Chapter 10. Types of IRB Review

All human subject research conducted at the University of Notre Dame or by its employees or agents must be prospectively reviewed and approved by ND’s IRB. No human subject research may be initiated or continued at the University of Notre Dame or by its employees or agents without prospective approval of the IRB.

A. Review by the Convened IRB. Federal regulations, the Federal Policy (Common Rule) for the Protection of Human Subjects, and FDA regulations require that the IRB conduct initial and continuing reviews of all non-exempt research at convened meetings at which a majority of the members are present, unless the research falls into one or more of the categories appropriate for expedited review (see item “D” of this Chapter).

A majority of the IRB members (or their designated alternates), including at least one member whose primary concerns are in nonscientific areas, must be present in order to conduct a convened meeting. In order for research to be approved, it must receive the approval of a majority of those members present at the meeting.

B. Initial Review by the Convened IRB. Prior to the convened meeting, IRB members will be provided detailed initial review materials describing the research in order to discuss the protocol adequately and determine the appropriate action during the convened review. These materials will include the proposed informed consent document and the IRB Research (Protocol) Application Form, which includes information about subject recruitment and selection, the research plan, risks and benefits, privacy and confidentiality protections, safety monitoring, informed consent procedures, protections for vulnerable subjects, as well as grant applications or proposals for Federally funded research, and any other information relevant to the approval criteria described in the regulations.

C. Continuing Review by the Convened IRB. The University of Notre Dame’s IRB is required to conduct substantive and meaningful continuing review of research at intervals appropriate to the degree of risk, but not less than once per year. Continuing reviews will be conducted by the convened IRB unless the research falls into one or more of the categories appropriate for expedited review (see item “D” of this Chapter).

Prior to the convened meeting, IRB members will be provided with detailed continuing review materials sufficient to conduct substantive and meaningful reviews. These materials will include the currently approved informed consent document and the IRB Continuing Review Application Form, which includes a summary of the research, a status report on the progress of the research, number of subjects enrolled and withdrawn, problems and adverse events, relevant recent literature, and other relevant information.

D. Expedited Review of Research. Federal regulations, the Common Rule, and FDA regulations permit the IRB to review research protocols through an expedited procedure if:

i. the research constitutes a minor change in previously approved research during the period for which approval is authorized; or

ii. the research is not greater than minimal risk and falls within the categories on the November 9, 1998 DHHS-FDA list of research eligible for expedited IRB review Under an expedited review procedure, the IRB Chairperson or an experienced reviewer designated by the Chairperson may review and approve the research on behalf of the IRB.

Documentation for expedited reviews maintained in IRB records will include the category and circumstances that justify using expedited procedures.

E. Expedited Review of Minor Changes in Previously Reviewed Research.

Investigators must report to the IRB any proposed changes in IRB-approved research, including proposed changes in informed consent documents. No changes may be initiated without prior approval of the IRB, except where necessary to eliminate apparent immediate hazards to subjects.

This IRB may utilize expedited procedures to review a proposed change to previously approved research if it represents a minor change to be implemented during the previously authorized approval period.

A minor change is one which, in the judgment of the IRB reviewer, makes no substantial alteration in (i) the level of risks to subjects; (ii) the research design or methodology; (iii) the number of subjects enrolled in the research; (iv) the qualifications of the research team; (v) the facilities available to support safe conduct of the research; or (vi) any other factor which would warrant review of the proposed by changes by the convened IRB.

F. Use of Subcommittees to Support IRB Activities. The University of Notre Dame’s IRB may utilize subcommittees to support IRB review activities. At the discretion of the IRB Chairperson, subcommittees may be appointed to perform expedited reviews or fulfill the duties of primary reviewers. The IRB Chairperson may also appoint subcommittees on an ad hoc basis to perform additional functions as needed. Subcommittees cannot substitute for the IRB in any other situation.

G. Review of Reports of Unanticipated Problems or Adverse. Investigators are required to report adverse events and/or unanticipated problems in order to assure protection of human subjects involved in research.

H. Outcomes of IRB Review. The University of Notre Dame’s IRB will notify investigators in writing of its determinations.

Although research approved by the IRB may be disapproved by other University of Notre Dame’s committees or officials, no human subject research may be conducted without IRB approval. No University of Notre Dame committee or official may approve or authorize the proceeding of any human subject research that has not been reviewed and approved by the IRB.

IRB actions for review of research include the following:

i. Approved with no changes (or no additional changes). The research may proceed.

ii. Approvable with minor changes to be reviewed by a designated IRB member. Such minor changes must be clearly delineated by the IRB so the investigator may simply concur with the IRB’s stipulations. The research may proceed after the required changes are verified and the reviewer approves the protocol.

iii. Deferred pending receipt of additional substantive information. The IRB determines that it lacks sufficient information about the research to proceed with its review. The research may not proceed until the convened IRB has approved a revised application incorporating all necessary information.

iv. Disapproved. The IRB has determined that the research cannot be conducted at the University of Notre Dame or by its employees or agents.

I. Expiration of Approval Period. The IRB is required to conduct substantive and meaningful continuing review of research not less than once per year. Thus, for research requiring review by convened IRB, the IRB approval period may extend no more than 365 days after the convened meeting at which the research was last approved. For research within categories appropriate for expedited review, the IRB approval period may extend no more than 365 days after the expedited review at which the research was last approved.

The regulations permit no grace period and no exceptions to the one year requirement. Research that continues after the approval period expires is research conducted without IRB approval.

Consequently, the IRB will automatically suspend the enrollment of new subjects in any ongoing research that does not receive continuing review and approval prior to the end of the stipulated approval period. Previously enrolled subjects may continue their involvement in suspended research only where the IRB determines that continued involvement is in the best interest of the subjects.

J. Suspension or Termination of IRB Approval. All investigators conducting research approved by the University of Notre Dame IRB are required to notify the IRB promptly of any serious adverse events or unanticipated problems involving risks to subjects or others; OR of any serious or continuing noncompliance with applicable regulatory requirements or with the determinations of the IRB.

The IRB may vote to suspend or terminate approval of research not being conducted in accordance with IRB or regulatory requirements or that has been associated with unexpected problems or serious harm to subjects.

The IRB will notify the principal investigator in writing of such suspensions or terminations and will include a statement of the reasons for the IRB’s actions. The investigator will be provided with an opportunity to respond in person or in writing.

Where the IRB Chairperson determines that such action is necessary to protect the rights and welfare of subjects, the Chairperson may require an immediate, temporary suspension of enrollment of new subjects or of continued participation of previously enrolled subjects, pending review of the situation by the convened IRB. IRB may permit continuation of current subjects if deemed in their best interest to continue participation.

It is the responsibility of the IRB Chairperson to provide prompt written notification to Vice President for Research of the suspension or termination or IRB approval as described in this section. The Vice President for Research is responsible to notify the OHRP.

Chapter 11. IRB Review and Approval Considerations

Federal regulations at 45 CFR 46.111, FDA regulations, and the Federal Policy (Common Rule) delineate specific criteria for the approval of research. The University of Notre Dame’s IRB will determine that all of the following requirements are satisfied before approving proposed research.

A. Levels of Risk. IRBs must consider the overall level of risk to subjects in evaluating proposed research, and investigators are required to minimize risks to subjects while maximizing research benefits. In general, the regulations require that the IRB distinguish research that is “greater than minimal risk” from research that is “no greater than minimal risk.” Under specific circumstances, research that is no greater than minimal risk may be eligible for expedited review, waiver or alteration of informed consent requirements, or waiver of the requirement to obtain written documentation of consent.

Under Federal regulations at 45 CFR 46.102(i), “minimal risk means that the probability and magnitude of harm or discomfort in the research are not greater in and of themselves than those encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

B. Risks Minimized. In order to approve research, the IRB must determine that risks are minimized by using procedures that are consistent with sound research design and do not expose subjects to unnecessary risks. Whenever appropriate, the research should utilize procedures that are already being performed on the subjects for diagnostic or treatment purposes.

The IRB is expected to consider the research plan, including the research design and methodology, to determine that there are no flaws that would place subjects at unnecessary risk. When the research design presents unnecessary or unacceptable risks to subjects without commensurate benefits to the subjects or to others, the research cannot ethically proceed.

In order to ascertain whether the research project is adequately designed and thus subjects protected, the IRB reserves the authority to seek opinions from consultants on proposed research and its design. The IRB may determine that proposed research must be re-designed to enhance subject autonomy, maximize benefits, reduce risks, select subjects equitably, minimize undue influence or coercion, etc.

The IRB will also consider the qualifications of the research team. Clinicians are expected to maintain appropriate professional credentials and licensing privileges. Overall, the research team must possess the professional and educational qualifications, as well as the resources, to conduct the research project and to protect the rights and welfare of subjects.

C. Risks Reasonable Relative to Anticipated Benefits. In order to approve research, the IRB must determine that the risks of the research are reasonable in relation to the anticipated benefits (if any) to subjects, and/or the importance of the knowledge that may reasonably be expected to result.

The IRB develops its risk/benefit analysis 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 should consider only those risks that result from the research, and should not consider long-range effects (e.g., public policy implications) of applying the knowledge gained in the research.

D. Equitable Selection of Subjects. In order to approve research, the IRB must determine that the selection of subjects is equitable. In making this determination, the IRB should evaluate the purposes of the research and the research setting, and should be especially cognizant of the problems of research involving vulnerable subject populations.

The IRB should carefully examine inclusion-exclusion criteria and recruitment procedures in order to determine that the burdens and benefits of the research are being distributed equitably. The IRB should be mindful of the importance of including members of minority groups in research, particularly when the research holds out the prospect of benefit to individual subjects or the groups to which they belong.

The IRB should be mindful of the desirability of including both women and men as research subjects and should not arbitrarily exclude the participation of persons of reproductive age. Exclusion of such persons must be fully justified and based on sound scientific rationale.

E. Informed Consent Procedures. In order to approve research, the IRB must determine that appropriate informed consent will be sought from each prospective subject or the subject’s legally authorized representative (see 45 CFR 46.116), unless informed consent requirements can be waived or altered under Federal regulations. Any such waiver must be consistent with applicable laws. The specific elements required for informed consent are discussed in detail in Chapter 12. The following informed consent procedures apply to all research conducted at ND or by ND’s employees or agents:

i. Informed consent may only be sought under circumstances that provide the subject (or the legally authorized representative) with sufficient opportunity to consider whether or not to participate and that minimize the possibility of coercion or undue influence.

ii. Informed consent information must be presented in language that is understandable to the subject (or the legally authorized representative).

iii. No informed consent process may include any exculpatory language (a) through which the subject is made to waive, or appear to waive, any legal rights as research subjects; or (b) through which the investigator, the sponsor, the University of Notre Dame, or its employees or agents are released from liability for negligence, or appear to be so released.

iv. Informed consent must be obtained prior to initiation of any clinical screening procedures that are performed solely for the purposes of determining eligibility for research.

F. Documentation of Informed Consent. In order to approve research, the IRB must determine that informed consent will be appropriately documented, unless documentation can be waived under Federal regulations.

Federal regulations at 45 CFR 46.117 provide two methods for documenting informed consent.

1. Written Consent Document. Consent may be documented through use of a written consent document that embodies all of the required elements of informed consent. The consent document must be signed by the subject (or the subject’s legally authorized representative), and a copy must be given to the person signing the form. FDA regulations require that the signature be dated.

2. Short Form Consent Document. Consent may also be documented through use of a short form consent document which states that the elements of informed consent have been presented orally to the subject (or the legally authorized representative). When this method is used, (1) there must be a witness to the oral presentation; (2) the IRB must approve a written summary of what is to be presented orally; (3) only the short form must be signed by the subject or the representative; (4) the witness must sign both the short form and the summary; (5) the person actually obtaining consent must sign the summary; and (6) a copy of the summary and the short form will be given to the subject or the representative.

G. Data Safety Monitoring. In order to approve research, the IRB must determine that, where appropriate, the research plan makes adequate provision for monitoring the data to protect the safety of subjects. For research in which risks are substantial, a general description of the data and safety monitoring plan should be submitted to the IRB as part of the proposal. This plan should contain procedures for reporting adverse events.

The University of Notre Dame IRB requires immediate and continuous monitoring of responses to suicide ideation measures. While it is typically the case the researchers will delay in analyzing data until the end of the data collection period, researchers must analyze suicide ideation measures as they are collected and be prepared to provide necessary referrals to health professionals in the event of a subject’s intent to harm themselves or others.

H. Privacy of Subjects and Confidentiality of Data. In order to approve research, the IRB must determine that, where appropriate, there are adequate provisions to protect the privacy of subjects and the confidentiality of data.

In reviewing confidentiality protections, the IRB will consider the nature, probability, and magnitude of harms that would be likely to result from a disclosure of collected information outside the research. It will evaluate the effectiveness of proposed anonymizing techniques, coding systems, encryption methods, storage facilities, access limitations, and other relevant factors in determining the adequacy of confidentiality protections.

I. Additional Safeguards for Vulnerable Subjects. In order to approve research, the IRB must determine that, where appropriate, additional safeguards have been included to protect the rights and welfare of subjects who are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, persons with mental disabilities, or economically or educationally disadvantaged persons.

Should this institution’s IRB find that they regularly review research involving such vulnerable subjects, the IRB will include among its reviewers persons who are knowledgeable about and experienced in working with these vulnerable subjects.

J. Review More Often Than Annually. The following factors will determine which studies require review more frequently than on an annual basis:

i. The probability and magnitude of anticipated risks to subjects.

ii. The likely medical condition of the proposed subjects.

iii. The overall qualifications of the principal investigator and other members of the research team.

iv. The specific experience of the principal investigator and other members of the research team in conducting similar research.

v. The nature and frequency of adverse events observed in similar research, if any.

vi. Any other factors that the IRB deems relevant.

In specifying an approval period of less than one year, the IRB may define the period with either a time interval or a maximum number of subjects studied or enrolled as specified by the IRB. If a maximum number of subjects studied or enrolled is used to define the approval period, it is understood that the approval period in no case can exceed 365 days and that the number of subjects studied or enrolled determines the approval period only when that number of subjects is studied or enrolled in less than 365 days.

K. Consent Monitoring. In reviewing the adequacy of informed consent procedures for proposed research, the University of Notre Dame’s IRB may on occasion determine that special monitoring of the consent process by an impartial observer (consent monitor) is required in order to reduce the possibility of coercion and undue influence.

L. Advertisements and Recruitment Incentives. The IRB is required to review and approve all advertisements and recruitment incentives associated with the research that they oversee. Approval must be obtained prior to the use of the proposed advertisement or recruitment incentive. Advertisements and incentives are directly related to the informed consent process and must be consistent with prohibitions on coercion and undue influence.

Any advertisement to recruit subjects should be limited to the information the prospective subjects need to determine their eligibility and interest. When appropriately worded, the following items may be included:

i. The name and address of the clinical investigator and/or research institution.

ii. The condition under study and/or the purpose of the research.

iii. In summary form, the criteria that will be used to determine eligibility for the study.

iv. A brief list of participation benefits, if any. The possible benefits should be presented in a conservative manner without any exaggeration or excessive enthusiasm.

v. The time or other commitment required of the subjects.

vi. The location of the research and the person or office to contact for further information.

Recruitment procedures should be designed so that informed consent is given freely and coercion or undue influence is avoided. In order to evaluate this aspect of the research, the IRB should know who the subjects will be, what incentives are being offered, and the conditions under which the offer will be made.

The IRB may require that advertisements and recruitment incentives for proposed research be modified to minimize the possibility of coercion or undue influence in recruitment.

N. Obtaining Consent from Non­English Speakers. Federal regulations at 45 CFR 46.116 require that informed consent be obtained in language that is understandable to the subject (or the subject’s legally authorized representative).

In accordance with these regulations, the IRB requires that informed consent conferences include a reliable translator when the prospective subject does not understand the language of the person who is obtaining consent.

Investigators can document informed consent in either of two ways:

i. A full–length informed consent document written in language understandable to the subject; or

ii. A “short-form” consent document in the language of the subject that states the general elements of informed consent.

O. Payment to Research Subjects. The IRB reviews all proposed payments to research subjects associated with the research that they oversee. Payments to research subjects may not be of such an amount as to constitute coercion or undue influence on the subject’s decision to participate. Payments may not be provided to subjects on a schedule that results in coercion or undue influence on the subject’s decision to continue participation.

Federal policy prohibits paying subjects to participate in research when the research is an integral part of a patient’s medical care and when it makes no special demands on the patient beyond those of medical care.

The IRB will review all proposals involving the payment of subjects (in excess of reimbursement for travel) on a case-by-case basis.

P. Certificates of Confidentiality. Where research involves the collection of highly sensitive information about individually identifiable subjects, the IRB may determine that special protections are needed to protect subjects from the risks of investigative or judicial processes.

In such situations, the IRB may require that an investigator obtain a DHHS Certificate of Confidentiality (CoC). The CoC protects against compulsory release of sensitive information about individual subjects for use in Federal, State, or local civil, criminal, administrative, legislative, or other legal proceedings.

The CoC does not prohibit disclosure of information by an investigator, to local authorities of child abuse or of a communicable disease. In addition, the CoC does not protect against the release of information to DHHS or FDA for audit purposes. Consequently, it is important for investigators to identify beforehand all conditions under which they will voluntarily release information to third parties. The IRB will require that these conditions for release be stated clearly and explicitly in the informed consent document.

Q. Compliance with All Applicable Laws. All human subject research conducted at the University of Notre Dame or by its employees or agents must comply with applicable laws.

R. Waiver or Alteration of Informed Consent Requirements: Federal regulations at 45 CFR 46.116(c) set forth the conditions under which an IRB may approve a consent procedure that eliminates or alters the required elements of informed consent, or may waive the requirement to obtain informed consent altogether. In order to approve such a waiver or alteration, the IRB must find and document that:

i. The activity constitutes a research or demonstration project that is to be conducted by, or subject to the approval of, state or local government officials, and is designed to study, evaluate, or otherwise examine: (1) public benefit or service programs; (2) procedures for obtaining benefits or services under those programs; (3) possible changes in or alternatives to those programs or procedures; or (4) possible changes in methods or levels of payment for benefits or services under those programs; and

ii. The research could not practicably be carried out without the waiver or alteration.

S. Waiver or Alteration of Informed Consent Requirements: Minimal Risk. Federal regulations at 45 CFR 46.116(d) permit an IRB to approve a consent procedure that eliminates or alters the required elements of informed consent, or to waive the requirement to obtain informed consent altogether. In order to approve such a waiver or alteration, the IRB must find and document that:

i. The research involves no more than minimal risk to the subjects.

ii. The waiver or alteration will not adversely affect the rights and welfare of the subjects.

iii. The research could not practically be carried out without the waiver or alteration.

iv. Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

These findings and their justifications will be clearly documented in IRB minutes when the IRB exercise this waiver provision. This waiver provision is not applicable to research governed by FDA regulations, and the IRB will not approve such alterations or waivers for FDA-regulated research

T. Waiver of Documentation of Consent. Federal regulations at 45 CFR 46.117(c) permit an IRB to waive the requirement to obtain written documentation of informed consent. In order to approve such a waiver, the IRB must find and document either of the following conditions:

i. The only record linking the subject and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality. In this case, each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern; or

ii. The research presents no more than minimal risk of harm to subjects and involves procedures or activities for which written consent is not normally required outside of the research context. In cases in which the documentation requirement is waived, the IRB may require the Principal Investigator to provide subjects with a written statement regarding the research.

These findings and their justifications will be clearly documented in IRB minutes when the IRB exercises this waiver provision.

Chapter 12. Required Elements of Informed Consent

Investigators must obtain the legally effective informed consent of the prospective subject, or the subject’s legally authorized representative, before the subject can be included in research.

Informed consent presumes two simultaneous concepts: informed decision making and voluntary participation. Prospective subjects must be given sufficient information about the research and its risks and benefits in order to reach an informed decision as to whether they will voluntarily participate.

For an effective informed consent process, Federal regulations at 45 CFR 46.116(a), the Common Rule, and FDA regulations at 21 CFR 50.25(a) mandate the inclusion of eight basic informed consent elements unless the IRB has specifically approved an alteration or waiver of these elements. The IRB may routinely, or on a case-by-case basis, require that additional information, beyond these eight basic elements, be included in the informed consent.

No informed consent process may include any exculpatory language through which the subject is made to waive, or appear to waive, any of their legal rights or through which the investigator, the sponsor, the institution, or the institution’s employees or agents are released from liability for negligence, or appear to be so released.

A. Research Statement (required element #1). Informed consent information must include the following:

i. A statement that the study involves research.

ii. An explanation of the purposes of the research including its long-term goals.

iii. An explanation of the expected duration of subjects’ participation.

iv. A description of what procedures will be followed.

v. Identification of any procedures that are experimental.

If the treating physician is also the research investigator, subjects may mistake their participation in research for therapeutic treatment. By specifying the purpose of the research and describing experimental procedures, subjects should be able to recognize the difference between research and treatment.

B. Reasonably Foreseeable Risks or Discomforts (required element #2). Informed consent information must describe any reasonably foreseeable risks or discomforts associated with the research.

C. Reasonably Expected Benefits to Subjects or Others (required element #3). Informed consent information must describe any benefits to subjects or to others which may reasonably be expected from the research. However, benefits must not be overstated so as to create an undue influence on subjects.

D. Appropriate Alternatives (required element #4). Informed consent information must include a disclosure of any appropriate alternative procedures or courses of treatment that may be advantageous to the subject. Enough detail must be presented so that the subject can understand and appreciate the nature of any alternatives. It is not sufficient simply to state that “the doctor will discuss alternatives to participating.”

E. Extent of Confidentiality (required element #5). Informed consent information must describe the extent to which confidentiality of records identifying the subject will be maintained (or not maintained). Research often poses the risk of loss of confidentiality to subjects who participate. Many persons who would not otherwise be privy to identifiable, private information about the subject may be involved in the research process. Consent information should describe any procedures that the research team will use to protect subjects’ private records. However, the informed consent information must emphasize the loss of confidentiality that is expected (e.g., study sponsor, FDA, OHRP, IRB) and indicate the other, unanticipated loss of confidentiality might occur despite the best efforts of the investigator.

F. Contact Information (required element #7). Informed consent information must include details, including telephone numbers, about whom to contact.

G. Voluntary Participation Statement (required element #8). Informed consent information must contain clear statements of the following:

i. Participation in the research is voluntary.

ii. Refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled.

iii. The subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

It is particularly important for subjects and prospective subjects to understand and have complete confidence that declining to participate in research will not jeopardize their standing.

H. Additional Elements Where Appropriate. Where appropriate, the regulations require that one or more of the following six additional elements be included in the informed consent information.

1. Unforeseeable Risks. Some research involves particular procedures or interventions that may result in unforeseeable risks to subjects. For research of such a nature, the informed consent information must warn subjects that there may be risks that are not known or not foreseeable.

2. Investigator-Initiated Termination of Participation. There may be instances that would require investigators to terminate the participation of particular subjects (e.g., subject noncompliance with research, subject not benefiting from direct-benefit research). The informed consent information should specify these circumstances.

3. Additional Costs. If subjects must bear any additional costs (transportation, time away from work, health costs, etc.), these must be disclosed in the informed consent information.

4. Early Withdrawal/Procedures for Termination. Subjects have the right to withdraw from the research. However, some studies involve medications or procedures that would be dangerous for subjects to discontinue abruptly. For studies of this nature, the informed consent information must provide subjects with knowledge of the consequences affecting a decision to withdraw. In addition, if there are procedures regarding how to withdraw safely from the research, these must also be described. It is not appropriate for research staff to administer any additional research- oriented questionnaires or interventions that do not affect the safety of subjects who have decided to withdraw.

5. Significant New Findings. Subjects will be informed of any new knowledge or findings about the medication or test article and/or the condition under study that may affect the risks or benefits to subjects or subjects’ willingness to continue in the research.

6. Approximate Number of Subjects. For certain types of research, the informed consent information should disclose the approximate number of subjects to be enrolled.