7. CUHS Review Process

7 CUHS Review Process

7.1 Human Subjects Research Determination

7.2 Exempt Research.

7.2.1 Categories of Research Permissible for Exemption

7.3 Expedited Review of Research

7.3.1 Categories of Research Eligible for Expedited Review

7.3.2 Informing the CUHS

7.4 Convened CUHS Meetings

7.4.1 Schedule of CUHS Meetings

7.4.2 Quorum

7.4.3 New Protocol Applications

7.4.4 Pre-Meeting Distribution of Documents

7.4.5 CUHS Member Conflicts of Interest

7.5 CUHS Review Process

7.5.1 Possible CUHS Actions Taken by Vote

7.5.2 Determination of Risk

7.5.3 Period of Approval

7.5.4 Review More Often Than Annually

7.5.5 Independent Verification Regarding Material Changes

7.5.6 Consent Monitoring

7.5.7 Conflicts of Interest

7.5.7.1 Protocol-Specific Conflict Management

7.5.7.2 Review of Proposed Conflict Management Plan

7.5.8 Other Committee Approvals

7.5.9 Reporting CUHS Actions

7.6 Continuing Review of Active Protocols (Renewals)

7.6.1 Continuing review process

7.6.2 Expedited Review at the time of Continuing Review

7.6.3 Determining the Continuing Review Date

7.6.4 Lapse in Continuing Review

7.6.5 Studies that are Approved but Never Started

7.7 Changes to an Approved Protocol

7.7.1 Expedited review of Protocol Changes

7.7.2 Full Board Review of Protocol Changes 

7.8 Reporting Harm to Subjects and Unanticipated Problems

7.8.1 CUHS Review of Harm to Subjects and Unanticipated Problems

7.9 Further Review/Approval of Human Subjects Research by Others within the Institution

7.10 Initiation of Research Projects

7.11 Appeal of CUHS Decisions

7.12 Sponsored Research Grants, Contracts, and Cooperative Agreement

7 CUHS Review Process 

Investigators may not conduct research involving human subjects without review by the CUHS. Upon initial evaluation by the CUHS Office staff, studies may be found not to be human subjects research, see 7.1, or to be human subjects 

research that is exempt from review, see 7.2, or that qualifies for expedited review, see 7.3. CUHS Office staff will examine applications that will be reviewed at convened committee meetings, see 7.4, and seek any additional information and documentation from investigators that may facilitate the convened committee’s consideration of the application. 

7.1 Human Subjects Research Determination 

While it is not obligatory, an investigator may request that the CUHS make a determination as to whether a proposed study constitutes human subjects research. If the request is oral (by phone or in person), it is the investigator’s responsibility to maintain documentation of the CUHS decision. An investigator submitting an inquiry by email or in other written form must include a sufficient description and documentation of the proposed research activity for the CUHS to come to an informed conclusion about whether the activity constitutes human subjects research. On an annual basis, the CUHS Executive Officer will designate committee members and CUHS Office staff to determine whether an activity is research involving human subjects. The CUHS will respond in writing to written submissions and will keep a copy of the submitted materials and determination letter/email on file in the CUHS Office. 

7.2 Exempt Research

Investigators may not decide for themselves that their own (or their students’) research projects involving human subjects are exempt. Determining whether a project qualifies for exemption requires familiarity with the Common Rule’s exemption categories listed at 45 CFR 46.101(b) [see below]. Furthermore, exempt human subjects research is subject to the ethical requirements of the Vote, see Appendix A, and the CUHS may require additional protections so the exempt project complies with the Vote. The CUHS Executive Officer will designate CUHS staff and committee members, and other qualified individuals, who may make exemption determinations. 

Investigators can initiate a CUHS exemption review orally or in writing. CUHS may require, depending on the nature of the proposed project, submission of any or all of the following before making a decision: 

1. A complete description of the proposed project, 

2. All recruitment materials (e.g., letter of invitation, recruitment script, flyer), 

3. Consent form (when appropriate), 

4. HIPAA authorization, waiver of authorization, or de-identification form (when appropriate), 

5. All surveys, questionnaires, instruments, interview scripts, etc., or drafts or outlines thereof, 

6. Letter(s) of permission from each non-University site of performance or a statement of how permission will be obtained 

7. Faculty sponsor approval, if the applicant is not qualified to act as a Principal Investigator 

Investigators will be given feedback either by phone or email as to the qualification of the application for exempt status. Once review is completed, if the exemption application is approved a notice of exemption will be sent to the investigator. In preparing a notice of exemption, the reviewer will document the category of research permissible for exemption within which the activity falls using the HIRBERT exemption category checklist. 

7.2.1 Categories of Research Permissible for Exemption 

[45 CFR 46.101(b)] 

Research activities in which the only involvement of human subjects is in one or more of the following categories will be deemed exempt, with the exception of research involving children or prisoners, as noted below: 

1. Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as 

a) research on regular and special education instructional strategies, or 

b) 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: 

a) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and 

b) 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. 

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 (2), if: 

a) the human subjects are elected or appointed public officials or candidates for public office; or 

b) 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. 

5. Research and demonstration projects which are conducted by or subject to the approval of Federal Department or Agency heads, and which are designed to study, evaluate, or otherwise examine: 

a) Public benefit or service programs; 

b) procedures for obtaining benefits or services under those programs; 

c) possible changes in or alternatives to those programs or procedures; or 

d) possible changes in methods or levels of payment for benefits or services under those programs. 

Such projects must be conducted pursuant to specific federal statutory authority, there must be no statutory requirements for IRB review, the research must not involve significant physical invasions or intrusions upon the privacy of subjects, the exemption must be invoked only with authorization or concurrence by the funding agency, and the program under study must deliver a public benefit (e.g., financial or medical benefits as provided under the Social Security Act) or service (e.g., social, supportive, or nutrition services as provided under the Older Americans Act). 

6. Taste and food quality evaluation and consumer acceptance studies, 

a) if wholesome foods without additives are consumed; or 

b) 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. 

Exemption Eligibility Exceptions: Vulnerable Populations

• Children: Exemption for research involving survey or interview procedures or observations of public behavior does NOT apply, except for research involving observations of public behavior when the investigator does not participate in the activities being observed. (See Section 10.1.1 for the definition of a child) 

• Prisoners: exemptions do NOT apply. CUHS review is required. 

Exemption Eligibility Exceptions: FDA Regulated Research, see Section 15 

7.3 Expedited Review of Research 

[45 CFR 46.110] 

The CUHS may use the expedited review procedure to review either or both of the following: 

1. some or all of the research appearing on the list established by the DHHS Secretary [reproduced below, at 7.3.1] and found by the reviewer(s) to involve no more than minimal risk, 

2. minor changes in previously approved research during the period (of one year or less) for which approval is authorized. 

A minor change in previously approved research is one that, in the judgment of the CUHS reviewer, makes no substantial alteration in (i) the level of risk to subjects; (ii) the research design or methodology; (iii) the number of subjects enrolled in the research; (iv) the qualifications of the research team; (v) the facilities available to support safe conduct of the research; or (vi) any other part of the research that would otherwise warrant review of the proposed changes by the convened CUHS. In order to be a minor change to previously approved research all added procedures must involve no more than minimal risk to subjects and fall into categories (1)-(7) of research that can be reviewed using the expedited procedure, see 7.3.1. 

Under an expedited review procedure, the review may be carried out by the CUHS Chair or by one or more experienced reviewers (e.g., a subcommittee of the CUHS) designated on an annual basis by the Chair and Executive Officer from among members of the Committee. For CUHS members to serve as designees to the Chair for expedited review, they must be experienced, defined as having expertise, acquired through education/training and experience, appropriate to the field of protocols to be reviewed. 

The CUHS Chair will provide a list of experienced CUHS members who are approved to review research under the expedited review procedure to the CUHS Office, and from the list, staff will choose one reviewer for each application. The CUHS Chair may appoint a subcommittee of members to review an application under the expedited procedure and make a recommendation; in this case responsibility for the expedited review decision will rest with the CUHS Chair. 

When reviewing research under an expedited review procedure, the CUHS Chair or designated member should receive and review all documentation that would normally be submitted for a full-board review, including the complete protocol. They should use the Informed Consent Checklist and the HIRBERT Expedited Review Checklist to determine that the regulatory criteria for use of such a review procedure are satisfied and to record the applicable category, when the research is undergoing initial review, continuing review, or review of modifications using the expedited procedure. 

In reviewing the research, the reviewers may exercise all of the authorities of the CUHS except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the non-expedited procedure set forth below. 

7.3.1 Categories of Research Eligible for Expedited Review 

[63 FR 60364-60367, November 9, 1998] 

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

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

• 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. 

• 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. 

Research Categories one (1) through seven (7) pertain to both initial and continuing IRB review: 

(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 (defined by DHHS as "persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted”), 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. [45 CFR 46.402(a)] 

(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 DHHS regulations for the protection of human subjects. See Exempt Categories and 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 DHHS regulations for the protection of human subjects. See Exempt Categories and 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.] 

(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. 

[Of note, category (8) identifies three situations in which research that is greater than minimal risk and has been initially reviewed by a convened IRB may undergo subsequent continuing review by the expedited review procedure. For a multi-center protocol, an expedited review procedure may be used by the IRB at a particular site whenever the conditions of category (8)(a), (b), or (c) are satisfied for that site. However, with respect to category 8(b), while the criterion that "no subjects have been enrolled" is interpreted to mean that no subjects have ever been enrolled at a particular site, the criterion that "no additional risks have been identified" is interpreted to mean that neither the investigator nor the IRB at a particular site has identified any additional risks from any site or other relevant source.] 

(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. [Under Category (9), an expedited review procedure may be used for continuing review of research not conducted under an investigational new drug application or investigational device exemption where categories (2) through (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 determination that "no additional risks have been identified" does not need to be made by the convened IRB.] 

7.3.2 Informing the CUHS 

All members of the CUHS will be apprised of all expedited review approvals by means of a monthly memorandum listing the investigators, protocol titles, and period of approval. Copies of the expedited review protocols will be made available for any optional review at the request of any CUHS member. 

7.4 Convened CUHS Meetings 

Except when an expedited review procedure is used, the CUHS must review non-exempt proposed research only at convened meetings at which a quorum (see below) is present. 

7.4.1 Schedule of CUHS Meetings 

The CUHS meets on a regular basis throughout the year, ordinarily at least monthly during the academic year. The schedule for the year’s meetings is published in advance to allow investigators time to plan their submissions. Ad hoc meetings may be called at the discretion of the Chair or as business requires. 

7.4.2 Quorum 

A quorum consists of a simple majority of the voting membership, including at least one member whose primary concern is in a non-scientific area. The CUHS Chair, with the assistance of the staff, will confirm that an appropriate quorum is present before calling the meeting to order. The Chair will be responsible for ensuring that the meetings remain appropriately convened. 

A quorum must be maintained for each vote to occur. If a quorum is not maintained, the proposal must be tabled or the meeting must be terminated. All members present at a convened meeting have full voting rights, except those designated as non-voting members, and except in the case of a conflict of interest (see below). In order for the research to be approved, it must receive the approval of a majority of those voting members present at the meeting. 

It is strongly recommended that CUHS members be physically present at the meeting. If physical presence is not possible, one or more members may be considered present if participating through teleconferencing or videoconferencing. In this case the member(s) must have received all pertinent material prior to the meeting and must be able to participate actively and equally in all discussions. 

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

7.4.3 New Protocol Applications 

Applications are screened by the CUHS staff for completeness and regulatory compliance prior to their placement on the agenda. 

The Protocol Application must, at a minimum, include enough information for reviewers to make determinations based upon the Criteria for IRB approval of Research [45 CFR 46.111]. Each application must include or address the following, except where inapplicable due to the nature of the proposed research: 

1. Title of the study 

2. Purpose of the study 

3. Sponsor of the study 

4. Subject inclusion/exclusion criteria 

5. Recruitment Procedures 

6. Whether some or all subjects are likely to be vulnerable, and if so, the justification for use of any special/vulnerable subject populations and a description of additional safeguards included in the protocol to protect their rights and welfare. 

7. Whether prospective subjects are vulnerable to coercion or undue influence 

8. The importance of the knowledge that might reasonably be expected, i.e., the scientific or scholarly rationale 

9. Study design (including, as needed, a discussion of the appropriateness of research methods) 

10. Setting in which the research will be conducted 

11. Description of procedures to be performed 

12. The possible/potential risks to the subjects 

13. Provisions for minimizing risks/managing adverse reactions 

14. Provisions for monitoring the data to ensure the safety of subjects, where research involves more than minimal risk 

15. The anticipated benefits of the research 

16. Circumstances of the consent procedure 

a. Setting 

b. Subject autonomy concerns 

c. Language difficulties 

d. Vulnerable populations 

e. Procedures for documenting informed consent 

f. Obtaining assent from minors 

g. Using witnesses and/or translators 

h. The person who would conduct the consent interview 

i. The person who would provide consent or permission 

j. Any waiting period between informing the prospective subject and obtaining consent 

k. Steps taken to minimize the possibility of coercion or undue influence 

l. The language used by those obtaining consent 

m. The language understood by the prospective subject or the legally authorized representative 

17. Document and data storage 

18. Compensation to subjects for their participation including the amount and timing of payments 

19. Compensation for injured research subjects 

20. Costs to subjects for their participation in the study 

21. Costs to third-party payers because of subject’s participation 

22. Provisions for protection of subject’s privacy 

23. Description of the resources available to protect research subjects, including: supervision, number, training, and qualifications of staff, appropriate support services. 

24. Protocol-specific conflict of interest information 

25. Indication whether the research requires review by other University research compliance committees, or other external committees or entities (other IRBs, other institutions granting subject access, school authorities, etc.) 

26. Assurances: The PI must certify that 

a. the study has been adequately designed to protect the human subjects; and 

b. the research does not present any conflict of interest for the PI or any other co-investigators, or, if a potential conflict exists, that the 

research will not proceed until an acceptable management plan has been developed and implemented (See Section 7.5.7.1). 

7.4.4 Pre-Meeting Distribution of Documents 

The place and time of meeting is set forth on the agenda cover sheet distributed to all CUHS members. 

The agenda, with review assignments, and all protocols and supporting documentation to be reviewed are provided to all CUHS members approximately five days prior to each meeting. 

The CUHS staff assigns a Presenter from the members of the CUHS for all protocols requiring full CUHS review. Presenters are assigned protocols based on related expertise. When making Presenter assignments, CUHS staff takes into consideration the vulnerable populations involved in the research. If CUHS Staff cannot identify reviewers with appropriate expertise, the Chair or the Executive Officer may solicit one or more consultants from the University or the community with competence in the appropriate areas (see “Use of Consultants,” Section 5.3). 

Before the meeting, each protocol application (including background information, project protocol, and informed consent) is carefully reviewed by the reviewing team. 

For initial review all CUHS members receive the following documentation, as applicable and are expected to review this information in enough depth to be able to discuss the information at the convened meeting: 

1. Complete Protocol Application form 

2. Recruitment materials / subject information (including all surveys and questionnaires) 

3. Proposed Consent / Parental Permission / Assent Form(s) 

4. Measures, Surveys, Interviews 

5. Debriefing sheets or scripts 

6. Copies of additional relevant approvals (other IRBs, institutional approval, etc.) 

In addition, for protocols supported by sponsored funds, at least one CUHS Officer will receive and review the grant/contract/cooperative agreement proposal, the DHHS-approved sample consent form, and the DHHS-approved protocol, when these exist. 

For renewal applications, the presenter will receive and review the original application and the complete protocol including any protocol modifications previously approved by the CUHS. All CUHS members will receive a protocol summary and a status report on the progress of the research, in the renewal application. 

For the review of modifications, all CUHS members will receive all modified documents and review them in enough depth to be able to discuss the information at the convened meeting. 

All CUHS members will use the CUHS Protocol Review Cover Sheet as a guide to completing their review, including initial review, continuing review, and review of modifications. 

The meeting agenda will set forth the presenter and review team for each protocol. The Chair and CUHS Officers will review all proposals on the agenda. 

Note: Principal Investigators who do not write their own protocols and responses to the CUHS must recognize that they bear ultimate responsibility for all studies submitted on their behalf. The PI signature signifies that s/he has approved all material that is submitted to the CUHS for review. 

At the meeting, any members with questions about the goals, design, study procedures, safety procedures, and qualifications of the investigators may inquire of the presenter or CUHS staff. The presenter should specifically address the Risk/Benefit Balance of the investigation and the adequacy of the consent form in conveying human subjects concerns. Problems identified by the presenter or by other CUHS members are discussed and suggestions for any necessary changes are agreed upon by the CUHS. These issues are considered in the vote to decide CUHS action. In addition to the presenter’s presentation, there may be presentations by Investigators or consultants, and then the Chair will lead discussion by Committee members until the Committee is prepared to vote. 

At the discretion of the Chair or CUHS staff, Principal Investigators may be invited to answer questions about their proposed or continuing research at the CUHS meeting, either in person or by telephone or videoconference. 

7.4.5 CUHS Member Conflicts of Interest 

A CUHS member is considered to have a conflicting interest when the CUHS member or an immediate family member (parent, sibling, spouse, or child) of the CUHS member: 

1. Is the Principal Investigator, project director, faculty adviser, or other member of the research team; 

2. Has a financial interest in NSF- or PHS-funded research with value that, when aggregated for immediate family, represents $10,000 or greater, 5% or greater interest in any one entity, $10,000/year or greater in compensation; 

3. Has a financial interest in an entity involved in the research with a value that exceeds the specified threshold in the conflict of interest policy of the University and/or the relevant Harvard faculty; or has an ownership interest (equity or stock options) in an entity involved in the research of any amount whose value could not be referenced to publicly traded prices or other measure of fair market value; 

4. Has received or will receive any compensation that may be affected by the outcome of the study; 

5. Has a proprietary interest in the research, meaning a property or other financial interest in the research including, but not limited to, a patent, trademark, copyright, or licensing agreement; 

6. Is an executive or director of the agency or entity sponsoring the research or an agency or entity with a financial interest in the research; or 

7. Any other situation where a CUHS member believes that another interest may conflict with his or her objective review of the protocol. 

Except when requested by the CUHS to be present to provide information, CUHS members will absent themselves from the meeting room when the CUHS reviews research in which they have a conflicting interest. The Chair will allow for discussion after the conflicted member has recused him/herself. The absent member is not counted toward quorum and his/her absence during the discussion and vote on the protocol will be noted in the CUHS meeting minutes. 

Before the first CUHS meeting of the academic year, a copy of Paragraph 7.4.5 will be distributed to each committee member, and CUHS will obtain and keep on file the members’ acknowledgement that they received and read it. At the start of each meeting, the Chair or a CUHS Officer will ask committee members to disclose any potential conflict of interest with respect to the proposals on the agenda. 

CUHS staff members are available to consult with investigators who are developing plans to conduct research involving human participants, to provide guidance regarding protection of participants and the CUHS application process. Where a Research Officer provides material input regarding study design before the investigator submits a Request for Approval, that Research Officer will not approve the application by expedited review. If the proposed research is reviewed by the convened committee, the Research Officer who has provided guidance in the development of the research plan will abstain. 

If a Research Officer who is a voting member of the committee concludes that his/her experience working with an investigator would potentially bias consideration of an application, either favorably or unfavorably, the Research Officer should not approve the application on an expedited basis or vote on it at a convened committee meeting. 

7.5 CUHS Review Process 

7.5.1 Possible CUHS Actions Taken by Vote 

Approved: The study is approved as submitted. 

Contingent approval: The protocol and/or consent form require minor revisions, such as wording changes, that are not directly relevant to the determinations the committee must make to approve, see 45 CFR 46.111, Section 8 below. The needed revisions are agreed upon at the meeting. These revisions are presented to the Principal Investigator for incorporation. The CUHS Chair, a subcommittee of the CUHS, or a CUHS staff committee member may approve the study upon receipt and review of the revisions without further action by the CUHS. 

Deferred: Substantive issues regarding the protocol and/or consent form must be addressed. This action is taken if substantial modification or clarification is required, or if insufficient information has been provided for the CUHS to judge the protocol application adequately (e.g., the risks and benefits cannot be assessed with the information provided). CUHS approval of the proposed research may not occur until the full Committee reviews all material submitted by the investigator, unless the investigator submits additional materials that make the revised project eligible for expedited review in its entirety. 

If the application is deferred the following will occur: 

1. The CUHS Office informs the investigator in writing of its decision, questions, and concerns. 

2. The investigator's response is sent to the CUHS Office. 

3. In order to receive approval for a deferred protocol, it must be submitted for full CUHS review at a subsequent, convened meeting unless the investigator’s response makes the revised project eligible for expedited review. The CUHS Office provides the CUHS with the investigator’s response, the revised protocol and the previously submitted protocol. The item is placed on the agenda for the following meeting. 

4. The protocol application is given full CUHS review again. 

5. The outcome of the CUHS deliberations is once again communicated to the investigator in writing. 

6. The CUHS determination concerning the subsequent amended submission will be documented in the minutes of that meeting. 

Not approved: Questions are of such significance that the CUHS feels approval of the study is unwarranted. The CUHS will provide the investigator a statement of the reasons for its decision and an opportunity to respond in person at a convened meeting or at a meeting with a subcommittee, or in writing. Subsequent approval will require full CUHS review unless the protocol is changed sufficiently that it is eligible for expedited review and approval; in such cases, the CUHS will be informed at the next scheduled meeting of the expedited approval. 

Approval pro tempore: [45 CFR 46.118] 

There are two circumstances in which the CUHS may grant approval required by a sponsoring agency without having reviewed all of the study procedures and consent documents: (1) where study procedures are to be developed during the course of the research, but IRB approval is required by the sponsoring agency; and (2) where the involvement of human subjects depends on the outcomes of work with animal subjects. Under either circumstance, the CUHS may grant approval without having reviewed the as-yet-undeveloped recruitment, consent, and intervention materials. However, if the proposal is funded, the Principal Investigator must request and receive CUHS approval before any human subjects may be recruited or involved in research (including pilot studies or pre-tests). Approval pro tempore is granted to satisfy sponsoring agency requirements or to allow investigators to have access to funding to begin aspects of the project that do not involve human subjects. See Section 7.12 for discussion of the integration of this process with the procedures at the Office for Sponsored Programs. 

7.5.2 Determination of Risk 

At the time of initial and continuing review, the CUHS will make a determination regarding the risks associated with the research protocols. Risks associated with the research will be classified as either “not greater than minimal” or “greater than minimal” based on the definition of minimal risk in the Common Rule, Sec. 46.102 (i) or, for those subjects who are prisoners, the definition at 46.303. The meeting minutes will reflect the Committee’s determination regarding risk levels. 

7.5.3 Period of Approval 

At the time of initial review and at continuing review, the CUHS will make a determination regarding the frequency of review of the research protocols. All protocols will be reviewed by the CUHS at intervals appropriate to the degree of risk but no less than once per year. In some circumstances, a shorter review interval (e.g., biannually, quarterly, or after accrual of a specific number of participants) may be required. The meeting minutes will reflect the CUHS’s determination regarding review frequency. 

7.5.4 Review More Often Than Annually 

Unless specifically waived by the CUHS, research that meets any of the following criteria will require review more often than annually: 

1. Significant risk to research subjects (e.g., death, permanent or long lasting disability or morbidity, severe toxicity) without the possibility of direct benefit to the subjects; 

2. The involvement of especially vulnerable populations likely to be subject to coercion (e.g., institutionalized psychiatric patients, incarcerated minors); or 

3. A history of serious or continuing non-compliance on the part of the Principal Investigator. 

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

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

2. The likely medical condition of the proposed subjects. 

3. The overall qualifications of the Principal Investigator and other members of the research team. 

4. The specific experience of the Principal Investigator and other members of the research team in conducting similar research. 

5. The nature and frequency of adverse events observed in similar research at this and other institutions. 

6. The novelty of the research making unanticipated adverse events more likely. 

7. Any other factors that the CUHS deems relevant. 

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

7.5.5 Independent Verification Regarding Material Changes 

Protecting the rights and welfare of subjects sometimes requires that the CUHS verify independently, from sources other than the investigator, information about various aspects of the study. These include, but are not limited to, adverse event reporting, information in the scientific literature (including information about drug toxicity or other risks), and confirmation that no material changes occurred during the CUHS-designated approval period. 

The CUHS will determine the need for verification from outside sources on a case-by-case basis and according to the following criteria: 

1. Protocols where concern about possible material changes occurring without CUHS approval have been raised based on information provided in continuing review reports or from other sources. 

2. Protocols conducted by investigators who have previously failed to comply with Federal regulations and/or the requirements or determinations of the CUHS. 

3. Protocols selected (systematically or at random) for post-approval review. 

4. Whenever else the CUHS deems verification from outside sources is relevant. 

The following factors will also be considered when determining which studies require independent verification: 

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

2. The likely medical condition, including mental health status, of the proposed subjects. 

3. The probable nature and frequency of changes that may ordinarily be expected in the type of research proposed. 

The CUHS may prospectively require that independent verification take place at predetermined intervals during the approval period, may retrospectively require such verification at the time of continuing review, or may require such verification at any time during the approval period in the light of new information. 

7.5.6 Consent Monitoring 

In reviewing the adequacy of informed consent procedures for proposed research, the CUHS may determine that special monitoring of the consent process by an impartial observer (a “consent monitor”) is required in order to reduce the possibility of coercion and undue influence, and to ensure that the informed consent process proceeds effectively and as described in the approved protocol. 

Such monitoring may be warranted where the research presents significant risks to subjects, or if subjects are likely to have difficulty understanding the information to be provided. Monitoring may also be appropriate as a corrective action where the CUHS has identified problems associated with a particular investigator or a research project. Monitoring may also be performed on a not-for-cause basis as part of the CUHS Quality Assurance/Quality Improvement program. 

When the CUHS deems it necessary to monitor consent, it will inform the investigator. 

7.5.7 Conflicts of Interest 

All Investigators and key research personnel must follow the Conflict of Interest Policy for their institution(s) as well as any applicable University policy. For the purposes of this section, “key research personnel” are those individuals who are responsible for the design, conduct, and/or reporting of study functions relating to human subjects, such as recruitment, obtaining consent, and recording data. 

7.5.7.1 Protocol-Specific Conflict Management 

The CUHS application requires that investigators certify that they have disclosed to the CUHS any actual, potential, or apparent conflict of interest for themselves, co-investigators, and key research personnel, and that no research will be carried out without a management plan for any conflict of interest. A conflict of interest is considered to exist if the investigator, co-investigator, or key research personnel, or any of their immediate family members (parent, sibling, spouse or child) has: 

1. Has a financial interest in NSF- or PHS-funded research with value that, when aggregated for immediate family, represents $10,000 or greater, 5% or greater interest in any one entity, $10,000/year or greater in compensation; 

2. A financial interest in an entity involved in the research with value that exceeds the specified monetary threshold in the conflict of interest policy of the University and/or the relevant Harvard faculty; or an ownership interest (equity or stock options) in an entity involved in the research of any amount whose value could not be referenced to publicly traded prices or other measure of fair market value; 

3. Received or will receive compensation with value that may be affected by the outcome of the study; 

4. A proprietary interest in the research, such as a patent, trademark, copyright, or licensing agreement; 

5. Received or will receive payments from the sponsor that exceed the specified monetary threshold in the University Conflict of Interest Policy in one year; 

6. Responsibility as an executive or director of the agency or entity sponsoring the research or an agency or entity with a financial interest in the research; or 

7. A financial interest that requires disclosure per sponsor policy; or 

8. Any other financial interest that the investigator believes may interfere with his or her ability to protect participants. 

As part of its review process, the CUHS Executive Officer or Chair will obtain any conflict of interest disclosure the investigator has filed that relates to the research, and any conflict management plan that has been prepared. If the investigators application indicates that an actual or potential conflict of interest may exist, but has not previously been disclosed, the Executive Officer or Chair will obtain details from the investigator and make a determination as to whether any conflict that has been disclosed could adversely affect the protection of human subjects. If so, a conflict management plan will be developed by the CUHS Executive Officer and/or Chair, conferring as necessary with the Committee on Professional Conduct for FAS studies, or with the equivalent body at other University-Area institutions. Conflict of interest management plans will be reviewed and approved by the convened committee and documented in the CUHS Minutes. If a conflict of interest exists, final CUHS approval cannot be given until a conflict management plan that adequately protects the human subjects in the protocol is in place. 

7.5.7.2 Review of Proposed Conflict Management Plan 

One or more CUHS Officers will review any proposed conflict management plan to determine if the conflict will adversely affect the protection of human subjects and if the management plan is adequate. Based on the significance of the conflict and the potential for adverse effects on the protection of subjects, conflict management plans can include: 

• Disclosure to subjects through the consent process 

• Modifications in the research plan 

• Monitoring by independent reviewers 

• Divestiture of financial interests 

• Appointment of a non-conflicted investigator 

• Prohibition of the conduct of the research at the University 

The officer(s) reviewing the proposed conflict management plan can: 

1. Accept the management plan and recommend approval to the CUHS 

2. Recommend changes in the management plan 

3. Refer the review to the Committee on Professional Conduct (for FAS investigators) or to the equivalent committee at the investigator’s school. Any plan must ultimately be acceptable to the referring CUHS officer(s) and to the CUHS. 

A copy of the final, approved conflict management plan will be filed with the relevant protocol(s) in the CUHS Office. 

7.5.8 Other Committee Approvals 

In the protocol application the investigator will be asked specific questions to determine if the research requires approval from other pertinent research compliance committees (Radiation Safety Committee, Committee on Microbiological Safety, IACUC, ESCRO, IRBs at other institutions, etc.). If the investigator answers yes to any of the questions, then documentation of approval from the other committees will be required. Final approval from the CUHS will be contingent on receipt of the required documentation. 

7.5.9 Reporting CUHS Actions 

The CUHS will notify investigators and, where appropriate, other interested parties, in writing, of its decision to approve or disapprove the proposed research activity or of modifications required to secure CUHS approval of the research activity. 

For approved research: 

1. The CUHS will send the Principal Investigator the “Report of Committee Action,” which is signed by a CUHS Officer. 

2. Certification (approval) letters are signed by the CUHS Executive Officer or designated Research Officer. 

3. Written notification of approval will include the following elements: 

a. Name and affiliation of principal investigator; 

b. Title of project as submitted to the CUHS 

c. Funding source 

d. Dates of CUHS approval 

e. Notification of any fulfilled contingencies 

f. Notice that modifications of approved projects must be reviewed and approved by the CUHS before they are initiated; 

g. Notice that adverse events/unanticipated problems must be reported to the CUHS promptly and that the research may not proceed further until the CUHS has given permission. 

h. Notice that approval of the protocol will expire on a date determined by the CUHS, unless renewed prior to that date. The period of approval will not exceed one year and there is no provision for a grace period after the expiration date. The deadline for submission of renewal materials is also specified. 

4. For investigators who receive CUHS approval for applications sponsored by federal departments or agencies adopting the Common Rule [56FR28003, June 18, 1991], the CUHS Certification Memo will be provided to the investigator with a signed Protection of Human Subjects Assurance Identification / Certification / Declaration of Exemption form. 

If the CUHS decides to disapprove a research activity, it will include in its written notification a statement of the reasons for its decision and give the investigator an opportunity to respond in person or in writing. 

The CUHS reports its findings and actions to the institution in the form of an Annual Report, which are distributed to the Institutional Official and relevant University Area Deans. 

7.6 Continuing Review of Active Protocols (Renewals) 

Approved research is subject to continuing CUHS review at least yearly, or more frequently if specified by the CUHS [45 CFR 46.109(e)]. For CUHS approval to remain current, this review must take place before the approval expiration date. If continuing review is conducted earlier than 30 days prior to the approval expiration date (e.g., due to the scheduled CUHS meeting date), the protocol will be assigned a new approval date, that of the early continuing review. The approval expiration date will be based upon the new approval date for the purposes of future continuing reviews. 

The approval date and the termination (expiration) date are clearly noted on all CUHS certifications sent to the PI and must be strictly adhered to. The expiration date is the last date that the protocol is approved. Investigators should allow sufficient time for development and review of renewal submissions. 

To assist investigators the CUHS Office will send out renewal notices to investigators 75, 45, and 15 days in advance of the expiration date; however, it is the investigator’s responsibility to ensure that the continuing review of ongoing research is approved prior to the expiration date. By federal regulation, absent continuing review and approval, no extension to that date can be granted. 

If approval lapses, subject enrollment and participation must stop, unless discontinuation of participation would be harmful to the subjects; see Section 7.6.4 below. 

Research activities are subject to review and verification from sources other than the investigator that no material changes have occurred since the last CUHS approval. 

7.6.1 Continuing review process 

In accordance with DHHS regulations at 45 CFR 46.108(b) and at 46.115(a)(2), continuing review by the convened CUHS, with recorded vote on each study, is required unless the research is otherwise appropriate for expedited review under Section 46.110 (see below). Furthermore, DHHS regulations at 45 CFR 46.111 set forth the criteria that must be satisfied in order for the CUHS to approve research. These criteria include, among other things, determinations by the CUHS regarding risks, potential benefits, informed consent, and safeguards for human subjects. The CUHS must ensure that these criteria are satisfied at the time of both initial and continuing review 

In conducting continuing review of research not eligible for expedited review, all CUHS members receive a copy of the renewal application, which includes the following information from the past year (cumulative data must also be included after the first renewal): 

• the number of subjects enrolled; 

• number of subjects who withdrew prematurely and reason(s) for their withdrawal, if known; 

• the Description of Study; 

• a summary of 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 CUHS review; 

• any other relevant information, including information about risks associated with the research; 

• a copy of the current informed consent document and any proposed changes. 

Where appropriate (e.g., if the study involves treatment interventions and/or multi-site clinical trials) the investigator must also submit: 

• summary of any relevant recent literature, interim findings, and amendments or modifications to the research since the last review; 

• any relevant multi-center trial reports; 

• a copy of the current HIPAA Authorization document, if any. 

The assigned CUHS Officer receives a copy of the complete protocol including any modifications previously approved by the CUHS. Upon request, any CUHS member may have access to the complete CUHS protocol file and relevant CUHS minutes prior to or during the convened CUHS meeting. 

When reviewing the current informed consent document(s), the CUHS should ensure the following: 

• The currently approved or proposed consent document is still accurate and complete; 

• Any significant new findings that may relate to the subject's willingness to continue participation are provided to the subject in accordance with DHHS regulations at 45 CFR 46.116(b)(5). 

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

7.6.2 Expedited Review at the time of Continuing Review 

Generally, if research did not qualify for expedited review at the time of initial review, it does not qualify for expedited review at the time of continuing review, except in limited circumstances described by expedited review categories (8) and (9) at 63 FR 60364-60367, November 9, 1998 (see Expedited Review Categories). It is also possible that research activities that previously qualified for expedited review in accordance with 45 CFR 46.110, have changed or will change, such that an expedited continuing review would not be permitted. 

7.6.3 Determining the Continuing Review Date 

DHHS regulations at 45 CFR 46.108(b) and 109(e) require, respectively, that: 

“… except when an expedited review procedure is used … [the IRB must] review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns are in nonscientific areas,” and 

“…[an IRB must] conduct continuing review of research … at intervals appropriate to the degree of risk, but not less than once per year.” 

CUHS determination of the review interval and the need for additional supervision and/or participation is made on a protocol-by-protocol basis, as necessary to ensure the continued protection of the rights and welfare of research subjects. For example, for an investigator who is performing particularly risky research, or for an investigator who has recently had a protocol suspended by the CUHS due to regulatory concerns, an on-site review by a subcommittee of the CUHS might occur or approval might be subject to an audit of study performance after a few months of enrollment, or after enrollment of the first several subjects. 

Several scenarios for determining the date of continuing review apply to protocols reviewed by the CUHS at a convened meeting. The date by which continuing review must occur depends on the date of the convened meeting at which CUHS approval occurs. (These examples presume the CUHS has determined that it will conduct continuing review no sooner than within one year). 

Scenario 1: The CUHS reviews and approves a protocol without any conditions at a convened meeting on October 1, 2002. Continuing review must occur within one year of the date of the meeting, that is, by midnight of the expiration date, September 30, 2003. 

Scenario 2: The CUHS reviews a protocol at a convened meeting on October 1, 2002, and approves the protocol contingent on specific minor conditions the IRB chair or his/her designee can verify. On October 31, 2002, the CUHS chair or designee confirms that the required minor changes were made. Continuing review must occur within one year of the date of the convened CUHS meeting at which the CUHS reviewed and approved the protocol, that is, by midnight of the expiration date, September 30, 2003. 

Scenario 3: The CUHS reviews a study at a convened meeting on October 1, 2002, and has serious concerns or lacks significant information that requires IRB review of the study at subsequent convened meetings on October 15 and October 29, 2002. At their October 29, 2002 meeting, the CUHS completes its review and approves the study. Continuing review must occur within one year of the date of the convened meeting at which the CUHS reviewed and approved the protocol, that is, by midnight of the expiration date, October 28, 2003. 

For a study approved under expedited review, continuing review must occur within one year of the date the CUHS Chair or designated CUHS member gives final approval to the protocol. 

Review of a change in a protocol ordinarily does not alter the date by which continuing review must occur. This is because continuing review is review of the full protocol, not simply a change to it. 

The regulations make no provision for any grace period extending the conduct of research beyond the expiration date of CUHS approval. Therefore, in order to avoid a lapse in approval, continuing review and re-approval of research must occur on or before midnight of the date when CUHS approval expires. 

When continuing review occurs annually and the CUHS performs continuing review within 30 days before the CUHS approval period expires, the CUHS may retain the anniversary date as the date by which the continuing review must occur. This would be, for example, October 1, 2003, in the above Scenarios 1 and 2, and October 29, 2003, in Scenario 3, even if the continuing reviews took place up to 30 days prior to these dates. 

7.6.4 Lapse in Continuing Review 

The CUHS and investigators must plan ahead to meet required continuing review dates. If an investigator does not provide continuing review information to the CUHS or the CUHS has not reviewed and approved a research study by the end of the approval period specified by the CUHS, research activities must stop, including recruitment, advertisement, screening, enrollment, consent, interventions, interactions, data collection, and data analysis. 

However, if the investigator is actively pursuing renewal with the CUHS and the CUHS Chair or Executive Officer believes that an over-riding safety concern or ethical issue is involved, the CUHS Chair or Executive Officer may permit already-enrolled subjects to continue their participation in the study for the brief time required to complete the review process. 

As a courtesy, the CUHS Office will send out renewal notices via email 75, 45, and 15 days before the studies expire. However, it is ultimately the investigator's responsibility to initiate a renewal application, allowing sufficient time for the review and re-approval process to be completed before the current approval expires. 

7.6.5 Studies that are Approved but Never Started 

When the CUHS approves a study, continuing review should be performed at least annually. For the purposes of continuing review, the review date is 

be received from the investigator for all studies that are in approved status prior to the date of expiration of CUHS approval. If subjects were never enrolled, and no new risks were identified, the investigator's progress report would be brief. Such studies may receive continuing review using expedited procedures [expedited category (8)(b)]. If the study is finally canceled without subject enrollment, records will be maintained for at least three years after cancellation [21 CFR 56.115(b)]. 

7.7 Changes to an Approved Protocol 

Investigators may wish to modify or amend their approved applications during the period for which approval has been given. Investigators must seek CUHS approval before making changes unless the change is necessary to eliminate an immediate hazard to the subject (in which case the CUHS must then be notified at once). 

Changes may be approved if they are within the scope of what the CUHS originally authorized. For example, if a researcher wishes to add a population to an existing study, but not alter the study procedures or purpose, a modification request is usually appropriate. Likewise, modifying a procedure without changing the study's purpose or study population may also be appropriate. 

Investigators must submit documentation to inform the CUHS about the requested changes to the study, including, but not limited to: 

• Written request to modify protocol; 

• Revised protocol application if changes are complex or involve multiple aspects or elements of the protocol; 

• Revised approved consent/parental permission/assent documents (if applicable) or other documentation that would be provided to subjects when such information might relate to their willingness to continue to participate in the study; 

• Revised or additional recruitment materials; 

• Any other relevant documents. 

CUHS Office staff will determine whether the proposed changes may be approved through an expedited review process or whether the changes warrant full board review. 

7.7.1 Expedited review of Protocol Changes 

The CUHS may use expedited review procedures to review minor changes in ongoing previously-approved research during the period for which approval is authorized [45 CFR 46.110; 63 FR 60364-60367, November 9, 1998 and 63 FR 60353-60356, November 9, 1998; 21 CFR 56.110(b)]. Research that was previously approved on an expedited basis may receive expedited review for 

modifications that do not take the study out of the expedited review categories. An expedited review may be carried out by the CUHS Chair or by one or more qualified reviewers designated by the CUHS Chair and Executive Officer, see Section 7.3. 

7.7.2 Full Board Review of Protocol Changes 

When a proposed change in a research study is not minor (e.g., procedures involving increased risk or discomfort are to be added), then (1) the CUHS must review and approve the proposed change at a convened meeting before the change can be implemented, or (2) if the revised protocol will not involve greater than minimal risk and includes only procedures eligible for expedited review, a complete new application may be submitted for expedited review. The only exception is a change necessary to eliminate apparent immediate hazards to the research subjects [21 CFR 56.108(a)(4)]. In such a case, the CUHS should be promptly informed of the change following its implementation and should review the change to determine that it is consistent with ensuring the subjects' continued welfare. 

When the CUHS reviews changes to previously approved research, the CUHS considers whether information about those changes might relate to participants’ willingness to continue to take part in the research and, if so, whether to provide that information to participants. 

7.8 Reporting Harm to Subjects and Unanticipated Problems 

Research-related harm to subjects or others must be reported to the CUHS, except in the limited circumstances described below. In addition, investigators must report any research-related event or development that suggests that subjects or others face risks that are different or greater than those disclosed to participants in the consent process and described in the protocol application or renewal (an “Unanticipated Problem”). Harm should be considered “research-related” if participation in the research is known or suspected to have been a contributing factor in its occurrence. 

Investigators must report serious harm or risk of serious harm immediately; other harm or Unanticipated Problems must be reported within 10 working days. 

It is not necessary for investigators to report minor, transitory research-related harm to subjects that was specifically disclosed in the consent process and the protocol application or renewal, so long as it occurs no more frequently than anticipated. 

Examples include: 

• Subjects expressing frustration while completing commonly used questionnaires; 

• Subjects expressing embarrassment or discomfort about answering personal questions in interviews or questionnaires; 

• Subjects expressing upset and discontinuing participation in a study as a result of being shown disturbing photographs 

Even when an investigator deems it unnecessary to promptly report minor, transitory harm to (or affronts to the rights and wellbeing of) subjects to the CUHS, if the investigator wishes to make changes to the protocol to eliminate or reduce the incidence of such occurrences, a request to amend the protocol should be submitted to the CUHS. Such occurrences should also be reported in any renewal application. 

Not all Unanticipated Problems involve direct harm to subjects. New circumstances may arise that increase the risk of harm to subjects without directly harming them. Such events may present unanticipated risks to others (e.g., the sexual partners of the subjects, individuals the subject may come in contact with, family members, research personnel, etc.) in addition to the subjects. 

While the event may not cause any detectable harm or adverse effect to subjects or others, it should be promptly reported to the CUHS. Examples of such events include: 

• Any change to the protocol made without prior CUHS review to eliminate apparent immediate hazard to a research participant; 

• Any deviation from the protocol (protocol violation) related to participant safety, significant new findings, a defined subset of adverse events, or IND safety reports; 

• Any publication in the literature, safety monitoring report, interim result, or other finding that indicates an unexpected change to the risks or potential benefits of the research; 

• Any complaint of a participant that indicates an unanticipated risk or that cannot be resolved by the research staff; 

• Breach of confidentiality of research data; 

• Breach of privacy/confidentiality/data security/loss of study data/destruction of study data due to noncompliance, 

• Incorrect labeling/dosing of study medication or test article 

• Any event that requires prompt reporting according to the sponsor. 

An investigator’s report to CUHS shall include the following information: 

(a) Appropriate identifying information, such as (i) the title of the research protocol; (ii) the Investigator’s name; (iii) the CUHS protocol number; (iv) the name of the funding sponsor; 

(b) A complete, detailed description of the event or development and the investigator’s assessment of its significance for the risk profile of the study; 

(c) A description of any actions that have been taken or proposed by the investigator, the study sponsor, the study coordinating site, and/or any other monitoring entity, in response to the event or development (e.g., suspension of new subject enrollment, modification of the research protocol, and/or modification of the informed consent information and/or process). 

7.8.1 CUHS Review of Harm to Subjects and Unanticipated Problems 

1) An unanticipated problem involving risks to subjects or others is defined as any problem that is (1) unforeseen and (2) indicates that subjects are at increased risk of harm. 

2) The CUHS Chair in consultation with the Executive Officer reviews all reports and determines whether they represent an unanticipated problem involving risks to subjects or others as defined above. 

3) If the CUHS Chair in consultation with the Executive Officer determines that the problem does not represent an unanticipated problem involving risks to subjects or others, no further action is taken under this policy. 

4) If the CUHS Chair in consultation with the Executive Officer determines that the problem represents an unanticipated problem involving risks to subjects or others, the CUHS Chair in consultation with the Executive Officer determines whether the problem involves more than minimal risk to subjects or others. 

5) If the CUHS Chair in consultation with the Executive Officer determines that the problem represents an unanticipated problem involving minimal risks to subjects or others, the CUHS Chair or other CUHS Officer may handle the problem or the problem may be reviewed by the convened IRB as described below for an unanticipated problem involving more than minimal risks to subjects or others. 

6) All unanticipated problems involving more than minimal risks to subjects or others are reviewed by the convened IRB. 

7) Following review of an unanticipated problem involving risks to subjects or others the problem is reported to the relevant regulatory agencies and institutional officials according to the procedures in Section 12. 

Review of Unanticipated Problems Involving Risks to Subjects or Others by the Convened Committee 

1) When the CUHS Chair in consultation with the Executive Officer place an unanticipated problem on the agenda of the convened committee, they will designate a member to present the matter, making their selection on the basis of familiarity with the protocol and any investigation of the problem. The CUHS Chair and Executive Officer may present the matter. 

2) The entire CUHS file for the protocol will be made available to the presenter. 

3) The presenter, in consultation with the CUHS Chair and the Executive Officer, will decide what documents will be provided to all committee members; at a minimum, the original application form and consent document will be provided. 

4) The actions considered by the convened IRB: 

a. Modification of the protocol. 

b. Modification of the information disclosed during the consent process. 

c. Providing additional information to past subjects. 

d. Notification of current subjects when such information might relate to subjects’ willingness to continue to take part in the research. 

e. Requirement that current subjects re-consent to participation. 

f. Modification of the continuing review schedule. 

g. Monitoring of the research. 

h. Monitoring of the consent process. 

i. Suspension of the research. 

j. Termination of the research. 

k. Referral to other organizational entities. 

7.9 Further Review/Approval of Human Subjects Research by Others within the Institution 

While ordinarily there are no institutional reviews of human subjects protocols after the CUHS grants approval, in some cases research that has been approved by the CUHS may be subject to further review within the University. However, no one at Harvard may approve human subjects research if it has not been approved by the CUHS. [45 CFR 46.112] 

7.10 Initiation of Research Projects 

All research involving human subjects must be reviewed and approved by the CUHS prior to initiation of the research project. Approved research is subject to continuing review by the CUHS at least yearly, or more frequently if specified by the IRB [45 CFR 46.109(e)]. The date of continuing review will be based on the date of CUHS approval. [see Continuing Review, section 7.6, for further details.] 

The effective date and the termination (expiration) date are clearly noted on all CUHS approval letters sent to the PI. Investigators must allow sufficient time for development and review of renewal submissions. By federal regulation, no extension to the expiration date can be granted. 

Research activities are subject to internal audit and verification from sources other than the investigator that no material changes have occurred since the last CUHS review. The need to verify information independently will be determined by CUHS staff or by the CUHS at a convened meeting. The purpose of the verification will be to provide necessary protection to subjects when deemed appropriate by the CUHS. 

The CUHS reserves the right to observe the consent process conducted under any research protocol and to inspect the records of investigators to ensure the protection of the human research subjects. 

7.11 Appeal of CUHS Decisions 

If a subcommittee of the CUHS makes a decision that the investigator believes will unduly restrict the proposed research, the investigator may request review at a convened CUHS meeting. 

If the CUHS at a convened meeting makes a decision that the investigator believes will unduly restrict the proposed research, the investigator should first discuss the matter with the Chair or Executive Officer, taking care to explain the reasons why he or she believes that the proposed procedures comply with University policy and with federal regulations. If the issue cannot be resolved satisfactorily by negotiation, the investigator may appeal the decision of the CUHS in writing. The CUHS will consider the appeal based upon any new information provided and will continue to review a protocol as long as the investigator wishes to appeal; however, no committee or entity other than the CUHS may reverse a decision made by the CUHS

7.12 Sponsored Research Grants, Contracts, and Cooperative Agreements 

Sponsored awards will be reviewed by both the local University-Area School administration and the Office of Sponsored Programs (OSP) to determine if the award will include research involving human subjects. If the determination is affirmative, or if there is any question, the reviewers will consult with the CUHS office to determine whether the project will require determination of exemption by an individual other than the Principal Investigator, or will require submission of an application to the CUHS for review and approval. 

If the proposed award will include activities that constitute research involving human subjects, the individual at OSP responsible for entering the project into the University’s Grants Management Application Suite (GMAS) will check the field in GMAS indicating that human subjects are involved. No sponsored funds may be released for expenditure on the project until the CUHS has reviewed and approved, or until a determination of exemption is made. The date and period of approval, or date of exemption determination, and any relevant comments, will be noted in GMAS. 

Some sponsored awards (such as projects to develop and then administer a test procedure or instrument, or to test a procedure on animals before testing on humans) may include human subjects research procedures that will not begin until after the start of the award period. In such cases, the CUHS may grant “Approval pro tempore” (see section 7.5.1) to allow use of sponsored funding for support of activities prior to the involvement of human subjects. In consultation with the CUHS office and the Principal Investigator, an appropriate end date for the Approval pro tempore period will be entered in GMAS, and funds may not be expended on the award after that date without evidence that CUHS approval has been obtained or exemption determination has been granted. However, if project activities are continuing at a pace slower than anticipated, and the involvement of human subjects is still significantly distant, a new end date for Approval pro tempore may be assigned in GMAS, with the concurrence of CUHS staff.