, activities, time commitment
• Risks and benefits
• Privacy and confidentiality
• Voluntary
Qualification for use of oral consents:
• Minimal risk and involves no procedures for which written consent is normally required
outside of the research context; OR
• Only record linking the subject and the research would be the consent document and the
principal risk would be potential harm resulting from a breach of confidentiality

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But understand and remember….
Informed Consent is a process of information exchange that includes:
• Participant recruitment materials
• Verbal instructions
• Written materials
• Question / answer sessions
• Agreement - documented by a signature when required

50
Thank you
Contacts:
Telephone: On request
Email: qihindas@gmail.com
https://www.linkedin.com/in/kelvin-qihindas-a19bbba8/

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