Human
Research Protection Program (HRPP)
DOMAIN
II: RESEARCH COMPLIANCE OFFICE,
INCLUDING IRBs
Chapter 9: Risks
to Research Participants
The IRB staff and the IRBs systematically evaluate risks to participants and potential benefits as part of the initial review and ongoing review of research. (AAHRPP Standard II-4)
Risk in the context of human subject research: The probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study. Both the probability and magnitude of possible harm may vary from minimal to significant.
Minimal risk: Federal regulations define only "minimal risk." A risk is minimal where 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 [FDA 21 CFR 56.102(i)]. For example, the risk of drawing a small amount of blood from a healthy individual for research purposes is no greater than the risk of doing so as part of routine physical examination.
The definition of minimal risk for research involving prisoners differs somewhat from that given for non-institutionalized adults. [See 45 CFR 46.303(d)]
From the OHRP Institutional Review Board Guidebook
at http://www.hhs.gov/ohrp/irb/irb_glossary.htm.
As discussed above, risks may affect physical, psychological,
social, legal or economic well-being, including loss of privacy or breach of
confidentiality.
Potential risks to a participant in a research, development, or related activity which departs from the application of those accepted methods necessary to meet his or her needs, or which increases the ordinary risks of daily life, may result as a consequence of :
·
Use of an
investigational device
·
Use of an
investigational drug
·
Use of
commercially available drugs, reagents or chemicals
·
Radioisotopes/radiation
producing machines
·
Recombinant
DNA/biohazardous agents, etc.
9.1 Measuring and Minimizing Risk
The IRB has the following written policies and
procedures for identifying and analyzing potential sources of risk and measures
to minimize risk, including physical, psychological, social, legal, or economic
risks. The analysis of risks includes a determination that
the risks to participants are
reasonable in relation to potential benefits to participants and to society. (AAHRPP
Element II.4.A)
These policies and
procedures are based on:
Common Rule 45 CFR
46.111(a) (1),(2); FDA 21 CFR 56.111(a)(1),(2);
VHA Handbook
1200.5 Sections 7 & 10.
From review of the
completed protocol application submitted by the Protocol Director (PD), the IRB
analyzes levels of risk, ensures risks are minimized, and ensures risks are
reasonable relative to anticipated benefits, before approving
the proposed research. (See Chapter 14.3.)
Identifying Potential Risks (PD Input)
The PD must describe in the Protocol Application:
·
Potential risks
to participants, including a scientific estimate of their frequency, severity,
and reversibility.
·
The statistical
incidence of complication and the mortality rate of the proposed procedure, if
known.
·
The planned
procedures for protecting against or minimizing potential risks, including risks
to confidentiality. Two plans are
necessary:
i.
One to ensure
necessary medical or professional intervention in the event of harm to
participants
ii. One to ensure the safety of participants and the validity and integrity of research data. Data and safety monitoring must be commensurate with risks and the size and complexity of the trials. (See Chapter 9.2 below).
Additionally, PDs must submit a Modification
application for proposed changes in the research, describing any resulting changes
in the level of risk to participants, and explaining the risk level and potential
benefits.
Analyzing Levels of Risk (PD Input)
When the PD submits a new Protocol Application, Modification
Form, or a Continuing Review Form they must indicate the level of risk as
being:
·
Low (innocuous
procedures, e.g., phlebotomy; no therapeutic agent)
·
Medium (“safe”
therapeutic agent)
·
High, which can
be further categorized as:
a. Therapy with chemotherapy, antibodies, or a
potentially toxic drug
b. Risky procedures (e.g., insulin clamp, organ biopsy)
c. Vulnerable participants (e.g., children, prisoners,
pregnant women, economically and educationally disadvantaged, decisionally
impaired, and homeless people).
Educational
materials delineating these levels of risk are included in the human research
educational program that key study personnel must successfully complete. IRB staff are available to answer questions
regarding risk levels.
Ensuring Risks Are Minimized (IRB Determination)
The IRB considers
the overall level of risk to participants in evaluating proposed research in
accordance with the conditions outlined in 45 CFR 46.111(a)(1-7), 21 CFR
56.111(a)(1-7) and the ethical principles outlined in the Belmont Report.
Having an IRB membership representative of broad range of scientific disciplines (see Chapter 6) also provides a critical
assessment of the research, scientific merit, and feasibility, and the IRB
consults with additional experts when aspects of research design seem to pose a
significant concern. [45 CFR
46.111(a)(1)(i), 21 CFR 56.111
(a)(1)(i)]
Before approving a research protocol, the IRB must
determine that risks are minimized as follows by:
·
Ensuring that
the proposed research has a sound research design
[45 CFR 46.111(a)(1)(i) , 21 CFR 56.111.(a)(1)(i)]
·
The research does
not expose subjects to unnecessary risks
[45 CFR
46.111(a)(1)(i) , 21 CFR 56.111.(a)(1)(i)] and
·
Whenever
appropriate, utilizing procedures that are already being performed on the
subjects for diagnostic or treatment purposes
[45 CFR
46.111(a)(1)(ii), 21 CFR 56.111.(a)(1)(ii)].
The IRB examines
the research plan, including research design and methodology, to determine that
there are no inherent flaws that would place research participants at
unnecessary risk. This includes the risk
that the research is lacking in statistical power such that meaningful results
cannot be obtained. Appropriate safeguards can also minimize risk to
participants, for example: having an adequate data monitoring plan, or
protecting confidentiality by using coded data. If risks are not adequately
minimized, the protocol may not be approved as written. See guidance Evaluating
Sound Study Design.
The IRB also
considers the professional qualifications and resources (including time,
equipment, support services) of the research team to protect and minimize
potential harm to participants. Research
personnel must have received appropriate training, and clinicians involved in the research must maintain
appropriate professional credentials and licensing privileges. See Chapter 14.5 and Chapter 15.1.
Potential Risks v.
Anticipated Benefits (IRB Determination)
The IRB determines whether the risks of the research are reasonable in
relation to the anticipated benefits (if any) to research participants and the
importance of the knowledge that may reasonably be expected to result. (45 CFR
46.111(a)(2), 21 CFR 56.111(a)(2), 38 CFR 16.111(a)(2))
The Protocol Application requires that the PD
describe the potential benefit(s) to be gained by participants or by the
acquisition of important medical knowledge which may benefit future
participants. The PD must explain how the potential benefits to the participant
or community outweigh the risks inherent in the research.
The IRB develops
its risk/benefit analysis based on the information provided by the PD and by evaluating the most current information
about the risks and benefits of the interventions involved in the research, in
addition to information about the reliability of this information. The IRB considers only those risks that result
from the research, and does not consider long-range effects (e.g., public
policy implications) of applying the knowledge gained in the research. The IRB does not consider those risks and
benefits that participants would receive even if not participating the
research. [45 CFR 46.111(a)(2) and 21
CFR 56.111(a)(2)]
The IRB reviews the plan for data and safety
monitoring in research protocols, when applicable, and determine that the plan
provides adequate protection for participants.
(AAHRPP
Element II.4.B)
To approve research, the IRB must determine that,
where appropriate, the research plan makes adequate provisions for monitoring
the data to ensure the safety of research participants. (45 CFR 46.111(a)(6),
21 CFR 56.111(a)(6), 38 CFR 16.111(a)(6))
PDs are required to describe their Data Monitoring
Plan, if applicable, on the Protocol Application.
The Data
Monitoring Plan must be commensurate with the level of risk, size and
complexity of the study. See:
·
Guidance Data Monitoring Plans - for detailed information on
what a data monitoring plan might address, and a data monitoring plan template
·
Chapter 15.4 - discusses PD responsibilities, and VA
requirements.
·
VHA
Handbook 1200.5 7 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418
·
OHRP Guidance on Reviewing and Reporting Unanticipated
Problems
Involving Risks to Subjects or Others and
Adverse Events at http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm
The IRB requires a Data Monitoring Plan for:
·
All studies
considered more than low risk, including but not limited to:
-
Phase III
clinical interventions,
-
New, unfamiliar
interventions not otherwise categorized as phase III clinical trials,
·
Blinded
studies, multiple sites, vulnerable research participants, or high-risk
interventions [VHA
Handbook 1200.5 7 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418]
·
Multi-site
research where STANFORD is the coordinating site
·
Studies where
there is an NIH or FDA requirement for a plan
·
Studies when
requested by the IRB
A DSMB or DMC may
be required as part of the monitoring plan by NIH, FDA, other sponsors or the
IRB. See:
·
Data
Monitoring Committees - FDA March
2006 “Guidance for Clinical Trial Sponsors” at http://www.fda.gov/cber/gdlns/clintrialdmc.pdf
·
Data
Monitoring Plans and Data Monitoring Committees – NIH and NCI policies at
o http://grants.nih.gov/grants/guide/notice-files/not98-084.html
o http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html
o http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm
o http://cancertrials.nci.nih.gov/clinicaltrials/conducting/dsm-guidelines/page3
IRB Review of the Data Monitoring Plan
The IRB primary
reviewer will review and assess the proposed Data Monitoring Plan, and the administration
and composition of the monitoring entity, when applicable. The Data Monitoring Plan should include the appropriate
elements, and address reporting as specified in the guidance Events and Information that Require Prompt Reporting to the IRB.
If additional expertise is needed to assess the Data
Monitoring Plan or the monitoring entity (if one is specified in the plan), the
IRB consults with persons with appropriate clinical, scientific or
biostatistical expertise.
Continuing Review; Timeframe for Reporting Data Monitoring Findings to the IRB
It is not the role of the IRB to perform data
monitoring, but to ensure that appropriate monitoring is taking place, and to
review reports from the monitoring entity.
The IRB must ensure that the
conditions satisfied in order for initial IRB approval of the research are
still satisfied at continuing review. These include, but are not limited to,
determinations by the IRB regarding risks, potential benefits, informed
consent, and safeguards for participants.
Thus, the PD must include in the
continuing review application the outcomes of data and safety monitoring
including a summary of adverse events, any unanticipated problems, and any
new information pertaining to the research - either from the research itself or
from other sources, which have occurred since the previous IRB review. (See OHRP Guidance on Continuing
Review at http://www.hhs.gov/ohrp/humansubjects/guidance/contrev0107.htm.) The amount of detail required depends on the
type of research being conducted. In
many cases, an appropriate summary would be a simple brief statement that there
have been no unanticipated problems and that adverse events have occurred at
the expected frequency and level of severity as documented in the research
protocol, the informed consent document, and any investigator brochure [OHRP].
In addition,
periodic (usually annual) reports from the monitoring entity are submitted by
the PD to the IRB at continuing review. (When a monitoring entity is used, the
IRB conducting continuing review of the research may choose to rely on a
current statement from the monitoring entity indicating that it has and will
continue to review study-wide AEs, interim findings, and any recent literature
that may be relevant to the research.)
Whether the method
of monitoring is by PD oversight or from the establishment of a DSMB, the IRB
can tailor a specific timeframe for future reporting of data monitoring
findings to the IRB. The IRB can set the
date of continuing review for the protocol as being less then the maximum of a
year, if they determine that interim reporting of data monitoring information
will serve to better protect participants.
Alternatively, the IRB can request a report after a specific number of
participants are enrolled or after a serious adverse event has been reported.
9.3 Risks to Vulnerable Populations
The IRB staff and the IRBs have the
following written policies and procedures for determining the risks to
vulnerable populations as defined in applicable federal regulations, and
specifically for determining the required risk categories in protocols
involving children and prisoners. (AAHRPP Element II.4.C)
The IRB is cognizant of the vulnerable
nature of many participants. Food and Drug Administration (FDA) regulations and
the Common Rule require IRBs to give special consideration to protecting the
welfare of vulnerable participants.
In order to approve research involving
vulnerable populations, the IRB must determine, where appropriate, that additional
safeguards have been included to protect the rights and welfare of participants
who are likely to be vulnerable to coercion or undue influence, such as:
·
Children (45
CFR 46 Subpart D; 21CFR 50 Subpart D),
·
Prisoners (45
CFR 46 Subpart C),
·
Pregnant women,
human fetuses, or neonates (45 CFR 46 Subpart B),
·
Veterans
(because veterans have a history of obeying orders and making sacrifices, and
because some veterans may not have access to other health care, the VA considers
veterans may be deemed a potentially vulnerable population),
·
Persons with
mental disabilities or economically, or
·
Educationally
disadvantaged persons,
The IRB includes among its members persons who are
knowledgeable about and experienced in working with vulnerable
participants. (45 CFR 46.107(a); 21 CFR
56.107(a)).
See also Chapter 12.2 for consent procedures for vulnerable
populations.
Considerations
in Reviewing Research involving Vulnerable Participants
The IRB considers the following elements of the research plan when reviewing research involving vulnerable participants:
·
Strategic issues that involve inclusion and exclusion criteria for selecting
and recruiting participants; informed consent and willingness to volunteer;
coercion and undue influence; and confidentiality of data.
·
Group characteristics, such as economic,
social, physical, and environmental conditions, to ensure that the research
incorporates additional safeguards for vulnerable participants.
·
Participant selection to prevent over-selection or
exclusion
of certain participants based on perceived limitations or complexities
associated with those participants. For
example, it is not appropriate to target prisoners as research participants
merely because they are a readily available “captive” population.
·
Application of state or local laws that bear on the
decision-making abilities of potentially vulnerable populations. State statutes (as discussed in Chapter
12) often address issues related to competency to consent for
research, emancipated minors, legally authorized representatives, the age of
majority for research consent, and the waiver of parental permission for research.
·
Procedures for assessing and ensuring participants’ capacity,
understanding, and informed consent or assent.
When weighing the decision whether to approve or disapprove research
involving vulnerable participants, the IRB verifies that such procedures are a
part of the research plan. In certain
instances, it may be possible for investigators to enhance understanding for
potentially vulnerable participants.
Examples include requiring someone not involved in the research to
obtain the consent, the inclusion of a consent monitor, a participant advocate,
interpreter for hearing-impaired participants, translation of informed consent
forms into languages the participants understand, and reading the consent form
to participants slowly and ensuring their understanding paragraph by paragraph.
·
Need for additional safeguards to protect potentially
vulnerable populations. For example, the
IRB may require that the investigator submit each signed informed consent form
to the IRB, that someone from the IRB oversee the consent process, or that a
waiting period be established between initial contact and enrollment to allow
time for family discussion and questions.
For information on the
recruitment of vulnerable populations see:
·
Observation of the Consenting Process
·
Guidance Recruitment
·
Human Subjects Research website
·
Chapter 14.4.
Children
Children: Under the regulations, children are persons who
have not attained the legal age for consent to treatments or procedures
involved in the research under the applicable jurisdiction in which the
research will be conducted.
The IRB follows the requirements of the DHHS regulations at 45 CFR 46, Subpart D and FDA regulations at 21 CFR Part 50,
Subpart D in reviewing protocols involving children. The IRB makes the findings and determinations
required by the DHHS and FDA regulations related to the risks before allowing
research involving children to proceed.
See guidances:
·
Additional Protections for Inclusion of Children in Research (OHRP)
·
Additional Safeguards for Children in Clinical Investigations (FDA)
·
Chapter 12.2 for
consent requirements for research involving children participants.
VA Research Involving Children
Research
involving children must not be conducted by VA investigators while on official
duty or at VA or approved off-site facilities unless a waiver has been granted
by the Chief Research and Development Officer. If the waiver is granted, the
research must be in accordance with applicable Federal regulations pertaining
to children as research subjects (see 45 CFR Part 46, Subpart D 46.401 –
46.409). See VHA Handbook 1200.5 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418.
Prisoners
Prisoner:
Any individual involuntarily confined or detained in a penal institution. This includes individuals:
· sentenced to such an institution under a criminal or
civil statute,
· detained in other facilities by virtue of statutes
or commitment procedures which provide alternatives to criminal prosecution or
incarceration in a penal institution,
· detained pending arraignment, trial, or sentencing.
DHHS details special protections for research
involving prisoners, who due to their incarceration may have a limited ability
to make truly voluntary and un-coerced decisions about whether or not to
participate as participants in research.
[45 CFR 46,
Subpart C]. The IRB will apply the standards of Subpart C
to all prisoner research, whether or not DHHS-supported.
For DHHS-supported
research the IRB must certify to the Secretary (of DHHS), via the Office for
Human Research Protections (OHRP) that it has reviewed and approved the
research under 45 CFR 46.305; additionally, the Secretary (through OHRP must
determine that the proposed research falls within permissible categories [45
CFR 46.306(a)(2)].
If biomedical or behavioral research is
conducted or supported by DHHS, approval must be obtained from the Secretary of
DHHS (through OHRP) before commencing research.
Note: For Non-DHHS-supported
research certification to OHRP is not
required, and the IRB substitutes a comparable risk assessment measure in place
of the review and approval by the Secretary of DHHS.
Refer to guidance Involvement of Prisoners in Research for:
·
Special
requirements regarding IRB composition and additional duties
·
Categories of
permissible research
·
Other
requirements pertaining to DHHS-supported research
·
IRB required
findings.
In order to consider research involving
prisoners, the IRBs must:
·
Ensure a
majority of its members are not otherwise associated with the prison(s)
involved in the research, and
·
Include a
prisoner or a prisoner advocate, who can adequately represent the interests of
the prisoners, unless the research has already been reviewed by an IRB that
included a prisoner advocate.
Note: OHRP discourages expedited review
of any research involving prisoners as participants.
When a previously enrolled research
subject becomes a prisoner and the relevant research protocol was not reviewed
and approved by the IRB [under 45 CFR 46, Subpart C] the PD should promptly
notify the IRB of this event through the IRB Report Form. The PD should state that all research
interactions and interventions with, and obtaining identifiable private
information about, the now-incarcerated prisoner-participant will cease until
the requirements of subpart C have been satisfied with respect to the relevant
protocol, unless the PD asserts that it is in the best interests of the participant
to remain in the research study while incarcerated, in which case the IRB Chair
may determine that the participant may continue to participate in the research
until the requirements of subpart C are satisfied. Upon receipt of notification
that a previously enrolled research participant has become a prisoner, the IRB
should promptly re-review the protocol in accordance with the requirements of
subpart C if the PD wishes to have the prisoner participant continue to
participate in the research.
Research Involving
Prisoners in
If the research involves prisoners in a
DHHS Conducted or
Supported Epidemiologic Research Involving Prisoners as Subjects
See Federal Register Vol 68 No.119,
Under certain conditions DHHS conducted
or supported epidemiologic research may be approvable by the Secretary of DHHS,
as outlined in the Federal Register Notice No.119.
VA Research Involving
Prisoners
Research involving prisoners must not be
conducted by VA investigators while on official duty, or at VA-approved
off-site facilities unless a waiver has been granted by the Chief Research and
Development Officer. If the waiver is granted, the research must be in
accordance with applicable Federal regulations pertaining to prisoners as
research subjects (45 CFR Part 46, Subpart C 46.301 – 46.306).
See VHA Handbook
1200.5 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418
or the VA research website
for requirements for requesting a waiver.
Decisionally Impaired Participants
The IRB reviews the risk-benefit analysis including
the possibilities of coercion and undue influence, and must determine whether such participants should be recruited and
whether support mechanisms, such as surrogate consent, are appropriate. See Chapter 12.2 for more information on the consent process,
and criteria for including decisionally impaired participants in research.
Pregnant Women,
Human Fetuses, and Neonates
The Department of Health and Human Services (DHHS) details special protections for research involving
pregnant women, human fetuses, and neonates.
[45 CFR 46, Subpart B.]
Under these
regulations, the IRB is required to document specific findings to minimize the
potential for risk or harm to the fetus, and additional attention must be given
to the conditions for obtaining informed consent, in accordance with the
guidance Research Involving Pregnant Women, Fetuses, and Neonates.
In general, Subpart B requires that research
involving pregnant women, human fetuses, and neonates should involve the least
possible risk. Persons engaged in the
research may have no part in the timing, method, or procedures used to
terminate the pregnancy, or to determine the viability of the fetus. No inducements may be offered to terminate a
pregnancy.
Four separate
conditions, each with their own requirements and IRB determinations, apply to
research with pregnant women, human fetuses, and neonates:
1.
Research Involving Pregnant Women. No pregnant
women may be involved as a participant in research unless either of the
following conditions applies: The
purpose of the activity is to meet the health needs of the mother, and the
fetus is placed at risk only to the minimum extent necessary to meet such
needs; OR the risk to the fetus is
minimal. The mother and the father must
be legally competent and provide consent, unless the purpose of the research is
to meet the health needs of the mother, or the father is not reasonably
available, or the pregnancy resulted from rape.
2.
Research Directed at Human Fetuses. The IRB
must find that: the purpose of the
research is to meet the health needs of the individual fetus and shall be
conducted in a way that will minimize risk; OR the research will pose no more than minimal risk to the fetus, and the
purpose of the activity is to ascertain important biomedical knowledge that is
unobtainable by other means. These
activities are permitted only if the mother and father are legally competent
and have given their informed consent, unless the father is not reasonably
available or the pregnancy resulted from rape.
3.
Research Involving Neonates. For research
involving neonates, the IRB must distinguish between viable and non-viable neonates. Viable is defined in the regulations as being
able to survive to the point of independently maintaining a heartbeat and
respiration, given the benefit of available medical therapy. If the neonate is viable, it is considered a
“child” and may be involved in research to the extent permissible under 45 CFR 46,
Subpart D, which is discussed later in this chapter.
·
A non-viable neonate may not be involved in research unless all of the
following conditions apply: The vital
functions of the neonate are not artificially maintained; experimental
activities that would of themselves terminate the heartbeat or respiration are
not employed; AND the purpose of the research is development of important
biomedical knowledge that cannot be obtained by other means. Research involving a non-viable neonate is
permitted only when both parents have given their informed consent, unless one
parent is not reasonably available or the pregnancy resulted from rape or
incest. In the case of non-viable
neonates consent by a parent’s legally authorized representative is not
allowed.
·
A neonate of uncertain viability may not be involved in research unless one of the
following conditions applies: There is
no added risk to the neonate and the purpose of the research is to obtain important
biological knowledge that cannot be obtained by other means; OR the purpose of
the activity is to enhance the probability of survival of the individual
neonate. Research involving a neonate of uncertain viability is
permitted only if either parent or the parent’s legally authorized
representative gives their permission.
Non-pregnant women of reproductive potential
Unilateral
exclusion of non-pregnant women of reproductive potential from research is not
permitted by the IRB. Exclusion requires
compelling scientific justification.
Where such justification exists, it may also be appropriate to exclude
men of reproductive potential.
VA
Research – special requirements
Pregnant Women: See VHA Handbook
1200.5 Appendix D (http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418)
for specific requirements.
Fetuses: Research in which the subject is a fetus,
in-utero or ex-utero (including human fetal tissue) must not be conducted by VA
investigators while on official duty, or at VA facilities, or at approved
off-site facilities.
In Vitro Fertilization: Research related to in vitro
fertilization must not be conducted by VA investigators while on official duty,
or at VA facilities, or at approved off-site facilities.
Other Potentially Vulnerable Participants
The context of the research is an
important consideration for the IRB when reviewing research that involves other
potentially vulnerable participants such as research involving homeless
persons, members of particular minority groups, or the economically or
educationally disadvantaged. Research
involving significant follow-up procedures or offering significant monetary
compensation may unduly influence certain types of participants and the IRB
takes such considerations into account.
Nevertheless, research involving these participants is socially
important for understanding and eventually improving adverse health and general
well-being in these populations.
Employees and
Students
Employees, lab
personnel, students, and trainees at STANFORD and other facilities under the purview
of the IRB are considered vulnerable participants, in particular because of the
risk of coercion and undue influence.
The IRB has the same standards for approving research involving these
groups as other vulnerable participants.
9.4 Suspension or Termination of IRB approval
The IRB has the
following written policies and procedures for suspending or terminating a
previously approved protocol if warranted by findings in the continuing review
or monitoring process. (AAHRPP Element
II.4.D)
Suspension: Temporary
withdrawal of IRB approval of some or all of a protocol or the permanent
withdrawal of IRB approval of part of a protocol. Continuing review of the
research is still required. A sponsor-imposed
suspension alone does not constitute such a suspension, as it is not an action
by the IRB to withdraw approval of a previously approved protocol. Similarly, an action by the Protocol Director
(PD) that halts or materially changes some or all of the PD’s protocol as
previously approved by the IRB does not constitute such a suspension (but may
need to be submitted to the IRB as a modification to the protocol).
Termination: Permanent
withdrawal of IRB approval of a previously approved protocol. Continuing review
of the research is still required.
Suspension or Termination
by the Convened IRB
The IRBs have the
authority (45 CFR 46.113; 21 CFR 56.113) to suspend or terminate a previously
approved protocol (i.e., both from the approval of this policy by the Vice
Provost and Dean of Research and through the charge to IRB Chairs and members at the time of their
appointment.)
The IRB may act to
suspend or terminate a protocol for any of the following reasons including but
not limited to:
·
Not conducting
research in accordance with IRB requirements
·
Unexpected
serious harm to subjects.
The IRB Chair
shall:
·
Notify the PD
in writing of it the IRB decision to suspend or terminate its approval along
with a statement of the reasons for the IRB action and any terms and conditions
of any suspension.
·
Report the
decision to suspend or terminate to the Vice Provost and Dean of Research and
others in accordance with the procedure set forth in Chapter 3.9.
The PD shall be
provided with an opportunity to respond in person or in writing to the IRB on a
suspension or termination.
If the IRB
action in relation to the suspension or termination involves the withdrawal or
modification of participation of current participants from the research, the
IRB shall direct the PD to contact the participants to:
·
Make such
notification with an explanation, after its review and approval by the IRB
·
Describe any
monitoring and follow-up for safety reasons that will be conducted
·
Provide contact
information for the PD and the IRB where the participant may report any adverse
events or unanticipated problems.
Suspension or Termination by an Authorized Individual
The following
STANFORD officials are authorized to suspend or terminate IRB approval pending
review by the IRB responsible for continuing review of the protocol: the Vice
Provost and Dean of Research, the Chair of the IRB responsible for continuing
review of the protocol, the Director of Research Compliance, and any other
STANFORD official who is authorized to take such action by virtue of his or her
office or of a policy or procedure of the relevant STANFORD organization. The STANFORD official who makes a suspension
of a protocol shall immediately:
· Notify the PD: (i) to halt the portion of the IRB
approved protocol that poses immediate, material risk to participant health and
welfare, (ii) of the reasons for the suspension or termination, and (iii) of
the opportunity to respond in person or in writing to the official and IRB on
the suspension or termination
· Report the suspension or termination and its basis
to the IRB.
The IRB staff shall:
· Report the suspension or termination as a
“suspension or termination of IRB approval” to the Vice Provost and Dean of
Research and others in accordance with the procedure set forth in Chapter 3.9
· Immediately initiate the appropriate procedure for
review of the basis for the suspension or termination (e.g., the procedure for
reviewing possible non-compliance or a possible unanticipated problem. See Chapter 3.9, 3.10).
If the halt in some or all of the protocol involves the withdrawal from
the research or modification of participation of current participants, the
official or IRB shall direct the PD to contact the participants to:
· Make such notification with an explanation, after
its review and approval by the IRB
· Describe any monitoring and follow-up for safety
reasons that will be conducted
· Provide contact information for the PD and the IRB
where the participant may report any adverse events or unanticipated problems.
Protection of Participants Who May Be Affected by the IRB Action
If the suspension
or termination will affect participants in the protocol (e.g., requires
withdrawal of participants), the IRB shall utilize a process that takes into
account the impact on their health and safety.
This should occur before the suspension or termination, when it is
feasible and delay will not jeopardize their health and safety. Examples include:
·
Requiring the
PD to submit proposed procedures for any withdrawal of participants
·
Allowing
participants to continue (e.g., treatment with an investigational drug) if the
IRB determines that it is in their best interests
·
Requiring
submittal for review and approval of the IRB or its designee of all
communications by the PD to participants about the IRB action
·
Designating an
investigator other than the PD to be responsible for carrying out the IRB
decision
·
Requiring the
appointment of a new PD or transferring responsibility for participants to
another investigator
·
Requiring the
PD to carry out follow-up or monitoring of participants appropriate to the
circumstances (e.g., for any adverse impact on participants after suspension or
termination)
· Requiring special reporting (e.g., adverse events or outcomes) concerning participants by the PD.
VA Research
See VHA Handbook 1200.5 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418 for additional procedures and reporting requirements for suspension or termination of IRB approval for VA research.