Operational Policies and Procedures of the Committee on the Use of Humans as Experimental Subjects
The Committee on the Use of Humans as Experimental Subjects (COUHES) was established to act as the Institutional Review Board (IRB) for the Massachusetts Institute of Technology (MIT). MIT has an Assurance of compliance with Federal Regulations for the Protection of Human Subjects (45 CFR 46) as amended, approved by the Office for Human Research Protection (OHRP), Health and Human Services.
Research is defined as a systemic investigation designed to add to the body of general knowledge. Human subject research is the collection of data from an individual, either through a direct intervention/interaction or by the use of private identifiable information.
COUHES is governed by the Ethical Principles and Guidelines for the Protection of Human Subjects, generally known as the “Belmont Report”.
Scope of Authority
COUHES is responsible for the review of all research activities that involve human subjects, whether directly or indirectly, that will be conducted by investigators at or from MIT. In addition, COUHES is responsible for reviewing all research activities that qualify for exemption from, or waiver of IRB review, as outlined in 45 CFR 46101.
COUHES has the authority to:
- approve, require modifications to secure approval of, defer action on or disapprove research protocols involving human subjects
- require progress reports from the investigators
- oversee the conduct of research
- suspend or terminate approval of a study
- place restrictions on a study
- conduct reviews and inquiries regarding research activities as needed to obtain information necessary for the fulfillment of their responsibilities under the institutional Assurances
COUHES, as well as appropriate ancillary committees, must approve the research protocol and, when applicable, the consent form(s) to be used to obtain informed consent of subjects prior to the initiation of the research and enrollment of subjects. The decision of COUHES to disapprove a research protocol cannot be overruled by any other institutional body or individual(s).
COUHES is composed of at least 5 members with varying backgrounds to promote complete and adequate review of research activities commonly conducted at MIT. The membership includes:
- at least one member unaffiliated with MIT and who is not part of the immediate family of a person who is affiliated with the institution
- at least one member whose primary concerns are in nonscientific areas, such as lawyers, ethicists, and clergy
Members include both men and women and members of minority groups. Designated alternates may be used. The membership lists are updated when membership changes and are submitted to the Office for Human Research Protections (OHRP) as required by MIT’s Assurance.
Management of Human Research Activities
COUHES is an autonomous committee of MIT. The administrative activities of COUHES are overseen by the Vice President for Research.
COUHES is supported by administrative staff consisting of a human research compliance administrator and two administrative assistants.
The Chairperson is appointed by the President of MIT. There are no term limits placed on length of service. The Chairperson is generally selected from among experienced members of COUHES or the MIT community is very familiar with regulatory requirements and ethical considerations. The Chairperson is are required to attend at least one IRB-related workshop or meeting every year.
The Chairperson is responsible for:
- presiding at COUHES meetings during which initial and continuing review of all research protocols involving human subjects are conducted
- involving human subjects are conducted
- conducting initial and continuing review of research protocols involving human subjects that may be approved using expedited review procedures
- determining exempt status of research involving human subjects
- reviewing adverse events, amendments to protocols, and other activities as required to fulfill institutional responsibilities as set forth in the Assurances
Human Research Committee members are appointed by the President of MIT. Members are selected based on reputations for fairness, objectivity and commitment to exercise faithfully their responsibilities for protection of human subjects in research according to the Belmont Report, and relevant federal regulations. There are no term limits placed on length of service.
New members are provided with IRB-related information, including, but not limited to, COUHES forms, COUHES Policies and Procedures Manual, and access to the COUHES web site, which links to applicable Federal regulations and the Belmont Report. New members are also required to take and pass the COUHES web-based training course on human subjects’ research
All members receive copies of various IRB-related publications, e.g., IRB, Human Research Report and IRB policy related communications from OHRP, FDA, or other governing agencies.
Members are responsible for initial and continuing review of all research protocols involving human subjects that require review at a convened meeting. Members are expected to attend at least 2/3 of the scheduled COUHES meetings. Attendance records are reviewed annually. Members who have not attended one-half of the scheduled meetings during the past year will be removed from the voting membership, unless the member has a designated alternate.
COUHES members are responsible for the review of research protocols scheduled for the meeting and for considering:
- the appropriateness of the study population
- the appropriateness of the methods of recruitment and process for informed consent of subjects
- the risks and anticipated benefits to subjects as well as the importance of the knowledge that may reasonably be expected to result
- the accuracy and completeness of information in the consent form as well as the language used and presentation of the information
Although rarely needed because of the depth and breadth of the membership on COUHES, consultants may be used to supplement or provide expertise not available on the Committees. When used, consultants are asked to attend the meeting and/or provide a written summary of their findings relative to the scientific merits of the study and risks and benefits to subjects. Consultants are not voting members.
Members of COUHES are required to recuse themselves from participating in the deliberations and vote on research protocols with which they have a conflict of interest by virtue of being listed as an investigator/study staff on the protocol or otherwise having a conflict of interest.
Functions of COUHES
COUHES is responsible for the following:
- conducting initial and continuing review of all research protocols under their purview
- reporting, in writing, findings and actions of COUHES to the investigator
- determining which studies require review more often than annually
- determining which studies need verification from sources other than the investigators that no material changes have occurred since previous COUHES review
- ensuring prompt reporting to COUHES of changes in research activities
- ensuring that changes in approved research are not initiated without COUHES review and approval except where necessary to eliminate apparent immediate hazards
- ensuring prompt reporting to COUHES, appropriate MIT officials, OHRP and the FDA of (1) unanticipated problems involving risks to subjects or others, (2) serious or continuing noncompliance with regulations governing research involving human subjects or the requirements of COUHES; and (3) suspension or termination of COUHES approval
- determining which device studies pose significant vs. non-significant risk, according to guidance provided by the United States Food and Drug Administration (21 CFR 812)
Operations of COUHES
COUHES meets monthly, generally on the third Thursday of every month. The meeting dates and times are posted on the COUHES website.
Initial and continuing review of research protocols is conducted either at a convened meeting of a quorum of the membership of COUHES, or using expedited review procedures as authorized in 45 CFR 46.
Review at a Convened Meeting of a Quorum of the Membership
Initial and continuing review of research protocols that cannot be reviewed using expedited review procedures are reviewed at a convened meeting of COUHES at which a quorum of the membership is present, including at least one physician/scientist and at least one member whose primary concerns are in nonscientific areas. A quorum is defined as one more than one-half the voting membership.
As protocols, amendments, and continuing review questionnaires are received in the COUHES office, the Chairperson, or any other COUHES members designated by the Chairperson, will conduct a primary review and correspond with the investigator as needed. Approximately one week prior to the meeting, copies of all forms and research protocols, amendments, continuing review progress reports, reports of adverse events and other correspondence or documents relevant to the protocols listed on the agenda for the meeting are distributed to all members of COUHES.
The discussion of each new research protocol, continuing review questionnaire, amendment or adverse event listed on the meeting agenda is led by the Chairperson. At the end of the discussion, the Chairperson make a motion to approve, require modifications in the protocol and/or consent form to secure approval (approve with modifications), or defer action on the protocol. When the motion is to approve (or approve with modifications), the motion includes the period for which COUHES approval is to be granted, i.e., one year or less. The duration for which COUHES approval is granted is based upon the level of risk to subjects, and the analysis of this risk as it relates to risks of standard care, if applicable. COUHES performs this risk assessment as part of the review of each protocol at the convened meeting. When the risk is great in relation to the risk associated with alternative procedures, if any, COUHES will consider requiring continuing review be conducted in less than one year, or for one year with case-by-case reporting. A vote on the motion is taken (for, against, abstain) and recorded in the minutes. Any member with a conflict of interest recuses him/herself from review of the protocol and leaves the room before the discussion of and vote on the research protocol takes place. The names of those members who were recused from voting due to a conflict of interest are recorded in the minutes. Recused members are not counted towards the quorum requirement; therefore if a quorum of the membership is not present for the review of any protocol, action on the protocol is deferred automatically.
Review Using Expedited Review Procedures
Research protocols involving no more than minimal risk, and in which the only involvement of human subjects will be in one or more of the categories of research procedures that may be reviewed through an expedited review procedure as authorized by 45 CFR 46.110, are reviewed by the Chairperson or by a COUHES members designated by the Chairperson. The reviewer(s) may approve or require modifications in the protocol and/or consent form to secure approval or defer action pending additional information; however the reviewer(s) may not disapprove a study. A list of all research protocols involving human subjects that have been approved using expedited review procedures is provided to COUHES at the next convened meeting.
Criteria for Approval
- COUHES will approve a research protocol only if the following criteria for approval are satisfied
- risks to subjects are minimized
- risks to subjects are reasonable in relation to anticipated benefits
- selection of subjects is equitable
- informed consent is adequate and appropriately documented
- where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects
- where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data
- appropriate safeguards have been included to protect vulnerable subjects (i.e., children, prisoners, and pregnant women in accordance with 45 CFR 46 Subparts B, C, and D
Notification of Investigators
Principal investigators are notified in writing of the results of COUHES review
- approval pending ancillary committee review and approval
- approval subject to modifications to the protocol and/or consent form required by the Committee in order to secure approval
- deferral subject to provision of additional information and response to questions and/or concerns raised by the Committee during the review
- disapproval, as not meeting ethical standards for conduct of human-subject research
When the research protocol is approved, the investigator is notified of the following:
- requirement to use only COUHES approved copies of the consent form(s), questionnaire(s), letter(s), advertisement(s)
- requirement to obtain COUHES approval of any modifications or changes to the protocol and consent form prior to initiation of the proposed changes
- requirement to report any serious and unexpected adverse events
- requirement to keep a research file containing all protocol related forms and correspondence for 3 years after completion of the research
- expiration date of COUHES approval
Responses to COUHES Review
Whenever modifications are required to a protocol and/or consent form to secure COUHES approval or a research protocol is deferred for additional information, investigators are asked to provide a point-by-point response to the Committee’s requests for modifications or response to questions and concerns as well as a revised protocol and/or consent form, if indicated.
Responses to Committee vote to require modifications in the protocol and/or consent form are reviewed by the Chairperson. The Chairperson may give final approval once all required changes have been made. COUHES approval is affirmed once all modifications are made to the protocol and/or the consent form consistent with the requirements of the Committee. When, in the opinion of the Chairperson, an investigator fails to meet the requirements of the Committee the investigator’s response is placed on the Committee agenda for reconsideration at a convened meeting.
Responses to Committee vote to defer action on a research protocol are reviewed at the next scheduled convened meeting of COUHES.
Review and Approval by Ancillary Committees
When the research protocol involves the exposure to ionizing or non-ionizing radiation, or involvement by the Clinical Research Center (CRC), respective approval of the Committee on Radiation Exposure to Human Subjects (COREHS) or the Advisory Committee of the CRC, are required prior to activation of the study to enrollment of subjects.
Copies of research protocols involving radiation exposure or use of the CRC are forwarded to the appropriate ancillary committees for review and approval. Notification of review and action taken by the ancillary committees is forwarded to COUHES. When all of the applicable ancillary committees have given their approval, investigators are notified of approval to activate the study to the enrollment of subjects.
Notification of Need for Continuing Review
Sixty days prior to expiration of COUHES approval, the investigator is notified that continuing review of their research protocol is coming due. A form is provided to obtain the required information and documents. Once the completed form and required documents are received, the protocol is reviewed either at a convened meeting of COUHES or using expedited review procedures as described previously.
If a continuing review progress report has not been submitted by the date COUHES approval expires the investigator is notified in writing: that the study has been automatically terminated; that subjects may no longer be enrolled in the study until the protocol and consent form have been re-approved by COUHES; and that research grants related to the study will be suspended. Enrolled subjects actively on study may continue on study while continuing review is in process. If the study has been completed or if the study is not active currently and there is no plans to activate or re-activate the study, the investigator is requested to submit a final report using the Continuing Review Questionnaire.
Review of Proposed Changes in the Research During Period of Approval
Investigators are required to submit proposed changes to protocols and/or consent forms to COUHES for approval prior to implementation. A form is provided for submission of proposed changes. Proposed changes (or amendments) are reviewed by the Chairperson who determines whether or not the change is minor, based upon the nature of the proposed change and whether the change alters the risks and benefits considered by the Committee at the time of initial review.
When a proposed change is not minor, or the Chairperson determines full Committee review is necessary, it is reviewed by COUHES at a convened meeting as described previously. The only exception is the rare circumstance in which a change is necessary to eliminate apparent immediate hazards to the research subjects. When the proposed change is minor, it is reviewed by the Chairperson using expedited review procedures described previously. The investigator is notified of review as described previously. If ancillary committee review(s) is required, activation of the proposed change is subject to approval by the appropriate ancillary committee as well as COUHES.
The procedures COUHES uses to ensure prompt reporting to COUHES of proposed changes in a research activity, and for ensuring that such changes in approved research, during the period for which COUHES approval has already been given, may not be initiated without COUHES review and approval except when necessary to eliminate apparent immediate hazards to the subject are:
- inclusion of statement in the approval letter reminding investigators of requirement to submit any changes to the protocol and/or consent form to COUHES for approval prior to initiation of the change
- inclusion of requirement to obtain COUHES approval of changes to the protocol and/or consent form prior to initiation of changes in the required education program for research personnel
- performance of random audits of investigator’s protocol-specific records and files by the COUHES staff and the MIT Audit Office.
Review of Serious and Unexpected Adverse Events and Sponsor Safety Reports
Investigators are required to report serious and unexpected adverse events to COUHES within 48 hours by telephone, fax or e-mail followed by a complete written report within 10 working days. All other adverse events must reported to COUHES within 10 working days. A form is provided to facilitate on-site reporting and to obtain the required information. Adverse event reports are reviewed by the Chairperson to determine the relationship of the event to the study procedures, drug, and/or device, and whether any further action needs to be taken.
If the event is felt to be possibly, probably or definitely related, the reviewer will determine whether:
- changes to the protocol are needed to minimize risks to subjects;
- changes to the consent form are needed to accurately reflect the nature, frequency or severity of the event;
- subjects should be asked to re-consent to study participation;
- the study should be placed on temporary hold to new enrollment and/or the study procedures should be discontinued because, based on the information available, the risk benefit ratio appears to be unfavorable to the subjects.
Investigators are notified of review and whether any modifications are required to the protocol and/or consent form. When the reviewer determines that the study must be placed on temporary hold pending further review by the Committee, the principal investigator and site responsible investigators are notified immediately by fax or e-mail. A copy of the notification is sent to the department head of the principal investigator.
A serious adverse event is defined as any event that suggests a significant hazard, contraindication, side effect, or precaution. A serious adverse event includes any event that results in any of the following outcomes:
- a life threatening experience
- hospitalization or prolongation of existing hospitalization
- a persistent or significant disability/incapacity
In addition, events may be considered serious when, based upon appropriate medical judgment, they may jeopardize the subject and require an intervention to prevent one of the outcomes listed above.
An unexpected event is defined as any event, the specificity or severity of which is not consistent with the risk information described in the general investigative plan or elsewhere in the current application, as amended.
Investigators are required to submit copies of sponsor safety reports promptly to the COUHES for their review. Sponsor safety reports are reviewed by the Chairperson to determine the relationship of the event to the study procedure/drug/device and, if possibly, probably or definitely related, whether changes to the protocol are needed to minimize the risks to subjects or changes in the consent form are needed to accurately reflect the nature, frequency or severity of the event. Investigators are notified when changes are required to the protocol and/or consent form.
Serious or Continuing Noncompliance with Human Subjects Regulations or COUHES Requirements
When COUHES becomes aware of possible serious or continuing noncompliance with the regulations governing research involving human subjects or the requirements of COUHES, the possible serious or continuing noncompliance will be investigated by the Chairperson, or a member of COUHES designated by the Chairperson.
The Chairperson, or his designee, will prepare and forward a report to COUHES and other MIT Officials, as appropriate, who are responsible for the oversight of the protocol for review and action. If COUHES finds that there has been serious or continuing noncompliance on the part of an investigator(s), appropriate action will be taken and a report filed with the Vice President for Research, the Office for Human Research Protections, and the Food and Drug Administration as appropriate.
Suspension or Termination of Research
Whenever COUHES suspends or terminates a research protocol involving human subjects for any reason, the following individuals, in addition to the investigators listed on the protocol and departments/institutions involved in the research, may be notified, if applicable:
- MIT Official(s)
- Office for Human Research Protections (OHRP)
- Food and Drug Administration (FDA)
- Commonwealth of Massachusetts Department of Public Health
Non-Significant Risk (NSR) Determination in Medical Device Clinical Studies
During the initial review COUHES assesses whether the investigation involves significant or non-significant risk. In accordance with 21 CFR part 812 COUHES defines two types of medical device studies: those entailing "significant risk (SR) and those entailing "non-significant risk (NSR). An SR device study is a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and (1) is intended as an implant; or (2) is used in supporting or sustaining human life; or (3) is of substantial importance in diagnosing, curing, mitigating or treating a disease, or otherwise prevents impairment of human health; or (4) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject. An NSR device investigation is one that does not meet the definition for a significant risk study. For both SR and NSR device studies, COUHES approval prior to conducting clinical trials and continuing review by COUHES are required. In addition, informed consent must be obtained for either type of study.
If COUHES determines that a device study entails SR, the investigation may not begin until both COUHES and the FDA approve the investigation. To help in the determination of risk status of the device, COUHES will review information such as reports of prior investigations conducted with the device, the proposed investigational plan, a description of subject selection criteria, and monitoring procedures. COUHES expects the sponsor to provide the committee with a risk assessment and the rationale used in making its risk determination.
Additionally, COUHES policy indicates that the FDA has the ultimate decision in determining if a device study entails SR or NSR. If the FDA does not agree with COUHES decision that a device study presents an NSR, an IDE application must be submitted to the FDA and an exemption granted.
All COUHES determinations on the SR/NSR status of a medical device study shall be recorded in the minutes of the COUHES meeting at which these determinations are made.
Emergency Use of an Investigational Drug or Biologic
COUHES allows the emergency use of an investigational drug or biologic if the FDA requirements for emergency use, contained in 21 CFR 56.102(d) and 104(c ), are met.
Emergency use of an investigational drug or biologic is defined as the use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain approval from COUHES.
COUHES will allow a single emergency use of a test article without prospective review. This emergency use provision is an exemption from prior review and approval by COUHES. Any subsequent use of the investigational product at MIT must have prospective COUHES review and approval. However, in accordance with FDA guidelines, COUHES may consider it inappropriate to deny emergency treatment to a second individual if the only obstacle is that COUHES has not had sufficient time to convene a meeting to review the issue.
Investigators implementing these emergency use provisions shall do the following:
Determine if the proposed use meets the regulatory definition for emergency use of an investigational drug or biologic. Emergency uses must meet ALL of the following criteria:
- The subject has a disease or condition which is life-threatening (e.g., the likelihood of death is high) or severely debilitating (e.g., may cause irreversible morbidity, such as blindness, loss of limb, loss of hearing, paralysis or stroke)
- The subject’s disease or condition requires intervention with the investigational drug or biologic before review at a convened meeting of COUHES is feasible
- No standard acceptable treatment is available.
Contact the manufacturer of drug/biologic to determine if it can be provided under an existing IND or, if not available through the manufacturer, contact the FDA for an Emergency IND.
Contact the COUHES office at MIT at 617-253 6787 to notify it of a planned emergency use of a drug or biologic.
Contact the MIT Pharmacy 617-253 1517 to inform them of the planned use and shipment of drug.
Obtain informed consent from subject or, if incompetent to give informed consent, the subject’s next of kin or legally authorized representative. The requirement for informed consent may be waived if the investigator and a physician who is not otherwise participating in the clinical investigation certifies in writing to all of the following:
- The subject is confronted by a life-threatening (or severely debilitating) situation necessitating the use of the investigational drug or biologic
- Informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject
- Time is not sufficient to obtain consent from the subject’s next of kin or legal representative
- No alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life
Submit to COUHES within 5 working days after the use of the investigational drug or biologic a comprehensive written report on the circumstances for the use of the test article.
Emergency Use of an Unapproved Device
COUHES will allow for the emergency use of an unapproved device if the FDA requirements for emergency use are met and, whenever possible, the COUHES Office is notified of intent to use an unapproved device.
Emergency use of an unapproved device is defined as the use of an unapproved device for a purpose or condition for which the device requires, but does not have, an approved application for premarket approval (FDA approval for marketing) with a human subject in a life-threatening situation where the unapproved device may offer the only possible life-saving alternative, but an IDE for the device does not exist, or the proposed use is not approved under an existing IDE, or the physician or institution is not approved under the IDE.
If a physician chooses to use an unapproved device in such an emergency, the physician must later justify to FDA that an emergency actually existed. Each of the following conditions must exist to justify emergency use:
- the patient is in a life-threatening condition that needs immediate treatment
- no generally acceptable alternative for treating the patient is available
- because of the immediate need to use the device, there is no time to use existing procedures to get FDA approval for the use
Even in an emergency situation, the investigator is required to obtain informed consent from the subject or the subject's legally authorized representative unless both the investigator and an independent physician certify in writing all of the following:
- the subject is confronted by a life-threatening situation necessitating the use of the investigational device
- informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject
- time is not sufficient to obtain consent from the subject's legal representative
- no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the life of the subject
Although COUHES does not have to prospectively review the emergency use of an unapproved device in a life-threatening situation, whenever possible, investigators are required to contact the COUHES Office and document that an emergency exists.
Investigators are required to submit a report on the emergency use to COUHES within 5 working days. The report is reviewed by the Chairperson to ensure that the emergency use meets FDA regulations. The investigator is informed that if he/she anticipates the need to use the investigational device in additional subjects, prospective review by COUHES is required.
COUHES Record keeping Requirements
COUHES maintain records of their activities for at least 3 years after completion of the research. The records are available for inspection and copying by the Food and Drug Administration (FDA), federal or state government agencies, or hospital accrediting agencies in the course of carrying out their respective duties.
The following records are maintained:
- written policies and procedures
- minutes of meetings that include members present, summary of discussion where appropriate on protocol-related issues, actions taken by COUHES, and record of voting (for, against, abstain)
- copies of research protocols reviewed, approved sample consent documents, continuing review progress reports, amendments to research protocols, adverse event reports as well as any other protocol-related correspondence between COUHES and the investigator
Information Provided By Investigators For COUHES Review
Investigators are required to submit research protocols in accordance with COUHES submission instructions. The submission requirements include the following:
- Initial Review
- signed application form
- recruitment materials (letters, advertisements, postings, e-mail announcements, etc.)
- questionnaires, interview outlines and standardized instruments
- consent form
- IRB approvals from collaborating institutions, if applicable
- FDA approvals (IND, IDE), if applicable
- grant application, if applicable
- Continuing Review
- signed Continuing Review Questionnaire
- consent form
- grant application (new or continuation), if applicable
- Adverse Events Experienced by Subjects at Sites Covered by Partners HRC
- signed adverse event form
- revised consent form (if applicable)
- Proposed Changes to Protocol and/or Consent Form
- signed change form
- detailed description of proposed changes
- rationale for the changes
- revised consent form (if applicable)
Changes and Modifications of Policies and Procedures
From time to time, as may be necessary or appropriate to ensure fulfillment of institutional responsibilities under existing Assurances, to improve operational efficiency, or to address other concerns that may arise, these Policies and Procedures may be revised. All revisions will be documented as an addendum until such time as a revised version of this document is prepared.