Stanford University Office of the Dean of Research

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)]

9.2 Data Monitoring Plan

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)

· Parental Permission

· 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 California

If the research involves prisoners in a California facility, the IRB must comply with the additional limitations and requirements in California Penal Code Sections 3501 - 3523. Those provisions limit the types of biomedical research that may be conducted and place additional requirements on other types of research. Guidance Research Involving Prisoners – California Penal Code: Section 3501 – 3523 is referred to when the IRB reviews a protocol involving prisoners in California facilities.

DHHS Conducted or Supported Epidemiologic Research Involving Prisoners as Subjects

See Federal Register Vol 68 No.119, June 20, 2003.

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.