Project applications will be processed according to one of three initial levels of review as determined by the CHS: a) Exempted from IRB Review; b) Expedited Review; c) Full IRB Review.
Research Protocols which have been previously reviewed but which continue in effect beyond the first year of the study period must also be submitted to the CHS for Continuing (reapproval) Review.
When submitting applications, investigators must apply for the specific level of review that they believe is most appropriate. Investigators must submit their completed research protocols to the CHS even in cases of (claimed) Exempted research. The CHS makes the final determination as to the level of review required for each protocol. (See §2 of this manual for more information on the application process.)
At the discretion of the CHS staff or the request of the applicant, an acknowledgement of CHS receipt of a protocol application may be issued to the PI.
In accordance with 45 CFR 46.101(b)(1-6), research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from IRB review:
(1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as
(i) research on regular and special education instructional strategies, or
(ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
(2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:
(i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
(ii) any disclosure of the human subjects’ responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects’ financial standing, employability, or reputation.
Note: If research involves anyone below the age of 18, this category does not apply and the research is not Exempt. See §4.5.5 of this manual concerning research involving children.
(3) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if:
(i) the human subjects are elected or appointed public officials or candidates for public office; or
(ii) Federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
(4) Research involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.
Note: Such materials must already exist at the time the research is proposed. This category for Exemption does not apply to activities involving prospective collection of such materials.
(5) Research and demonstration projects which are conducted by or subject to the approval of Department or Agency heads, and which are designed to study, evaluate, or otherwise examine:
(i) public benefit or service programs;
(ii) procedures for obtaining benefits or services under those programs;
(iii) possible changes in or alternatives to those programs or procedures; or
(iv) possible changes in methods or levels of payment for benefits or services under those programs. (Note: This applies only to Federal agencies or departments, not State or Local agencies)
(6) Taste and food quality evaluation and consumer acceptance studies,
(i) if wholesome foods without additives are consumed or
(ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.
Note: The preceding Exempt categories do not apply to research involving prisoners, fetuses, pregnant women, or in vitro fertilization. Further, a claim of Exemption in the application does not necessarily exempt investigators from the requirement of gaining written consent from subjects. For studies where there are no subject identifiers (anonymous data is collected), an information sheet, cover letter or statement may be substituted in place of a written and signed consent form. Only the CHS can authorize this exemption. (See §4 of this manual for more information on CHS informed consent guidelines)
1. Exemption reviews will be initiated by the PI. A completed CHS New Application or Declaration of Exemption will be submitted and all required documents will be attached to the application: a PI claiming an exemption must submit a written summary of the research project following the same format as research submitted under the other levels of review; in this case, the PI should include a memo indicating that s/he believes the project is exempt and requesting that the application be reviewed for formal exemption status rather than for Expedited review, Full review or reapproval. As part of the summary, the PI must explain which Federal exemption (from 45 CFR 46.101(b)(1-6), outlined above) applies to the proposed research. In addition, the investigator should attach any interview guides, survey questions or other instruments to be used in the gathering of information. In all other cases, initial review will be conducted by the CHS Executive Secretary who will recommend an Exemption Review by checking the review form.
2. The CHS Executive Secretary will review the application for determination of exemption. The Executive Secretary may contact the PI for additional information and clarification of issues. All discussions will be documented in writing, attached to the application and included in the project file.
3. If the Executive Secretary determines the application to be Exempt, the specific exemption paragraph of the Federal regulations (45 CFR 46.101(b)) will be indicated on the Review Form and initialed.
4. If approved, the Executive Secretary will place the application on the agenda for the next regularly scheduled IRB meeting. The application will be listed on the agenda as approved Exempt research.
5. An Exemption letter will be sent to the PI. The letter will inform the PI that the project is determined to be exempt, but that the exemption is subject to the final review and concurrence of the full IRB at its next regularly scheduled meeting.
6. If the IRB concurs with the Exemption, the determination stands as final. If the IRB does not concur, or expresses specific concerns, the PI will be notified in writing of the specific concerns or that the project was approved but determined not to be exempt. The PI will be informed that the project will be subject to Continuing review in accordance with the regular CHS review process.
7. Exempt projects are not subject to continuing formal review by the IRB. The CHS must be notified, however, of any proposed changes to the previously reviewed project. The PI should contact the Executive Secretary to determine whether the proposed changes affect the Exemption status of the project or otherwise require full IRB review prior to making the changes. If full IRB review is required, IRB approval must be obtained before implementing the changes. In some cases, changes to an Exempt project may result in change of project status to non-exempt; the project would therefore be subject to regular and continuing IRB review and reporting requirements. (See §3.4 of this manual)
8. The CHS Certificate is the document issued to the PI evidencing IRB review and Exemption status. The certificate will show the IRB review date and the specific categories under which the project qualified for Exemption. This Certificate is valid for the duration of the project so long as there are no changes. In some cases, a PI requests that an updated Certificate be issued. In order for an updated Certificate to be issued, the PI must submit a Status Report Form or other acceptable form of notification describing any changes or affirming that no changes have been or will be made.
9. Unless notification of study completion (or continuation) is submitted to the CHS, research project files will be classified as “inactive” three years after project approval for studies with student PIs; and five years after project approval for studies with faculty PIs. The CHS will retain records relating to “inactive” research for three additional years.
Expedited Review is a CHS review procedure which does not require review by the full IRB. If the conditions for Expedited Review are met, and the procedures for requesting such a review are followed, CHS approval may be obtained within two weeks of submittal of the CHS application.
The CHS may conduct an Expedited Review only if an application meets the criteria established by the Federal regulations at Federal Register Volume 63, No. 216 (63 FR 60364-60367) (listed below); in order to qualify for Expedited Review, all activities in the project must meet these requirements. A study must be reviewed in its entirety; separate components of the study may not be reviewed separately. If any component of the study does not qualify for Expedited Review, the entire study must be reviewed by a full IRB.
Research activities involving no more than minimal risk and in which all of a project’s activities involving human subjects fall within one or more of the categories at 63 FR 60364-60367 (carried out through standard methods) may be reviewed by the CHS through the Expedited Review procedures authorized in 45 CFR 46.110 and 21 CFR 56.110.
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.
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.
In reviewing the research, the reviewer may exercise all of the authorities of the IRB except that the reviewer may not disapprove the research. A research activity may be disapproved only after full IRB review.
Note: Categories (1) through (7) below pertain to both initial and continuing CHS review. (See §3.4 of this manual for further information on Continuing Review)
Per 63 FR 60364-60367, the specific permissible categories for Expedited Review are:
(1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met.
(a) 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.)
(b) 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:
(a) from healthy, nonpregnant 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
(b) 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.
(3) Prospective collection of biological specimens for research purposes by noninvasive means.
Examples: (a) hair and nail clippings in a nondisfiguring 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) 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; (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.
(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. (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 nonresearch 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 subjects. 45 CFR 46.101(b)(4). 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 HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)
(8) Continuing review of research previously approved by the IRB as follows:
(a) where (i) the research 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; or
(b) where no subjects have been enrolled and no additional risks have been identified; or
(c) where the remaining research activities are limited to data analysis.
(9) 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.
Per 45 CFR 46.110(b)(2), the CHS may also use the Expedited Review procedures to review minor changes in previously approved research during the current approval period. Minor modifications to Expedited Review studies may include, but are not limited to addition of questions and/or instruments not presenting any additional risk to subjects, addition of subjects (in already approved populations), or addition of research sites.
1. A completed CHS application, along with all required attachments, must be submitted to the CHS before Thursday of the first week of the month if the application is to be placed on that month’s agenda. The PI can request an Expedited Review if s/he believes the Expedited Review requirements apply. Otherwise, the CHS Executive Secretary will make the initial determination at the time of review of the application. If eligible for Expedited Review, the appropriate category will be identified by the Executive Secretary on the Application Review Sheet.
2. Once a determination is made that an application qualifies for Expedited Review, the application with all supporting documents will be forwarded to the IRB Chair (or IRB member designated by the Chair). The application will be attached to the CHS Expedited Review form.
3. The Chair will review the application and may:
a. make a final determination that the application does not qualify for Expedited Review and return the application to the Executive Secretary to be placed on the agenda for the next regularly scheduled IRB meeting;
b. approve the application; or
c. approve the application with stipulations. (See §1.3.10)
4. If the application is returned to the Executive Secretary unapproved, the Chair will state specific reasons for non-approval. Any conditions imposed will also be specified. A notice describing these reasons and/or conditions will be prepared by the Executive Secretary and sent to the PI.
5. If approved, the Chair will determine the appropriate approval period for the application based on the degree of risk involved or any other factors the Chair determines to be important. The approval period may not exceed one year.
6. An application may not be disapproved by Expedited Review. It can be returned to the PI if incomplete, or referred to the full IRB which has the authority to disapprove the application.
7. Approval letters and certificates will be prepared and sent to the PI (and agency, if applicable).
8. All Expedited Review applications which have been approved or referred to the full IRB will be listed on the agenda for the next regularly scheduled IRB meeting.
9. The full IRB will have an opportunity to review and acknowledge each application approved through Expedited Review procedures. If concerns are raised at the IRB meeting, then, by majority vote, the IRB may reconsider the application. The full IRB decision will supercede any previous Expedited Review decisions.
10. Follow-up letters will be sent to the PI (and agency, if applicable) transmitting the IRB’s determination.
Note: CHS approval may be revoked and/or modified by the full IRB at any time if the IRB considers it necessary.
For both Expedited and Full Reviews, the Chair or full IRB, as appropriate, will review the amount of compensation (monetary as well as other forms) in order to be assured that it (1) is neither coercive nor unduly compelling and (2) is equitable in distribution.
Financial or other forms of compensation are not considered a benefit to be derived from research participation. Although the subject may consider financial compensation a desirable outcome, this fact will not be used in the IRB’s analysis of the risks and benefits of a study.
Note: In its review of protocols, the IRB must ensure that all participants will be equally compensated for their participation in a study. To this end, the CHS will not approve studies which have lotteries, or other types of chance-based drawings as their means of compensating participation in research. By their nature, lotteries and chance-based drawings do not recompense each research subject equally for their participation, and as such are not adequate forms of subject compensation.
All project applications not eligible for Exemption or Expedited Review will be reviewed by the full IRB. In addition, all projects involving special populations (e.g., pregnant women/fetuses, prisoners [with the exception of certain types of record reviews], etc.) will automatically be subject to review by the full IRB
Per 45 CFR 46.111, in order for a project to be approved, the IRB (in a meeting at which a majority of the members are present, including at least one member whose primary concerns are in nonscientific areas (i.e., a quorum)) must determine that all of the following requirements are satisfied:
(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 will 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 will 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 will 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 disabled 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 45 CFR 46.116.
(5) Informed consent will be appropriately documented, in accordance with, and to the extent required by 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.
When some or all of the subjects are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons), additional safeguards have to be included in the study to protect the rights and welfare of these subjects. (See §4.5 of this manual)
Research that does not qualify for either Exempt status or Expedited Review must be submitted to the CHS for a full review by a quorum of IRB members at a convened meeting. The application process remains the same as for the other levels of review, but investigators should note that a Full Review can take up to two months from the time of submission. Investigators should also be aware that the initial Full Review process frequently does not result in an outright approval of the research; minor or major revisions and written clarifications are often requested.
1. A completed CHS application, along with all required attachments, must be submitted to the CHS before Thursday of the first week of the month if the application is to be placed on that month’s agenda.
2. Materials for each scheduled IRB meeting are provided to each IRB member approximately one week in advance of the meeting.
3. All protocols submitted for Full Review are assigned to one or more primary (and/or secondary) reviewer(s) who will present the protocol to the full IRB for discussion. These reviewers will review the protocol, the proposed informed consent document(s), and any recruitment materials, including advertisements intended to be seen or heard by potential subjects. Primary reviewers may contact the PI for any additional information, as necessary. Reviewers are guaranteed anonymity, which they may waive by way of contacting the PI; the CHS office will not disclose the names of primary reviewers or IRB committee members.
Note: IRB members who have a potential conflict of interest as a PI, researcher, participant, or interested party in a study, or who hold a financial interest in the study being reviewed are required to disclose the conflict prior to the study’s review. In this event, the member may not take an active part in study review, except to provide requested information, and must abstain from the final discussion and vote.
4. All other IRB members will receive a protocol summary of sufficient detail to make the determinations required under 45 CFR 46.111, the proposed informed consent document(s), and any recruitment materials, including advertisements intended to be seen or heard by potential subjects. In addition, the complete documentation may be made available to all members for review if desired.
Note: for DHHS-supported multi-center clinical trials, the IRB should receive and review a copy of the DHHS-approved sample informed consent document and the complete DHHS-approved protocol, if they exist.
5. Discussion, comments and questions during the meeting are encouraged. After the recusal of any IRB members with a conflict of interest, the Chair accepts motions to approve, approve with stipulations, defer, or disapprove studies. (See §1.3.10 below for a description of these types of action.) A majority vote is necessary for project approval. Studies will not be approved unless all of the following criteria are satisfied, unless specifically waived by the IRB and documented in meeting minutes:
a. risks to subjects are minimized
b. risks to subjects are reasonable in relation to anticipated benefits;
c. selection of subjects is equitable;
d. informed consent is adequate and appropriately documented;
e. where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects;
f. where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data;
g. appropriate safeguards have been included to protect vulnerable subjects.
6. Follow-up letters will be sent to the PI (and agency, if applicable) transmitting the IRB’s determination.
Note: see §3.2.1.1 (above) for a description of the required review of subject compensation.
Studies that have been approved as Exempted research do not need to submit for reapproval or Continuation Review. These studies should submit a notification of termination or notice of closure upon completion of the research.
Per 45 CFR 46.109(e), approval under the Expedited and Full Review categories are granted by the IRB for not more than one full year. Accordingly, the CHS will conduct Continuing Review of all ongoing research, including multi-year studies, not less than annually. The IRB sets the next review date at the time of initial approval.
In determining which projects require review more often than annually, the IRB will consider the perceived degree of risk of the study, the risk:potential benefit ratio (e.g., the higher the perceived risk, the earlier the IRB may set the expiration date of the approval), the participation of vulnerable subject populations (if any), investigator (in)experience, and other pertinent factors including, but not limited to, whether:
2. the researcher has failed previously to comply with the policies and procedures of the CHS or 45 CFR 46, or with the stipulations of the IRB;
3. there exist reasons to have concerns about possible material changes occurring without IRB approval.
If no material changes have occurred since the last annual or other period of IRB review, the PI must state that this is the case and that any changes in the future will be reported promptly to the CHS.
Continuing review is conducted at the same level at which the study was originally approved: projects that initially required Full Review most often will require Full Continuing Review, unless the project has changed in a manner that qualifies the study for an Expedited Review per 45 CFR 46.110(a)(8) or (9):
(8) Continuing review of research previously approved by the convened IRB as follows:
(a) where (i) the research 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; or
(b) where no subjects have been enrolled and no additional risks have been identified; or
(c) where the remaining research activities are limited to data analysis.
(9) 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.
For research where (i) the research is permanently closed to the enrollment of new subjects, and (ii) all subjects have completed all research related interventions, Continuing IRB review is still required even if the research remains active only for long-term follow-up of subjects. Furthermore, Continuing review of research is also required where the remaining research activities are limited to data analysis.
Under any of the review levels, if the approval date expires prior to submission and approval of the continuation application, the PI must suspend participant contact and all data collection until the reapproval is obtained from the CHS. No new participants may be contacted, recruited or enrolled during the interim period.
Note: If approval for a project lapses, conducting research beyond the expiration date is a violation of Federal regulations. In addition, a new application must be filed in order to gain continued approval for said project. When reaching a determination concerning research that is out of compliance due to lapse in continuing review, the IRB may consider (1) whether the non-compliance was willful or just an oversight; (2) how long the period of non-compliance has been; (3) whether the data that was collected during the period of non-compliance was collected under appropriate conditions (as outlined in the protocol) and with proper consent. Further, the IRB shall decide whether to (a) allow use of the data collected during a period of non-compliance; (b) not allow the use of the data collected during this time; (c) allow the use of the data, but require that a statement be included in any publication.
The purpose of Continuing Review is to review the progress of the entire study, not just changes in it. Continuing Review must be substantive and meaningful. The IRB applies the same criteria for continuing approval as it does to the initial review (i.e., acceptable risks, potential benefits, informed consent, and safeguards for human subjects). The same rules for deferral and stipulation of revisions apply to Continuing Review as described above for the initial review.
1. Approximately 60 days prior to a project’s expiration date, the CHS Executive Secretary will send an email notification to the PI stating that the project’s expiration date is approaching. In this notification, the PI will be asked to affirm that the project is still active and to submit a completed Status Report Form along with copies of currently approved consent forms (if applicable) no later than two weeks before the meeting at which the project will be reviewed.
2. For those projects initially approved under Full Review, and which do not now qualify for Expedited Review (see §3.2), the PI must submit all required forms no later than Tuesday of the first week of the month in order to be placed on that month’s agenda. (Note: it is highly recommended that PIs not wait until the final month of their approval period before submitting their protocols for continuing review. The IRB may require further information before reapproving a protocol, and PIs who have waited until the final month of their current approval period may be in danger of having their approval lapse before the committee is able to satisfactorily complete the continuing review procedure.)
3. Once all required paperwork has been submitted, the procedures for Expedited Review (§3.2.1) or Full Review (§3.3.1) (whichever is appropriate) will be followed.
4. In the event that Full Review is necessary, the primary reviewer will receive a copy of the complete protocol including any modifications previously approved by the IRB. Note: upon request, any IRB member may have access to the complete CHS study file and relevant IRB minutes prior to or during the convened IRB meeting.
5. The IRB will take particular note of :
i) the number of subjects accrued;
ii) any Adverse Events and any unanticipated problems involving risks to subjects or others and any withdrawal of subjects from the research or complaints about the research since the last IRB review;
iii) any relevant recent literature, interim findings, and amendments or modifications to the research since the last review (Note: submission of any recent literature, interim findings, etc. is the responsibility of the PI.);
iv) any relevant multi-center trial reports;
v) any other relevant information, especially information about risks associated with the research;
vi) the currently approved or proposed consent document is still accurate and complete;
vii) any significant new findings that may relate to the subjects’ willingness to continue participation are provided to the subjects as per 45 CFR 46.116(b)(5).
Note: With a study where the IRB had initially acted to Approve with Stipulations to be verified as being satisfied by the IRB Chair or designee, continuing review must occur no more than one year after the date the protocol was reviewed by the full IRB, not on the anniversary of the date the IRB Chair or designee verifies that IRB-specified conditions for approval have been satisfied.
All PIs are notified in their respective CHS project approval notifications that any unanticipated, serious or continuing problems involving risks to subjects or others, and any Adverse Events must be reported to the CHS.
An Adverse Event is any unanticipated reaction or event contemporary with the study that has a harmful effect on a subject, including adverse physical, psychological, or social events. Adverse Events which occur during the study, or in a post-study period of reasonable duration, regardless of treatment group or relationship to the research, must be reported to the CHS whether or not the researcher believes the events to be caused by the study.
All unanticipated problems involving risks to subjects or others and all Adverse Events are to be reported in writing to the CHS within 48 hours of their occurrence, or when the sponsoring agency is notified, whichever is sooner (the same Adverse Event reporting form used to notify the sponsor may also be used to notify the CHS). The PI must include the following:
1. the CHS routing number of the project;
2. the unit number of the subject;
3. a descriptive narrative of the event;
4. a descriptive narrative of any further action taken as a result of the event;
5. indicate the outcome of the event;
6. a statement as to whether the investigator feels the event was definitely related to the subject’s participation in the research, probably related, possibly related, or definitely not related and a statement as to whether the consent form has to be modified to incorporate the Adverse Event (if not already enumerated).
7. If the sponsoring agency requires that a special form be completed and submitted, the PI should forward a copy of that form to the CHS.
The Executive Secretary will evaluate each Adverse Event Report and determine whether further action is needed beyond that taken by the researcher. Upon receipt of a local Adverse Event Report, the Executive Secretary (after consultation with the relevant IRB Chair, if necessary) decides if urgent action is necessary to eliminate apparent immediate hazards to the human subjects, including, but not limited to, the following:
· requiring that subjects be asked to re-consent to participate in the study;
The Executive Secretary will discuss local Adverse Event Reports (and any actions taken by the Executive Secretary, Chair or designee upon receipt of the Adverse Event Report) at the next convened IRB meeting. The IRB shall determine appropriate action in response to the report, including one or more of the following:
All local Adverse Events are reported to the study’s sponsor, the FDA or other involved agency. All Adverse Event Reports will be initially screened by the CHS Executive Secretary. If sufficient information is not available to evaluate the situation, the Executive Secretary or Chair will contact the PI to follow up and obtain additional information. The Executive Secretary or Chair must determine if:
Once a complete review has been made, the Executive Secretary or Chair will determine if the situation is:
a. Not serious or continuing.
If it is determined that the event was not serious and is not continuing, then the report(s) will be placed on the agenda for review by the full IRB at its next meeting. The IRB will review the report and determine whether further action is necessary. The report, and all related CHS review and action materials such as correspondence with the PI, will be filed and provided to the IRB. If the IRB determines that no remedial action is necessary, or that the situation has been adequately resolved, an acknowledgement memo will be sent to the PI indicating that the event has been reviewed by the CHS. If the IRB determines that action is necessary, the PI will be notified immediately. If the reporter was not the PI, a memo should be sent informing the reporter of CHS actions taken in response to the report, if possible.
b. Serious or continuing.
If the Adverse Event Report appears to involve a situation of a serious or continuing threat of harm to the subject(s), the IRB Chair must determine or be consulted immediately to determine whether a special meeting of the IRB must be called in order to address the situation as soon as possible. The PI must be notified of the IRB’s review and recommendations. If the reporter is not the PI, then an information memo should be sent to the reporter, if possible.
The CHS may take whatever action it deems necessary to protect the welfare of human subjects, including suspending the project, requiring revised or additional safeguards, requiring closer monitoring of the research and additional reporting requirements by the PI to the CHS.
Upon notification of an Adverse Event, and if determination is made that research must be ceased, CHS may immediately notify the appropriate institutional officials (e.g., designated UH Institutional Official), the OHRP, the FDA (if applicable) and the study sponsor. The following information will be reported:
1. identification of research study and PI;
2. the nature of injuries to human subjects or other unanticipated problems involving risks to subjects or others;
3. any serious or continuing non-compliance with the regulations or requirements of the IRB;
4. any suspension or termination of IRB approval for research;
5. the outcome or resolution of the incident;
6. any UH institutional sanctions or CHS requirements imposed on the study.
Any project sponsor’s guidelines should be followed if available. If the PI has already notified the sponsor, then copies of the notification must be obtained by CHS; CHS follow-up with the sponsor may be necessary. If the sponsor has not been notified, then the CHS must notify the sponsor and inform the PI that the sponsor has been notified. The CHS will review the situation and determine whether further action is necessary. It may also follow the sponsor’s instructions, if any, in handling the situation. The CHS must ensure that the sponsor, the OHRP and the FDA (if appropriate) are notified. The CHS may also take other action as it deems appropriate.
It is the policy of the CHS that the PI is responsible for reporting actual or potential Adverse Events arising out of his/her study. The PI’s primary reporting responsibility is to the IRB of the hospital(s) at which the subject(s) was a patient and was being treated under the research protocol. That hospital has primary authority and responsibility for its patients. That hospital IRB must then ensure that all required reporting procedures are followed. If the study was initially approved by the UH Cooperative IRB, that IRB may assume primary responsibility rather than the IRB of the hospital(s) in which the subject(s) was being treated if the hospital IRB(s) did not have exposure to, or voting power in the initial approval process of the study. Regardless, the CHS will be notified of all Adverse Events and will review these Adverse Events as is its responsibility as recipient of the award and IRB of record.
Upon receipt of an Adverse Event Report, the Executive Secretary will review the report as described in §3.5 above. Notification of national (i.e., non-Hawaii) Adverse Event and safety reports under cooperative research clinical trials may be acknowledged by memoranda. Copies of the reports should be filed in a separate “Adverse Event” file for each project. Each report should be logged in the “Adverse Event/Safety Report log” located in the Adverse Event file. Periodically, these reports should be reported to the IRB for review (e.g., when the project is presented to the IRB for renewal). The reports should be presented for review at more frequent intervals if necessary.
Notification of local Adverse Events and safety reports will be reported to the IRB at its next meeting, unless the situation warrants immediate attention as described in §3.5 above. These reports should be filed in the Adverse Event file for their respective projects. Adverse Event files will be located with the CHS projects files. Once a report has been reviewed by the IRB, the date of IRB review should be annotated in the Adverse Event/Safety Report log.
Upon examination of the Adverse Event Report, the IRB can determine that:
1. the Adverse Event is not related to the research, in which case no change to the protocol will be required;
2. the Adverse Event is possibly related to the research, in which case the IRB can call for amendments to the approved consent requirements to consist of (a) new consent protocols for incoming subjects, and (b) re-consenting of current subjects informing them of the possibility of increased risk;
3. the Adverse Event is definitely related to the research, in which case all research activity must cease immediately.
Note: It is the responsibility of the IRB, not the PI to make one of the preceding three determinations regarding Adverse Events.
Approval to conduct proposed research is given only to the application and protocol as presented or amended at the time of approval. If there are any changes to the research protocol after this approval has been granted, these proposed changes must also be reviewed by the IRB before being implemented. This includes, but is not limited to, any changes in the selection of subjects, additional questions or additional survey items, changes in the approved protocol or any deletions or additions in the approved consent forms. This applies to research approved by Full IRB Review, Expedited Review, or Exempt approval.
Changes to approved protocols cannot be implemented prior to Continuing Reviews or approved modifications except when necessary to eliminate hazards to the subject. Any unanticipated risks to subjects, emergency changes in procedures, adverse events, or instances of noncompliance with UH, State or Federal regulations must be reported immediately to the CHS for appropriate and timely resolution.
Researchers planning changes in subject population, recruitment plans, advertising materials, consent requirements, research procedures, study instruments, study sites, or researchers or study personnel instrumental to the design or execution of the study must submit a request (typically on the Status Report Form) to the CHS for approval of the modification(s) prior to implementing the modification(s). Required information includes:
1. description of the proposed change(s);
2. description of the implications for the subjects;
3. revised consent documents if the change will affect subjects;
4. explanation of why the change is needed.
Requests for modifications to studies are reviewed at the initial level (i.e., modifications to Full IRB Review approved studies are reviewed by the full IRB, etc.). If the IRB Chair determines that a requested modification to a Full Review study is minor in nature and can thus be reviewed at the Expedited Level (per 45 CFR 46.110(b)(2)), the Chair can review and approve the requested modification. Minor modifications to Full Review studies may include, but are not limited to addition of questions and/or instruments not presenting any additional risk to subjects, addition of subjects (in already approved populations), or addition of research sites.
Note: each revision to a research study should be incorporated into the CHS study file to ensure that there is only one complete file.
In reviewing minor changes in the Protocol and/or the consent form of a research project during its approved period, the IRB may use the Expedited Review procedure as set out in §3.2.1 of this manual. This Expedited Review will be carried out by the IRB Chair. However, when a proposed change is not minor (e.g., involves increased risk or discomfort) then the change must be reviewed by the full IRB and cannot be implemented until the change is approved at a convened meeting of the IRB.
The IRB Chair is authorized to approve by Expedited Review any change that falls into Expedited categories (see §3.1.2), with the exception of interviews and surveys with children.
Modifications to the protocol or consent form that the IRB Chair is not authorized to approve by expedited review include, but are not limited to:
Federal regulations require that institutions and IRBs conduct self-monitoring activities in order to insure that investigators comply with regulations and carry out protocols as approved by the IRB. To ensure that human subjects are adequately protected, the CHS may conduct routine, targeted or random audits subject to its jurisdiction. Verification can take place by observing research in progress, especially the enrollment and consenting of participants, auditing of research records on a sample basis, and by establishing procedures for the receipt and proper review of complaints from participants in the research. The CHS may conduct periodic reviews to determine if protocols are implemented as approved. Data reviewed at the time of audits include: the currently approved protocol; recruitment procedures as implemented; status of participant enrollments; individual subject records; consent and assent forms as implemented and filed; modifications to protocols; and the reporting of adverse events, if any.
The CHS reserves the right to request verification from sources other than the researcher that no material changes have occurred since the initial or previous Continuing Review if,
2. the researcher has failed previously to comply with the CHS’s requirements as per 45 CFR 46, or the stipulations of the IRB;
3. there exist reasons to have concerns about possible material changes occurring without IRB approval.
The CHS shall make use of such sources other than the researcher whenever the IRB determines (based on information available such as adverse event reports, deficiencies noted in the CHS files, media or scholarly reports or research activity, etc.) that monitoring is in the best interests of the research subjects.
The results of any targeted or random audits by the CHS will be reported to the full relevant IRB on the agenda of the next regularly scheduled meeting. However, if the information gained during the monitoring or auditing process indicates that human subjects of a research project are exposed to unexpected harm, the CHS staff may temporarily suspend the research prior to the next regularly scheduled IRB meeting.
Per 45 CFR 46.113 and 21 CFR 56.108(b)(2), 56.113, the CHS has the authority to suspend or terminate approval of research that is not being conducted in accordance with CHS requirements, or if there is evidence of serious or continuing non-compliance with UH, State or Federal regulations.
If the investigator fails to submit a Continuing review Status Report form or a final report prior to the end of the IRB approval period, a notice will be sent to the investigator indicating that the study has been suspended and subject accrual should be suspended pending re-approval of the research by the IRB. Subjects may not be enrolled nor data collected during this period; contact between researcher(s) and subject(s) must cease except where issues of subject safety require continued contact.
If it is necessary to close the study, the investigator will be required to submit a final report or a new application to the CHS; IRB approval must be received before the project can be reinstated and the use of human subjects can be resumed. A brief grace period may be approved by the IRB Chair when closure may cause risk to the human subject(s), if there is an extenuating circumstance, or to allow for the submission and receipt of required documentation for the CHS review process. The reason and time frame for the grace period must be clearly documented by the Chair and made a part of the CHS file.
If protocol changes are not reported in a timely manner or are implemented prior to obtaining IRB approval, the investigator will be notified of the non-compliance with CHS policies and procedures. Repeated instances of non-compliance will be reported to the IRB for review and action.
The CHS will take appropriate action to insure the safety and welfare of human research subjects. These actions may include:
For CHS purposes, Non-Compliance means: conducting research involving human subjects in a manner that disregards or violates Federal regulations and/or CHS guidelines governing such research. This can include, but is not limited to, failure to obtain CHS approval for research involving human subjects, inadequate or non-existent procedures for informed consent, inadequate supervision in research involving experimental drugs, devices or procedures, failure to follow stipulations made by the IRB to insure the safety of subjects, failure to report Adverse Events or proposed protocol changes to the CHS, and failure to provide ongoing progress reports.
There are two ways allegations of Non–Compliance may be submitted:
The PI will be notified of the concern and advised that the CHS will conduct an inquiry to determine the validity of the concern. The Executive Secretary may contact the PI by phone to conduct an initial inquiry; should the concern prove valid, the Executive Secretary has the authority to place a temporary suspension on all research until further investigation is completed. A memo describing the CHS’s concern should also be prepared by the Executive Secretary offering the investigator an opportunity to respond at an informal conference, or in writing. The Executive Secretary, in consultation with the relevant IRB Chair will specify a time period within which the investigator should respond and will advise the investigator of such.
During this inquiry stage, factual information is gathered and expeditiously reviewed to determine if a more in-depth investigation of the complaint is warranted. An inquiry is not a formal hearing or an in-depth analysis of the allegations; it is designed to separate allegations deserving further investigation from those that are frivolous, unjustified or related to minor infractions.
If the investigator offers a timely and satisfactory explanation for the concern, and the IRB Chair accepts, the inquiry process will be terminated and the investigator will be notified in writing. If the investigator offers an explanation that the Chair rejects, or if the investigator fails to respond within the specified time period, the Chair will determine whether the investigator should remain eligible to continue to conduct the research and make a recommendation for further action.
Recommendations for Further Action:
At the conclusion of the inquiry phase, the Chair will make a recommendation to the IRB. Possible recommendations include:
· require a response from the investigator with a plan for corrective actions;
· dismissal of the allegation or complaint as unjustified;
· initiate audits of the active protocols;
· referral of the matter to another more appropriate system within the UH for resolution (e.g., Grievance, Student Conduct Code, Academic Misconduct, etc.);
· resolution through corrective or educational measures where the violation of human subjects regulations is minor or inadvertent;
· a formal CHS investigation where the allegation or complaint appears founded and is of a serious nature. If the Non-Compliance is found to be serious in nature, the IRB may:
o require that subjects previously enrolled in the study be contacted and provided with additional information and/or re-consented;
o terminate the study;
o determine that the data collected cannot be used for publication;
o report to the sponsor, administrative officials, and government agencies (e.g., OHPR, FDA, etc.)
At any time during the inquiry and investigation process, the IRB may determine that it is necessary to suspend accrual of research subjects or suspend approval of research project(s) to assure the protection of human subjects. The authority to formally suspend research rests with the Chair (as opposed to the temporary suspension institutable by the Executive Secretary). If formal suspension is warranted, it normally will occur at the end of the inquiry phase. Except in cases of imminent harm to research subjects, the CHS will not suspend approval of research studies until the researcher has had an opportunity to respond to the initial allegation of Non–Compliance.
When the CHS makes a decision to formally suspend approval of research, it will notify the Institutional Official and other appropriate UH officials. These may include the researcher’s department head, the senior administrative officers, and officials at any area hospitals if their patients are involved. The Institutional Official may send written notice on behalf of the CHS to the following entities, as required under Federal regulations:
Reports should be filed within five working days of suspension.
In some cases reporting to professional licensing boards or state agencies also may be required. These reports will be made by the Executive Secretary or other appropriate UH officials.
The purpose of a formal investigation is to explore serious allegations by assembling and examining relevant information. The investigation will generate a report that summarizes the information it considered, its conclusions as to whether there was serious Non–Compliance with human subjects regulations and recommendations for action. During an investigation, additional information may emerge that justifies broadening the scope of the investigation beyond the initial allegations. The researcher shall be informed if new and different allegations are discovered during the course of the investigation.
The investigation will be conducted (depending on the nature and scope of the complaint) either by CHS staff or by an ad hoc panel of IRB members established by the Chair (the “Investigation Panel”). For an ad hoc panel, at least one member will be an IRB member whose areas of expertise are suited to reviewing the complaint and area of study.
The Investigation Panel may use any and all materials and reports gathered during the inquiry phase. The Investigation Panel may obtain documents and other records relevant to the investigation, such as researcher records, medical charts, grant applications and other scientific or scholarly data. The Investigation Panel may interview any persons who may have information relevant to the complaint. All interviews may be tape recorded. The Panel may draw on the resources of the institution or external consultant(s) to assist in the review of issues which require expertise beyond or in addition to that available on the Investigation Panel.
The researcher under investigation will be given an opportunity to submit written comments prior to the Panel issuing its report. The researcher may offer relevant information to the Panel and suggest other individuals to be interviewed.
At the conclusion of its investigation, the Investigation Panel will prepare a report summarizing the information it considered and outlining its conclusions and recommended actions. The Investigation Panel will forward a copy of this preliminary report to the researcher and give the researcher ten working days in which to submit comments on the report. The Investigation Panel will review any comments received from the researcher and decide based on these comments whether to modify its preliminary report. When finalized, the Investigation Panel will send the Chair its report with any comments received from the researcher.
The Chair will base the final decision on the report of the Investigation Panel and any comments submitted by the researchers. Actions the Chair may take with respect to the investigation include, but are not limited to:
1. dismissal of the complaint as unjustified;
2. remediation or educational measures;
3. increased reporting by the researcher of his/her human subjects research activities;
4. restrictions on research practice, such as limiting the privilege to minimal risk or supervised projects;
5. suspension of approval for one or more of the researcher’s studies;
6. termination of approval for one or more of the researcher’s studies;
7. referral to other UH officials or committees for possible further review and action by those bodies.
The Executive Secretary will issue the final investigative report and send it to the researcher. The decision becomes final within five working days of release unless the researcher files a written statement of appeal within that time frame.
A. Purpose
The purpose of an appeal is to give the researcher an opportunity to request reconsideration of the Chair’s decisions under certain limited circumstances. Grounds for appeal are limited to:
2) new information not reasonably available during the investigation;
3) material failure to follow these policies and procedures;
4) sanction exceeds the severity of the violations.
No other grounds will be considered.
B. Process
The full IRB will review the written statement of appeal by the researcher and make a recommendation as to whether the Chair should reconsider any aspect of the decisions based on the grounds outlined above. In reaching this recommendation, the IRB may seek a response from the Investigation Panel. The decision whether to forward a request for reconsideration should be made within 10 working days.
If the IRB denies the appeal, the Chair’s prior decision becomes final. If the IRB recommends reconsideration, the Chair re-opens the case. When the Chair re-opens the case, s/he may choose to reconvene the Investigation Panel or reconsider the matter on his/her own. The Chair, or the Investigation Panel, if reconvened, may offer the researcher the opportunity to appear personally to present the appeal.
Upon reconsideration, the Chair determines whether to modify or uphold the original decision. This action is final. Consistent with the CHS’s regulatory authority, no other entity may override a CHS decision which limits, imposes conditions or in any way restricts a researcher’s privileges.
At the stage when the Chair’s decision becomes final (i.e., 5 working days after the original decision if there is no appeal; upon a decision by the IRB to deny the appeal; or upon the Chair’s final determination if the case is forwarded for reconsideration), the Chair will release the findings to the researcher and to appropriate UH and governmental officials as required under Federal regulations. The same guidelines as set forth above for reporting suspensions will apply. Further, it may be necessary to inform these same officials of the status of the proceedings while they are pending. Decisions whether to release the IRB’s findings to the public will be made by institutional officials outside the CHS in conformance with UH policy and State statutes. The CHS will not initiate any public disclosure of findings.
Some complicated cases may require review by other institutional or external entities. The IRB will cooperate in the review of allegations of academic misconduct, financial mismanagement, FDA inspections, etc. In cases that appear to involve academic misconduct, the Investigation Panel may report allegations of such misconduct to appropriate institutional officials. Where academic misconduct and CHS investigations are pending against the same researcher, the CHS will participate in a close coordination of processes to avoid duplication of effort and minimize competing use of resources.
As with all CHS processes, all IRB members who have conflicts of interest or commitments relating to the matter under review will excuse themselves from the proceedings.
Generally, the researcher under review should have access to the identity of complainant(s) and others who provide information. However, if such individuals are in a status subordinate to the researcher and wish to maintain their anonymity, the CHS will make every effort to protect their identifies while at the same time affording the researcher access to the substance of the allegations and information presented against him/her. The CHS cannot guarantee absolute anonymity.
Reviewing complaints and allegations of Non–Compliance is critical to the CHS’s ability to protect human subjects. A climate free of fear of sanction is required to foster appropriate reports and ensure a fair review of allegations. Retaliation against good faith “whistle blowers” is illegal and will not be tolerated. Whistle blowers who report CHS related concerns may utilize other mechanisms at the UH for protection from retaliation (call the UH Ethics Committee at 956-7651 for more information).
PIs should terminate a protocol when human subjects are no longer being followed or studied. As long as subjects (patients or otherwise) are still being followed, even if the protocol is closed to subject accrual, a protocol is considered active and Continuing review must be completed. When research has been terminated, the responsible investigator must notify the CHS; another mechanism for terminating a study is through the Continuing review survey process.
When faculty members leave the UH, they should terminate their active protocol(s), or submit a request that the protocol(s) should be transferred to another investigator who will take over responsibility for the research. This request should be co-signed by the new investigator recognizing that s/he is now responsible for the study. Appropriate changes to consent forms, advertisements, etc. must be submitted to the CHS when transferring a protocol.
When an investigator chooses to transfer status as PI on an approved protocol to another investigator, the CHS must be notified. The new investigator must be eligible to serve as PI. To effect this transfer, a Status Report form should be submitted to the CHS with a statement that the protocol will be transferred to another investigator who will take responsibility for the research. This form should be co-signed by the existing investigator and the new investigator recognizing that s/he is now responsible for the study. Appropriate changes to consent forms, advertisements, etc. must also be submitted to the CHS when transferring a protocol. CHS staff will inform the investigator when the modification is approved.