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Chapter XI - General Procedures for IRB Submission Involving Non-Exempt Huma Participant Research

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Investigators involved in the conduct of non-exempt human participant research will be provided with instructions and guidelines for the submission of research studies and informed consent documents for IRB review and approval. Template IRB applications with instructions are available and can be provided to all interested investigators. These may include:

  • PEER simple IRB template;
  • Genetic Alliance Initial IRB application with instructions;
  • GA IRB Amendment Template;
  • GA IRB Continuing Review Template;
  • GA IRB Final Progress Report and Study Closure Template.

EXPEDITED REVIEW PROCEDURE
An expedited review procedure consists of the review of human participants’ research by the GA IRB Chair, or by an experienced reviewer designated by the Chair from among the IRB members in accordance with the requirements set forth in 32 CFR 219.110. In conducting expedited review, the IRB reviewer may exercise all the authorities of the IRB except that s/he may not disapprove the research. A research activity may be disapproved only after review by the convened GA IRB in accordance with the procedure at 32 CFR 219.108(b).

  • The IRB may use the expedited review procedure to review either or both of the following:
    • Research appearing on the Federal Register list of expedited categories (below); AND
    • Found by the reviewer(s) to involve no more than minimal risk.
  • Minor changes in previously approved research during the period of one year or less for which approval is authorized (32 CFR 219.110; 21 CFR 56.110). Minor changes in approved research cover the following situations:
    • Studies may be approved for implementation following the IRB reviewer’s administrative review of responses submitted to comply with specific stipulations of the IRB (i.e., protocols approved pending receipt of specific modifications or additional documents);
    • Administrative amendments, minor modifications to an already approved protocol or consent form, additional versions of approved consent forms, recruitment posters or advertisements, and changes in study staff if the IRB reviewer has found that the change(s) would have no significant impact on the conduct of the study or detriment to the previously approved plan for protection of human participants.

The requirements for informed consent (or its waiver or alteration) and special considerations for vulnerable populations apply to protocols eligible for expedited review.

All protocols initially reviewed and approved by expedited procedure are reviewed for continuation by the IRB reviewer at least once per year. The date of initial conditional or full approval determines the date by which the first continuing review must occur.

CATEGORIES OF EXPEDITED REVIEW
The IRB reviewer determines whether the proposed research qualifies for expedited review in accordance with the “Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure” as published by the OHRP, 45 CFR 46.110 and FDA 21 CFR 56.110.

CATERGORIES OF RESEARCH THAT MAY BE REVIEWED BY THE IRB THROUGH AN EXPEDITED REVIEW PROCEDURE1

APPLICABILITY

  • Research activities that (1) present no more than minimal risk to human participants, and (2) involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR 46.110 and 21 CFR 56.110. The activities listed 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 participants;
  • The categories in this list apply regardless of the age of participants, except as noted;
  • The expedited review procedure may not be used where identification of the participants and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to the participants’ 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 participants;
  • IRBs are reminded that the standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review--expedited or convened--utilized by the IRB;
  • Categories one (1) through seven (7) pertain to both initial and continuing IRB review.

1An expedited review procedure consists of a review of research involving human participants by the IRB chairperson or by one or more experienced reviewers designated by the chairperson from among members of the IRB in accordance with the requirements set forth in 45 CFR 46.110.

RESEARCH CATEGORIES

  • Clinical studies of drugs and medical devices only when condition (a) or (b) is met;
    • 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);
    • 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.
  • Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:
    • From healthy, nonpregnant adults who weigh at least 110 pounds. For these participants, 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
    • From other adults and children [2], considering the age, weight, and health of the participants, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these participants, 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.
  • Prospective collection of biological specimens for research purposes by noninvasive means. Examples:
    • Hair and nail clippings in a nondisfiguring manner;
    • Deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction;
    • Permanent teeth if routine patient care indicates a need for extraction;
    • Excreta and external secretions (including sweat);
    • Uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue;
    • Placenta removed at delivery;
    • Amniotic fluid obtained at the time of rupture of the membrane prior to or during labor;
    • 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;
    • Mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings;
    • Sputum collected after saline mist nebulization.
  • Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving xrays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (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:
    • 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 participant or an invasion of the participant’s privacy;
    • Weighing or testing sensory acuity;
    • Magnetic resonance imaging;
    • Electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography;
    • Moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.
  • 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 HHS regulations for the protection of human participants. 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt);
  • Collection of data from voice, video, digital, or image recordings made for research purposes;
  • 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 HHS regulations for the protection of human participants. 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt);
  • Continuing review of research previously approved by the convened IRB as follows:
    • Where (i) the research is permanently closed to the enrollment of new participants; (ii) all participants have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of participants; OR
    • Where no participants have been enrolled and no additional risks have been identified; OR
    • Where the remaining research activities are limited to data analysis.
  • Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

The IRB reviewer may also utilize as guidance the OHRP Decision Chart # 8 – “May the IRB review be done by Expedited Procedures” 45 CFR 46.110. 

Minor modifications that would not materially affect an assessment of the risks and benefits of the study or does not substantially change the specific aims of the study are eligible for expedited review. Modifications that do not meet this definition will be reviewed at a convened meeting.

Examples of minor modifications may include:

  • The addition of research activities that meet expedited criteria under 45 CFR 46.110 or 21 CFR 56.110;
  • An increase or decrease in proposed human research participant enrollment supported by a statistical justification;
  • Narrowing the range of inclusion criteria;
  • Broadening the range of exclusion criteria;
  • Alterations in the dosage form (e.g., tablet to capsule or oral liquid) of an administered drug, provided the dose and route of administration remain constant;
  • Decreasing the number or volume of biological sample collections, provided that such a change does not affect the collection of information related to safety evaluations;
  • An increase in the length of confinement or number of study visits for increased safety monitoring;
  • A decrease in the length of confinement or number of study visits, provided that such a decrease does not affect the collection of information related to safety evaluations;
  • Alternations in human research participant payment or liberalization of the payment schedule with proper justification;
  • Changes to improve the clarity of statements or to correct typographical errors, provided that such a change does not alter the content or intent of the statement;
  • The addition or deletion of study sites;
  • Minor changes specifically requested by the IRB, Human Use Subcommittee, Radiation Safety Committee, Radioactive Drug Research Committee, or Clinical and Translational Research Center.

Initial expedited review is not applicable to research studies where the participants are known to be prisoners.

CONVENED IRB MEETINGS
All protocols not eligible for expedited review and approval are reviewed by the convened IRB.

DISTRIBUTION OF PROTOCOL-RELATED DOCUMENTS TO IRB MEMBERS
Approximately two weeks prior to scheduled meetings, GA IRB members are contacted by email/phone by the GA Office staff to determine their availability for the meeting. At least five calendar days prior to an IRB meeting, read-ahead packets of materials to be reviewed at that meeting are delivered to each attending IRB member. Board members’ receipt of their read-ahead packets is verified by email or delivery service confirmation. All members of the GA IRB are provided the same documentation in their read-ahead packets and all are expected to actively participate in the review and discussion of the protocol.

The read-ahead packets contain the protocols or other actions for review, an agenda with primary reviewer member assignments, minutes from previous IRB meetings (when available), a list of protocol actions approved by an expedited procedure, educational materials, and other administrative items as necessary.

Components of the protocol read-ahead packet:

  • A review document summarizing the protocol, the risks and benefits to the participants, the regulatory issues involved, and any IRB Chair recommendations to be considered by the IRB;
  • Any checklists used in the pre-review of the protocol;
  • Any expert consultant report and recommendations;
  • Consent form(s) and/or assent forms (when applicable);
  • Copy of the full protocol;
  • Curriculum Vitae (CV) or NIH-style Biosketch of the Principal Investigator and study coordinator;
  • Any data collection instruments/case report forms;
  • Any advertisements and other recruitment materials;
  • Anyproduct and/or device information;
  • The review summaries completed by a primary reviewer;
  • Additional correspondence, as needed;
  • Other regulatory documents as appropriate.

For review of FDA-regulated protocols involving Investigational products and/or devices the read-ahead packet will also contain the following additional items:

  • Investigator’s Brochure or Device Manual;
  • Form FDA 1572.

USE OF A PRIMARY REVIEWER SYSTEM
To promote a thorough review of protocols, the GA IRB uses a primary reviewer system in which studies are assigned to one or more voting members for an in-depth review of all materials in the read-ahead packet and presentation of the protocol at the meeting.

One or more IRB members with experience/expertise in the subject matter of the protocol are assigned as primary reviewers. When appropriate, at least one of the primary reviewers is a physician member.

Primary reviewers are provided a review template to aid in their assessment and presentation of the protocol. Review summaries completed by a primary reviewer before the meeting are circulated to all attending Board members and are included in the enclosures to the minutes.

PRE-MEETING QUESTIONS AND RESPONSES
The primary reviewer(s) and all IRB members may submit questions for the Principal Investigator to the IRB Office staff before the scheduled IRB meeting in sufficient time for the Principal Investigator to respond to the questions in writing before the meeting. The GA Office staff sends the Principal Investigator’s responses to the Board members scheduled to attend the meeting. (Written responses received the day of the meeting will only be forwarded to members at the direction of the IRB Chair to alleviate confusion among Board members who do not receive the Principal Investigator’s response in time for the meeting.)

Pre-meeting questions for which responses were circulated to attending IRB members are included in the enclosures to the minutes.

MEETING CONDUCT

MEETING LEADERSHIP
GA IRB Chair – The Chair presides over convened meetings and serves as a voting member.

Quorum – Unless quorum is attained and maintained throughout the meeting, the GA IRB may not vote on protocol actions or other issues presented. The IRB Chair (or designee) will confirm that the GA IRB’s quorum requirements are met prior to the IRB’s review of protocol actions, and will monitor quorum status throughout the meeting, e.g., if any IRB members recuse due to conflict of interest (COI) or are not present for the review and discussion of a given protocol action.

CONFLICT OF INTEREST
No GA IRB member may participate in the IRB’s review of any project in which the member may have an actual, apparent, or perceived COI. It is essential that the members of the IRB are perceived as, and in fact are, free from any conflict of interest or the appearance of COI in their daily duties and especially regarding the protocols they review.

At the start of each meeting, the GA IRB Chair will solicit information regarding any member having any real, potential, or perceived COI in any of the submissions to be reviewed at that meeting. For each review by the IRB, any member with any type of conflict of interest is required to fully disclose that interest and to completely recuse him/herself from the review of that proposal/protocol. Recusals are recorded by name in the minutes of the meeting, under the discussion of that specific protocol, and the member(s) so recused are considered as absent from the meeting, other than to provide IRB-solicited information, and must leave the meeting room prior to deliberations and vote.

REVIEW AND ACCEPTANCE OF MINUTES FROM PREVIOUS GA IRB MEETINGS
Minutes from previous GA IRB meetings are presented to IRB members in the read-ahead packet. The Chair will ask Board members if they have any additions or corrections to the minutes and accept the minutes as written if no changes are required. Acceptance of previous meeting minutes to include any corrections will be documented in the minutes.

PROTOCOL REVIEW
The IRB Chair will initiate the protocol’s review and ask the IRB primary reviewer(s) to provide a summary of the protocol and any issues identified during its review. After general discussion of the protocol, the Principal Investigator (and research team members) will be invited into the meeting room (or connected by teleconference) to answer questions and any succeeding questions and clarifications. The discussion with the Principal Investigator is initiated by the primary reviewer(s).

The Principal Investigator or her/his designee(s) is encouraged to be available to respond to questions during the IRB review of the protocol. The purpose of the Principal Investigator’s presence is to provide any additional information and/or clarifications as sought by the reviewers during the review process.

When the Chair is satisfied that the issues have been reasonably examined, s/he will thank the visitors for assisting in the review process and ask them to leave the room. Any GA IRB members with a COI will also leave the room. The IRB will consider whether the criteria for approval of human participants’ research are met. After a final discussion of remaining issues, any stipulations and the period of approval will be agreed upon, a motion will be made and seconded, and the vote will be recorded. Actions by the Board will be based on a simple majority vote of members present (32 CFR 219.108).

Recommendations from the protocols’ pre-review by the Chair, Review summaries by the primary reviewer(s) and any items that investigators agreed to modify during the pre-meeting exchange of questions and answers or at the time of the review will be included as stipulations unless resolved.

DETERMINING WHICH PROJECTS REQUIRE REVIEW MORE OFTEN THAN ANNUALLY
32 CFR 219.103 (4)(ii) requires written procedures that the IRB will follow for determining which projects require review more often than annually. Although the maximum period of IRB approval may extend for one year from the date of initial approval, the GA IRB may designate an approval period of less than one year. As with annual review, this designation will require a review for continuation prior to the end of the approval period. The following factors may influence the duration of a protocol’s approval period:

  • Projects that involve significantly high risk to participants;
  • Phase I or II clinical trial protocols for which little documentation of potential risks is available;
  • Protocols involving novel procedures involving unknown risks and hazards;
  • Protocols involving multiple requests for amendments;
  • Protocols with many unexpected AEs or other problems;
  • Situations involving investigators, institutions, or other contextual factors for which the GA IRB has reason to be extra cautious;
  • Protocols from investigators who are known to have not complied with regulatory  requirements in the past.

As an alternative to requiring that continuing review be conducted in less than 12 months, the GA IRB may require a review after a specific number of participants have been exposed to the test article or research intervention. The IRB may also specify rules for stopping the study early, require an interim review of study results and adverse effects, require review of an assessment done by a Data Monitoring Committee (DMC), and/or specify submission of data for early review prior to continuation of the study.

When the GA IRB recommends an approval period shorter than 12 months, the minutes will include the reason(s) for the shorter term of approval and specify any requirements to be fulfilled by the investigator by the end of this period.

The GA IRB will consider the criteria for approval identified in 32 CFR 219.111 and other applicable laws, regulations, or policies. The GA IRB can make the following recommendations:

  • Approval. The protocol is approved without further revisions;
  • Conditional Approval. Approval of the protocol is contingent upon the Principal Investigator making specific modifications as stipulated and/or providing additional information;
    • A conditional approval may be given only when the convened IRB stipulates minor modifications or changes requiring simple concurrence by the investigator. These modifications include requirements for specific changes in wording or inclusion of additional but non-critical information to amplify or clarify the current protocol where the exact answer would not change the IRB’s approval of the research.
    • Examples include identifying study personnel or specifying the type of randomization methodology for a simple study. A conditional approval authorizes the Chair (or designee) to subsequently approve the revised study under an expedited review procedure;
    • The GA IRB Office staff will forward the IRB’s specific and detailed stipulations and recommendations in writing to the Principal Investigator. When appropriate, the Chair (or designee) makes provisions for a telephone conversation about the identified issues, in order to help the Principal Investigator, understand the required revisions or requested additional information;
    • The protocol’s expiration date is set based on the date that the IRB granted conditional approval of the protocol, not on the date that final approval is granted.
  • Deferral. The deferral of a protocol action is due to substantive concerns or lack of clarity about the conduct of the protocol and/or safety of the participants;
    • Deferral is appropriate whenever more information is needed before IRB members are prepared to recommend approval or disapproval;
    • The IRB Office staff will forward the IRB’s specific and detailed stipulations and recommendations in writing to the Principal Investigator. When appropriate, the Chair (or designee) makes provisions for a telephone conversation about the identified issues, to help the investigator, understand the required revisions or requested additional information;
    • The Principal Investigator must address all the IRB’s stipulations and recommendations before re-submitting the protocol to the IRB Office for coordination of re- review by the IRB;
    • In its consideration of revised materials, the IRB will focus on the responses of the investigator and determine if the revised protocol satisfies all the review requirements.
  • Disapproval. The protocol is disapproved as currently written. Disapproval of a research plan will be communicated in writing by the GA IRB Chair or designee, to the Principal Investigator. This written notification will include a statement of the reasons for the IRB’s decision and give the investigator an opportunity to respond in person or in writing. To ensure an investigator adequately understands the reasons for a protocol’s disapproval, the IRB Chair will arrange a teleconference with the Principal Investigator to discuss the IRB’s concerns. The prospects and conditions of eventual approval will be discussed candidly. Any protocol disapproved by the IRB may be resubmitted, but only with a complete summary of responses to all the IRB concerns.

MEETING MINUTES
The IRB Office staff record the Board’s discussion, controverted issues and their resolution, and the Board’s stipulations, recommendations, and considerations. The GA IRB meetings may also be audio taped to verify the accuracy of the information discussed for purposes of inclusion in minutes of the meeting. These tapes are erased immediately after the minutes of a meeting are approved by the Chair. This generally occurs within a few weeks of the meeting.

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