The IRB will review and ensure that University of Virginia research involving human subjects meets all required ethical and regulatory criteria for initial and continuing review and any modifications of approved research. The IRB may conduct their review using the following review methods:

• Expedited Review
• Review by Convened IRB (Full Board Review)

The following describe the procedures required for the review of research by the University of Virginia IRB. (See section 9 for a description of the procedures for review of research by non– University of Virginia IRBs.)

Definitions

Minimal Risk. Minimal risk means that 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.

Minor Change. A minor change is one which, in the judgment of the IRB reviewer, makes no substantial alteration in:

1. The acceptability of the risk-to-benefit analysis or increases the level of risks to subjects
2. The research design or methods (adding procedures that are not eligible for expedited review (See Section 7.2.2) would be considered more than a minor change)
3. The number of subjects enrolled in the research (if not significant in the number increased usually not greater than 10% of the total requested locally)
4. The qualifications of the research team
5. The facilities available to support safe conduct of the research
6. Any other factor which would warrant review of the proposed changes by the convened IRB

Quorum. A quorum of the IRB consists of a majority (more than half) of the voting membership, including at least one member whose primary concern is in a non-scientific area. When research involving an investigational new drug is on the agenda for review, a physician should be included in the quorum.

Suspension of IRB approval. A suspension of IRB approval is a directive of the IRB to temporarily stop some or all previously approved research activities. Suspended research studies remain open and require continuing review. Investigators must continue to provide reports on adverse events and unanticipated problems to both the IRB and sponsors just as if there had never been a suspension (i.e., all events that need to be reported during a study need to continue to be reported during the suspension period). If a suspension is lifted and IRB approval of the suspended research study has expired; a continuing review is required before the study may resume.

Termination of IRB approval. Termination of IRB approval is a directive of the convened IRB to permanently stop all activities in a previously IRB approved research study. Terminated research studies are closed and no longer require continuing review.

Expedited Review

An IRB may use the expedited review procedure to review either or both of the following:

1. Some or all the research appearing on the list of categories of research eligible for expedited review and found by the reviewer(s) to involve no more than minimal risk.
2. Minor changes in previously approved research during the period (of one year or less) for which approval is authorized. Note: review of minor changes does not alter the end- date of study approval.

The standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review--expedited or convened--used by the IRB.

Categories of Research Eligible for Expedited Review

The University of Virginia applies the categories of research eligible for expedited review, which were published in the Federal Register notice 63 FR 60364-60367, November 9, 1998.

The activities listed below should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.

The categories in this list apply regardless of the age of subjects, except as noted in category 2.

The expedited review procedure may not be used where identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the subjects financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal.

The expedited review procedure may not be used for classified research involving human subjects.

Research Categories one (1) through seven (7) may be used for both initial and continuing IRB review:

1. Clinical studies of drugs and medical devices only when condition (a) or (b) is met.
   1. Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)
   2. Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.
2. Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:
   1. from healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8-week period and collection may not occur more frequently than 2 times per week; or
   2. from other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8-week period and collection may not occur more frequently than 2 times per week. (Note: Children are defined as "persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.)

3. Prospective collection of biological specimens for research purposes by noninvasive means.

   Examples: (a) hair and nail clippings in a non-disfiguring manner; (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) un-cannulated saliva collected either in an unstimulated fashion or stimulated by chewing gum base or wax or by applying a dilute citric solution to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization (k) vaginal swabs that do not go beyond the cervical os; rectal swabs that do not go beyond the rectum; and nasal swabs that do not go beyond the nares.

4. Collection of data through noninvasive procedures, not involving general anesthesia or sedation, routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Note: Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

   Examples: (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject’s privacy; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, Doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.

5. Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may be exempt from the DHHS regulations for the protection of human subjects. See Exempt Categories and 45 CFR 46 101(b)(2) and b(3). This listing refers only to research that is not exempt.)
6. Collection of data from voice, video, digital, or image recordings made for research purposes.

7. Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior); or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (NOTE: Some research in this category may be exempt from the DHHS regulations for the protection of human subjects. See Exempt Categories and 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)

   Categories 8 and 9 apply only to continuing review.

8. Continuing review of research previously approved by the convened IRB as follows:
   1. Where (i) the research at University of Virginia is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects (Note: “Long-term follow-up” includes research interactions that involve no more than minimal risk to subjects (e.g., quality of life surveys); and collection of follow-up data from procedures or interventions that would have been done as part of routine clinical practice to monitor a subject for disease progression or recurrence, regardless of whether the procedures or interventions are described in the research study, but not interventions that would not have been performed for clinical purposes, even if the research interventions involve no more than minimal risk.); or
   2. Where no subjects have ever been enrolled at University of Virginia and no additional risks have been identified (Note: “no additional risks have been identified” means that neither the investigator nor the IRB has identified any additional risks from any institution engaged in the research project or from any other relevant source since the IRB’s most recent prior review.); or
   3. Where the remaining research activities at University of Virginia are limited to data analysis. (Note: Simply maintaining individually identifiable private information without using, studying, or analyzing such information is not human subject research and thus does not require continuing review.
9. Continuing review of research previously approved by the IRB at a convened meeting that meets the following conditions:
   1. The research is not conducted under an investigational new drug application (IND) or an investigational device exemption (IDE);
   2. Expedited review categories (2) through (8) do not apply to the research;
   3. The IRB has determined and documented at a convened meeting that the research, or the remaining research activity involving human subjects, involves no greater than minimal risk to the subjects; and
   4. No additional risks of the research have been identified. (Note: “no additional risks have been identified” means that neither the investigator nor the IRB has identified any additional risks from any institution engaged in the research project or from any other relevant source since the IRB’s most recent prior review.)

Expedited Review Procedures

Under an expedited review procedure, the review may be carried out by the IRB Chair or by a designated experienced IRB member from among members of the IRB Board. IRB members who serve as designees to the IRB Chair for expedited review will be matched with their field of expertise to the study when possible.

The IRB members are eligible to conduct expedited review. The designee must be an experienced (having been employed by the IRB for at least 6 months and/or have recent experience serving as an IRB member) voting member or alternate member of the IRB. Selected reviewers will have the qualifications, experience, and knowledge in types of research to be reviewed, as well as be knowledgeable of the requirements to approve research under expedited review. IRB members with a conflict of interest in the research (see Section 21.2) will not be selected.

When reviewing research under an expedited review procedure, the IRB Chair, or designated IRB member(s), will receive and review all documentation that would normally be submitted for a full-board review. This requirement applies to all categories of submissions including initial reviews, continuing reviews, and modifications. The reviewer determines and documents the regulatory criteria allowing use of the expedited review procedure in applicable review checklists and/or in the IRB’s electronic system. The reviewer(s) will complete the appropriate review checklist to determine whether the research meets the regulatory criteria for approval. The same criteria of approval apply to reviews conducted via expedited review as to those conducted by the convened board. If the research does not meet the criteria for expedited review, then the reviewer will indicate that the research requires full review by the IRB and the research study will be placed on the next available agenda for an IRB meeting.

In reviewing the research, the reviewers will follow the Review Procedures described in Sections 7.2 and 7.4 and may exercise all the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non-expedited procedure by the convened IRB (see Section 7.3).

If the reviewer determines the research may be approved, the reviewer documents that the research meets the regulatory criteria using the Review form/online system for approval and proceeds with the approval.

If modifications are required, the reviewer or responsible IRB staff member will notify the investigator via email /the IRB electronic system.

If expedited review is carried out by more than one IRB member and the expedited reviewers disagree, the IRB Chair may make a final determination, or the study will be referred to the convened IRB for review.

Informing the IRB

All members of the IRB will be apprised of all expedited review approvals by means of a list in the agenda for the next scheduled meeting. Any IRB member can request to review any study by contacting the IRB Office.

Convened IRB Meetings

Except when an expedited review procedure is used, the IRB will conduct initial and continuing reviews of all non-exempt research at convened meetings at which a quorum (see below) of the members is present.

IRB Meeting Schedule

The IRB meets on a regular basis throughout the year. The schedule for the IRB may vary due to holidays or lack of quorum. The schedule for IRB meetings is posted on the IRB websites Ad hoc meetings may be called at any time by the Chair, IRB Director or the HRPP Directors.

Pre-Review

Qualified IRB Staff will perform a pre review of all submissions for determination of completeness, accuracy, and compliance with regulations and university policies. Only complete submissions will be placed on the IRB agenda for review. The investigator will be informed either electronically, by phone, or in person of the missing materials and the necessary date of receipt for inclusion on the agenda. If an investigator is submitting for the first time or is not well-versed in the submission procedures, consultations can be arranged with IRB staff.

Primary and Secondary Reviewers

After it has been determined that the submission is complete, an IRB Staff member (with the assistance of the IRB Chair as needed), will assign submissions for review, paying close attention to the subject matter of the research, the potential reviewer’s area(s) of expertise and representation for any vulnerable populations involved in the research. Primary and secondary reviewers will be assigned to each submission and receive and review the full submission materials. Reviewers may be assigned several submissions or other items for review. When the IRB is presented with a research study which may be outside of the knowledge base or representative capacity of the IRB members, an outside consultant will be sought (See Section 4.5). Research studies for which appropriate expertise cannot be obtained for a given meeting will be deferred to another meeting when appropriate expertise is available.

Primary and secondary reviewers are responsible for:

1. Having thorough knowledge of all the details of the proposed research.
2. Performing an in-depth review of the proposed research.
3. Beginning the discussion of the proposed research at the convened meeting, by summarizing the proposed research, and leading the IRB through the regulatory criteria for approval. (See Section 7.4).
4. Making suggestions for changes to the proposed research, where applicable.
5. Completing all applicable IRB reviewer forms or certifications.

Secondary reviewers are paired with a primary reviewer for each submission. A secondary reviewer may be assigned to review the full submission materials or may be asked to review specified sections of the submission (e.g., the consent/assent/permission forms).

All IRB members receive and are expected to review all studies, not just those assigned as primary and secondary reviewers.

When it can be anticipated that the primary reviewer may be absent from the meeting, a new primary reviewer may be assigned, providing that they have sufficient time to review the materials in advance of the meeting. Additionally, an absent reviewer can submit their written comments for presentation at the convened meeting. A secondary reviewer may serve as primary reviewer in a given meeting. If an absent reviewer submits comments, those can indicate a recommendation regarding approval, but such recommendation will not be counted as a vote.

Materials received by the IRB

All required materials need to be submitted to the IRB office 6-10 business days prior to the convened meeting for inclusion on the IRB agenda. The meeting agenda will be prepared by the IRB Staff in consultation as needed with the IRB Director and/or IRB Chair. All IRB members receive the IRB agenda and research submission materials no later than 4-10 business days before the scheduled meeting to allow sufficient time for the review process.

Each IRB member receives and reviews the following documentation, as applicable, for all studies on the agenda:

• Research protocol
• IRB Study Application
• Consent/parental or guardian permission/assent forms, letters, or scripts
• Recruitment materials including advertisements intended to be seen or heard by potential subjects
• Supporting documents such as training documentation, interview guides, surveys, or other data collection tools
• Data Security Plan
• Ancillary review documentation
• Investigator brochure(s)

Additionally, for DHHS-supported multi-site clinical trials, the primary reviewer should receive and review a copy of the DHHS-approved sample informed consent document(s) and the complete DHHS-approved protocol/research plan (if available).

If an IRB member requires additional information to complete the review, they may contact the investigator directly or may ask the IRB Office to request information from the investigator.

Reviewers will use an IRB reviewer checklist as a guide to complete their review.

Quorum

A quorum of the IRB consists of a majority (more than half) of the voting membership, including at least one member whose primary concern is in a non-scientific area. When research involving an investigational new drug is on the agenda for review, a physician should be included in the quorum. At meetings of the IRB, a quorum must be established and maintained for the deliberation and vote on all matters requiring a vote.

The IRB Chair, with the assistance of the IRB staff, will confirm that quorum is present before calling the meeting to order. The IRB Chair, with the assistance of the IRB staff, will be responsible to ensure that the IRB meeting remains appropriately convened. If a quorum is not maintained, either by losing a majority of the members, losing all non-scientific members or another required member, the IRB cannot take further actions or vote on regulatory determinations until quorum is restored, even if half of the members are still present.

The IRB Staff will document the arrival and departure for all IRB members and notify the IRB Chair if a quorum is not present. Attendance and vote count are documented or monitored by the IRB staff for each study. It is generally expected that at least one unaffiliated member and at least one member who represents the general perspective of participants (one individual can serve in both capacities) will be present at all IRB meetings. The IRB may, on occasion, meet without this representation; however, this should be the exception.

If the IRB regularly reviews research that involves a vulnerable category of subjects, such as children, prisoners, pregnant women, or persons with impaired decision-making capacity, one or more individuals (e.g., IRB members, alternate members, or consultants) who are knowledgeable about and experienced with those subjects should be present during the review of the research.

When the IRB is presented with a research study which may be outside of the knowledge base or representative capacity of the IRB members, an outside consultant will be sought. Research studies for which appropriate expertise cannot be obtained for a given meeting will be deferred to another meeting when appropriate expertise is available.

IRB members are considered present and participating at a duly convened IRB meeting when either physically present or participating through electronic means (e.g., teleconferencing or video conferencing) that permits them to listen to and speak during IRB deliberations and voting. Whether or not physically present, the IRB member must have received all pertinent materials prior to the meeting and must be able to participate actively and equally in all discussions.

Opinions of absent members that are transmitted by mail, telephone, facsimile or e-mail may be considered by the attending IRB members but may not be counted as votes or to satisfy the quorum for convened meetings.

Meeting Procedures

The IRB Chair will call the meeting to order, once it has been determined that a quorum is in place. The Chair will remind IRB members to recuse themselves from the discussion and votes by leaving the room when they have a conflict.

The IRB reviews all submissions for initial and continuing review, as well as requests for modifications. The Primary Reviewer presents an overview of the research and assists the Chair in leading the IRB through the discussion of the regulatory criteria for approval. For the research to be approved, it must receive the approval of a majority of those voting members present at the meeting.

The IRB Staff take notes of the proceedings and are responsible for preparing the meeting minutes.

Guests

Investigators and research staff may be invited to the IRB meeting, at the discretion of the IRB, to make a brief presentation or to answer questions about proposed or ongoing research. The investigator/research staff may not be present for the deliberations or vote on the research.

The IRB Directors and staff regularly attend IRB meetings and may participate in the IRB discussion and deliberations but may not vote unless they are serving as an IRB member for the meeting.

Other guests may be permitted to attend IRB meetings at the discretion of the IRB Chair or IRB Staff. Such guests may be asked to sign a confidentiality agreement and do not participate in discussion unless requested by the IRB, under no circumstances may they vote.

Criteria for IRB Approval of Research

For the IRB to approve human subjects research, either through expedited review or by the convened IRB, it must determine that the following requirements are satisfied. These criteria apply to all categories of IRB reviews including initial reviews, continuing reviews, and modifications of previously approved research.

1. Risks to subjects are minimized: (i) by using procedures which are consistent with sound research design, and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
2. Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.
3. Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disable persons, or economically or educationally disadvantaged persons.
4. Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with, and to the extent required by the Federal Regulations [45 CFR 46.116].
5. Informed consent will be appropriately documented, in accordance with, and to the extent required by the Federal Regulations [45 CFR 46.117].
6. When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
7. When appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.
8. When some or all the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these subjects.

Risk/Benefit Assessment

The goal of the assessment is to ensure that the risks to research subjects posed by participation in the research are justified by the anticipated benefits to the subjects or society. Toward that end, the IRB must:

• Judge whether the anticipated benefit, either of new knowledge or of improved health or other direct benefit for the research subjects, justifies asking any person to undertake the risks; and
• Disapprove research in which the risks are judged unreasonable in relation to the anticipated benefits.

The assessment of the risks and benefits of proposed research involves a series of steps:

1. Identify the risks associated with the research, as distinguished from the risks of activities, diagnostic tests, treatments, or therapies the subjects would receive even if not participating in research;
2. Determine whether the risks will be minimized to the extent possible by evaluating the necessity of procedures that impart risk and whether the data could be gained by procedures that are already being performed for other purposes or by alternative procedures that impart less risk;
3. Identify the anticipated benefits to be derived from the research, both direct benefits to subjects and possible benefits to society, science and others;
4. Determine whether the risks are reasonable in relation to the benefits, if any, and assess the importance of the knowledge to be gained;

In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research - as distinguished from risks and benefits subjects would receive even if not participating in the research.

In addition to evaluation of the risks in the research, the IRB determines, based on the materials submitted by the investigator, that research studies have the resources necessary to protect participants, such as adequate time for the researchers to conduct and complete the research, adequate number of qualified staff, adequate facilities, access to a population that will allow recruitment of the necessary number of participants, availability of medical or psychosocial resources that participants might need as a consequence of the research.

The IRB should not consider possible long-range effects of applying knowledge gained in the research (e.g., the possible effects of the research on public policy) as among those research risks and benefits that fall within the purview of its responsibility.

Scientific or Scholarly Review

To assess the risks and benefits of the proposed research, the IRB must determine that:

• The research uses procedures consistent with sound research design; and
• The research design is sound enough to reasonably expect the research to answer its proposed question.

In making this determination, the IRB may draw on its own knowledge and expertise, or the IRB may draw on the knowledge and expertise of others, such as reviews by a funding agency, or departmental review. When scientific or scholarly review is conducted by a consultant, an individual or entity external to the IRB, documentation that the above questions were considered must be provided to the IRB for review and consideration. Scientific or scholarly review is documented and provided to the IRB via written documentation. This type of consultation is key to providing the IRB with specialized information to better understand the risks and benefits associated with the proposed research.

Scientific or scholarly review can be delegated to a departmental or other appropriate review committee.

Equitable Selection of Subjects

The IRB determines by reviewing the application, protocol/research plan and other materials that the selection of subjects is equitable with respect to gender, age, class, ethnicity, etc. The IRB will not approve a study that does not provide adequately for the equitable selection of subjects or has not provided an appropriate scientific and ethical justification for excluding classes of persons who might benefit from the research. In making this determination, the IRB evaluates:

• The purposes of the research;
• The setting in which the research occurs;
• Scientific and ethical justification for including vulnerable populations such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons;
• The scientific and ethical justification for excluding classes of persons who might benefit from the research; and
• The inclusion/exclusion criteria, and the procedures/materials intended for use for the identification and recruitment of potential subjects.

Recruitment of Subjects

The investigator will provide the IRB with a plan for recruitment of all potential subjects for approval. All recruiting materials will be submitted to the IRB, including advertisements, flyers, scripts, letters, information sheets and brochures. The IRB should ensure that the recruitment plan and materials appropriately protect the rights and welfare of the prospective subjects (e.g., do not present undue influence). See Section 7.5.10 for a discussion of IRB review of advertisements and Section 7.5.11 for a discussion of IRB review of payments.

Informed Consent

The IRB will ensure that informed consent will be sought from each prospective subject or the subject’s legally authorized representative, in accordance with, and to the extent required by 45 CFR 46.116 and 21 CFR 50.20. In addition, the IRB will ensure that informed consent will be appropriately documented, in accordance with, and to the extent required by 45 CFR 46.117 and 21 CFR 50.27. The IRB will ensure, as part of its review, that the information in the consent document and process is consistent with the research plan, and, when applicable, the HIPAA authorization. See Section 11 below for detailed policies on informed consent.

Data and Safety Monitoring

For all research that is more than minimal risk, the investigator should submit a data and safety monitoring plan. The initial plan submitted to the IRB should describe the procedures for safety monitoring, reporting of unanticipated problems involving risks to subjects or others, descriptions of interim safety reviews and the procedures planned for transmitting the monitoring results to the IRB. This description should include information regarding an independent Data and Safety Monitoring Board (DSMB), if one exists, or an explanation why an independent data safety monitor is not necessary.

The IRB reviews the safety monitoring plan and determines if it makes adequate provision for monitoring the reactions of subjects and the collection of data to ensure the safety of subjects and to address problems that may arise over the course of the study. If a plan was not submitted, the IRB determines whether a plan is required, and, depending on the circumstances, what the plan should include. The overall elements of the monitoring plan may vary depending on the potential risks, complexity, and nature of the research study.

The factors the IRB will consider in determining whether the safety monitoring plan is adequate for the research are as follows:

1. Monitoring is commensurate with the nature, complexity, size and risk involved.
2. Monitoring is timely. Frequency should be commensurate with risk. Conclusions are reported to the IRB.
3. For low-risk studies, continuous, close monitoring by the study investigator or an independent individual may be an adequate and appropriate format for monitoring, with prompt reporting of problems to the IRB, sponsor and regulatory bodies as appropriate.
4. Data and Safety Monitoring plans should specify:
   1. The entity or person(s) who will perform the monitoring, and the independence or affiliation that the entity or person(s) has with the sponsor or investigator
   2. The safety information that will be collected and monitored, including serious adverse events and unanticipated problems
   3. The frequency or periodicity of review of safety data
   4. The procedures for analysis and interpretation of the data
   5. The procedures for review of scientific literature and data from other sources that may inform the safety or conduct of the study
   6. The conditions that trigger a suspension or termination of the research (i.e., stopping rules), if applicable
   7. The procedures for reporting to the IRB, including a summary description of what information, or the types of information, that will be provided
5. For a Data Safety Monitoring Board (DSMB) or Data Monitoring Committee (DMC), the plan should describe:
   1. The composition of the board or committee. Generally, a DSMB should be composed of experts in all scientific disciplines needed to interpret the data and ensure subject safety. Clinical trial experts, biostatisticians, bioethicists, and clinicians knowledgeable about the disease/condition and treatment under study should be part of the monitoring group or be available if warranted.
   2. Frequency and content of meeting reports
   3. The frequency and character of monitoring meetings (e.g., open or closed, public or private)
   4. The Charter should be provided, when one exists

In general, it is desirable for a DSMB or DMC to be established by the study sponsor for research that is blinded, involves multiple sites, involves vulnerable subjects, or employs high- risk interventions. For some studies, the National Institutes of Health (NIH) require a DSMB. The IRB has the authority to require a DSMB or DMC as a condition for approval of research where it determines that such monitoring is needed. When DSMBs or DMCs are used, IRBs conducting continuing review of research may rely on a current statement, or the most recent report, from the DSMB or DMC which indicates that it has and will continue to review study-wide adverse events, study wide interim findings, and any recent literature that may be relevant to the research, in lieu of requiring that this information be submitted directly to the IRB.

Privacy and Confidentiality

The IRB will determine whether adequate procedures are in place to protect the privacy of subjects and to maintain the confidentiality of the data.

Definitions

Privacy. Having control over the extent, timing, and circumstances of sharing oneself (physically, behaviorally, or intellectually) with others. It is the state or condition of being free from unauthorized intrusion, being observed or disturbed by other people.

Confidentiality. Methods used to ensure that information obtained by investigators about subjects is not improperly divulged.

Private information. Information that has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record).

Sensitive Information. data or information, on any storage media or in any form or format, which requires protection due to the risk of harm that could result from inadvertent or deliberate disclosure, unauthorized access, misuse, alteration, or loss or destruction of the information (e.g., could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subject’s financial standing, employability, or reputation).

Identifiable information. Information where the identity of the subject is or may readily be ascertained by the investigator or associated with the information.

Privacy

The IRB must determine whether the activities in the research appropriately protect the privacy of potential and actual subjects. To make that determination, the IRB must obtain information

regarding how the investigators plan to access subjects or subjects’ private, identifiable

information and the subjects’ expectations of privacy in the situation. Investigators must have appropriate authorization to access the subjects or the subjects’ information.

In developing strategies for the protection of subjects’ privacy, consideration is given to:

1. Methods used to identify and contact potential participants
2. Settings in which an individual will be interacting with an investigator
3. Appropriateness of all personnel present for research activities
4. Methods used to obtain information about participants, and the nature of the requested information including minimizing the information obtained to achieve the aims of the research
5. Information that is obtained about individuals other than the “target subjects,” (e.g., a subject provides information about a family member for a survey) and whether such individuals meet the regulatory definition of “human subject”

Confidentiality

The IRB must determine if appropriate protections are in place to minimize the likelihood that information about subjects will be inappropriately divulged. Safeguards designed to protect confidentiality should be commensurate with the potential of harm from unauthorized, inappropriate or unintentional disclosure.

At the time of initial review, continuing review and with any requests for modification, the IRB assesses whether there are adequate provisions to protect data confidentiality. The IRB does this through the evaluation of the methods used to obtain, record, share, and store information about individuals who may be recruited to participate in studies and about subjects. The investigator will provide the IRB with a plan regarding the procedures to be taken to protect the confidentiality of research data and sensitive information. Additionally, the investigator will provide information regarding information security procedures and plans to address the protection of paper documents, other physical media (e.g., audio or videotapes), and electronic data and information including the use, maintenance, storage, and transmission of information. The IRB will review all information received from the investigator and determine whether the confidentiality of research data is sufficiently protected. In some cases, the IRB may also require that a Certificate of Confidentiality be obtained to additionally protect research data (See Section 25.8) and/or obtain approval from the University of Virginia Information Security Office (InfoSec).

In reviewing confidentiality protections, the IRB shall consider whether the data or other information accessed or gathered for research purposes is sensitive and the nature, probability, and magnitude of harms that would be likely to result from a disclosure of collected information outside the research. The IRB in consultation with the InfoSec staff shall evaluate the effectiveness of proposed de-identification techniques, coding systems, encryption methods, methods of transmission, storage facilities, access limitations, and other relevant factors in determining the adequacy of confidentiality protections. In reviewing confidentiality protections, the IRB and the InfoSec staff shall also consider regulations and organizational requirements and policies regarding the use of information and information security.

Research regulated by the FDA that involves the use of electronic data collection/storage systems must comply with the requirements of 21 CFR Part 11.

Vulnerable Populations

Certain individuals, by nature of their age or mental, physical, economic, educational, or other situation, may be more vulnerable to coercion or undue influence than others. At the time of initial review, the IRB will consider the scientific and ethical reasons for including vulnerable subjects in research. The IRB may determine and require that, when appropriate, additional safeguards be put into place for vulnerable subjects, such as those without decision-making capacity.

For an extensive discussion about the IRB’s review and approval process for individual

populations of vulnerable subjects, please refer to Section 12.

Additional Considerations

Determination of Risk

At the time of initial and continuing review, the IRB will make a determination regarding the risks associated with the research plan. Risks associated with the research will generally be classified as either “minimal” or “greater than minimal” with additional classifications as required by the various subparts or FDA regulations. Risk determinations may vary over the life of a research plan depending on the procedures and risks that subjects will be exposed to as the research progresses. The level of risk associated with the research influences eligibility for expedited review. The meeting minutes will reflect the convened IRB’s determination regarding risk levels; expedited reviewers will document the determination of risk level on the IRB reviewer form or certification checklist.

Period of Approval

At the time of initial review and at continuing review, the IRB will make a determination regarding the period of approval. All non-exempt studies will be reviewed by the IRB at intervals appropriate to the degree of risk but no less than once per year. In some circumstances, a shorter review interval (e.g., semi-annually, quarterly, or after accrual of a specific number of participants) may be required (see below). The meeting minutes will reflect the convened IRB’s determination regarding review frequency; expedited reviewers will document the determination of risk level on the IRB reviewer or certification checklist.

IRB approval is considered to have lapsed at midnight on the expiration date of the approval (i.e., the expiration date is the last day research can be conducted). For a new study reviewed by the IRB, the approval commences on the date that the IRB conducts its final review of the study; that is, the date that the convened IRB or expedited reviewer approves the research or the date that it is verified that the requirements of the IRB have been satisfied following an

action of “Conditions Required for Approval”. The expiration date of the initial approval period, which is the date by which the first continuing review must occur, may be as late as one year after the last determination of approval or approvable with conditions.

For all continuing reviews of a research study subject to convened board review, the date the convened IRB or the date that the expedited reviewer conducts continuing review and approves the study (with or without conditions) determines the latest permissible date of the next continuing review.

The approval date and approval expiration date are clearly noted on IRB determination letters and must be strictly adhered to. Investigators should allow sufficient time for development and review of continuing review submissions..

IRB review of a proposed modification to research ordinarily does not alter the date by which continuing review must occur. This is because continuing review is review of the full research project, not simply a change to it.

The regulations make no provision for any grace period extending the conduct of research beyond the expiration date of IRB approval. Therefore, continuing review and re-approval of research must occur by midnight of the date when IRB approval expires. If the IRB performs continuing review within 30 days before the IRB approval period expires, the IRB may retain the anniversary date as the date by which the continuing review must occur.

Review More Often Than Annually

The following factors will be considered when determining which studies require review more frequently than on an annual basis:

• The probability and magnitude of anticipated risks to subjects.
• The likely medical/psychological/social/legal/educational condition of the proposed subjects.
• The overall qualifications of the investigator and other members of the research team.
• The specific experience of the investigator and other members of the research team in conducting similar research.
• The nature and frequency of adverse events observed in similar research at this and other institutions.
• The novelty of the research increasing the likelihood of unanticipated adverse events/unanticipated problems.
• The involvement of especially vulnerable populations likely to be subject to undue influence or coercion (e.g., terminally ill)
• A history of serious or continuing non-compliance on the part of the investigator.
• 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 either studied or enrolled. 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 one year 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 one year. If an approval period of less than one year is specified by the IRB, the reason for more frequent review must be documented in the minutes, the reviewer’s checklist or electronic comments.

Independent Verification That No Material Changes Have Occurred

The IRB recognizes that protecting the rights and welfare of subjects sometimes requires that the IRB use sources other than the investigator to independently verify that no material changes occurred during the IRB-designated approval period.

The IRB will determine the need for verification from outside sources on a case-by-case basis. The following factors will be considered when determining which studies require independent verification:

• The probability and magnitude of anticipated risks to subjects.
• The likely medical/psychological/social/legal/educational condition of the proposed subjects.
• The probable nature and frequency of changes that may ordinarily be expected in the type of research proposed.
• Concern about possible material changes occurring without IRB approval have been raised based on information provided in continuing review reports or from other sources.
• Investigators who have previously failed to comply with federal regulations and/or the requirements or determinations of the IRB.
• Research without a routine monitoring plan.
• Any other factors the IRB deems verification from outside sources is relevant.

In making determinations about independent verification, the IRB may prospectively require that such verification take place at predetermined intervals during the approval period or may require such verification at the time of continuing review, review of modification requests and/or unanticipated problems.

If any material changes have occurred without IRB review and approval, the IRB will decide the corrective action to be taken (see Section 16 on Non-compliance).

Consent Monitoring

In reviewing the adequacy of informed consent procedures for proposed research, the IRB may on occasion determine that special monitoring of the consent process by an impartial observer (e.g., consent monitor) is required to reduce the possibility of coercion and undue influence, ensure that the approved consent process is being followed, or ensure that subjects are truly giving informed consent.

Such monitoring may be particularly warranted for:

• High risk studies;
• Studies that involve particularly complicated procedures or interventions;
• Studies involving highly vulnerable populations (e.g., ICU patients, children who are wards);
• Studies involving study staff with minimal experience in administering consent to potential study participants; or
• Other situations when the IRB has concerns that consent process may not be/is not being conducted appropriately (e.g., prior investigator non-compliance, etc.).

Monitoring may also be appropriate as a corrective action where the IRB has identified problems associated with a particular investigator or a research project.

If the IRB determines that consent monitoring is required, the IRB Members will determine the requirements for consent monitoring. The consent monitoring may be conducted by University of Virginia Post Approval Monitoring (PAM) Staff or other institutional research compliance staff and/or educator(s). The investigator and PAM Office will be notified of the IRB’s determination and the reasons for the determination. PAM or other compliance staff will make arrangements with the investigator for the monitoring of the consent process, typically for a specified number of subjects. When observing the consent process, the monitor will determine:

• Whether the informed consent process was appropriately conducted and documented;
• Whether the participant had sufficient time to consider study participation;
• Whether the consent process involved coercion or undue influence;
• Whether the information was accurate and conveyed in understandable language; and
• Whether the subject appeared to understand the information and gave their voluntary consent.

Following the monitoring, a report of the findings will be submitted to the IRB, which will determine the appropriate action to be taken.

Investigator Qualifications

The IRB research application asks specific questions regarding the investigator and research team’s credentials to determine whether investigators and members of the research team are appropriately qualified to conduct the research. The IRB may rely upon other University of Virginia processes (e.g., credentialing) to inform this determination.

Investigator Conflicts of Interest (COI)

The IRB research application includes specific questions regarding the investigator and the research team’s compliance with disclosure requirements and whether any COI management plans are in place. As part of its review process, the IRB will make a final determination as to whether any conflict of interest is adequately addressed and protects the human subjects in the research. The IRB has final authority to determine whether the declared COI and the management plan, if any, allow the study to be approved. (See Section 21 for a more detailed discussion of COI)

Institutional Conflicts of Interest

As with individual conflict of interest, the IRB has final authority to determine whether the Institutional Conflict, the Financial Interest, and the management plan, if any, allow the study to be approved. See Section 21.3 for a more detailed discussion of Institutional COI.

Significant New Findings

During the course of research, significant new knowledge or findings about the research, the test article, and/or the condition under study may develop. The investigator must report any significant new findings to the IRB and the IRB will review them with regard to the impact on the subjects’ rights and welfare. Because the new knowledge or findings may affect the risks or benefits to subjects or subjects' willingness to continue in the research, the IRB may require, during the ongoing review process, that the investigator contact the currently enrolled subjects to inform them of the new information. The IRB will communicate this requirement to the investigator. If the study is still enrolling subjects, the consent document should be updated.

IRB may require that the currently enrolled subjects be re-consented or otherwise provided with the new information. The IRB may also require that former subjects be provided with new information, e.g., if it impacts their rights or welfare.

Advertisements and Recruitment Materials

The IRB must review and approve all advertisements prior to posting and/or distribution for studies that are conducted under the purview of the University of Virginia. The IRB will review:

• The information contained in the advertisement.
• The mode/method of its communication.
• The final text and images that will be utilized for advertisements, with the exception of changes from UVA Branding and Marketing.
• The proposed script and final audio/video taped advertisements.

This information should be submitted to the IRB with the initial application or, if recruitment is proposed after study approval, as a modification request.

The IRB reviews the material to assure that the material is accurate and is not coercive or unduly optimistic, creating undue influence on the subject to participate. This includes but is not limited to:

• Statements implying a certainty of favorable outcome or other benefits beyond what was outlined in the consent document and the research plan.
• Claims, either explicitly or implicitly, that the test article (drug, biologic or device) is safe or effective for the purposes under investigation.
• Claims, either explicitly or implicitly, that the test article was known to be equivalent or superior to any other drug, biologic or device.
• Using terms like “new treatment,” “new medication,” or “new drug” without explaining that the test article was investigational.
• Promising “free medical treatment” when the intent was only to say participants will not be charged for taking part in the investigation.
• Emphasis on payment or the amount to be paid, such as bold type or larger font on printed media.
• Offers for a coupon good for a discount on the purchase price of an investigational product once it has been approved for marketing.
• The inclusion of exculpatory language.

Recruitment materials 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:

• The name and address of the investigator and/or research facility.
• The condition being studied and/or the purpose of the research.
• In summary form, the criteria that will be used to determine eligibility for the study.
• The time or other commitment required of the subjects.
• The location of the research and the person or office to contact for further information.
• A clear statement that this is research and not treatment.
• A brief list of potential benefits (e.g., no-cost health exam).
• Approved IRB study number.

Once approved by the IRB, an advertisement cannot be altered or manipulated in any way without prior IRB approval, with the exception of changes from UVA Branding and Marketing.

Directory listings of research such as ClinicalTrials.Gov are not considered advertisements and therefore do not require IRB review and approval if the listing is limited to the following basic trial information: title, purpose of the study, research plan summary, basic eligibility criteria, study site location(s), and how to contact the study site for further information.

The first contact prospective study subjects make is often with a person who follows a script to determine basic eligibility for the specific study. The IRB should ensure the procedures followed adequately protect the rights and welfare of the prospective subjects.

Payments to Research Subjects

Payment to research subjects may be an incentive for participation or a way to reimburse a subject for travel and other experiences incurred due to participation. However, payment for participation is not considered a research benefit. Regardless of the form of remuneration, investigators must take care to avoid unduly influencing subjects. The amount of compensation must be proportional to the time and inconvenience posed by participation in the study.

Investigators who wish to pay research subjects must submit to the IRB the amount and schedule of all payments. Investigators should indicate in their research project application the justification for such payment. Such justification should substantiate that proposed payments are reasonable and commensurate with the expected contributions of the subject and do not constitute (or appear to constitute) undue pressure on the potential subject to volunteer for the research study.

The IRB must review both the amount of payment and the proposed method and timing of disbursement to assure that neither entails problems of coercion or undue influence.

Credit for payment should be prorated and not be contingent upon the participant completing the entire study. The IRB does not allow the entire payment to be contingent upon completion of the entire study. Any amount paid as a bonus for completion of the entire study should not be so great that it could unduly induce subjects to remain in the study when they otherwise would have withdrawn.

The consent form must describe the terms of payment including the amount and schedule of payments and any conditions under which subjects would receive partial payment (e.g., if they withdraw from the study before their participation is completed) or no payment.

Unless the study is confidential, the University of Virginia Procurement Office requires identifying information to issue checks, cash, or gift certificates to subjects if total amount exceeds one hundred dollars. The consent form must inform subjects that they may be asked to provide their Social Security Number to receive payment.

Non-Monetary Gifts and Incentives

Like financial incentives, non-monetary gifts or incentives can also present problems of undue influence or coercion that impact a potential subject’s ability to fully and freely consider participation in research.

If subjects are to be provided with non-monetary gifts or tokens of appreciation, such as totes, books, toys, or other such materials, the item and approximate retail value must be submitted to the IRB.

The IRB will review all gifts and incentives, being particularly sensitive to the influence of power or authority, whether perceived or actual, over free decision-making. Overt coercion (e.g., threatening loss of credit, or access to services or programs, to which the potential subjects are otherwise entitled) is never appropriate. Moreover, it must be clear that choosing to not participate will not adversely affect an individual’s relationship with the organization or its staff or the provision of services in any way (e.g., loss of credits or access to programs).

Investigators should carefully structure incentives and methods of disbursement so that while the incentives may serve as a factor in a subject’s decision to participate, that they have not served to unduly influence or coerce participation.

State and Local Laws

The IRB considers and adheres to all applicable state and local laws in the jurisdictions where the research is taking place. The IRB relies on the University of Virginia Counsel for the interpretation and application of Virginia law and the laws of any other jurisdiction where research is conducted as they apply to human subjects research. The IRB will ensure that consent forms are consistent with applicable state and local laws.

Possible IRB Actions

Approval The initial research submission, proposed modification to previously approved research, or continuation of previously approved research is approved. The IRB has made all the determinations required for approval [i.e., approval criteria and any applicable special determinations (e.g., waivers, alterations, vulnerable population determinations, etc.)]. No further action is needed. The board will move to approve actions like determinations, acknowledgements or other corrective action plans.

Approvable with Conditions The research, proposed modification to the previously approved research, or other item is approved but conditions must be satisfied before the approval becomes effective.

The IRB may approve research with conditions if, given scope and nature of the conditions, the IRB is able, based on the assumption that the conditions are satisfied, to make all the determinations required for approval [i.e., approval criteria and any applicable special determinations (e.g., waivers, alterations, vulnerable population determinations, etc.)]. Any time the IRB cannot make one or more of the determinations required for approval, the IRB may not approve the study with conditions.

The IRB may require the following as conditions of approval of research:

1. Confirmation of specific assumptions or understanding on the part of the IRB regarding how the research will be conducted (e.g., confirmation that research excludes children);
2. Submission of additional documentation (e.g., certificate of training);
3. Precise language changes to the study, consent, or other study documents; or
4. Substantive changes to the study, consent, or other study documents along with clearly stated parameters that the changes must satisfy.

When the IRB approves research with conditions, the conditions will be documented in the IRB minutes for research reviewed at a convened meeting or in the electronic review system for research reviewed under an expedited review procedure.

When the convened IRB approves research with conditions, the IRB may designate the IRB Chair (and/or other qualified individual(s)) to review responsive materials from the investigator and determine that the conditions have been satisfied. If the conditions have not been satisfied, or are only partially satisfied, or when conditions are refuted, the responsive materials must be referred to the convened IRB for review. When an expedited reviewer approves research with conditions, the original expedited reviewer (and/or other qualified individual(s)) will receive the response materials.

After verification, the following will be documented in IRB records and written communication to the investigator:

• The date when the IRB determined that the criteria for approval were satisfied (i.e., the "approval date");
• The date when verification was made that all IRB conditions have been satisfied (i.e., the “effective date”), and;
• For initial approval and continuing reviews, the date by which continuing review must occur 
• The date of approval is the date the conditions were determined to be met. If the research expires before the conditions are reviewed and approved, all research activities must stop until approval is obtained.

Deferred. (This action is sometimes referred to as tabled.) This action is taken by the IRB when modifications are required (of the nature or amount that the full IRB cannot make or specify exact changes or parameters), or additional information or clarification is needed to determine that one or more criteria for approval are satisfied (e.g., the risks and benefits cannot be assessed with the information provided).

The deferral and the basis for the deferral are documented in the IRB minutes (for convened review) or Reviewer Checklist (for expedited review) and is communicated to the investigator in writing.

When the convened IRB defers approval, the responsive materials from the investigator will be provided to the convened IRB for review at a subsequent meeting.

When an expedited reviewer defers approval, the original expedited reviewer will review the response materials whenever possible. If the original expedited reviewer is unavailable, the response will be reviewed by the IRB Chair or other qualified IRB member who has been designated to conduct expedited review.

Disapproved. The IRB may determine that the proposed research cannot be conducted at University of Virginia or by employees or agents of University of Virginia or otherwise under the auspices of University of Virginia. Disapproval can only be decided at the convened IRB meeting. An expedited reviewer cannot disapprove a study.

Approval in Principle. As per federal regulations, [45CFR46.118], there are circumstances in which a sponsoring agency may require certification of IRB approval as a condition of submitting for or releasing funds but before definitive plans for the involvement of human subjects have been developed (e.g., certain training grants or grants in which the procedures involving human subjects are dependent on the completion of animal studies or instrument development). In these circumstances, the IRB may grant “approval in principle” without having reviewed the as yet undeveloped procedures or materials. The IRB Chair or designee will review the available information (i.e., the grant or proposal and any supplemental information provided by the investigator) and, if appropriate, will provide certification of IRB approval in principle. If the proposal is funded, the investigator must submit such materials for approval at least [60] days before recruiting human subjects into the study, or into any pilot studies or pre- tests.

Continuing Review

The IRB will conduct a continuing review of ongoing research at intervals that are appropriate to the level of risk for each research plan, but not less than once per year. The date by which continuing review must occur will be recorded in the IRB minutes or other IRB records and communicated in writing to the investigator. Continuing review must occur as long as the research remains active including when the remaining research activities are limited to the analysis of private identifiable information.

Continuing Review Process

As a courtesy to investigators, the IRB staff will send out renewal notices to investigators approximately two months and again one month in advance of the expiration date; however, it is the investigator’s responsibility to ensure that the continuing review of ongoing research is approved prior to the expiration date. By federal regulation, no extension to that date can be granted.

Investigators must submit the following for continuing review:

• The current protocol and IRB application
• The current consent document
• The most recent report(s) from the DSMB or DMC (if applicable);
• The most recent multi-site progress report (if applicable);
• Copy of any audits performed during the review period and
• The continuing review status report.

IRB members can request the study file or any additional materials from the IRB staff prior to the meeting or during the expedited review process.

Approval Considerations

To re-approve research at the time of continuing review, the IRB must determine that the regulatory criteria for approval continue to be satisfied. Because the research was previously found to satisfy the criteria for approval, the IRB focuses its considerations at the time of continuing review on whether any new information is available that would affect the IRB’s prior determination that the criteria for approval are satisfied. The IRB pays particular attention to four aspects of the research:

• Risk assessment and monitoring;
• Adequacy of the informed consent process;
• Local investigator and organizational issues;
• and Research progress.

Convened Board Review

In conducting continuing review of research not eligible for expedited review, all IRB members are provided with access to all the materials listed in Section 7.7.2 and are responsible for reviewing the protocol, the current consent documents or materials, the status report, and, if applicable, the data and safety monitoring report, and multi-site study progress reports. The assigned reviewers are responsible for reviewing the complete materials submitted for continuing review and are given access to the complete IRB file and relevant IRB meeting minutes. At the meeting, the Primary and Secondary Reviewers assist the Chair in leading the IRB through the completion of the regulatory criteria for approval in the IRB reviewer or certification checklist.

Review of currently approved or newly proposed consent documents must occur during the scheduled continuing review of research by the IRB, but consent documents should be reviewed whenever new information becomes available that may require modification of information in the consent document.

Expedited Review

In conducting continuing review under expedited procedures, the reviewers receive all of all the previously noted materials. The reviewer(s) complete the IRB reviewer or certification checklist to determine whether the research meets the criteria allowing continuing review using the expedited procedure, and if so, whether the research continues to meet the regulatory criteria for approval.

Generally, if research did not qualify for expedited review at the time of initial review, it does not qualify for expedited review at the time of continuing review, except in limited circumstances described by expedited review categories (8) and (9) (see Expedited Review Categories in Section 7.2.1). It is also possible that research activities that previously qualified for expedited review, have changed or will change, such that expedited IRB review would no longer be permitted for continuing review.

Possible IRB Actions after Continuing Review

As with Initial Review, at the time of Continuing Review, the Convened IRB or IRB Member(s) conducting expedited review may take any of the following actions (see Section 7.6 for a detailed description of these actions):

• Approved
• Approvable with Conditions
• Deferred

Additionally, the convened IRB may vote to disapprove the study. If an IRB member conducting expedited review believes that the study should be disapproved, it will be referred to the convened board for review. If the IRB has significant concerns, the IRB may vote to suspend or terminate the research (See Section 8 for a detailed discussion of suspensions and terminations).

If a research study receives Approvable with Conditions at the time of the Continuing Review, the IRB will specify whether any conditions need to be satisfied before an investigator can continue research activities related to those conditions or requirements that must be adhered to until the conditions of approval have been satisfied. For example, if at the time of continuing review, the IRB requires the investigator to change the research protocol to include a specific new procedure for screening prospective subjects, the IRB could approve the research with the following condition: research activities involving currently enrolled subjects may continue, but no new subjects may be enrolled until a designated IRB member reviews a revised protocol and verifies that the protocol includes the new screening procedure. Additionally, the IRB may specify a period, such as 1, 2, or 3 months, for the condition(s) to be satisfied as long as the activity with conditions is not begun/restarted until approval is granted.

Lapses in Continuing Review

The regulations permit no grace period or approval extension after approval expiration. Research that continues after the approval period has expired is research conducted without IRB approval. If re-approval does not occur within the time set by the IRB, all research activities must stop, including recruitment (media advertisements must be withdrawn), enrollment, consent, interventions, interactions, and data collection. This will occur even if the investigator has provided the continuing information before the expiration date. Therefore, investigators must submit their continuing review materials enough in advance of expiration to allow sufficient time for IRB review before the expiration date.

The lapse of IRB approval due to a failure to complete continuing review does not ordinarily constitute grounds for reporting to federal agencies as would a suspension or termination of the research. If the IRB notes a pattern of non-compliance with the requirements for continuing review (e.g., an investigator repeatedly or deliberately neglects to submit materials for continuing review in a timely fashion or the IRB itself is not meeting the continuing review dates), the IRB should determine the reasons for the non-compliance and take appropriate corrective actions. The IRB must report to FDA/OHRP any instance of serious or continuing non- compliance with FDA regulations or IRB requirements or determinations.

When the IRB approves research with conditions at the time of continuing review before the expiration date of the preceding IRB approval period, IRB approval does not lapse if the investigator needs additional time – beyond the date on which the preceding IRB approval would have expired – to satisfy some or all the IRB’s conditions. However, the investigator and the IRB should make every effort to resolve any conditions and finalize approval in as timely a manner as possible.

The IRB Office is responsible for notifying the investigator of the expiration of approval and that all research activities must stop.

However, the IRB recognizes that, while enrollment of new subjects cannot occur after the expiration of IRB approval, temporarily continuing participation of already enrolled subjects may be necessary or appropriate, for example, when the research interventions hold out the prospect of direct benefit to the subjects, or when withholding those interventions or safety monitoring procedures, would place subjects at increased risk. In these instances, the investigator should, at the earliest opportunity, contact the IRB office and submit a request to continue those research activities that are in the best interests of subjects. Such a request should specifically list the research activities that should continue, and provide justification, and indicate whether the request applies to all or only certain subjects. The IRB Chair or designee will review the request and provide a determination regarding what activities, if any, may continue during the lapse. Such a determination may include a time limit or other conditions or restrictions. If the IRB decides that already enrolled subjects should continue to receive the interventions that were being administered to subjects under the research project, data collection (especially safety information) should also continue for such subjects.

When there is insufficient time to obtain an IRB determination (e.g., the study regimen includes daily administration of an investigational agent), the investigator may make an initial determination, in consultation with the subjects' treating physician, if appropriate. In such cases, the investigator must, as soon as possible, contact the IRB office and submit a request for confirmation that the IRB agrees with the determination. The IRB Chair or designee will review the request and provide a determination. In the event that the IRB does not agree with the investigator's determination, or only agrees in part (e.g., agrees that some but not all of the activities are in the best interests of subjects), the IRB will notify the investigator who must then comply with the IRB's requirements or request a re-review of the determination by providing additional justification or information that the IRB may not have considered.

Modification of an Approved Protocol

Investigators may wish to modify or amend their approved applications. Investigators must seek IRB approval before making any changes, no matter how minor, in approved research - even though the changes are planned for the period for which IRB approval has already been given - unless the change is necessary to eliminate an immediate hazard to the subject (in which case the IRB must then be notified at once). Changes in approved research that are initiated without IRB approval to eliminate apparent immediate hazards to the participant are reviewed by the IRB to determine whether each change was consistent with ensuring the participants’ continued welfare.

Modifications may be permanent (Protocol Modification) which make changes to the protocol for all remaining subjects or temporary (Protocol Exceptions) circumstances in which the specific procedures called for in a protocol are not in the best interests of a specific patient(s)/subject(s) (examples: patient/subject is allergic to one of the medications provided as supportive care; patient/subject is not eligible in a direct benefit study). Usually, an exception is a change that is planned and has prior agreement from the sponsor. See Section 7.8.5 for details on Protocol Exceptions.

(Note: Protocol Deviations [see Section 14.1] are unplanned and are reported to the IRB after the fact.)

Investigators should consider whether the proposed changes to the research alter the original scope, purpose, or intent of the research. When the research itself is fundamentally changed, the IRB will typically require a new study submission rather than allow such changes to be made through a modification to the existing research plan.

Procedures

Investigators must submit documentation to inform the IRB about the proposed changes to the study, including, but necessarily limited to:

• Completed modification request form;
• For protocol modifications, a revised protocol, application, and/or study materials (in tracked changes or with a detailed summary of changes and the locations of those changes);
• Revised consent/consent addendum, parental or guardian permission/assent documents (if applicable); When the proposed change(s) to the research might relate to current subjects' willingness to continue to participate in the study and they won't be asked to re-consent using the revised consent form, an information sheet, letter, script, or other mechanism of providing information; and
• Any other relevant documentation provided by the sponsor or coordinating center.

Qualified IRB staff will review the submission and make an initial determination whether the proposed changes may be approved through an expedited review process, if the changes are minor, or whether the modification warrants convened board review. The reviewer(s) using the expedited procedure has the ultimate responsibility to determine that the proposed changes may be approved through the expedited review procedure and, if not, must refer the proposed modification to the research study to the convened board for review.

Convened Board Review of Modifications

When a proposed change in a research study is not minor, then the IRB must review and approve the proposed change at a convened meeting before the change can be implemented. The only exception is a change necessary to eliminate apparent immediate hazards to the research subjects. In such a case, the IRB should be promptly informed of the change following its implementation and should review the change to determine that it is consistent with ensuring the subjects' continued welfare.

All IRB members are provided with and review all documents provided by the investigator.

At the meeting, the assigned reviewers present an overview of the proposed modifications and assist the IRB Chair in leading the IRB through the completion of the regulatory criteria for approval. The IRB will also determine whether the research with the proposed modifications continues to meet the regulatory criteria for approval.

When the IRB reviews modifications to previously approved research, the IRB considers whether information about those modifications might relate to participants’ willingness to continue to take part in the research and if so, whether to provide that information to future/current/past participants.

Expedited Review of Modifications

An IRB may use expedited review procedures to review minor changes in ongoing previously approved research during the period for which approval is authorized. An expedited review may be carried out by the IRB Chair and/or experienced designee(s) among the IRB members.

The reviewer(s) complete the appropriate IRB reviewer or certification checklist to determine whether the modifications meet the criteria allowing review using the expedited procedure, and if so, whether the research with the proposed modifications continues to meet the regulatory criteria for approval.

The reviewer will also consider whether information about those modifications might relate to future/current/past participants’ willingness to continue to take part in the research and if so, whether to provide that information to participants.

Possible IRB Actions after Modification Review

As with Initial Review, at the time of Continuing Review, the Convened IRB or IRB Member(s) conducting expedited review may take any of the following actions (see Section 7.6 for a detailed description of these actions):

• Approved
• Approvable with Conditions
• Deferred

Additionally, the convened IRB may vote to disapprove the proposed changes. If an IRB member conducting expedited review believes that the proposed modifications should be disapproved, they will refer the proposed modification to the convened board for review. If the proposed changes raise significant concerns on the part of the IRB, the IRB may vote to suspend or terminate the research (See Section 8 for a detailed discussion of suspensions and terminations

Protocol/Research Plan Exceptions

Protocol/Research Plan exceptions are circumstances in which the investigator wishes to deviate from eligibility criteria or one or more of the specific procedures called for in a research plan. Unlike modifications that apply to all subsequent subjects in the research, a protocol/research plan exception only applies to a specific subject or group of subjects.

Exceptions are planned, and the investigator gets approval from the sponsor and the IRB ahead of time. For sponsored research, prior approval from the sponsor is generally required. Depending on the nature of the exception, an expedited review is possible. In order to be approved under expedited review exceptions must not increase risk or decrease benefit, change the risk/benefit analysis, negatively affect the participant’s rights, safety, welfare, or negatively affect the integrity of the resultant data. Review of exceptions that represent more than minor changes or risks levels greater than minimal must be done at a convened meeting of the IRB.

Procedures for exceptions may be reviewed as a Protocol Modification. The investigator must submit a modification request if appropriate along with any revised documentation to be presented to the subject(s) and documentation of sponsor approval, if applicable.

The only time a protocol/Research Plan exception would not require prior sponsor or IRB approval is when the exception is necessary to avoid an immediate hazard to the participant. In such cases, the exception must be submitted to the IRB as soon as possible.

Closing a Research Study

The completion or early termination of the study is a change in activity and must be reported to the IRB. Although subjects will no longer be "at risk" under the study, a final report to the IRB allows it to close its files as well as providing information that may be used by the IRB in the evaluation and approval of related studies.

Studies may be closed when the involvement of human subjects ceases (interventions, interactions, observations, and the gathering, use, study, and analysis of identifiable private information, including specimens, are all complete). Studies may be closed when the only remaining research activity involves the analysis of unidentifiable individual level data, or aggregate data sets.

For multi-site research, the study may be closed once all research activities (as above) are complete at the University of Virginia and any sites for which the IRB is the “IRB of record”. If the investigator is serving as the lead investigator or the University of Virginia is the coordinating center, please note that the study must remain open as long as the coordinating center is still receiving, studying, using, or analyzing identifiable private information from other sites (even if local interventions, interactions, observations, and data gathering is complete).

Investigators may submit study closures to the IRB using a closure form. With closure submissions, the investigator must provide a summary of the research activity and any findings available at that time.

Investigators may maintain the data that they collected, including identifiable private data, if this is consistent with the IRB-approved research protocol and data security plan if applicable. However, investigators may not conduct any additional analysis of identified data without re- applying for IRB approval. Investigators must continue to protect the confidentiality of the data as described to the IRB and honor any other commitments that were agreed to as part of the approved research including, for example, future use of data or specimens, provision of research results to subjects, and provision of any outstanding payments or compensation.

The IRB will provide a Receipt Acknowledgment of any Closure documentation received from the study team and note the closure in the IRB files.

Reporting IRB Actions. All IRB actions are communicated to the investigator, and/or designated contact person for the research study, in writing within ten (10) working days via an Approval/Assurance form prepared by the IRB staff and signed by the IRB Chair or designated IRB member. For an approval, along with written notification of approval, a copy of the approved consent/assent/permission form/s (if applicable) will be shared with the study team. For approvable with conditions, the notification will include a listing of the conditions that must be satisfied. For a deferral, the notification will include the modifications and/or clarifications required along with the basis for requiring those modifications. For a disapproval, termination or suspension, the notification will include the basis for making that decision and give the investigator an opportunity to respond in person or in writing.

All letters to investigators must be available in the study files maintained by the IRB.

The IRB reports its findings and actions to the organization in the form of its minutes, which are made available by IRB staff to the University of Virginia Institutional Official upon request.

Failure to Respond

Failure to submit a response to IRB requirements for an unapproved protocol within 6 months of the IRB date of determination may result in administrative withdrawal of the IRB file (for new study submissions). When research has IRB approval, and an investigator fails to respond to requirements related to a subsequent submission (e.g., a request for modification), the IRB Chair or IRB Staff member will review the circumstances, including any potential impact on human subjects, and will contact the investigator to try to secure a response. If the investigator continues to be unresponsive, the failure of the investigator may be considered non- compliance and will be reviewed in accordance with the procedures in Section 16. The investigator will receive notification, including an explanation. An extension beyond 6 months may be granted by the IRB if sufficient cause is provided by the investigator.

Appealing or Responding to IRB Decisions of Non-approval

When an IRB research study is disapproved or deferred, the IRB will notify the investigator in writing about the specific deficiencies and the modifications that are necessary for appropriate IRB approval. The IRB shall include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. Similarly, when research is suspended in part or in full, or terminated, the IRB will notify the investigator in writing of the suspension or termination and the reasons for its decision. The investigator may ask that the decision be reconsidered by submitting a request in writing to the IRB Chair. The request must contain the basis for the appeal, including any substantive new information that the Board did not have the opportunity to consider previously. The request is scheduled for review at a convened IRB meeting and the Investigator invited to attend the meeting. If an investigator feels that a condition for approval is unacceptable, they can appeal to the IRB with justification.

In cases where there is disagreement between the IRB and the investigator regarding the nature and extent of the requested changes or the necessity of or basis for a suspension or termination, and these disagreements cannot be resolved, the investigator and/or the IRB may make an appeal to the IO for a resolution of the matter. The IO may organize a meeting to help facilitate discussion between the IRB and the investigator. While the IO may provide input and make recommendations to the investigator and IRB for expeditious resolution of the matter, final determinations for approval/disapproval remain under the purview of the IRB.

Because the IO is responsible for policies and procedures followed by the IRB, the IO may review IRB decisions to ensure that the decision-making process is appropriate. If the IO has concerns regarding the process that the IRB has followed in making a decision, he/she may request that the IRB reconsider the decision. However, the IO cannot overrule an IRB decision.

Research Previously Approved By Another IRB

When an investigator transfers research to the University of Virginia that was previously approved by another IRB, the investigator must submit the research for review under the procedures covered by this section. No research activity may take place under the University of Virginia auspices without the appropriate review and approval.

Research approved as exempt at the previous institution will be reviewed according to the procedures in Section 6. All other research must be submitted as if it were undergoing initial review and will be reviewed under expedited review or by the convened IRB. Research that solely involves the analysis of existing identifiable data may be considered under Expedited Review Category 5.

For research transfers where stopping research interventions might harm subjects, the investigator can request permission from the IRB to continue research interventions under the oversight of the prior organization’s IRB until final University of Virginia approval is obtained.