Policy 6: Continuing Review of Ongoing IRB-Approved Research

POLICY:

The IRB shall conduct continuing review of all research activity in compliance with 45 CFR Part 46 and 21 CFR Part 56. Continuing review is required for all research protocols approved by a NS-LIJHS IRB (unless the protocol was categorized as "exempt" by the IRB at the time of submission) for the term of the research, as long as individually identifiable follow-up data are being collected or analyzed.

It is the responsibility of the principal investigator (PI) to comply with continuing review requirements.

Continuing review includes, but is not limited to, the following:

GUIDANCE/PROCEDURES:

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6.1 Progress Reports (Revised 1/23/08)

According to federal regulations, a research protocol can only be approved for a maximum of 365 days. Within that time period, continuing review is conducted at intervals specified at the time of initial approval. Those intervals are based on the degree of risk to study subjects. If the risk/benefit ratio changes at any time during the study, the IRB has the authority to modify the continuing review interval and/or request changes to the protocol. The IRB also has the authority to require additional information at any time or to request an audit of the research to assure the safety of subjects and compliance by the research team.

To renew the approval period, the PI must submit a progress report and any requested relevant documents to the IRB before the project's expiration (the date at which the current approval ends). Since the IRB does not have the authority to extend the approval period beyond the expiration date, it is essential that the PI submit a complete progress report by the due date set by the IRB.

In order to afford the PI sufficient time to comply with institutional policy, the IRB will request a progress report well in advance of a project's expiration date. If the PI successfully complies with the progress report request by the due date set by the IRB, the study will be presented at the next convened IRB meeting for renewal.

When continuing review of a research protocol does not occur prior to the end of the approval period specified by the IRB, IRB approval expires automatically.

The following table illustrates the time frame established by the IRB for progress report submission and the consequences for non-compliance.

If a progress report is submitted and received prior to the expiration date but is deficient, the Office of the IRB will contact the PI with details regarding the deficiencies. If a complete and correct progress report is not received within the required time frame, the project is subject to the same warning/enrollment hold and termination procedures outlined above. The IRB is not authorized to extend the approval period for any research project.

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6.2 Re-activation of Terminated Protocols (Revised 1/23/08)

A protocol that has been terminated, for any reason, cannot be re-activated unless it is re-reviewed and approved by the IRB. If a PI wants to re-activate a terminated protocol, he/she must submit a progress report within 90 days of the study expiration date. If a progress report is not submitted within 90 days of the expiration date, the PI must re-submit it to the IRB as a complete application packet in accordance with the requirements for new protocols (see Policy 2: How to Submit a Protocol to the IRB).

In addition to the protocol application, the PI may be required to submit a memorandum to the IRB, detailing the circumstances that led to the protocol closure, along with his/her reasons for re-activating the protocol. If termination was due to administrative problems (e.g., a delinquent progress report), he must include a description of the corrective action he/she has taken in order to avoid such closures in the future.

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6.3 For-Cause Compliance Audits

When necessary, the IRB may request information beyond regular progress reports in order to ensure that the rights and welfare of research subjects are protected. Upon discovery of a potential problem, the IRB or IRB chair/designee will consider the issues and has the authority to suspend a protocol if a deficiency or situation poses a risk to subjects.

The IRB will notify the Office of Research Compliance (ORC) in writing with a summary of the issues and ask that a "for cause" audit be conducted. The ORC will notify the PI in writing that an audit has been requested. The letter will outline the reason for the request and detail any information that is needed. The PI will be given adequate opportunity to respond. The ORC staff or designee will arrange a time to review the investigator's study files and any other information necessary for the conduct of the audit. The IRB shall be kept apprised of any such action at their monthly meeting. If the ORC audit indicates monitoring is necessary to investigate an immediate concern regarding the safety of study subjects, the IRB chair/designee may act accordingly without convening an IRB meeting, however, no protocol may be permanently terminated without the concurrence of the committee at a convened meeting.

Under HHS regulations, a for-cause suspension of IRB approval must be reported to OHRP. Any suspension resulting from a for-cause audit will be immediately reported to the Institutional Official, department chair, funding agency (if applicable), OHRP, and, if a drug or device is involved, the FDA. Other IRBs that are relied upon by the NSLIJHS may also be notified regarding findings regarding investigator compliance as appropriate.

For-cause audits may also be prompted by information obtained from sources outside the IRB, such as internal/external whistleblowers, regulatory agencies, industry sponsors, or research subjects. Information from any of these sources that raise concerns about a protocol will be directed to the ORC.

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6.4 Routine Audits (Revised 2/7/08)

The ORC will conduct routine audits of IRB approved studies. The IRB, in conjunction with the ORC, will select the studies to be audited.

The goals of the routine audits are to:

• assure protection of human subjects and data integrity,
• provide education and training to research staff,
• ensure that federal, state, and institutional regulatory standards are met.

• study personnel CVs and licenses,
• source documents and case report forms,
• regulatory binder documents,
• review of information about recruitment and the consent process,
• informed consent forms (blank and signed versions),
• subject files and data,
• subject inpatient or outpatient medical records as appropriate,
• drug or device accountability records,
• study samples and shipping receipts,
• laboratory licenses and certifications,
• any other documents deemed appropriate.

The ORC will generate a report summarizing the audit findings and recommendations. The ORC will send a draft version of the audit report to the PI for review and will provide the PI with adequate opportunity to respond. A final version will be disseminated to the PI, the IRB, the ORC, department chairs, and appropriate health system leadership. Any routine audit found to have significant issues will be presented to the IRB, which will determine if any action is required (i.e., enrollment hold, etc.). The PI will be required to develop a corrective and preventive action plan, which may require follow-up by the IRB or ORC.

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6.5 Modifications

Changes (amendments/modifications) to a protocol may not be initiated without prior IRB approval, except when necessary to eliminate immediate hazards to the subjects. When changes are implemented to eliminate an immediate hazard, the IRB must be notified of the change promptly (within 3-5 business days).

Major modifications are changes to the protocol that:

• alter the risk/benefit ratio for study subjects,
• significantly change or affect the conduct of the study, and
• include any new information that may affect safety and/or willingness of subjects to participate.

Minor modifications are changes to the protocol that:

• do not alter the overall risk-benefit profile of the study,
• would not potentially affect the willingness of enrolled subjects to remain in the study, or the willingness of potential subjects to enroll in the study, and
• do not alter the scientific validity of the study design.

It is the responsibility of the PI to submit, in a timely manner, all protocol modifications, revised consent forms, changes in investigators, changes to FDA Form 1572 (for clinical trials), and any other information which may affect the conduct of the research study.

Minor changes in the protocol and/or consent form, may be reviewed through the expedited review procedure (see Expedited Review). However, all other changes will be reviewed by the IRB at a convened meeting, in which case deadline dates for submission apply.

How to Submit Modifications to the IRB
A request for a change of PI must be submitted using IRB Form 8d. Click here for further guidance.

All other study modifications must be summarized and reported to the IRB using IRBForm 8a. This form should accompany the complete revised version of the modified document (e.g. revised protocol, revised consent form, etc.) with an explanation of the modification and its impact on the risk/benefit assessment written by the PI. Click here for further guidance.

6.6 Protocol Exceptions

A protocol exception is any temporary protocol deviation that is approved by the IRB prior to its initiation, e.g., enrollment of a subject who does not meet the eligibility criteria. An exception request form (IRB Form 8b -Request for Protocol Exception) gives investigators the opportunity to request a change in procedure and/or protocol activity for a single, isolated event.

How to Request a Protocol Exception
In order to obtain approval for a protocol exception, the PI must submit a request to the IRB using IRB Form8b. The form should include:

• A description of the requested exception
• Justification for deviating from the protocol

All approved protocol exceptions should be listed on the progress report. See How to Submit a Protocol Exception Request.

IRB Response/Action
The Office of the IRB will process protocol exception requests. Each request will be evaluated on a case-by-case basis by the IRB chair or designee, and when appropriate, by the convened IRB committee.

Investigators will be informed in writing regarding the IRB’s decision. No exception may be implemented without IRB approval.

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6.7  Protocol Violations

A protocol violation is a deviation that is not approved by the IRB prior to its initiation or implementation. Protocol violations may be major or minor:

A major protocol violation:

• Affects subject safety
• Damages the scientific integrity of the data collected
• Affects a subject’s willingness to participate in the study

A minor protocol violation:

• Does not affect subject safety
• Has no effect on value of the data collected 
• Does not affect a subject’s willingness to be in a study

Examples of major protocol violations include (but are not limited to):

• Failure to obtain informed consent (i.e., no documentation of informed consent, consent obtained after study procedures were initiated)
• Informed consent for IND/IDE studies obtained by unauthorized individuals (i.e., someone other than a licensed physician investigator)
• Enrolling subject who does not meet inclusion/exclusion criteria
• Use of study procedures not approved by the IRB
• Failure to report serious adverse event to the IRB and/or sponsor
• Failure to perform a required lab test that could affect subject safety or integrity of data
   
• Error in dispensing or dosing of drug/study medication
• Error involving use of device
• Study visit conducted outside of required timeframe, only if it affects subject safety
• Failures to follow safety monitoring plan
• Failure to submit continuing review application to the IRB before study expiration
• Missing subject signature on consent form
• Missing investigator signature on consent form
• Use of invalid consent form (i.e., use of outdated or unapproved consent form)
   
• Enrollment of subjects after IRB-approval of study expired

 
Examples of minor protocol violations include (but are not limited to):

• Missing original signed and dated consent form (only photocopy available)
• Inappropriate documentation of informed consent, including:

• Copy not given to the person signing the consent form
• Someone other than the subject dated the consent form
• Deviations from the approved study procedure that do not affect subject safety or data integrity
  
  • Study procedure conducted out of sequence
  • Omitting an approved portion of the protocol
  • Failure to perform a required lab test
  • Missing lab results
  • Study visit conducted outside of required timeframe
     
• Failure of subject to return study medication

It is the responsibility of the PI to determine if a violation is major or minor. Major protocol violations must be reported to the IRB within ten (10) working days of discovery. Minor protocol violations may be reported at continuing review. Reports of protocol violations should be submitted to the sponsor according to the sponsor’s protocol.

 
How to Report a Protocol Violation to the IRB
If the protocol violation is major, it should be submitted to the Office of the IRB using IRB Form 8c -  Report of Major Protocol Violation. See How to Report a Major Protocol Violation.

If the protocol violation is minor, it may be reported and detailed on the Progress Report form at the time of continuing review.

IRB Response/Action
Reports of major protocol violations are reviewed by the IRB chair, IRB director and assistant director. The IRB chair may initiate further inquiry or review, depending on the violation. If the violation proves to be serious, the IRB chair may choose to suspend or terminate the protocol. If review indicates that the violation is a result of non-compliance, the matter will be referred to the Office of Research Compliance.

When a protocol has been suspended or terminated due to a major violation, the action will be reported to the Institutional Official, the department head, the FDA (as appropriate), any funding agency and the OHRP.  Any subsequent action, such as changing or lifting a suspension will also be reported to the appropriate agencies or department heads. Reports may also be shared with other IRBs upon which the NSLIJHS relies, when appropriate.

Investigators will be informed in writing of all IRB inquiries and determinations.

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6.8 Unanticipated Problems Involving Risk to Subjects or Others (Including Adverse Events) (Revised May 2011)

It is the responsibility of the PI to promptly report any unanticipated problems involving risks to subjects or others to the IRB. This reporting is in addition to, and does not supplant, periodic progress reports (see Progress Reports).

Definitions

Adverse event: Any unfavorable medical event that occurs in a study.  It does not necessarily have to have a causal relationship with the study procedures. An adverse event can include:

• an abnormal laboratory finding, 
• unfavorable symptom, disease, or occurrence, or 
• any other unanticipated event involving risk to subjects or others in a research study, whether or not considered related to the product, device, treatment, research procedure, or behavioral intervention being studied.

• results in death,
• is life-threatening (i.e. the subject was at risk of death at the time of the event.  It does not include events that hypothetically might have caused death if it were more severe), 
•  requires inpatient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity,  
• is a congenital anomaly/birth defect, or 
• results in unanticipated serious risk/harm to subjects and others. 

1. All related/possibly related internal, serious adverse events that are expected or unexpected which occur during a study, or in a post-study period of reasonable duration (i.e. during follow-up), MUST be reported to the IRB and the study sponsor, as appropriate.  Reporting to the IRB must be done within 5 business days of occurrence or knowledge of event by the investigator. 
2. Any internal events that are expected but not serious should NOT be submitted.
3. Any internal adverse events that are not related should NOT be submitted.
4. Reports should identify subjects by unique code numbers rather than by subjects’ names, personal identification numbers, and/or addresses.
5. Report should be submitted on IRB Form 7a and include:
   -   A detailed description of the event Category of event - expected or unexpected
   -   Any resultant changes to the consent form
   -   Event relation to study intervention
   -   Rationale for assessment 
   -   Outcome Site of incident
6.  The PI should also attach any supporting information and materials such as progress notes, lab findings, discharge notes, death certificates, etc.
7. The IRB may determine that modifications be made to the consent form and/or protocol to assure the safety and willingness of the subjects to remain in the study.
   
   Note: The PI is the sponsor of investigator-initiated studies. As such, he/she must follow mandatory FDA reporting requirements. (See www.fda.gov/medwatch/how.htm).  Copies of any reports submitted to the FDA should be sent to the IRB.

B.  External Adverse Events

1. External adverse event reports must be submitted to the IRB if the events are serious, deemed related to the study agent, and unexpected. 
2. Before submitting the report to the IRB, the PI should assess the relationship of the event to the study and determine whether or not a change to the consent form is necessary as a result of the information in the report.
3. If reports are received by an investigator in the form of a series of safety reports, or a periodic Data Safety Monitoring Board (DSMB) Report (often a compilation of adverse events), and meets the reporting requirements outlined above (i.e., serious, unexpected and related events) the investigator shall provide a written summary to the IRB along with the report. When sponsor submission requirements and IRB policy are discordant, the IRB policy shall be followed.
4. Reports should be submitted on IRB Form 7b and include:
   -    A detailed description of the event 
   -    Any resultant changes to the consent form
   -    NS-LIJ investigator’s assessment of event
   -    Site of incident
5. The PI should also attach supporting information and materials such as letters from sponsor, Medwatch reports, site investigator reports, progress notes, etc.
6. The following types of external adverse event reports should NOT be sent to the Office of the IRB: (1) Expected Events, (2) Unrelated Events, (3) Non-serious Events.  If the Office of the IRB receives an external adverse event report that fits any of these three criteria, it will be sent back to the PI without acknowledgement.

C.  Unanticipated Problems involving risks to subjects or others (which are not adverse events)

    1.  Report should be submitted on IRB Form 7c and include:
             -    A detailed description of the event
             -    Effect on subjects
             -    Effect of study validity
             -    Corrective action

IRB Review Procedure

1. The IRB will review all reported serious adverse events and unanticipated problems that are required to be reported to the IRB.  The protocol and consent form will be evaluated to determine if changes are needed. 
2. If the IRB designee determines that the event does not qualify as an unexpected problem involving risks to subjects or others the event will be acknowledged and filed. The IRB committee will not review them.  A copy of the stamped IRB Form will be sent to the PI.
3. Follow-up reports will be stamped and filed, unless there is a significant change in the assessment of causality.
4. If a study is closed to patient entry and no subjects are on active treatment, the reports will be stamped and filed, unless a change to the protocol alters the follow-up procedures for patients.
5. If the IRB chair/designee determines that the report does not meet criteria for expedited review, it will be forwarded to the Full Committee for review. 
6. The IRB or IRB chair/designee has the authority to suspend, and the IRB has the authority to terminate approval of research at its site that has been associated with unexpected serious harm to participants.  When the IRB or IRB chair/designee takes such action, a statement of reasons for such action shall be included in a notification letter to the PI.  The IRB or IRB chair/designee shall promptly report its findings to the investigator and, if warranted, to Institutional officials, study sponsor, Office of Human Research Protection (OHRP), and the FDA.

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6.9  Termination of a Protocol Revised 2/20/08

The following are two different mechanisms by which a protocol may be terminated:

• Voluntary termination by the investigator or sponsor (study ends, investigator leaves the institution, etc.).
• Administrative termination by the IRB due to safety concerns, investigator non-compliance, or delinquent progress reports (failure to renew a protocol prior to expiration of IRB approval).

If a study is voluntarily terminated, the PI must notify the IRB by completing and submitting a Termination Report.
The IRB will formally acknowledge the termination of a study by the PI or sponsor in writing.

If a protocol is administratively terminated, the IRB Chair/designee will notify the PI in writing that the protocol has been terminated by the IRB or IRB Chair due to delinquent progress reports, concern for safety of human subjects, non-compliance, etc.  In a case of immediate hazard to subjects, initial notification may be in the form of a telephone call or e-mail from the IRB Chair or designee.

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6.10  Withdrawal of a Protocol

If a PI decides not to implement an IRB approved study, a written request for study withdrawal must be sent to the IRB.

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6.11  Other Activity as Determined by the IRB

The IRB has the authority to request additional information, as necessary, to assure patient safety and compliance with federal and state regulations and institutional policy and evaluated in accordance with the basic principles governing human subject protections.

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POLICY:

Research involving vulnerable populations at the NSLIJ Health System will be reviewed and conducted according to regulations of the Department of Health and Human Services (DHHS) - Subparts B (fetuses, pregnant women, and in vitro fertilization), C( prisoners), and D (children) of the DHHS regulations (45 CFR 46) and FDA regulations (21 CFR 50) subpart D, as well as New York State law governing such research.

GUIDANCE:

Vulnerable populations include those whose diminished autonomy compromises their ability to give informed consent to participate in research. Children, pregnant women, fetuses, the mentally handicapped, prisoners, and the economically or educationally disadvantaged are among the groups most often identified as being vulnerable. However, depending on context or circumstances, students, employees, patients in emergency rooms, institutionalized persons and people who are not fluent in English may also be considered vulnerable. As a rule, anyone in a situation where his or her ability to give informed consent is compromised or eliminated should be considered vulnerable.

7.1 Research Involving Children

GUIDANCE:

Children are considered a vulnerable research population because their emotional and intellectual capacities may be limited and they are not of a legal age to give informed consent. The IRB is responsible for assuring that principal investigators conducting research with children comply with additional requirements as set forth by the DHHS in 45 CFR 46 Subpart D and FDA regulations at 21 CFR 50 Subpart D. During its deliberations, the IRB will consider the degree of risk and potential benefit of the proposed activity and whether it is appropriate to obtain the assent of the minor.

Categories of Risk
Depending on the risk/benefit ratio, research involving children is divided into four categories of risk.Investigators must consider the appropriate category for their research in order to meet the requirements outlined below:

Permission by Parents or Guardians
When children are involved in research, federal regulations require the permission (consent) of the parent(s) or legal guardian(s), in place of the consent of the minor subject. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under categories 1 and 2 (45 CFR 46.404 or 46.405).

Where research is covered by categories 3 and 4 (46.406 and 46.407) and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. See When Permission from Both Parents is Required for Research Involving a Child for further guidance.

If the research is designed for conditions or for a subject population for which parental/guardian permission is not a reasonable requirement to protect the subjects (i.e., neglected or abused children), the IRB may waive the consent requirement but must provide an appropriate mechanism for protecting the children.

Assent by Children
Although they are legally incapable of giving informed consent, children (generally 7-9 years of age or older) may possess the ability to assent, or refuse participation in a research study. Assent is a child's affirmative agreement to participate in are search study. Failure to object to participation cannot be construed as assent [45 CFR 46.402(b)] and assent is not valid if coerced.

Assent is always required when the research:

1. Does not involve interventions with the prospect of benefit to the subject,and
2. The child is able to comprehend and appreciate what it means to be a volunteer for the benefit of others.

A child who is asked to assent should be given an explanation of the proposed research procedures in a vocabulary and language that is appropriate to the child's age, experience, maturity, and medical condition. This explanation should include a discussion of any discomforts and inconveniences the child may experience if he or she agrees to be in the study.

Assent must be respected. If assent is solicited, the investigator must abide by the child's decision. If the child refuses to assent to participation in a study, and the IRB has determined that assent of the child is required, the child's parent(s) or legal guardian may not override the child's decision.

To obtain valid written assent, the investigator must use an IRB approved assent form. Upon reaching age18, the subject should sign the IRB approved adult consent form for the study.

The IRB will determine that adequate provisions are made for soliciting the assent of children, when, in their judgment, the children are capable of providing assent. In order to make that judgment, the IRB will consider the ages, maturity and psychological state of the subjects. This judgment may be made for all children to be involved in research under a particular protocol, or on an "as appropriate" basis for each child, as the IRB deems appropriate.

Documentation of Permission and Assent
In cases where permission of a parent/guardian is required, it must be documented in accordance with informed consent requirements (see Informed Consent). For research where assent is also required, the IRB will determine whether and how it is to be documented. Generally, the use of an assent form is appropriate.

Waiver of Assent
If an investigator believes that assent is not appropriate, a waiver must be specifically requested, described, and justified in the protocol.

If the IRB determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under the same circumstances in which consent may be waived. (See Policy 5.2: Waiver of Informed Consent Requirements).

Emancipated Minors
Individuals under the age of 18 who are considered emancipated minors by New York State may be able to consent to research participation for themselves. Although not specifically addressed by NYS statute, there may be instances where participation in a clinical trial is the subject's only way to receive a particular form of treatment that may be beneficial. The IRB shall consider the inclusion of emancipated minors in research, absent parental or guardian consent, on a case-by-case basis. The IRB shall consider the subject's ability to comprehend what is being proposed, and the intervention or procedure involved in the research must offer a prospect of direct benefit that is important to the health or well-being of the minor and is not available outside the context of the research protocol.

Children Who are Wards (Revised 11/07)

Note: The enrollment of wards of the state in any research protocol must be prospectively approved by the IRB before the subject is enrolled.

Children who are wards of the state or other agency, institution or entity, can be included in research under categories 1 and 2 without any additional requirements posed by their status.

However, they may only be included in research under categories 3 and 4 described above if such research is:

1. related to their status as wards; or
2. conducted in schools, camps, hospitals, institution, etc., in which the majority of the children involved are not wards.

Research approved under categories 3 and 4 shall require the appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. The IRB will be responsible for appointing an individual who has the background and experience to act in, and agrees to act in, the best interest of the child for the duration of the child's participation in the research. The advocate must not be associated in any way (except in the role as advocate) with the research or clinical investigation, the investigator(s), or the guardian organization. When circumstances allow, a member of the IRB may serve as an advocate. One individual may act as advocate for more than one child.

The advocate must be present during the informed consent process and be available throughout the duration of the research to address any questions or concerns encountered by the subject. The PI will send reports on the subject's participation to the advocate at regular intervals. The IRB will determine the frequency of that reporting based on issues including the level of risk to subjects, on a protocol-by-protocol basis.

PROCEDURES:

Submission Requirements for Protocols Involving Children to the IRB
The principal investigator (PI) must submit the following in addition to all other required documents for protocol submission to the Office of the IRB. (See Policy 2: How to Submit a Protocol to the IRB).

1. Complete Section G on the Application for Research Involving Human Subjects (ARIHS) - IRB Form 4.
2. For protocols that will require assent from the subject, an assent form must be included as part of the consent form.

Regarding wards of the state: Investigators who anticipate enrolling wards of the state must obtain approval from the IRB at the time of initial submission. If an investigator who did not anticipate enrolling wards of the state at the time of initial review and approval subsequently wishes to do so, he/she must first obtain approval from the IRB, as a protocol modification or protocol exception.

IRB Review of Research Involving Children
Protocols involving children will be assigned to reviewers with the appropriate expertise to evaluate the use of the procedure/intervention in a pediatric population. The IRB will determine which category of risk is applicable to an individual protocol and conduct its review accordingly.

7.2 Research Involving Pregnant Women, Human Fetuses, and Neonates

POLICY:

All research involving pregnant women, human fetuses and neonates shall be conducted and reviewed in compliance with the additional DHHS requirements as set forth in 45 CFR 46 Subpart B.

GUIDANCE:

Research Involving Pregnant Women or Fetuses
Pregnant women or fetuses maybe involved in research if all of the following conditions are met:

(A) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;

(B) If the research offers the prospect of direct benefit for the pregnant woman or the fetus where:

1. The risk to the fetus is caused solely by the research interventions or procedures and
2. The risk to the fetus is NOT more than minimal risk and
3. The risk is the least possible to achieve the objectives of the research and
4. Informed consent is obtained from the pregnant woman in accordance with the provisions of subpart A.

• The risk to the fetus is caused solely by the research interventions or procedures and
• The risk to the fetus is NOT more than minimal risk and
• The risk is the least possible to achieve the objectives of the research and
• Informed consent is obtained from the pregnant woman and the father in accordance with the provisions of subpart A

(D) If the research offers no prospect of direct benefit for the pregnant woman or the fetus where:

� The research is the development of important biomedical knowledge which cannot be obtained by any other means;and

• The risk to the fetus is caused solely by the research interventions or procedures and
• The risk to the fetus is NOT more than minimal risk and
• The risk is the least possible to achieve the objectives of the research and
• Informed consent is obtained from the pregnant woman in accordance with the provisions of

(E) Each individual providing consent under paragraph (b), (c) or (d) of this section is fully informed regarding the reasonably foreseeable impact ofthe research on the fetus or neonate;

(F) No inducements, monetary or otherwise, will be offered to terminate a pregnancy;

(G) 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

(H) Individuals engaged in the research will have no part in determining the viability of a neonate.

Research Involving Neonates
Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met:

(1) Scientifically appropriate, preclinical and clinical studies have been conducted and provided data for assessing potential risks to neonates.

(2) Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the neonate.

(3) Individuals engaged in the research will have no part in determining the viability of a neonate.

(4) The requirements of the following sections,"Neonates of Uncertain Viability" and "Nonviable Neonates," have been met as applicable.

Neonates of Uncertain Viability
Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions have been met:

(1) The IRB determines that:

• The research offers the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or
• The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and

(2) The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent's legally authorized representative is obtained in accordance with 45 CFR 46 subpart A of this part, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.

Nonviable Neonates
After delivery nonviable neonates may not be involved in research covered by this subpart unless all of the following additional conditions are met: