Required Findings &
Determinations
Jeffrey M. Cohen, Ph.D. CIP
President
HRP Associates, Inc.
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Overview
Three types of required findings and
determinations
 Required findings for all protocols
 Required findings where appropriate to the
protocol
 Other determinations
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Required Findings: All Protocols
For each protocol, the IRB must determine and
document:
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The research meets all of the criteria for approval
in 45 CFR 46.111
Additional safeguards to protect vulnerable
populations
The level of risk (minimal or more than minimal)
Approval period
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Required Findings: Where Appropriate
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When approving research that involves populations
covered by Subparts B, C, or D of 45 CFR 46, the
IRB must find and document that the research meets
the criteria in the Subparts
When waiving consent, the IRB must find and
document that the research meets the criteria in 45
CFR 46.116(d)
When waiving documentation of consent, the IRB
must find and document that the research meets the
criteria in 45 CFR 46.117(c)
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Other Determinations
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Investigator Conflict of Interest
Serious or Continuing Noncompliance
Unanticipated Problems
Multi-site/Collaborative Research
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Criteria for Approval
Criteria for IRB Approval of Research
45 CFR 46/21 CFR 56 §111(a)
“In order to approve research covered by these
regulations the IRB shall determine that all of
the following requirements are satisfied”
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Criteria for IRB Approval
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Risks to subjects are
minimized
Risks are reasonable in
relation to anticipated
benefits
Selection of subjects is
equitable
Informed consent is sought
from each subject
Informed consent is
appropriately documented
46.111
When appropriate:
 data collection is monitored to
ensure subject safety
 privacy and confidentiality of
subjects is protected
 additional safeguards are
included for vulnerable
populations
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46.111
Criteria for IRB Approval
BENEFICENCE
JUSTICE
Risk/Benefit Analysis
Data Safety
Experimental Design
Qualifications of PI
Subject selection
Inclusion/exclusion
Recruitment
RESPECT FOR PERSONS
Informed consent
Surrogate consent
Assent
Privacy & Confidentiality
Vulnerable Populations
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Risk/Benefit
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Identifying Risks
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The term “risk” involves two dimensions
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Magnitude of harm
Probability of harm
Assessing the level of risk involves taking
both into account
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Identifying Risks
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Identifying risk requires scientific expertise
on the part of the IRB
When the IRB does not have the necessary
expertise it must use outside consultants
An IRB that reviews research without the
necessary expertise is not in compliance with
the regulations
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Minimizing Risk
Three ways to minimize risk
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Alternatives
– other procedures that are less risky
Precautions
– procedures to decrease the likelihood that harms
will occur
Contingencies
– procedures to deal with harms if they occur
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Subject Selection &
Recruitment
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Subject Selection
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Justice requires equitable distribution of both the burdens and
benefits of research
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Individuals and groups that bear the burden should share in the
benefits
Individuals and groups that benefit from research should share in
the burden
Selection of subjects should be justified by the science
IRBs should not overprotect vulnerable populations so that they
are excluded from participating in beneficial research
If the study is funded by NIH, exclusions of women, minorities
or children MUST be justified.
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Subject Recruitment
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Subject recruitment is part of the consent process
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Information in recruitment should be consistent with protocol
Recruitment should not be coercive or unduly enticing
Recruitment should clearly indicate that it is for research
and not make unfounded claims (e.g., “cure” or “free
treatment”)
IRBs must review recruitment procedures, including
any advertising
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Difference between FDA and OHRP guidance
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Informed Consent
Beyond the
Consent Form
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The Consent Process
Informed consent is not a single event or just a form to be
signed -- rather, it is an educational process that takes
place between the investigator and the prospective
subject.
The basic elements of the consent process include:
 full disclosure of the nature of the research and the
subject's participation,
 adequate comprehension on the part of the potential
subjects, and
 the subject's voluntary choice to participate.
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Procedures for Obtaining Consent
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Subject has the legal and mental capacity to give
consent
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legally authorized representative;
Sufficient opportunity is provided to consider
The possibility of coercion or undue influence is
minimized
Language understandable to the subject
No “exculpatory” language
46.116
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Documentation of Consent
Documentation of "legally effective informed consent"
usually involves the use of a written consent form
signed by the subject or the subject's legal
representative.
 The consent form is merely the documentation of
informed consent and does not, in and of itself,
constitute informed consent.
 The fact that a subject signed a consent form does
not mean that he/she understood what was being
agreed to or truly gave their voluntary consent.
46.117
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Data Safety Monitoring
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Safety Monitoring
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Oversight and monitoring to ensure the
safety of participants
Investigators need Data Safety Monitoring
Plan
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How subject reactions and data being monitored
Unanticipated Problems detected and reported
What to do in case of problems
Privacy and Confidentiality
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Definitions
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Privacy - having control over the extent,
timing, and circumstances of sharing oneself
(physically, behaviorally, or intellectually)
with others.
Confidentiality - methods used to ensure that
information obtained by researchers about
their subjects is not improperly divulged.
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Regulations
46.102(f) Human subject means a living
individual about whom an investigator…
conducting research obtains
(1) data through intervention or interaction
with the individual,
or
(2) identifiable private information.
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Regulations
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Private information - information which has been
provided for specific purposes by an individual and
which the individual can reasonably expect will not
be made public (for example, a medical record).
Identifiable information – information where the
identity of the subject is or may readily be
ascertained by the investigator or associated with
the information.
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Confidentiality
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Confidentiality and anonymity are not the
same
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Anonymous means no one, anywhere, ever can
identify individual subjects
Names are not the only identifiers
Subjects’ participation in the research may
need to be kept confidential as well as their
data
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Confidentiality
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More elaborate procedures may be
necessary for studies in which data are
collected on sensitive matters such as sexual
behavior or criminal activities.
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Any written record linking subjects to the
study can create a threat to confidentiality,
including consent forms
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Vulnerable Populations
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Vulnerable Populations
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Federal regulations involving human subjects in
research include specific protections for children,
pregnant women and fetuses (Subpart B), prisoners
(Subpart C), and children (Subpart D).
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In addition, the IRB expects the investigator to
provide additional information regarding cognitively
impaired individuals in research or others who are
likely to be vulnerable to coercion or undue
influence.
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Conclusion
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The IRB must be satisfied that all of the
review criteria have been met before it
approves a protocol
The IRB must have sufficient information
upon which to base its decision
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OHRP frequently cites IRBs for not having
enough information to make a decision
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Risk Level
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Risk Level
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For each protocol the IRB must determine
and document the level of risk
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Minimal risk
More than minimal risk
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Minimal Risk
“…the probability and magnitude of harm or
discomfort anticipated in the research are not
greater in and of themselves than those
ordinarily encountered in daily life or
during the performance of routine physical or
psychological examinations or tests.”
45 CFR 46.102(i)
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Approval Period
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Continuing Review
“An IRB shall conduct continuing review of
research covered by this policy at intervals
appropriate to the degree of risk, but not less
than once per year”
45 CFR 46.109(e)
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Approval Period
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Appropriate to the degree of risk and not less
than once per year
Should be set for each protocol, not a routine
annual review
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Continuing Review
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Must be substantive and meaningful
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Criteria for approval still being met
Whether any new information has emerged, either from the
research itself or from other sources, that could alter the
IRB’s previous determinations, particularly with respect to
risk to subjects
At least one member should review entire protocol
Full IRB reviews summary and progress report
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45 CFR 46 Subparts
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Subpart B -Pregnant Women, Human
Fetuses and Neonates
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Applies to all research involving pregnant women,
human fetuses, neonates of uncertain viability, or
nonviable neonates
For research where the risk to the fetus is no more
than minimal and is not funded by DHHS, no
additional safeguards are required and there are no
restrictions on the involvement of pregnant women.
For research involving more than minimal risk to
fetuses not funded by DHHS or research funded by
DHHS, pregnant women or fetuses may be involved
if the IRB must find and document that the following
criteria are met.
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Subpart B -Pregnant Women, Human
Fetuses and Neonates
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Where appropriate, preclinical studies have been
done
Direct benefit to woman or fetus
If no direct benefit, no more than minimal risk to
fetus and knowledge can’t be obtained by other
means (For DHHS-funded research: biomedical
knowledge)
Any risk is the least possible for achieving the
objectives of the research
If benefit is solely to fetus, then consent from father,
if available, is required. Otherwise only mother’s
consent required
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Subpart B -Pregnant Women, Human
Fetuses and Neonates
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Each individual providing consent is fully informed
regarding the reasonably foreseeable impact of the
research on the fetus or neonate;
For children who are pregnant, assent and
permission are obtained in accord with the
provisions of subpart D of this part;
No inducements, monetary or otherwise, will be
offered to terminate a pregnancy;
Individuals engaged in the research will have no part
in any decisions as to the timing, method, or
procedures used to terminate a pregnancy; and
Individuals engaged in the research will have no part
in determining the viability of a neonate.
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Subpart B -Pregnant Women, Human
Fetuses and Neonates
Research involving neonates
 Neonates of uncertain viability
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Nonviable neonates
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Either research holds out prospect for enhancing
viability or no added risk
Consent from either parent allowed
Vital functions not artificially maintained
Research will not terminate heartbeat or respiration
No added risk
Consent from both parents required
Viable neonates are children and come under
Subpart D
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Subpart C - Prisoners
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Definition of Prisoner
– Involuntarily confined or detained in a penal
institution as a result of sentencing
– Detained in alternative institutions as a result of
sentencing
– Detained pending arraignment, trial, or
sentencing
– Includes individuals who are prisoners at the time
of enrollment in the research or who become
prisoners after they become enrolled in the
research
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Subpart C - Prisoners
IRB Findings:
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Research is in one of the permissible categories
Advantages from research can’t be coercive
Risks commensurate with risks acceptable to nonprisoners
Selection fair to all prisoners
Information understandable to population
Can’t have an effect on parole
If applicable, provisions made for follow-up after
release
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Subpart C - Prisoners
Permissible Categories:
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Study of the possible causes, effects, and processes
of incarceration, and of criminal behavior, provided
that the study presents no more than minimal risk
and no more than inconvenience to the subjects;
Study of prisons as institutional structures or of
prisoners as incarcerated persons, provided that the
study presents no more than minimal risk and no
more than inconvenience to the subjects;
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Subpart C - Prisoners
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Research on conditions particularly affecting
prisoners as a class (only after special panel)
Research which has the intent and reasonable
probability of improving the health or well-being of
the subject (control groups require special panel)
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Subpart C - Prisoners
Waiver for Epidemiology Research: The categories of
permissible research do not apply for epidemiology
research where the IRB has approved the research
and determined and documented that
– The research presents no more than minimal risk
and no more than inconvenience to the prisonersubjects, and
– Prisoners are not a particular focus of the
research.
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Subpart D - Children
Definition:
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"Children" are 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. [46.402(a)]
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Subpart D - Children
Parental Permission:
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Adequate provisions are to be made to secure
permission from the parents or guardians of each
child.
– For minimal risk research or risk research with
direct benefit, the IRB may allow permission from
one parent.
– For risk research without direct benefit,
permission from both parents is required.
[46.408(b)]
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Subpart D - Children
Categories of Research
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Minimal Risk
– Assent & Parental Permission required
[46.404]
Risk but with direct benefit to subjects
– Risk justified by benefits
– Risk/Benefit at least as favorable as alternatives
– Assent & Parental Permission required
[46.405]
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Subpart D - Children
Categories of Research
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Risk but with no direct benefit
– Minor increase over minimal risk
– Intervention or procedure reasonably
commensurate with what they already experience
– Likely to yield generalizable knowledge about the
subject’s disorder or condition
– Assent & Parental Permission required
[46.406]
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Subpart D - Children
Categories of Research
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Research not otherwise approvable which
presents an opportunity to understand,
prevent, or alleviate a serious problem
affecting the health or welfare of children
– can be approved if the Secretary consults
with panel of experts.
[46.407]
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Other Vulnerable Populations
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Decisionally or cognitively impaired
Non-English speaking
Desperately ill
Economically disadvantaged
Educationally disadvantaged
Students
Employees
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IRB Review
How should IRBs review vulnerability?
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IRBs and investigators need to be sensitive to possible
vulnerabilities of subjects
IRBs need to ask detailed questions on the characteristics
of the potential populations
IRBs need to evaluate potential vulnerabilities
IRBs need to ask investigators what extra protections are in
place for vulnerable subjects
IRBs need to asses adequacy of extra protections
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IRB Review
IRBs need sufficient expertise on vulnerable
populations
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46.107(a) If an IRB regularly reviews research that
involves a vulnerable category of subjects, such as children,
prisoners, pregnant women, or handicapped or mentally
disabled persons, consideration shall be given to the
inclusion of one or more individuals who are knowledgeable
about and experienced in working with these subjects
Outside Consultation
Community Consultation
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Consent Waivers
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Waiver of Consent
46.116(d)
An IRB may approve a waiver or alteration of some or
all of the consent requirements provided the IRB
finds and documents that:
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The research involves no more than minimal risk to
subjects;
The waiver will not adversely affect the rights and welfare of
subjects;
The research could not practicably be carried out without
the waiver; and
Whenever, appropriate, the subjects will be provided with
additional pertinent information after they have participated
in the study.
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Waiver of Documentation
46.117(c)(2)
An IRB may waive the requirement for the investigator
to obtain a signed consent form for some or all
subjects if it finds and documents that:
– the research presents no more than minimal risk;
and
– the research involves procedures that do not
require written consent when performed outside
of a research setting.
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Waiver of Documentation
46.117(c)(1)
An IRB may waive the requirement for the investigator
to obtain a signed consent form for some or all
subjects if it finds and documents that:
– the principle risks are those associated with a
breach of confidentiality concerning the subject’s
participation in the research;
and
– the consent document is the only record linking
the subject with the research
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Other Determinations
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Conflict of Interest
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Initial review made by Chair or designee
Chair makes recommendation that the
disclosed financial interest is:
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not acceptable (in which case the financial interest must be
divested or other action taken); or
acceptable with some form of management (such as
disclosure, restrictions on the activities of the investigator,
or such other form as determined appropriate); or
acceptable without any need for management.
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Conflict of Interest
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IRB makes final determination regarding COI
management.
Possible management plans:
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Disclosure to subjects through the consent process
Modification of the research protocol or safety monitoring plan
Monitoring of research by independent reviewers
Disqualification of the conflicted party from participation in all or a portion of
the research
Appointment of a non-conflicted Principal Investigator
Divestiture of significant financial interests
Severance of relationships that create actual or potential conflicts.
Prohibition of the conduct of the research at the hospital
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Noncompliance
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Definition
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failure to comply with or adhere to rules,
regulations, policies and standards of conduct
that govern human subject research,
failure to follow the determinations of the IRB,
failure to follow institutional policies.
Noncompliance may be minor or serious, or
it may be sporadic or continuing.
Noncompliance
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Serious noncompliance.
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Noncompliance which increases risks to
participants, decreases potential benefits, or
compromises the integrity of the human research
protection program.
Research being conducted without prior IRB
approval is always considered serious
noncompliance.
Noncompliance
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Continuing noncompliance.
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A pattern of noncompliance that suggests a
likelihood that without intervention instances of
noncompliance will continue.
Failure to respond to a request to resolve an
episode of noncompliance.
Noncompliance
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The IRB makes a determination about
whether the incident is serious or is part of a
pattern of non-compliance.
The IRB then makes a determination about
what action is warranted, including taking
any additional action it deems necessary to
protect the rights and welfare of the research
subjects involved in the study.
Noncompliance
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Possible actions
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Corrective action plan
Education
Modification of protocol
Increased monitoring
Informing subjects
Suspension or termination of research
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Unanticipated Problems
Unanticipated Problems involving risk to
subjects or others, include any incident,
experience, or outcome that meets ALL of
the following criteria:
– Unexpected
– Related to the research
– Increased risk of harm
Unanticipated Problems
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Not all Adverse Events are Unanticipated
Problems
– Some are not unanticipated
 Depressed
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subject commits suicide
Some are not related
 Child
falls out of bed and is injured
Unanticipated Problems
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Not all Unanticipated Problems are Adverse
Events
– Determined by risk of harm, not actual
harm
 Lost
laptop
 New risk in literature
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Unanticipated Problems
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Not all Unanticipated Problems involve the
subjects – “…risk to subjects or others.”
– Researcher injured by subject
– Family member “outed” by subject
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Unanticipated Problems
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IRB makes final determination as to whether
an event is an unanticipated problem
Possible actions
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Change protocol
Change consent form
Inform subjects
Suspension or termination of research
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Multi-site/Collaborative Research
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For multi-site or collaborative research, the
IRB must determine that the procedures for
dissemination of protocol information (IRB
initial and continuing approvals, relevant
reports of unanticipated problems, protocol
modifications, and interim reports) between
all participating institutions are adequate.
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Multi-site/Collaborative Research
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If McLean Hospital is the coordinating facility,
the Principal Investigator must document
(and the IRB approve) how important human
subject protection information (such as safety
information or information affecting an
individual’s willingness to participate or
continue in the study) will be communicated
to the other participating facilities engaged in
the research study.
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Documentation of
Required Findings
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Documentation
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For each of the required findings the IRB must
provide protocol-specific information justifying why
the IRB considers the research to meet each
criterion or the IRB’s agreement with the findings
and justifications as presented by the investigator on
IRB forms.
For full-review protocols the findings must be
documented in the IRB minutes
For expedited-review protocols the findings must be
documented in the record along with the reviewer’s
signature
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