CHS Policies and Procedures
Harvard University Faculty of Medicine Committee on Human Studies Policies and Procedures
(version date: 23 November 2011)
The preamble to Harvard University’s “Statement of Policies And Procedures Governing the Use of Human Subjects in Research,” voted by President and Fellows of Harvard College on September 22, 2003 (Appendix 1), informs the oversight of all research covered by these policies and procedures:
Harvard University is guided by the ethical principles regarding research involving human subjects set forth in the report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Ethical Principles and Guidelines for the Protection of Human Subjects of Research [the “Belmont Report”]). The minimum standard is set by the Department of Health and Human Services [DHHS] regulations at 45 CFR 46 (the “Common Rule”). Harvard University has additional provisions beyond that standard, which help to establish the highest expectations for performance and oversight by investigators, Institutional Review Boards (IRBs), and the University.
The actions of Harvard University regarding research involving human participants also must conform to all other applicable federal, state, and local laws and regulations.
To oversee and regulate research involving human participants most effectively, the University maintains three Institutional Review Boards, with three separate Federal Wide Assurances (FWAs): one for the Faculty of Medicine (comprised of Harvard Medical School (HMS) and the Harvard School of Dental Medicine (HSDM)), one for the “University Area” (which includes the Faculty of Arts and Sciences; Harvard Graduate School of Education; John F. Kennedy School of Government; Harvard Divinity School; Harvard Business School; Harvard Law School; Harvard Graduate School of Design; and the Radcliffe Institute for Advanced Study); and one for the School of Public Health. Each of these three IRBs reviews research protocols involving human participants and evaluates risk to participants, protection against risks, and potential benefits likely to result from proposed research. It is the function of each IRB to 1) determine and certify that all projects reviewed by the IRB conform to policies and procedures set forth by the University’s “ Statement of Policies And Procedures Governing the Use of Human Subjects in Research,” and, as appropriate, applicable regulations of the Department of Health and Human Services (DHHS) and other federal agencies regulating (e.g. the Food and Drug Administration) the health, welfare, safety, rights, and privileges of human participants; and 2) assist the investigator in complying with relevant federal, state, and local laws and regulations, and University policy.
While the three Harvard IRBs operate independently, the Directors and Administrators from the three IRBs participate in an Operations group that meets at least quarterly, and from time to time includes the Institutional Officials, Chairs, the Vice Provost for Research and representatives from the Office of General Counsel. This meeting serves as a forum to discuss issues affecting the University and the University’s IRBs.
In fulfillment of its FWA, the Harvard University Faculty of Medicine has established the Committee on Human Studies (the “CHS,” also referred to as the Committee, the IRB, or the Research Review Unit), which reviews research projects and activities that involve human participants and oversees the implementation of all policies and procedures for human studies research. The Faculty of Medicine Office for Research Subject Protection (ORSP) has been established as the appropriate administrative oversight office for the CHS. The ORSP is supervised by the Dean for Faculty and Research Integrity, an official with sufficient standing, authority, and independence to ensure implementation and maintenance of the HMS and HSDM Human Research Protection Program (HRPP).
The CHS is authorized to function independently as the entity authorized to review human research proposals for the Faculty of Medicine. In accordance with federal requirements, the decision of the CHS disapproving or restricting research proposals cannot be overruled elsewhere at Harvard; nor can another individual or entity at the Faculty of Medicine approve human research under the purview of the CHS that the CHS has not reviewed and approved. Research reviews are conducted in a manner ensuring the independent judgment of Committee members, who will be excluded from voting on projects or activities in which they have a role, or a personal, professional, or financial conflict of interest.
The Faculty of Medicine holds a FWA with DHHS. This FWA is the Institution’s assurance of compliance with human studies regulations at 45 CFR § 46 and the ethical principles of the Belmont Report. The Faculty of Medicine FWA registration number is: FWA00007071 (Appendix 2). The IRB registration number for the CHS is: IRB00000298.
The CHS has been assigned the responsibility to determine that each study planned and conducted meets the following criteria: 1) Risks to participants are minimized by using procedures consistent with sound research design and which do not unnecessarily expose participants to risk, and whenever appropriate, by using procedures already being performed on the participants for diagnostic or treatment purposes; 2) Risks to participants are reasonable relative to anticipated benefits to participants, if any, and importance of the expected knowledge to be gained; 3) Selection of participants is equitable taking into account the purpose and setting; 4) Informed consent will be sought from each prospective participant or the participant’s legally authorized representative, in accordance with, and to the extent required by the regulations; 5) Informed consent will be appropriately documented , in accordance with, and to the extent required by the regulations; 6) The research plan, as defined in the CHS application and protocol, provides for ensuring the privacy of participants and confidentiality of the data; 7) When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of participants; and 8) When some or all of the participants are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, persons with cognitive disabilities, or those with educational or economic disadvantages, additional safeguards have been included in the study to protect the rights and welfare of these participants.
All research involving human participants (also referred to as subjects) will be reviewed, administered and overseen in accordance with all applicable federal and state regulatory requirements and institutional policies when any of the following are true:
- The research is funded by or through HMS or HSDM;
- The research is conducted by HMS-based and HSDM-based faculty, acting in their capacities as such;
- The research is conducted by students of HMS or HSDM acting in their capacity as such;
- The research is conducted by non-faculty employees of HMS or HSDM acting in their capacities as such;
- The population from which participants will be drawn is exclusively or substantially composed of individuals who are patients, students or employees of HMS or HSDM;
- The research makes substantial use of the property or facilities of HMS or HSDM;
- The research involves the use of HMS or HSDM non-public information for the purposes of the research, or to identify or contact prospective participants.
- No funds (federal, foundation, private, corporate, departmental, or other) may be expended for research involving human participants unless the requirements of the FWA have been satisfied and a CHS approval or exemption has been documented.
- Any studies subject to regulations of the Food and Drug Administration (FDA) will be conducted in accordance with those regulations.
Additionally, the CHS follows the Department of Health and Human Services (DHHS) Office for Human Research Protections (OHRP) Guidance on Engagement of Institutions in Human Subjects Research, which states “In general, an institution is considered engaged in a particular non-exempt human subjects research project when its employees or agents for the purposes of the research project obtain: (1) data about the subjects of the research through intervention or interaction with them; (2) identifiable private information about the subjects of the research; or (3) the informed consent of human subjects for the research.”
The CHS reviews mostly social and behavioral research studies with a wide array of participant populations, including, for example, persons with mental illnesses or addictions to substances. Other studies involve medication adherence, program evaluations, and Medical and Dental School curriculum. The CHS does review a number of clinical studies that take place at the Harvard Dental Clinic, the Veterans Administration Boston Healthcare System and at international sites. However, the majority of the clinical studies performed by Harvard faculty are reviewed by the IRBs at the hospitals or clinics where the research is taking place.
The mission of the CHS is to ensure that all participants are protected from any unnecessary risk when enrolled in a research study; to ensure participants make an informed decision to participate, and when possible, ensure that participant and/or society at large benefits from the knowledge gained from the research study. The goal of the CHS is to assist Investigators in developing appropriate research protocols in accordance with federal, and University policies, and within accepted ethical guidelines.
The CHS is guided by the ethical principles set forth in the Belmont Report. The Belmont Principles apply regardless of whether the research is subject to Federal regulation, with whom the research is conducted, or source of support or sponsorship.
In addition to the Belmont Report, HMS/HSDM faculty, staff and students are expected to comply with all applicable provisions of the HMS Faculty Policies on Integrity in Science (Appendix 3), as well as Harvard University’s Statement of Policies and Procedures Governing the Use of Human Subjects in Research, its Enterprise Security Policy and Research Data Security Policy (Appendix 4a and 4b), the HMS Information Security Policy (Appendix 5) and the Harvard University Statement of Values (Appendix 6).
As Harvard Medical and Dental Schools are educational institutions, the CHS also reviews student projects that do not fall under the federal definition of “human subjects research” (such as program evaluations or community service projects that are not designed to contribute to generalizable knowledge). The CHS reviews such projects to ensure that appropriate institutional and ethical standards have been incorporated into the project design and materials to be used with project participants.
All institutional and non-institutional performance sites, domestic or foreign, will be obligated to conform to ethical principles which are at least equivalent to those of HMS and HSDM. In the case of federally funded studies, all sites (including international sites) will be asked to apply for an FWA and to obtain protocol review by an IRB or equivalent ethical review board.
1.2.1. IRB Independence from Undue Influence
The Faculty of Medicine takes seriously allegations that the CHS, its staff or any of its members have been subjected to any form of coercion or undue influence by Investigators, Harvard officials, study sponsors or other individuals. These incidents should be reported so that appropriate investigation may be made to assure that the independence of the CHS is not compromised. Allegations may be made to a number of officials, including the Dean of the Faculty of Medicine, the Dean for Faculty and Research Integrity, the Faculty of Medicine and HSPH Ombudsman, the CHS Chair, the ORSP Director, the CHS Associate Director, and the Director of Research Compliance. In cases involving allegations of undue influence or coercion by faculty members, the processes set forth in the HMS Principles and Procedures for Dealing with Allegations of Faculty Misconduct (Appendix 7) will ordinarily be followed.
1.2.2. Institutional Conflict of Interest
Harvard University is in the process of developing an institutional conflict of interest policy and procedures to ensure that research involving human participants at the University is conducted free from any influence stemming from the University's financial investments. After review by appropriate offices and officials, the draft policy and procedures will then go before the Risk Management Committee and Provost, prior to going before the Corporation for approval.
1.2.3. Conflicts of Interest Policies for Faculty, Senior Officers and Others
The Faculty of Medicine has developed individual conflict of interest policies for its faculty (Appendix 8) and in addition the University has conflict of interest policies for its senior officials (Appendix 9) and members of its governing boards, as well as policies relating to conflicts of interest in procurement, in the granting of technology licenses (Appendix 10), and the creation of start-up companies (Appendix 11). These policies specify various limitations on Harvard and its trustees, officers, and employees in making a range of business and academic related decisions, some of which might involve or have an affect (real or perceived) on human research studies or the protection of research participants. As the University is a non-profit educational corporation, no one, including University officials, faculty, staff or students, is able to own equity in it.
All requirements of 45 CFR § 46 and subparts A (Protection of Human Subjects), B (Additional Protections for Pregnant Women, Human Fetuses and Neonates involved in Research), C (Additional Protections Pertaining to Biomedical and Behavioral Research involving Prisoners as Subjects), D (Additional Protections for Children Involved as Subjects in Research) and E (Registration of Institutional Review Boards) will be met for all research, regardless of sponsorship, except if otherwise noted in the CHS FWA.
Any studies that fall under the jurisdiction of the FDA will be conducted in accordance with applicable FDA administered statutes and regulations, including the Code of Federal Regulations 21 CFR § 50 (Protection of Human Subjects), 21 CFR § 56 (Guidance for IRBs and Clinical Investigators), 21 CFR § 312 (Investigational New Drug/IND), and 21 CFR § 812 (Investigational Device Exemptions/IDE), as applicable.
In addition to federal regulations, the CHS follows certain Commonwealth of Massachusetts requirements relating to the ethical conduct of research. Where state regulations differ from federal regulations, the more stringent regulations shall be followed. This is noted in the appropriate policy sections.
2.1. Responsibilities of the Institution
The Faculty of Medicine bears responsibility for the performance of research involving human research participants covered by its FWA, including compliance with previously noted federal and state laws as they may relate to such research.
The Faculty of Medicine, including all its named components (Appendix 12), acknowledges and accepts its responsibilities for protecting the rights and welfare of research participants covered by its FWA, including:
- Ensuring that CHS and University policies are in compliance with evolving laws and regulations.
- Publicizing policies and requirements regarding research with human participants for the research community.
- Establishing and maintaining an appropriately qualified CHS.
- Providing both meeting space and sufficient staff and resources to support the CHS, its review and record-keeping responsibilities.
The Faculty of Medicine provides appropriate staff, office space, computer equipment, finances, materials and other resources for the CHS. The budgets supporting the CHS are reviewed annually as part of the budget review cycle. The budget reviews include annual assessments of staffing and salary levels, and of non-salary resources, including equipment, materials and training needs. The Dean for Faculty and Research Integrity (the CHS Institutional Official, or IO) and the ORSP Director undertake the budget review with the HMS Budget Director from Financial Operations and Analysis (FOA).
As part of the provision of sufficient resources to the CHS, the Faculty of Medicine provides written materials and training opportunities to CHS members and to CHS staff, including policy and procedure manuals, checklists to assist research reviewers, continuously updated educational material relating to recent developments in human subjects research, opportunities to attend training sessions, and other guidance. The resources provided are sufficient to assure timely review of research projects, comprehensive meeting minutes, timely notifications and useful assistance to Investigators.
The IO has the responsibility to ensure that the CHS is provided with sufficient resources. Each quarter, the CHS Associate Director provides the IO and the ORSP Director with a spreadsheet of protocols reviewed by the CHS staff. Included with this list are the type of reviews (exempt, expedited, full committee and designated) and the approximate time from submission of the protocol to the office to the time the protocol is approved. Given the volume of the workload and the nature of the reviews performed in a thorough and timely manner, the IO has determined that the present single CHS for the Faculty of Medicine is sufficient to meet the needs of the research program.
2.2. Responsibilities of the Institutional Official
The Dean for Faculty and Research Integrity, who serves as the Institutional Official (IO), is responsible for the implementation and maintenance of the HRPP and the CHS (Appendix 13). The IO has direct access to the Dean for Academic and Clinical Programs and to the Dean of the Faculty of Medicine. The budgets for the CHS, Office for Research Issues, and Office for Research Compliance, each of which supports the HRPP, are under the IO’s supervision. In addition to the Dean of the Faculty of Medicine, the Dean for Academic and Clinical Programs, and members of the Office of the General Counsel, the IO has direct access to the Dean of the HSDM and the University Provost’s Office.
The responsibilities of the Institutional Official include:
- Ensuring that research participants are protected;
- Ensuring that HMS/HSDM Investigators comply with University and CHS policies and Federal regulations protecting human research participants;
- Selecting a qualified CHS Chair;
- Selecting qualified CHS members in accordance with OHRP guidance;
- Assuring that the CHS Associate Director and CHS staff demonstrate appropriate knowledge and experience for their roles;
- Reviewing periodically the qualifications, knowledge and experience of the CHS Chair, members and staff.
- Assuring adequate resources for the CHS office (including office and meeting space, staff, supplies, and training);
- Assuring adequate compensation and/or recognition of the CHS Chair, members and staff;
- Providing appropriate educational opportunities to the CHS Chair, members and staff;
- Assuring independent actions of the CHS; including freedom from undue influence or coercion by University officials;
- Ensuring access for the CHS to legal counsel with expertise in human subjects protection issues;
- Providing guidance with complex issues, such as faculty or CHS member conflict of interest; Investigator non-compliance with federal regulations; and serious adverse events/unexpected problems, privacy, confidentiality and emergency issues involving research participants.
2.3. Responsibilities of the CHS
The CHS must understand and apply the University’s rules, and federal, state and local regulations on the use of human participants in research. The CHS will ensure effective knowledge of participant populations, institutional constraints, differing legal requirements, and other factors which can foreseeably contribute to a determination of risks and benefits to participants, and can properly judge the adequacy of information to be presented to participants in accordance with requirements of 45 CFR §§ 46.103(d), 107(a), 111, and 116. Additionally, the CHS will assure equitable selection of research participants, respect the autonomy of the participants and seek knowledge of the local research context.
The CHS will review and have the authority to approve, require modification to, disapprove, suspend or terminate research activities (including proposed changes to previously approved research) of the faculty, staff and students under the jurisdiction of the CHS. The CHS may observe, or have a third party observe, the consent process and the conduct of research.
Convened meetings of the CHS occur on a monthly basis. The CHS may hold interim review sessions, called by the Chair at the request of any CHS member or IO, to consider matters regarding the rights and welfare of any participant, or participant population. Additionally, CHS members will serve as reviewers for minimal risk studies meeting expedited and exempt research category requirements.
CHS reviews are in accordance with the basic ethical principles (respect for persons, beneficence, and justice) articulated in The Belmont Report to determine that:
- Risks to participants are minimized.
- Risks to participants are reasonable in relation to anticipated benefits, if any.
- Selection of participants is equitable.
- Informed consent is adequately obtained in accordance with federal regulations.
- Informed consent is appropriately documented, in accordance with federal regulations.
- Adequate provisions have been made for monitoring data collected, when appropriate.
- Adequate provisions have been made to protect privacy of participants and maintenance of confidential data, when appropriate.
- Additional safeguards are in place to protect vulnerable participants and others likely vulnerable to coercion, when appropriate.
- Timely continuing review of approved research is conducted as appropriate to each study.
- The CHS applications are in concordance with the grant application funding the research.
The CHS will also, in accordance with federal regulations and institutional policies, perform continuing reviews of all approved studies, and review and consider all reported adverse events, and unanticipated problems, as required, which it receives from the Investigator, from data and safety monitoring committees, or from Investigators at other sites in multi-center studies. The CHS will also, in appropriate cases, based on a serious adverse event, or other relevant information it receives after commencement of the study, terminate, suspend, or require modifications to a study, or take other appropriate steps to protect participants, such as requiring changes in the informed consent form, requiring re-consent, or requiring the provision of information to current participants or those who have already completed the study. In addition, the CHS, in many cases with the assistance or support of the CHS staff, the Office for Research Compliance or other Harvard offices or officials, will investigate and review instances of actual or alleged noncompliance, and will take appropriate action based on the results of its review and deliberations.
2.4. Responsibilities of the CHS Office
The CHS office is responsible for ensuring that the institution, its investigators, and its members follow the guidelines set forth in the following policies and procedures, and adhere to federal regulations regarding the protection of human research participants, as set forth in 45 CFR § 46, its subparts, and the ethical principles of the Belmont Report.
The CHS office is responsible for facilitating constructive communication among the CHS, investigators, department heads, administrators, institutional officials, and research participants, as a means of maintaining a high level of awareness regarding the safeguarding of the rights and welfare of research participants.
Responsibilities of the CHS office include:
- The application of and compliance with federal regulations, state/local laws and institutional policies regarding CHS procedures.
- Supporting and facilitating the CHS processes.
- Developing and implementing institutional CHS policies and procedures.
- Protection of human participants involved in research activities conducted at HMS and HSDM.
- Ensuring compliance with the institution’s FWA and other assurance processes.
- Developing and conducting training and education programs for CHS staff, CHS members, and research staff.
2.5. Responsibilities of the Investigator
The Investigator bears primary responsibility for the protection of human participants in research studies. Research Investigators must adhere to federal regulations regarding the protection of research participants as set forth in 45 CFR § 46, the ethical principles of the Belmont Report, and the guidelines set forth by the CHS and the Institution. Investigators must communicate with the CHS office, and submit timely applications and continuing renewal forms, as well as other required documentation on a yearly basis (or more frequently, if determined by the CHS). All researchers under the aegis of the CHS will:
- Take personal responsibility for their actions in pursuit of individual and organizational excellence.
- Uphold the highest standards of ethical and professional conduct in accordance with the Belmont Report, and Faculty of Medicine and University policies governing research.
- Complete periodic training to remain up-to-date on federal regulations, CHS policies and procedures and compliance expectations. In addition, direct key personnel involved in their research projects to do the same.
- In consultation with the CHS, determine whether their research requires CHS approval.
- Ensure the CHS application and protocol contain the same information as the funding proposal for extramural or intramural support. Provide accurate human studies approval information when corresponding with sponsoring agencies.
- Receive CHS approval before commencing research activities.
- Submit continuing review form, current informed consent forms, and associated study material for renewal at least annually to the CHS for review and approval.
- Obtain (and document, as required) informed consent from all participants, unless the CHS has issued a waiver of such.
- Ensure the confidentiality of participant data.
- Report the following study events to the CHS: adverse events, unanticipated problems with the study/study participants, non-compliance with the approved protocol, suspensions or terminations of research, complaints about the research (from study participants or others), protocol deviations and violations, and data safety monitoring reports (as applicable), in accordance with CHS policies and procedures. Report adverse events to sponsors and appropriate federal agencies as applicable and as required by those entities.
- Apply to the CHS for approval of changes to the study or study materials prior to implementing the changes.
- Maintain applications, protocols, approved informed consent forms, surveys and associated material related to the study as required by federal, state and HMS policies/procedures.
- Adhere to federal regulations, state and local laws, institutional and CHS policies and procedures regarding the safety and protection of human subjects.
- In conducting studies involving investigational drugs and devices, adhere to all requirements of FDA regulations, including reporting adverse events and unanticipated problems to the study sponsor as required by the protocol, and properly storing, using and documenting the receipt, use or disposal of controlled articles.
- Participate and cooperate in quality assurance reviews, investigations and other oversight, monitoring and investigative activities of HMS, HSDM or their designated representatives or personnel.
2.6. Responsibilities of Unaffiliated Investigators and Unaffiliated Institutions
Each unaffiliated Investigator at an unaffiliated research site (e.g., a private practice physician not otherwise an employee or appointee of HMS or HSDM or who otherwise would not ordinarily be bound by the provisions of the CHS FWA or any other or any other applicable institutional policies) involved in human studies research of this institution must request from the CHS office either an Agreement for an Independent Investigator or a Non-institutional Investigator Agreement, as appropriate, depending on the nature of the research activity.
Performance sites that are legally separate from the Faculty of Medicine are not authorized to cite the CHS FWA unless agreed to by the CHS and documented in an IRB Authorization Agreement citing this institution as the IRB of record.
2.7. Additional Institutional Support and Responsibility
There are many separate components of the Faculty of Medicine Human Research Protection Program (HRPP) that work with the CHS and the CHS office to ensure the protection of research participants and research compliance at HMS and HSDM, including the following Harvard offices and committees:
Financial Operations and Analysis (FOA) – provides budget support to the CHS and HMS/HSDM department administrators who manage grants/contracts/funding for Investigators. Responsibilities include providing the CHS budget and billing of other institutions that rely on the Faculty of Medicine for CHS review.
Sponsored Programs Administration (SPA) – provides pre- and post- grant award support for the Faculty of Medicine. SPA is responsible for ensuring that research projects have been approved before grant money is allocated for human research purposes. SPA has access to the CHS database to confirm the study status and that Investigator training requirements have been met, and additionally, the CHS copies the appropriate SPA representative on its human research approval notices. SPA is responsible for notifying the funding sources when research is suspended or terminated by the CHS office. Faculty of Medicine policy is to not release funds for human research of a primary, supplemental, subcontract, or renewal award until current CHS approval is documented.
Office of Technology Development (OTD) – negotiates intellectual property (IP) issues in Clinical Trial Agreements (CTAs) and Sponsored Research Agreements (SRAs), and approves Material Transfer Agreements (MTAs) with institutions that may support human research at HMS/HSDM. SRAs and CTAs received by the CHS or Sponsored Programs Administration are forwarded to OTD for review and negotiation. CHS, with assistance from ORC, ORI and OGC as needed, reviews terms related to any protocol-specific issues, including but not limited to, the proposed scope of work, compensation for researchers and research participants, terms related to any provision of equipment or medications, the management of adverse events and unanticipated problems, financial responsibility in case of injury, the confidentiality and privacy of participants and their data, and consistency with applicable guidelines, federal regulations and Harvard University/HMS/HSDM policies pertaining to the protection of participants in research and the integrity of science.
OTD is responsible for reviewing/approving MTAs. IRB staff are responsible for referring Investigators to OTD when MTAs have not already been negotiated. OTD is responsible for referring Investigators to the CHS, if IRB approval has not already been obtained.
Committee on Microbiological Safety (COMS) – provides independent health and safety reviews of studies involving the use or manipulation of rDNA molecules and other etiological biological agents of concern to the CHS including but not limited to retroviral vectors and toxic or select agents used in human studies. Responsibilities include reviewing and registering studies involving recombinant DNA and agents pathogenic for animals, including humans, plants, and biological toxins. Two kinds of human studies are reviewed and approved by COMS - those involving gene transfer and those involving the transplantation of animal tissues into humans. These reviews by COMS are intended to ensure that all potentially hazardous biological materials used in a study will be properly contained and used, and to ensure the health and safety of researchers, employees, study participants and the public. Approval by COMS is required prior to final approval from the CHS for studies of this nature. Representatives from COMS regularly attend CHS meetings.
Countway Library of Medicine (Countway) – works with the CHS on access to faculty and medical research records housed in the library that are under the CHS and/or Privacy Board purview (such as waiver of HIPAA Authorization for Protected Health Information (PHI) contained in archived medical records). Responsibilities include referring researchers to the CHS for appropriate applications for review and final approval of projects. Countway staff are responsible for forwarding access requests to the CHS/Privacy Board, and the CHS is responsible for communicating the results of the reviews/approvals back to Countway staff. Countway staff will notify the requesting party of the results of the review.
Office of Research Compliance (ORC) – helps to ensure that sponsored funds are managed in a manner consonant with agency guidelines, serves as a resource for research administration in the resolution and enforcement of research compliance issues, facilitates and coordinates training, education, and outreach initiatives, helps design and implement various auditing, monitoring and quality assurance activities and programs, assists or leads non-compliance inquiries and investigations, collects non-compliance trending data and employee survey information to identify compliance risk areas, and helps to provide policy guidance and clarify roles and responsibilities within HMS and HSDM.
The Director of the ORC is responsible for the negotiation of CTAs and RSAs and works closely with OTD to manage IP issues, and with the CHS to ensure the proper language regarding scope of work, along with compensation (for the researchers and research participants), provision of equipment or medications, management of adverse events and unanticipated problems, responsibility in case of injury, confidentiality and privacy of participants and their data, and other protocol-specific issues are included in these Agreements. Additionally, the ORC Director works with the Office of the General Counsel at Harvard to ensure that the terms and conditions of all negotiated CTAs, SRAs and other research related agreements with industry sponsors are consistent with all applicable guidelines, federal regulations and Harvard University/HMS/HSDM policies pertaining to the protection of participants in research and the integrity of science.
The Director of the ORC regularly attends CHS meetings to observe practices and measure them against relevant standards. ORC will also perform its own risk analyses and compliance analyses concerning the CHS on a periodic basis.
Office of the General Counsel (OGC) – counsel in the OGC of Harvard University assists the CHS on complex matters including cooperative institutional amendments, policies and procedures, interpretation of state and federal regulations, federal audits, and official institutional communications. Responsibilities include working with the CHS on issues pertaining to federal guidelines, Harvard policies/guidelines, CHS policies/procedures and Commonwealth laws pertaining to research involving human studies and research participants.
Risk Management and Audit Services (RMAS) – provides the CHS, the Privacy Board, and the University with guidance on HIPAA regulations, internal policies, procedures and forms. Responsibilities include providing guidance on the HIPAA Privacy Rule policies and guidelines, and conducting routine and for-cause audits of departments which may include reviews of human studies research activities and recordkeeping throughout the University.
Office of the Provost – the Office of the Provost at Harvard University supports IRB initiatives, such as the accreditation process, the creation of the IRB database HIRBERT (Harvard Institutional Review Board Electronic Reporting Tool), and the University of Miami’s online human studies training program, the Collaborative Institutional Training Initiative (CITI).
The Academy at Harvard Medical School (The Academy) – reviews and approves research involving medical school students as research participants (including medical school curriculum studies) prior to CHS review. Such research applications are submitted directly to The Academy by Investigators and once approved by The Academy, forwarded by The Academy to the Dean for Medical Education (for review and signature) whose office forwards the research materials for CHS review. The Academy approval is required before the CHS will review the researchh.
Scholars in Medicine Office (SMO) – provides fellowships and funding for student research projects, community services projects and language immersion programs for HMS and HSDM students. SMO supports students and their faculty mentors and assists them in study design. SMO assists with any communication issues between the CHS and the student or mentor and will not provide any funding to a student for a research project unless CHS approval is documented. The CHS office copies SMO on communications to the student, and on the approval notice for the student project.
HSDM Office of Research – assists HSDM faculty and students with human studies proposals as needed prior to CHS submission. The Administrative Director works closely with the CHS to support initiatives and training opportunities for faculty, advanced graduate and graduate students at HSDM. The HSDM Office of Research requires review and approval of human research protocols prior to CHS approval, and it is the Investigator’s responsibility to obtain the HSDM approval prior to submitting the protocol to the CHS office.
Office for Research Issues (ORI) - is responsible for implementing the policies adopted by the Faculty of Medicine as well as the policies promulgated by the federal government in the areas of research integrity/scientific misconduct and conflict of interest. ORI works directly with two standing committees (Faculty Conduct Committee and Faculty Committee on Conflict of Interest) that review and make recommendations to the Dean (and to the President of a Harvard affiliated institution when appropriate). ORI provides oversight and implementation of the Faculty of Medicine Conflict of Interest Policy applicable to all faculty and fellows at HMS and HSDM and also handles allegations of scientific misconduct under a policy that applies to all faculty and trainees.
SPA and the CHS office forward positive financial disclosures of Investigators (e.g., those responsible for the design, conduct and reporting of research) to ORI for review. ORI will assess each disclosed financial interest to determine whether a potential conflict of interest exists with the proposed research. ORI then works with the relevant Investigator to reduce, manage and/or eliminate any potential conflict and to ensure compliance with University policy and federal regulations. ORI then notifies CHS regarding any potential conflict it has identified, including any management plan proposed by ORI to reduce, manage and/or eliminate the potential conflict. The CHS Chair, or the convened CHS, if the Chair so determines, shall have ultimate authority, however, to review the disclosed financial interests of Investigators and to determine whether potential conflicts exist that pose a particular risk to human subject participants. CHS may propose additional restrictions to manage a potential conflict and will work with ORI to ensure that such additional restrictions are incorporated into a proposed management plan. All conflicts must be managed and risks mitigated to the satisfaction of CHS before CHS approves a particular human research project.
The ORI also publishes Faculty Policies on Integrity in Science, which includes guidelines for investigators involved in clinical and scientific research, investigating allegations of faculty misconduct, conflict of interest and commitment, and authorship guidelines for the Faculty of Medicine. ORI works closely with the CHS on all issues relating to human studies research.
In order to monitor and measure the effectiveness of its human research protection program, the institution has established a Leadership Team as described below. This team ordinarily meets on a quarterly basis to review, evaluate and provide guidance on: reports from the Quality Assurance Coordinator; the CHS outreach activities; current regulations and guidance related to human research policy as issued under OHRP, FDA or other federal agencies or any state or local legal or ethical issues involving human research; changes within the Faculty of Medicine and the University. The Leadership Team will decide how to implement new best practices and improvements in the HRPP.
The CHS will be continuously monitored through the Quality Assurance Coordinator’s actions in evaluating of study files and CHS proceedings as described below. Additionally, the effectiveness of the CHS will be assessed through the Leadership Team as well as by yearly assessment by the IO in collaboration with the Dean for Academic and Clinical Programs regarding membership and the ability of the Chair to fulfill their duties, and the ability of the CHS to deal effectively with issues of non-compliance, unanticipated problems and/or investigator conflict of interest.
2.8.1.1. Quality Assurance Coordinator
The HMS Quality Assurance (QA) Coordinator performs evaluations and assessments of Faculty of Medicine active human studies, Investigator study files and the files of the CHS to provide full-circle evaluations of compliance (Appendix 15). The QA Coordinator is responsible for the following core functions: development of appropriate review checklists and forms (Appendix 16); conducting (or participating in) for cause and not for cause review of approved studies; reporting results of reviews to the CHS Leadership Team and other HMS/HSDM and Harvard University offices and officials as appropriate; providing education and technical assistance to Investigators and their staffs; and other duties and activities as assigned. The QA Coordinator reports to the ORSP Director, with a “dotted-line” relationship to the Director of Research Compliance (ORC). Post approval monitoring of research protocols is assessed in two separate stages:
CHS Evaluation
The QA Coordinator provides a dual-role in ensuring CHS study files are in concordance with Investigator study files, such that the CHS has accurate records of study activities, and that the CHS and the Investigator have the same version of materials requiring CHS approval. Additionally, the QA Coordinator assesses CHS performance pertaining to compliance with applicable laws, regulations, and institutional policies relating to the CHS, and evaluates CHS files to ensure that the CHS review has been conducted appropriately (such as risk:benefit analysis, equitable selection of participants, safety and confidentiality of participants and their data, appropriate consent language, and extra protections for vulnerable populations) as well as any other legal or ethical consideration involved in a study.
Investigator Evaluation and Education
The Investigator Evaluation includes a review of the Principal Investigator’s project files to assure that the PI is maintaining accurate records of study activities and that the PI and the CHS have the same version of materials requiring CHS approval. The QA Coordinator also evaluates PI performance pertaining to compliance with the approved protocol, applicable laws, regulations, and institutional policies, as well as any other legal or ethical consideration involved in a study. Additionally, whenever possible, the QA conducts a site visit to assess the security of research records and confidential participant data.
The CHS has established a leadership team comprised of the IO, CHS Chair, ORSP Director, and CHS Associate Director, as well as a representative from OGC, the Director of ORC, the Director of Faculty Integrity, the Assistant Director of Research at HSDM, and representatives from other offices (such as SPA and OTD) as necessary. The purpose of this team is to meet on a quarterly basis (more often if necessary) to discuss any new federal regulations or guidance, state laws, University policies, incorporation of new best practices, as well as issues of policy and procedure, including common recurrent problems, and CHS management and operational issues.
The Leadership Team will undertake activities aimed at implementing the standard elements of compliance found in government guidance documents as follows:
- The Leadership Team will advise the CHS regarding implementation of new federal/state regulatory mandates and communication of those mandates to the HMS/HSDM community.
- The Leadership Team will evaluate all new and existing policies to ensure that they are sufficiently detailed and clear and easily accessible by the CHS staff, members, and the HMS/HSDM community.
- The Leadership Team will evaluate the roles and responsibilities of the CHS (including the Chair, members and staff) and Investigators to insure that these roles and responsibilities are well defined and understood by the CHS (Chair, members and staff) and the HMS/HSDM community.
- The Leadership Team will review appropriate reports of the QA Coordinator (described in the preceding section) and evaluate the necessity of policy changes or CHS actions as a result of the reports.
- The Leadership Team will present planned improvements to the institution’s HRPP to the University wide Committees to evaluate where changes would be best implemented across the University.
- The Leadership Team will assist in the further development of the CHS’s outreach activities to the community and evaluate its effectiveness.
2.8.1.3. Institutional Official
The HMS Dean for Faculty and Research Integrity, who serves as the IO of the CHS is responsible for the implementation and maintenance of the HRPP and the CHS.
Provost Office: The Office of the Provost at Harvard University supports IRB initiatives, such as the accreditation process, the use of the University of Miami Collaborative Institutional Training Initiative (CITI), and the creation of the IRB database HIRBERT (Harvard Institutional Review Board Electronic Reporting Tool).
OHRP is the federal agency overseeing the compliance of the IRB’s in relation to the federal regulations and also provides assistance to the IRBs in the interpretation and enforcement of the federal regulations. OHRP occasionally performs site visits of IRBs.
2.8.2. Researcher Grievances, Comments, or Suggestions
Filing grievances, concerns and suggestions may be sent to the CHS Associate Director (Meg Johnson, meg_johnson@hms.harvard.edu, 617-432-2597), the ORSP Director (Carolyn Connelly, carolyn_connelly@hms.harvard.edu, 617-432-0651), the IO of the CHS (Gretchen Brodnicki, gretchen_brodnicki@hms.harvard.edu 617-432-2496) or to the Office of Research Compliance Hotline (617-432-5555). More contact information is listed on the CHS website: http://www.hms.harvard.edu/orsp/human/human.html (Appendix 17).
All grievances will be reported to the IO, who will determine the appropriate level of investigation (and by whom the investigation will be conducted). The person reporting the grievance will be contacted regarding resolution.
3. CHS Member and Staff Policies 
The Chair is selected by the Dean for Academic and Clinical Programs with the recommendation of the IO. The Chair's official appointment comes from the Dean for Academic and Clinical Programs and begins on July 1, the start of Harvard's fiscal year. There is no term limitation on length of service; however, Chairs are asked to serve for a minimum of three years. Each year the CHS Chair’s service is reviewed by the IO and the ORSP Director.
3.1.1. CHS Chair Qualifications
The CHS Chair should be a senior member of the Faculty of Medicine with significant human studies research experience. Selection is based on the person’s experience and knowledge of human studies research along with an in-depth understanding not only of the federal regulations governing such research, but also of the ethical concerns related to such research. Historically, Chairs have been long term members on an IRB and have achieved an Associate or Full Professor rank.
The CHS Chair must have undergone training in human subjects research within the past three years, must have a certificate from the Harvard Ethical Training in Human Research (HETHR) program (Appendix 14), CITI, or equivalent training from a certified source (not more than three years old), and must complete the OHRP Assurance training. Attendance at a Public Responsibility in Medicine and Research (PRIM&R) conference or other relevant conference is recommended yearly if possible, but at least every three years.
3.1.3. Expectations for the CHS Chair
For each year of his or her appointment, the Chair presides over the majority of CHS convened meetings. The Chair presents the meeting agenda, conducts the meeting, allowing sufficient time and opportunity for members present to discuss and vote on the studies under review, and provides clarification and leadership for CHS members. The Chair also performs expedited and exempt reviews, when necessary. The CHS Chair recommends, reviews and participates in the development and approval of CHS policies and procedures.
CHS members are selected by the IO upon the recommendation of the CHS Chair, ORSP Director, and/or the CHS Associate Director. The official appointment comes through the Dean for Academic and Clinical Programs. CHS members are asked to serve for a minimum of three years, however there is no term limitation.
The CHS membership roster is filed with the Office of Faculty Affairs (OFA), the CHS office, the OGC and OHRP. Each office is informed of changes to membership in a timely manner. In preparation for each new fiscal year, the CHS membership is reviewed by the IO, CHS Chair, ORSP Director and the CHS Associate Director to determine whether any change needs to be made to the Committee. The CHS members are evaluated on their attendance, performance and participation on the committee and any subcommittee and as reviewers of research qualifying for expedited review processes.
The CHS is made up of members in the scientific disciplines of research typically reviewed. When there are changes to the trends in scientific topics of research received by the CHS then an additional member with expertise in such disciplines will be considered. Also, if a particular vulnerable population (i.e. children or persons with cognitive impairments) is recruited for research projects, an ad hoc member of the Committee will be considered to represent the interests of that population. The CHS Associate Director is responsible for reporting all membership changes to OHRP.
The Faculty of Medicine is committed to diversity among its CHS members – whether it is diversity of ethnicity, culture, gender, faculty or non-affiliated persons of Harvard University, as well as professional disciplines within the Medical and Dental Schools. In accordance with 45 CFR § 46.107, the CHS is comprised of at least five members, with at least one member who is not affiliated with Harvard University (either directly or through an immediate family member); at least one member whose “primary concern” is in a scientific area, and at least one member whose “primary concerns” are in a non-scientific area and who must be present at each meeting. HMS research is primarily social-behavioral research while HSDM is primarily clinical with some social-behavioral components. The composition of the CHS thus reflects this research base; however it also meets Massachusetts Department of Public Health requirements for review of clinical studies involving schedule II narcotics and investigational new drugs (INDs), though the Committee ordinarily cedes its review of studies involving INDs.
Designated alternate members are appointed to the CHS and have similar qualifications and human studies training to the primary CHS member with whom they alternate. Alternate members are selected by the IO upon the recommendation of the CHS Chair, ORSP Director and/or CHS Associate Director. The official appointment of alternate members comes through the Dean for Academic and Clinical Programs. Alternate members are asked to serve for a minimum of three years, co-terminus with the terms of the primary CHS member with whom they alternate, however there is no term limitation. The alternate members are called upon to attend CHS meetings when their designated member cannot attend. Additionally these alternate members are asked to review studies qualifying for expedited review in their specific discipline or, in the case of the non-scientific alternate members, when community representation and/or opinion are needed. Alternate members are provided with and review the same material which the primary members are provided.
In the event that the CHS reviews research that involves prisoners, the IO, upon the recommendation of the CHS Chair, ORSP Director, or CHS Associate Director is responsible for ensuring that a qualified prisoner representative is appointed as a member of the CHS and serves in the capacity for all aspects of the study, or that it cedes its review to an IRB with a qualified prisoner representative (see Section 11.2.2).
CHS members must receive training in human studies protection (through CITI, HETHR or other training programs as required by their primary institutions), and they must have a certificate not more than three years old.
Each new CHS member receives a packet containing the following documents: 45 CFR § 46 and its subparts B, C and D; list of exempt and expedited categories; informed consent guidelines and the OHRP informed consent checklist; the Belmont Report; the Declaration of Helsinki; the Nuremburg Code; the International Conference on Harmonization, Guidelines to Good Clinical Practice; FDA regulations 21 CFR §§ 50 and 56; DHHS policies on the Inclusion of Women and Minorities, Children, and common compliance findings and guidance; FDA policies on Investigational Device Exemptions, Investigational New Drugs, Acute Care Waiver of Informed Consent, and the Bioresearch Monitoring Program; and the CHS Policies and Procedures. In addition to the above materials, any updated regulations, education and policy materials are circulated with the monthly meeting packets and reviewed at convened CHS meetings.
New CHS members attend several meetings before they are put on the agenda as Secondary Reviewers, or until they, and the Chair, believe they are ready act as Secondary Reviewers. This determination is generally made from the new member’s comfort in speaking-up at the meeting, and demonstrating through their comments that they understand their responsibility as an IRB member, the federal regulations and University policies, and the processes of the Committee. Secondary Reviewers review in conjunction with Primary Reviewers (see Section 3.6) for several months, thus the responsibility is not solely theirs until they have demonstrated as a Secondary Reviewer that they are ready to act as a Primary Reviewer. The Chair makes the final determination of when a Committee Member is appropriately trained and ready to be a Primary Reviewer, for both convened CHS meetings, and to conduct expedited reviews.
3.2.3. Expectations for CHS Members
CHS members attend monthly CHS meetings and prepare for these meetings by reading the materials sent to them a week in advance and by completing Reviewer Sheets (Appendices 18, 19, 20, 21, 22, and 23). CHS members must be knowledgeable about federal human research regulations and familiar with standards of professional conduct and practice. CHS members are expected to perform full committee, expedited and exempt reviews, as necessary. CHS members participate in study discussions, voicing any concerns they may have with the study under review, vote on protocols, and recuse themselves in the event that they have a conflict of interest (either financial, personal or professional) with the research under review.
CHS members who recuse themselves must leave the room for the discussion of the study and the vote. In the event that questions arise during the discussion for which the member is not present, the Chair may request that the CHS member come back into the room to answer any pointed questions pertaining to the study, but that member must leave again for any further discussion; any change in attendance by CHS members at a convened meeting is documented in the minutes
The performance of CHS members, both primary and alternate, is evaluated by the Leadership Team and on an annual basis by the IO in collaboration with the Dean for Academic and Clinical Programs. A three year evaluation by the IO, ORSP Director, CHS Associate Director and Chair is coincident with CHS member appointed terms. The performance of CHS members, both primary and alternate, may be reviewed more frequently if there are issues concerning participation, contributions and attendance.
When the CHS Associate Director suspects that a study involves a population or subject matter not within the CHS membership’s expertise (such as technical, cultural or scientific [See also Section 4.4.1 Additional Consultant for Scientific Review]), the Associate Director will confirm with the Chair. If the Chair agrees, the Associate Director will discuss with the Chair, the OSRP Director, and the IO, contacting a consultant with such expertise, and once confirmed and identified the Associate Director will contact the consultant. CHS members, faculty and other local IRBs may be asked to suggest individuals with knowledge and competence in the topic area. Committee members who do not feel that they have appropriate expertise to review a particular study may also request that the Associate Director seek a consultant to provide a review. When the CHS reviews research that involves categories of participants vulnerable to coercion or undue influence, the ORSP Director or CHS Associate Director is responsible for ensuring that one or more individuals who are knowledgeable about or experienced in working with such participants are present at the meeting (see Section 11).
3.3.1. CHS Consultant Qualifications
Consultants must have significant experience, background and expertise in the topic of the research study or knowledge of the particular population being recruited for the study. For consultants associated with Harvard, their faculty position and standing are considered when evaluating their expertise, however for Harvard and non-Harvard consultants alike, a CV or copies of publications, and references will be required to assure proper qualification in the field to consult for the CHS.
3.3.2. CHS Consultant Training
Consultants are not required to have human subjects training. Consultants are expected to provide technical or cultural expertise pertaining to a particular topic. The CHS will assimilate the information received from the consultant into its review and use its judgment to evaluate the information in accordance with the ethics of the study and the protection of research participants.
3.3.3. Expectations for CHS Consultants
Consultants will be asked to submit written comment about the study and/or attend the CHS meeting and participate in the discussions (per 45 CFR § 46.107 and FDA regulations at 21 CFR § 56.107). Consultants will be asked to complete the IRB Consultant Disclosure Form (Appendix 24), prior to research materials being sent to them, to disclose whether they have a conflict of interest (financial, personal or professional) with the particular research study under review, and if so, another consultant will be sought. Consultants cannot vote but can participate in the discussion of the review of the particular research project at the meeting.
The consultant may be given a list of questions by the CHS, and the CHS should receive enough information from the consultant to adequately review, evaluate and vote on the study. Documentation from the consultant will be filed with the CHS study file as well as with the meeting packet, if reviewed at a CHS meeting.
3.4. CHS Member Conflict of Interest
Separate sections on Conflict of Interest exist for Investigators (see Section 4.7.1) and the Institution (see Section 1.2.2).
At the beginning of each CHS meeting, the Chair, or the Chair’s designee asks the CHS if any members have a conflict of interest (professional, financial, or personal) with the particular research study under review that might influence his/her evaluation and thus might jeopardize the rights and welfare of the research participants or the credibility of the CHS. CHS members and consultants also have a conflicting interest when their spouse, partner, or relative has a professional or financial conflict of interest. All CHS members with a potential conflict identify themselves and the nature of the conflict. CHS members with conflicts may provide additional information about the project if so requested by the Chair; however they may not be present for the discussion or the vote. Consultants and ad hoc members must disclose any potential conflicts. CHS members conducting expedited reviews are required to sign the Reviewer Sheet indicating that they have no conflict with the study he/she has reviewed.
Any conflict revealed at the meeting is documented in the minutes and the CHS members who recuse themselves are not counted towards the quorum for that particular vote.
3.4.1. Professional/Personal Conflict of Interest
Professional conflicts of interest arise where, for example, a CHS member or ad hoc member (or consultant to the CHS): has a supervisory/mentoring role with respect to someone on the research team for the study being considered; is supervised/mentored by someone on the research team; has a role in the study (such as a co-investigator or collaborator); is a member of a board supporting the study; or may suffer a professional loss, such as standing in the professional community, if the study is or is not approved. To avoid any influence on the review of research, Faculty of Medicine personnel with competing business interests, such as those responsible for business development and raising funds, cannot serve as members of the IRB, nor be responsible for day to day operations of the IRB review process.
Personal conflicts of interest arise where, for example, a CHS member or ad hoc member (or consultant to the CHS) is the spouse, partner or relative of an Investigator on the study being considered, or of the investigator’s Department Head.
Note that CHS members who are members of a Principal Investigator’s Department are not necessarily considered to have a professional conflict and may in fact be called upon to review a study from their department.
3.4.2. Financial Conflict of Interest
Financial conflicts of interest arise where, for example, a CHS member or ad hoc member (or consultant to the CHS) has any financial interest in the study under review, including financial gains or losses through payments or consulting fees, equity interest or intellectual property rights from the research study or its sponsor or in the design, conduct, or reporting of the research. Proprietary interest related to the research includes, but is not limited to, a patent, trademark, copyright or licensing agreement. While it is possible for financial conflicts to be managed under the Faculty of Medicine’s specific policy on financial conflicts of interest for faculty members, CHS members must recuse themselves from all studies in which they have any financial conflict as defined above. CHS members who conduct Expedited reviews are required to disclose any conflicts of interest on the Reviewer Sheet; if a conflict is revealed, the protocol will be sent to another CHS member to review the protocol.
3.5. CHS Member Indemnification
CHS staff and members are agents of the University. Thus, they ordinarily will be indemnified by the University in the event of lawsuits against them based on their involvement with the CHS actions as CHS members, provided of course that they were acting within the scope of their duties and in good faith. Indemnification means that the University will defend a lawsuit (incurring all legal fees and other expenses) and pay any judgment or settlement.
3.6. CHS Primary Reviewer System
The Primary Reviewer system is a system whereby a designated CHS member is responsible for the review and presentation of a study at a CHS meeting (or for review and approval via expedited review procedures). Primary reviewers are used for initial and continuing reviews, as well as review of modifications to previously approved research. The CHS Chair serves as the Primary Reviewer for all reviews of unanticipated problems involving risks to participants or others and serious or continuing non-compliance (see Sections 13 and 14, respectively)
The CHS Associate Director will select a Primary Reviewer (herein referred to as the “Reviewer”) from the CHS membership (from which the Chair has designated as appropriately trained for such responsibility), for each study to be reviewed at a convened meeting, or review via expedited procedures. Whenever possible, the Reviewer shall have a field of expertise appropriate to the review of the study s/he is assigned. If this is not possible, or if the reviewer does not believe that s/he has the appropriate expertise, the CHS Associate Director will arrange for a consultation, or will defer the review of the protocol until appropriate expertise has been secured.
Occasionally, a Secondary Reviewer will be asked to provide additional review. The Secondary Reviewer is chosen to present the study if the Primary Reviewer is unable to be present at the CHS meeting or if the issues presented in the study are unusually complex. The Secondary Reviewer may have additional expertise relevant to the study. For example, for a HSDM study involving radiographs, the Primary Reviewer may be a dentist and the Secondary Reviewer may be a radiologist. The Secondary Reviewer may also be a new CHS member, added as a Reviewer to gain experience.
The Reviewer (Primary or Secondary) has the responsibility to conduct a thorough review of all protocol materials submitted by the Investigator (see required materials, Section 4), and to ensure that the Investigator’s submission provides sufficient information to permit the CHS to make an informed judgment about whether to approve the study. Where the submission requires more information, the Reviewer may either ask the CHS staff to request this information from the Investigator, or contact the Investigator directly. Direct communications between the Reviewer and Investigator are at the discretion of the Reviewer.
The Reviewer is responsible for presenting the research proposal at the CHS meeting, together with a clear recitation of any issues raised, and his/her recommendation for action (i.e., approval, contingent approval, deferral or disapproval of a research proposal).
If the Reviewer is unable to be present at the meeting, then s/he is responsible for providing the Secondary Reviewer and Chair with a written summary of any issues and his/her recommendations for CHS action. The Secondary Reviewer will present these concerns to the CHS at the meeting along with his/her own recommendation for action. In the event that a Secondary Reviewer is a new member, the Chair will determine who will act as Primary Reviewer; the Chair, or the Secondary Reviewer.
Following the CHS meeting, the Reviewer(s) are responsible for reviewing the portion of the minutes which pertain to the protocol(s) s/he presented, and for requesting any changes to the minutes to ensure accuracy (see Section 17.3).
CHS meetings ordinarily are held on the last Tuesday of the month from 4:00 pm to 7:00 pm. The December meeting is held earlier in the month due to the University winter break and holidays. On occasion, meetings during other times of the year are held on different days and times, depending on holiday or quorum issues, or emergency situations. Emergency meetings are not ordinarily called unless safety issues or significant regulatory issues with a study or Investigator have arisen. Subcommittee meetings are held on an ad hoc basis depending on necessity.
Research proposals are sent to meetings based on readiness for approval (i.e. methodologies are within the framework of 45 CFR § 46), as determined by CHS staff assigned to pre-review the study, and not based on the date the study materials were received by the CHS Office.
Quorum requirements are half of the CHS membership plus one, inclusive of at least one non-scientific member (i.e. if the membership is 14, then the quorum is 8, and if the membership is 15, then the quorum is 9). Committee members are encouraged to attend all CHS meetings (for reasons such as last minute quorum issues, scientific expertise, experience with previous reviews of a study, and familiarity of studies conducted by an Investigator).
CHS staff are selected by the CHS Associate Director and ORSP Director in accordance with the University’s personnel policies and procedures (see http://www.employment.harvard.edu/careers/). The requirements for the CHS staff positions are found in the University’s job descriptions or those position descriptions (Appendix 25). CHS staff are evaluated annually in accordance with the Harvard Medical School Performance Planning and Review Program (Appendix 26).
Each new CHS staff member receives a packet containing the following documents: 45 CFR § 46 and its subparts B, C and D; list of exempt and expedited categories; informed consent guidelines and the OHRP informed consent checklist; the Belmont Report; the Declaration of Helsinki; the Nuremburg Code; the International Conference on Harmonization, Guidelines to Good Clinical Practice; FDA regulations 21 CFR §§ 50 and 56; DHHS policies on the Inclusion of Women and Minorities, Children, and common compliance findings and guidance; FDA policies on Investigational Device Exemptions, Investigational New Drugs, Acute Care Waiver of Informed Consent, and the Bioresearch Monitoring Program; and the CHS Policies and Procedures.
CHS staff members must complete training in human studies protection through CITI upon employment and they must have a certificate not more than three years old. CHS staff members also receive initial and on-going training from the ORSP Director and the CHS Associate Director. In addition to the above materials, any updated regulations, education and policy materials are provided to CHS staff. CHS staff are afforded and encouraged to take advantage of opportunities to attend training sessions and conferences addressing human research protections offered through Harvard and/or outside organizations.
Each Investigator whose proposed research is subject to the jurisdiction of the CHS must submit an application, which can be found on the CHS website: http://www.hms.harvard.edu/orsp/human/human.html. In addition to the application, all materials related to the research study must be submitted to the CHS office. These materials include:
- CVs/Biosketches for the Investigator and research personnel with human studies responsibilities (including members of the team who interact with participants or handle data/specimens containing participant identifiers);
- CITI, HETHR or equivalent human subjects protection certification for all research personnel with human studies responsibilities (including members of the team who interact with participants or handle data/specimens containing participant identifiers);
- The appropriate Disclosure Statement Form (Sponsored Research or Protocol) for all research personnel (Appendix 27 and 28);
- IRB approvals from appropriate institutions, or letter of support if the institution does not require IRB review, as applicable;
- All funding application/s (including grants, subcontracts and clinical trial agreements) supporting the research;
- The full protocol;
- The sponsor protocol (when one exists);
- The complete DHHS-approved protocol (when one exists);
- Recruitment materials (cover letters, fliers, brochures, email notices);
- Study materials (telephone scripts, question guides, written questionnaires and surveys);
- Educational materials (information sheets, study guides);
- Consent materials, including any requests for waivers;
- HIPAA materials (including any waiver requests and proposed authorizations);
- Investigator’s Brochure (or package insert or pages from the Physicians Desk Reference, if a marketed drug).
4.1. Office Procedures for Processing New Applications
Applications received by the CHS office are date-stamped and screened for completeness (meaning that all questions on the application have been answered, including a “N/A” when a question is not applicable, and that appropriate signatures appear on the signature page); the relevant study information is entered into the HIRBERT database by CHS staff, and a study number and file is generated. The CHS Associate Director will designate a CHS staff member to be responsible for the study, including pre-reviewing the materials and seeing the proposal through the approval process.
The CHS staff will communicate with the Investigator (or personnel designated by the Investigator) regarding any requests for changes or additional documentation needed for a thorough review by the CHS, or CHS Chair or members for expedited review (see Section 4.9). The CHS staff serve as the primary liaisons between the Investigator and the CHS and, by virtue of their knowledge of the study, can provide information to assist the CHS in the decision making process.
Incomplete submissions (lacking requisite forms, signatures, or documentation) will not be placed on the CHS monthly agenda. However, should an Investigator exercise his/her discretion not to make recommended changes as a result of the CHS staff pre-review, the research proposal will be placed on the agenda along with a memorandum regarding the issues of concern for the CHS’s consideration.
The CHS uses the following definitions set forth in DHHS regulations 45 CFR § 46.102 and FDA regulations 21 CFR § 50.3 and 56.102:
i. Research as defined by DHHS regulations is a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.
ii. Research subject to regulation, and similar terms are intended to encompass those research activities for which a federal department or agency has specific responsibility for regulating as a research activity, such as IND requirements administered by the FDA. It does not include research activities which are incidentally regulated by a federal department or agency solely as part of the department's or agency's broader responsibility to regulate certain types of activities whether research or non-research in nature (for example, Wage and Hour requirements administered by the Department of Labor).
iii. Human subject as defined by DHHS regulations means a living individual about whom an Investigator (whether faculty, staff or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information.
iv. Research Involving Human Subjects: means an activity that meets the DHHS definition of “research” and involves “human subjects” as defined by DHHS, or that meets the FDA definition of “research” and involves “human subjects” as defined by the FDA.
v. Intervention includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject.
vi. Private information includes information about behavior that occurs in a context in which an individual could reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information) in order for obtaining the information to constitute research involving human subjects.
vii. Minimal Risk: The regulatory definition of "minimal risk" is the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.
For those studies involving clinical investigations, the CHS uses the FDA’s definitions (set forth in 21 CFR § 56.102 (23)) as follows:
viii. Clinical investigation or research defined FDA regulations means any experiment that involves a test article and one or more human subjects, and that either meets the requirements for prior submission to the FDA under section 505(i) or 520(g) of the Federal Food Drug and Cosmetic Act (i.e. 21 U.S.C. 355(i) or 360j(g)), or does not meet the requirements for prior submission to the FDA under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the FDA as part of an application for a research or marketing permit. The term does not include experiments that meet the provisions of part 58 (i.e. 21 CFR Part 58, “Good Laboratory Practice for Nonclinical Laboratory Studies”), regarding nonclinical laboratory studies. The terms research, clinical research, clinical study, study, and clinical investigation are deemed to be synonymous. In addition:
- An experiment is subject to the requirements for prior submission to the FDA under section 505(i) of the Food, Drug and Cosmetic Act when it involves any use of a drug other than the use of a marketed drug in the course of medical practice,
- An experiment is subject to the requirements for prior submission to the FDA under section 520(g) of the Food, Drug and Cosmetic Act when it involves the evaluation of the safety or effectiveness of a medical device.
ix. Human subject as defined by FDA regulations means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject is also an individual on whose specimens a medical device is used.
x. Test article means any drug for human use, biological product for human use, medical device for human use, human food additive, color additive, electronic product, or any other article subject to regulation under the Food and Drug Act or under sections 351 or 354-360F of the Public Health Service Act.
xi. Investigator means an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the test article is administered or dispensed to, or used involving, a subject) or, where an investigation is conducted by a team, the responsible leader of that team.
4.3. Proposals Not Meeting the Definition of Research Involving Human Subjects in Section 4.2
The CHS office pre-reviews all applications according to the same stringent criteria outlined in this policy and procedure manual. If the CHS staff determines through a preliminary review of the Determination of Human Subjects form (Appendix 29) or of one of its other application forms (Appendices 31, 32, 32a, 33, 34, 35, 36, 37, 38, 39, 40, 41, and 42), that a project does not meet the DHHS or FDA definitions of research involving human subjects in Section 4.2, the study materials are forwarded to a designated Committee Reviewer for final determination. The Reviewer performs an additional review and may require additional information from the Investigator. Once all of the information has been provided, and the Reviewer has made a final determination that the study does not meet the definition of research involving human subjects in Section 4.2 the CHS staff generates a determination letter (Appendix 43 and 44). The Letter is sent by the CHS staff to the Investigator, ordinarily within two business days of the determination.
If an Investigator (or his or her staff) would like to consult with the CHS staff to determine whether a project meets the definition of research involving human subjects as defined in Section 4.2, a copy of the complete grant/funding application must be submitted (if applicable), along with the Determination of Human Subjects form, as well as a list and description of all activities taking place by agents of the Faculty of Medicine and any activities taking place on Faculty of Medicine property. If there is no funding award for the research, a detailed plan (or protocol) of the proposed project will be required. CHS staff may require additional documentation (such as completion of a different CHS application, or data collection instruments), as necessary to make an appropriate determination. CHS staff will contact the individuals as needed by phone or email to clarify any questions they may have before a determination is made.
Any time a proposed activity involves any contact with participants whether through procedures, questionnaires, surveys, interviews, focus groups, sample tissue, cell lines or any material or data that may or may not be linked to participants, a determination must be made through the CHS office about whether the activity meets the definition of research with human participants with subsequent appropriate CHS review. Self-identification by Investigators of this determination is not allowed according to Faculty of Medicine policies. If the defined research involves any of the above broad categories, Investigators should contact the CHS office for an official determination.
In accordance with 45 CFR § 46.111(a)(1) and 21 CFR § 56.111(a)(1), the CHS considers whether risks to participants are minimized in research projects, in part by evaluating whether the research procedures are consistent with sound research design. The CHS review includes an assessment of the validity of the research question(s) and procedure(s), and the appropriateness of the study design. Review of the study design includes, without limitation, an evaluation of: the statistical analysis and power calculation; the adequacy of the sample size; and, where applicable, the dosage of any medication or radiation being proposed in the study. Attention is paid to the degree to which the hoped-for benefit to science and to study participants justifies the risks to participants, and to whether there is any unnecessary duplication of previous investigations in this subject area. CHS applications require the signature of the Department Head, which certifies that the proposal has scientific merit and is supported by the resources of the Department.
The CHS does not necessarily equate its scientific review to the National Institutes of Health (NIH), FDA, or Company peer review processes. Clinical research sent to the CHS may have received prior scientific review by one of the following entities:
- NIH Study Section
- FDA Review Committee
- Company Review Committees for industry-sponsored protocols
- Protocol Review by each Department Head or Department reviewing committee.
The CHS will consider these prior reviews as an indication that the scientific research design is sound, but these reviews do not release the CHS of its responsibility for scientific evaluation of the study protocol. Each protocol is pre-reviewed by CHS staff, and if, through this pre-review process, the CHS staff do not believe a CHS member has the expertise required to evaluate the scientific question or proposed research methods, the staff will alert the CHS Associate Director, who will consult with the ORSP Director, IO, and Chair to make a final determination, and to recommend an appropriate consultant, if necessary.
The CHS will disapprove any application that is not found to be scientifically sound, and will defer approval of a project if it requires modifications. In all circumstances, a protocol will not be approved unless it meets scientific standards, as well as ethical standards and regulatory criteria for approval.
4.4.1. Additional Consultant for Scientific Review
If outside scientific review has not been performed and the CHS believes it does not have the expertise required to evaluate the scientific question or proposed research methods, then the CHS will request outside scientific review by a consultant prior to before taking action on a protocol. The consultant may or may not have a Harvard affiliation. The CHS Associate Director (IO, Director or Chair) will ask the prospective consultant to disclose, in writing, the consultant’s (and his/her spouse’s, partner’s or immediate family member’s) current and anticipated financial interests, professional obligations and personal relationships related, in any manner, to the study, Investigator, or sponsor (Appendix 24). The CHS shall review the disclosed interests to determine if they could influence the consultant’s evaluation and pose a conflict of interest. The CHS will not accept the opinion of a consultant who has such a conflict.
Upon confirmation following a review of the disclosed interests that no potential conflict exists, the consultant will be sent the appropriate study information in order to make a determination on the scientific merit of the research project. The consultant’s written evaluation will be sent to the CHS members along with the materials necessary to review the protocol at least one week before the CHS meeting and will be available during the meeting for the discussion of the study. At the request of the Reviewer or Chair, the consultant may be asked to appear at the CHS meeting if the prospective research project is particularly complicated, or if the Reviewer or Chair requests their presence; however the consultant may not vote. Determination of scientific merit will be documented on the Reviewer Sheet and key information provided by the consultant will be documented in the minutes of the meeting. The consultant’s written evaluation will be maintained in the protocol file.
As noted earlier in these policies, the CHS is guided in its ethical review by the Belmont Report.
Under the dictum that “bad science is bad ethics”, any project found not to be scientifically sound is considered to be unethical. Consequently, any participant involvement would be unethical, as it would unfairly put the participants at risk. This risk may be as simple as having participants use their time and effort to be interviewed or as complex as being enrolled in a clinical trial.
In certain special situations a person with formal training in ethics may be contacted to offer an opinion about the ethics of a particular study. This opinion will be sent to the CHS in writing or the CHS may ask him/her to attend the meeting where the issue will be discussed.
When the CHS finds a study to be scientifically and ethically sound, the review process continues, and the CHS reviews other issues, such as level of risk, equitable selection of participants and issues surrounding consent, autonomy, safety, privacy and confidentiality, as noted elsewhere in these policies.
The CHS reviews all research funding applications and contracts that outline the resources and details of a study. This review ensures that the funding application and the CHS application contain consistent information (i.e. study sites, research personnel, conditions of research facility, study procedures, study goals), and ensures that the Investigator has adequate resources to address any commitments to or for the participants. Grants and contracts should contain adequate resources for research participants that will cover items such as compensation or treatment for any injuries that might be incurred from the research, compensation for participation (i.e. remuneration or transportation), and translational services (for participants and/or study documents), and other items as appropriate.
4.7. Investigator/Research Staff Experience
The CHS requires that Investigators submit CVs or biosketches as well as human subjects training certificates (or confirm completion of HETHR training) for themselves and all staff who will have responsibilities with study participants and/or data/specimens containing participant identifiers. The CHS requires this information to confirm that the Investigator and his/her staff have appropriate expertise to conduct the study and to protect the participants by safeguarding their rights and welfare, and the confidentiality of study data. CVs/ biosketches are included in the material sent to CHS members for their review. If the CHS determines that an Investigator is not qualified to conduct the study, then the CHS may request that the Department Head appoint a Co-investigator or an appropriate mentor.
The Faculty of Medicine requires Investigators to understand the responsibilities associated with conducting human studies research, as outlined in section 2.5. Investigators must comply with federal regulations; state and local law; and Faculty of Medicine, CHS and University policies. Investigators are responsible for ensuring that their research personnel have taken the appropriate training for work with human participants. Ultimately, Investigators are responsible for protecting the rights and welfare, safety, confidentiality and privacy of the participants in their studies.
The CHS staff has developed training material and presentations about human studies research that are given to Departments upon request for faculty, students, or others. Additionally, presentations are made to post-doctoral fellows on a monthly basis. There are also seminars in the Responsible Conduct of Research given each year that are required of research fellows receiving NIH training grants, and , training programs have been established through the Sponsored Programs Administration (SPA) to educate the Departmental Administrators about the need to contact the CHS office if there are any questions relating to research with human subjects. SPA grant administrators are also instructed to notify the CHS staff if there are any questions about a human study determination on a grant.
The CHS requires that all Investigators working with human participants renew their training certification every three years. The training program for Investigators working with human participants is the University of Miami’s Collaborative Institutional Training Initiative (CITI) . The CITI program requires completion of basic modules and electives covering specific topics about research with human participants. The CHS may require an Investigator to take a particular elective if it is relevant to his/her research (e.g. an Investigator working with children may be required to take the module on research with children).
4.7.1. Investigator Conflict of Interest
All Investigators who are members of the HMS and HSDM faculty must comply with the Faculty of Medicine Policy on Conflicts of Interest and Commitment (HMS COI Policy). The Policy has provisions specific to clinical and non-clinical researchers, with greater restrictions on Investigators conducting clinical research.
As a requirement of continued appointment, HMS and HSDM faculty must report all outside activities and financial interests on a regular basis to the Office of the Dean. The Faculty of Medicine’s Office for Research Issues (ORI) oversees the identification, management and resolution of individual conflicts of interest in compliance with the HMS COI Policy. Under the HMS COI Policy, faculty members submit the periodic disclosure forms, either electronically to the ORI database or in paper copy to the ORI office (which then manually enters the information into the database). If potential conflicts are identified, an appropriate official at HMS or the affiliated institution with whom the particular faculty member is affiliated contacts the faculty member. Resolution of the conflict is reported back to the ORI.
When conflicts are identified, they are reviewed by the Office of the Dean, in consultation with the Standing Committee on Conflicts of Interest. The Standing Committee on Conflicts of Interest is responsible for interpreting the HMS COI Policy and for imposing appropriate conditions and limitations, sometimes including oversight mechanisms, to ensure that conflicts are appropriately eliminated, minimized and/or managed.
All Investigators whose research funding is through HMS and or HSDM must comply with the Harvard University Government, Foundation, and Industry-Sponsored Activity Financial Disclosure Process (Appendix 27) at the time of grant submission. Investigators applying for federal Public Health Service or National Science Foundation Awards must comply with the provisions of federal regulations governing conflict of interest in research (42 CFR § 50 Subpart F, 45 CFR §§ 94 and 60, and Fed. Reg. 35820). Each Investigator submits a copy of relevant Sponsored Research Disclosure Statement form(s) to CHS if the research is subject to CHS approval. If a project does not have sponsored funding or any funding at all, CHS will require Investigators and research personnel submit Protocol Disclosure Statement Forms (Appendix 28). This purpose of these forms is to obtain disclosure by the individuals responsible for the design, conduct and reporting of research regarding such individuals’ financial interests and outside activities that might give rise to actual or potential conflicts of interest (including whether the Investigator has a financial interest in the sponsor or the company whose technology is being studied, and whether the Investigator may financially benefit if the study results are commercialized). When financial interests that pose potential conflicts are disclosed, the Disclosure Statement forms are submitted and reviewed by the Director for Scientific Integrity, who works within the ORI. ORI works with the relevant Investigator to manage, reduce and/or eliminate the potential conflict in compliance with the HMS COI Policy and the standards set forth under the federal regulations. Any management plan proposed by ORI to manage potential conflict(s) is then submitted to CHS for its review in connection with its evaluation of the particular study.
When a potential conflict(s) is disclosed, CHS approval is deferred until the financial interest is evaluated by ORI and the potential conflict(s) is resolved to ORI’s satisfaction under the HMS COI Policy and the federal regulations. The financial interest and ORI’s proposed management plan/resolution, if applicable, is then subject to heightened COI review by CHS in view of its interest in protecting human research participants. The CHS may decide to disapprove or restrict a proposal based upon an actual or potential conflict of interest, even if the relationship is not prohibited under the HMS COI Policy or the standards set forth under the federal regulations. The CHS may not, however, disregard a conflict that is not permitted by the foregoing.
General awareness and understanding within the Faculty of Medicine community (including among Investigators and their research staffs) about conflict of interest issues, and how they might affect research participants or the design, oversight, conduct, outcome, or reporting of research, is promoted in a number of ways. Prior to commencing work at HMS and HSDM, all Faculty of Medicine postdoctoral researchers must attend a presentation on Conflicts of Interest provided by the Dean for Faculty and Research Integrity at Orientation. The Dean for Faculty and Research Integrity also makes presentations to Department faculty on conflicts in interest issues, including the review and discussion of case studies. Conflict of interest training is also provided to research trainees through the required Responsible Conduct of Research Course.
4.8. Research Meeting Exempt Review Categories
All research proposals are reviewed in the office by CHS staff according to the same stringent criteria outlined in this policy and procedure document. In some instances, the CHS may determine that a particular research project meets federal exemption categories 45 CFR § 46.101(b)(1-6), 45 CFR § 46.201(b), 45 CFR § 46.301(a), 45 CFR § 46.401(b), and 21 CFR § 50.104 (see Section 4.8.3).
4.8.1. Review of Research Proposals for Exemption Criteria
The following materials must be submitted for the CHS to determine whether a research proposal meets exemption criteria (see Section 4.8.3):
- Exemption or CHS Application
- Grant or funding application/contract
- IRB approvals from other institutions (and applications, when appropriate)
- HIPAA Authorizations or Waiver of Authorization Request
- Consent forms
- Recruitment materials
- Study materials (including educational materials and any surveys, questionnaires or assessments)
- Communications with Investigator (to/from CHS staff and/or Reviewer)
If the CHS staff determines through a preliminary review that a project meets the federal criteria for an exemption, the study materials are forwarded to a designated Committee reviewer (designated by the Chair to approve studies meeting exemption criteria) for final determination. The Reviewer performs an additional review and may require additional information from the Investigator. Even when a study proposal has been identified as exempt (or does not meet the federal definition of research involving human subjects; see Section 4.3), it is reviewed for ethical and risk considerations including: 1) the risk/benefit ratio to participants; 2) equitable selection of participants; 3) issues of privacy; confidentiality and safety; and 4) autonomy and informed consent of the participants, as applicable.
If the Reviewer has made a final determination that a study is exempt, then the CHS staff generates a Letter of Exemption (Appendix 45), noting the applicable exemption category, and sends it to the Investigator, ordinarily within two business days of the determination. In the Letter, Investigators are notified that the exemption status is applicable to only the work outlined in the Exemption or CHS Application and the grant application or contract (if any) with which it is associated. Any changes to the application or the study must be reviewed by the CHS office de novo and a determination made as to whether continuation of the appropriate exempt status is appropriate, or whether the change instead requires expedited or full CHS review.
In cases where there is ambiguity regarding exemption status, the application will be sent to the CHS Chair for further review. All exemptions are reported to the CHS at the next convened meeting.
Prior to acceptance of a grant or contract award involving participants in research, the Faculty of Medicine Sponsored Programs Administration (SPA) office confirms through the HIRBERT database or receipt of a CHS Report on Action or Letter of Exemption, that a project has been approved. The SPA office will not set up a financial account for the Investigator’s award if it has not received confirmation of approval by the CHS office.
4.8.2. Unacceptability of Investigator Self-Exemptions
The CHS, and not the Investigator, must determine whether research activities qualify for exemption. The Faculty of Medicine requires that all research involving human intervention/interaction or identifiable private information as defined in these policies and procedures be subjected to CHS review.
The CHS follows the federal regulations and OHRP guidance on exemption (45 CFR § 46.101(b), 45 CFR § 46.201(b), 45 CFR § 46.301(a), 45 CFR § 46.401(b), and 21 CFR § 50.104), which state:
Unless otherwise required by [federal] department or agency heads, research activities in which the only involvement of human subjects will be in one or more of the following categories are exempt from [regulation under 45 CFR § 46]:
(1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as
(i) research on regular and special education instructional strategies, or
(ii) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.
*Additional criteria:
• The research does not involve prisoners as research participants.
• The research is not FDA regulated.(2) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:
(i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and
(ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation.
*Additional criteria:
• If the research involves children as participants, the activities must be limited to observation of public behavior where the Investigator does not participate in the activities being observed and to educational tests.
• The research does not involve prisoners as research participants.
• The research is not FDA regulated.(3) Research involving the use of educational tests (cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (b)(2) of this section, if:
(i) the human subjects are elected or appointed public officials or candidates for public office; or
(ii)federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.
*Additional criteria:
• The research does not involve prisoners as research participants
• The research is not FDA regulated.(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.
*Additional criteria:
• “Existing” means existing at the time the research is proposed
• The research does not involve prisoners as research participants
• The research is not FDA regulated.(5) Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:
(i) Public benefit or service programs;
(ii) procedures for obtaining benefits or services under those programs;
(iii) possible changes in or alternatives to those programs or procedures; or
(iv) possible changes in methods or levels of payment for benefits or services under those programs.
*Additional criteria:
• The research does not involve prisoners as research participants
• The research is not FDA regulated.Investigators who believe that their studies are eligible for exemption under 45 CFR § 46.101(b)(5), must forward a letter to the CHS office addressing the items noted in the OHRP guidance at http://www.hhs.gov/ohrp/policy/exmpt-pb.html:
(1) 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).
(2) The research or demonstration project must be conducted pursuant to specific federal statutory authority.
(3) There must be no statutory requirement that the project be reviewed by an IRB.
(4) The project must not involve significant physical invasions or intrusions upon the privacy of participants.
In addition, before making a determination about exemptions under 45 CFR § 46.101(b)(5), the CHS must consult with the DHHS funding agency as to whether the conditions stated above have been met. Both a letter from the Investigator and a letter from the DHHS agency must be submitted to OHRP by the CHS office before the exemption can be considered final.
(6) Taste and food quality evaluation and consumer acceptance studies,
(i) if wholesome foods without additives are consumed or
(ii) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe, by the FDA or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the US Department of Agriculture.
*Additional criteria:
• The research does not involve prisoners as research participants.
4.8.4. Applicability of Exemption Criteria to Vulnerable Populations
(45 CFR § 46 Subparts B, C and D)
Pregnant women, human fetuses and neonates involved in research (Subpart B): the exemptions at 45 CFR § 46.101(b)(1) through (6) do apply.
*For more information on Subpart B, please see section 11.1 of these policies and OHRP regulations at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb.
Prisoners (Subpart C): Presently, no research involving prisoners may be exempt.
*For more information on Subpart C, please see section 11.2 of these policies and OHRP regulations at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc.
Children (Subpart D): The exemptions at § 46.101(b)(1) and (b)(3) through (b)(6) are applicable to children. The exemption at § 46.101(b)(2) regarding educational tests is also applicable to children. However, the exemption at § 46.101(b)(2) for research involving survey or interview procedures or observations of public behavior does not apply to research involving children, except for research involving observation of public behavior when the Investigator(s) do not participate in the activities being observed.
*For more information on Subpart D, please see section 11.3 of these policies and OHRP regulations at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd.
4.9. Research Meeting Expedited Review Categories
Research proposals meeting federal categories for expedited review (see Section 4.9.2.2) may be eligible for an expedited review process. Expedited reviews are performed by the CHS chair or the Chair’s designated CHS members (herein referred to as the “Reviewer”). The Reviewer designated by the Chair must be an experienced CHS member, who is knowledgeable about the regulations as well as CHS and University policies, and confident in making risk:benefit assessments, and assuring appropriate safeguards for the participants. In accordance with 45 CFR 46.110(b), the Reviewer “may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research.” The same materials provided for the convened CHS review (initial and continuing reviews, and modifications to approved research; see Section 4) are required for expedited review, and are sent to Reviewers for their review of the research.
4.9.1. Review of Research Proposals for Expedited Criteria
All research proposals are pre-reviewed in the office by CHS staff according to the same stringent criteria outlined in this policy and procedure document. In some instances, the CHS may determine that a particular research project meets federal expedited review criteria set forth in 45 CFR § 46.110(a)-(d), and to make this determination, the same materials indicated in Section 4 must be submitted for CHS review. Expedited procedures may be used for initial and continuing review of research, and modifications to previously approved research under the criteria outlined in the following sections.
4.9.2. Categories of Research that may be Reviewed through an Expedited Review Procedure
OHRP guidance at http://www.hhs.gov/ohrp/humansubjects/guidance/expedited98.htm allows for expedited procedures to review minor modifications (modifications are minor if they involve the addition of no more than minimal risk and are limited to the addition of procedures listed in categories (1)-(7) of categories of research that can be approved by the expedited procedure) to previously approved research. The following conditions and categories of research may be reviewed by an expedited procedure:
(A) Research activities that (1) present no more than minimal risk to human subjects, and (2) involve only procedures listed in one or more of the following categories, may be reviewed by the IRB through the expedited review procedure authorized by 45 CFR § 46.110 and 21 CFR § 56.110. The activities listed should not be deemed to be of minimal risk simply because they are included on this list. Inclusion on this list merely means that the activity is eligible for review through the expedited review procedure when the specific circumstances of the proposed research involve no more than minimal risk to human subjects.
(B) The categories in this list apply regardless of the age of subjects, except as noted.
(C) 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.
(D) The expedited review procedure may not be used for classified research involving human subjects.
(E) IRBs are reminded that the standard requirements for informed consent (or its waiver, alteration, or exception) apply regardless of the type of review--expedited or convened--utilized by the IRB.
(F) 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 § 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 § 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, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or
(b) from other adults and children , considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.(3) Prospective collection of biological specimens for research purposes by noninvasive means.
Examples: (a) hair and nail clippings in a non-disfiguring manner; (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) 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 non-research purposes (such as medical treatment or diagnosis). (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR § 46.101(b)(4). This listing refers only to research that is not exempt.)
(6) Collection of data from voice, video, digital, or image recordings made for research purposes.
(7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR § 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)
(8) Continuing review of research previously approved by the convened IRB as follows:
(a) where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or
(b) where no subjects have been enrolled and no additional risks have been identified; or
(c) where the remaining research activities are limited to data analysis.(9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.
Upon making an initial determination that a study may qualify for expedited review under an appropriate category (or categories) the CHS staff will provide all of the research materials to the Reviewer. The materials will be accompanied by a Reviewer Sheet (Reviewer sheets are used for initial and continuing reviews of research, as well as review of modifications to approved research projects, for convened CHS meetings, as well as expedited and exempt review procedures) and a Review Confirmation Sheet (Appendix 46) for the Reviewer to complete. Reviewers may only approve or require modifications to the protocol or protocol materials to secure approval (disapprovals of research must be determined by the convened CHS).
All research proposals approved using expedited review procedures in a given month are reported via spreadsheet (along with the exemptions, ceded reviews, and closed studies) to the CHS at each convened meeting.
4.9.4. When there are Conditions for Expedited Approval
If conditions exist for the approval of a study eligible and submitted for expedited review, the CHS staff responsible for the file will send these conditions in writing to the Investigator, ordinarily within five business days. The Investigator will be responsible for satisfying the Reviewer’s conditions and will communicate with CHS staff until the conditions appear to have been satisfactorily addressed. The CHS staff will report the Investigator’s actions/changes to the Reviewer. When, in the opinion of the Reviewer, the conditions have been satisfied, a Report on Action (ROA, Appendix 47) will be generated and sent to the Investigator. The date of approval is the date that the conditions were approved by the CHS Reviewer.
In all cases, if the Reviewer determines that the study or the participants would be better served by a full CHS review, complete study materials will be sent to the next appropriate convened CHS meeting.
4.9.5. Notification to Investigators
CHS staff will send the ROA to the Investigator, along with any stamped or approved study documents, such as the consent form, recruitment materials, or study instruments. The approved consent form will contain the CHS stamp (unless it has already been stamped approved by another institution’s IRB), validating it for the period of approval. The period of approval for initial reviews is one year minus one day (364 days), unless otherwise noted on the ROA and accompanying documentation. Continuing approval of research will maintain the date of approval from the initial review, as long as it is approved within 30 days of the expiration date.
Included within the ROA is the link to the document entitled “Responsibilities of the Investigator” (Appendix 48) which serves as a reminder to the Investigator to report adverse events, unanticipated problems, incidents, complaints, protocol deviations/non-compliance, suspensions/terminations, and to seek approval of any modifications to the research (or research materials) prior to implementation, and to seek re-approval in a timely manner. The Investigator is responsible for using only the current, validated consent form with research participants. It is the responsibility of the Investigator or SPA to forward notification of approval to appropriate funding agencies.
4.9.6. CHS Approvals and Release of Funds for Research
The SPA office will only set up a financial account for an Investigator’s award if approval is documented by a current (unexpired) ROA from the CHS office, or if there is notification of current CHS approval in HIRBERT.
4.10. Research Requiring Full Committee Review
As with all other research projects submitted to the CHS office, a preliminary review of the application and supporting materials is performed by CHS staff. CHS staff are responsible for communicating with the Investigator in the same manner as other projects, and assisting them in preparation of materials to be reviewed at a convened CHS meeting (also referred to as full CHS review).
4.10.1. Research Involving More than Minimal Risk
All research proposals that may involve more than minimal risk (see Section 4.2) to participants, or that do not fit within exempt or expedited review criteria, are accorded full CHS review.
4.10.2. Proposals Not Involving More than Minimal Risk, but that Require Full Committee Review
On occasion, studies involving minimal risk procedures are brought for full CHS review, usually those involving vulnerable populations (see Section 11), sensitive topics or stigmatized conditions, or international sites. There also may be studies that, while technically falling within an exempt or expedited review category, are determined by the CHS Chair or members to warrant full CHS review.
Documents for initial, full CHS review are sent to all CHS members who will participate in the meeting, ordinarily seven days prior to the meeting. The following documents are provided to attending CHS members for each study to be reviewed at the convened meeting:
- CHS Application, inclusive of other required supplemental applications
- Grant application or funding application/contract
- The full protocol
- The sponsor protocol (if applicable)
- The complete DHHS-approved protocol (when one exists)
- The DHHS-approved sample consent document (when one exists)
- The Investigator’s brochure (or package insert or pages from the Physician’s Desk Reference, if a marketed drug)
- IRB approvals from other institutions (and applications, when appropriate)
- Waiver requests
- HIPAA authorizations
- Consent forms
- Recruitment materials
- Study materials (including educational materials and any surveys, questionnaires or assessments)
- Personnel Rosters with accompanying CVs, training certificates and Disclosure Statements
- Communications with Investigator (to/from CHS staff and/or Reviewer)
At the start of each meeting, the Chair takes attendance to assure a quorum (at least one half of the membership, plus one), and the CHS Associate Director keeps track of the quorum and any changes in the quorum to assure a valid vote throughout the meeting (voting does not take place without a valid quorum). The Chair reviews the agenda with the CHS members and asks the members whether they have any conflicts of interest with any study to be reviewed at the meeting and if so, reminds them to leave the room for the discussion and vote on that study. CHS members are reminded that the discussions during the meeting and the meeting materials are confidential and should not be discussed outside of the meeting or outside of their role as CHS members.
The Primary Reviewer summarizes the study (i.e. purpose, procedures, risks, and benefits), for which he or she is responsible, indicating any issues of particular concern, and initiating discussion. If a Secondary Reviewer has been assigned, the Secondary Reviewer provides any additional information not noted by the Primary Reviewer. While the Primary Reviewer is responsible for presenting the study at the meeting, all CHS members in attendance are expected to review the materials sent to them for each study in order to discuss the protocol at the meeting. Protocol files and copies of minutes are brought to convened meetings, should there be any questions requiring additional information (CHS members may also request from CHS staff, information from the files or minutes to assist in their review prior to the meeting). After the discussion, the Chair summarizes any remaining issues, asks for a motion, a second on the motion, and a hand vote of those in favor, those opposed and those abstaining from the vote. The vote is then announced and recorded by the CHS Associate Director on the Review Confirmation Sheet for the Chair to sign at the end of the meeting.
CHS members make determinations, or actions, in the form of a vote, or they may abstain from a vote on a study. There must be a quorum of CHS members eligible to vote on a study at the meeting (either in person or on a telephone conference call) for a vote to be valid.
In order for a motion to pass, it must be voted for by a majority, at least one half plus one, of CHS members present at the meeting (i.e. if attendance is 14, passing is 8; if attendance is 15, passing is 9). Votes include those in favor, against, or abstaining from a motion. Abstaining votes do not count against the quorum for the meeting. However, those who have declared a conflict of interest cannot vote and therefore are counted against the quorum. If the quorum is lost during a meeting, the CHS cannot take votes until the quorum is restored.
4.10.5.2. Participation by Telephone
Whenever possible, CHS members are encouraged to be physically present at the meeting. However, there are times when circumstances change and occasionally a member cannot be physically present. In such a circumstance, the CHS member may still participate in the discussion and vote via conference call, as long as s/he received the materials in ample time to review them before the meeting, and as long as s/he is able to hear and be heard for the discussion and vote. Participation in meetings via conference calls is noted in the meeting minutes.
4.10.5.3. CHS Actions and Notifications
Approval means that all aspects of the study have been reviewed and found to be scientifically, methodologically, and ethically sound. When a study is approved, the ROA (Appendix 49) is sent to the Investigator with any stamped/approved study materials (such as consent forms, recruitment materials and study instruments) by CHS staff, ordinarily within five business days of the meeting. Included within the ROA is the link to the document entitled “Responsibilities of the Investigator” which serves as a reminder to the Investigator to report unanticipated problems, incidents, complaints, protocol deviations/non-compliance, suspensions/terminations, and to seek approval of any modifications to the research (or research materials) prior to implementation, and to seek re-approval in a timely manner. Initial approvals and approved study materials are valid for one year minus one day (364 days) of the CHS meeting in which the protocol was reviewed, unless otherwise specified on the ROA. Continuing approval of research will maintain the date of approval from the initial review, as long as it is approved within 30 days before the expiration date.
Once the Investigator receives the ROA and signed/stamped approved study materials, s/he may commence study activities.
It is the responsibility of the Investigator to forward notification of approval to appropriate funding agencies.
4.10.5.3.2. Contingent Approval
Contingent approval means that the study requires only specific minor revisions or yes/no concurrence(s) by the Investigator before it can be fully approved. A letter or email outlining the contingencies will be sent to the Investigator by CHS staff within five business days of the CHS meeting. Minor revisions may include the addition of minor study procedures, interactions or interventions with study participants, or another change that does not alter the risk:benefit analysis of the study. Minor revisions cannot affect the safety of participants, or alter in any way the scientific integrity of the study, or include a procedure for which expedited review is not permissible.
A study that has been approved with contingencies may be fully approved when the concurrences and/or specific minor revisions have been made by the Investigator and confirmed/approved by the Primary Reviewer and/or Secondary Reviewer or Chair. If the concurred/revised materials are satisfactory, a ROA indicating full CHS approval will be sent to the Investigator as outlined in the approval section,4.10.5.3.2.1. The date of approval is the date that the met contingencies are confirmed by the Primary Reviewer and/or Secondary Reviewer or Chair.
When, in the opinion of the Reviewer(s), an Investigator fails to meet the contingency requirements, the CHS will reconsider the matter at the next full CHS meeting. Investigators who disagree with the contingency requirements may present their justifications in writing to the CHS to review at the next full CHS meeting.
Deferred approval means that the study requires more than specific minor revisions or modifications before it can be approved by the CHS. A letter or email including the reasons/justification for the CHS’s decision and suggestions to further develop the study design and/or study materials will be sent to the Investigator by CHS staff. The modifications must be reviewed at a full CHS meeting. When a deferred study has been revised and the materials returned to the full CHS meeting, the study shall be reviewed as though it were a new study.
Studies that receive a deferral should be resubmitted to the CHS within six months, unless the issue delaying the approval is not within the Investigator’s control, such as an Investigational Device Exemption from the FDA. If study modifications and a revised CHS application are not resubmitted within six months of the deferral, the CHS office will contact the Investigator to determine whether the study should be closed. If no information is forthcoming, the CHS office may decide to close the file and will notify the Investigator of its decision.
Disapproved means that the study is not scientifically, methodologically, and/or ethically sound and the CHS will not approve the study as designed. The CHS staff will send a letter to the Investigator, ordinarily with a copy to the Department Chair (or mentor if a student project) and SPA, indicating the reasons for its decision. In its letter, the CHS will afford the Investigator the opportunity to respond in person at a convened meeting, or the Investigator may choose to respond in writing and the response will be reviewed at a convened meeting.
4.11. Research Requiring Review More Often than Annually
While most approvals are granted for one year (minus one day, or 364 days for initial reviews), there are projects that may require more frequent review. For such projects (most often involving more than minimal risk for participants), the CHS will consider whether more frequent review is warranted to ensure adequate protection of the rights and welfare of research participants and will document its determination in the minutes of the meeting. In determining the frequency of review, the CHS will consider carefully the risk:benefit analysis especially with the participation of vulnerable populations (see Section 11) and other reasonable factors including but not limited to issues that may be sensitive to the public. The ROA specifies the required frequency for continuing review of the study.
Separate from the IRB Quality Assurance Coordinator (see Section 2.8.1.1.1), the CHS has the authority to appoint one or more individuals to observe the consent process and/or the research and to report back to the CHS with any findings. The CHS shall appoint such an individual whenever it determines, based on information available (such as reports of adverse events or unanticipated problems involving risks to participants or others, deficiencies noted in the CHS office files, reports or complaints from study personnel or participants, media or scholarly reports of research activity) that monitoring is in the best interests of the participants and/or integrity of the study. The CHS also may request that an Investigator design an instrument to document the understanding of consent by a (potential) research participant. The CHS may request that this documentation be provided for its review at any time during the study.
4.13. International or Off-Site Research and Knowledge of the Local Research Context
The CHS is required to have knowledge of the local research context, whether domestic or international, (http://www.hhs.gov/ohrp/humansubjects/guidance/local.htm) in order to provide a thorough review, to understand particular risks and benefits of the study population, and the relevance, customs and cultural significance of study procedures to the community in which the research is taking place. All sites are required to have a local IRB or Independent Ethics Committee (IEC) approval. When federal funds are supporting the research, the local IRB or IEC must have a FederalWide Assurance of compliance with OHRP (http://www.hhs.gov/ohrp/FWAfaq.html#q3) .
In the event that non-federal funds are supporting the research, IRB or IEC approval is still required, unless there is no such board at the site where the research is taking place. While some less populated communities may not have such a board, most communities have a structure (council or local leader) in place that approves the activities of that community. In addition to the approval of this committee or person, a letter of support from the local site (such as a school principal or superintendent, or a clinic director) where the research activities will be taking place should be obtained by the Investigator and provided to the CHS. The letter should include information pertaining to the appropriateness of the study to the local community, any required changes to the study, and a review and approval of the consent document, whenever possible. Letters not provided in English must be translated into English for CHS review and a duly signed Translation Attestation Form (Appendix 40) must accompany the letter.
Depending on the research or the risks (or level of risks) to participants and the support from the local community, the CHS may also request that someone (other than the Investigator) with special knowledge of the setting either review a particular protocol, or attend a convened CHS meeting to provide the CHS with recommendations based on his/her expertise. This person must be familiar with the customs, practices, or standards of care (and language, whenever possible) where the research will be taking place.
5. Continuing Review of Research
Research projects must be reviewed at least annually (unless otherwise specified on the ROA) and before the study expiration date (also on the ROA), if the research is ongoing. Research projects are considered ongoing until analyses of identified data are complete and Study Closure has been confirmed in writing by the CHS office (see section 5.6 regarding de-identified data analysis and study closure). Specifically, this means that continuing review must occur as long as the research remains active for long term follow-up of participants, even when the research is permanently closed to the enrollment of new participants and even though all participants have completed all research-related interventions. Additionally, continuing review still must occur when research is limited to data analysis, where the investigator has access to personally identifying information (including codes, links, or keys to identifiers); or if there exists the possibility that personally identifying information could be obtained given the nature of the dataset.
The HIRBERT database sends four automatic reminders via email to Investigators at 90, 75, 45, and 15 days in advance of the study expiration date. Notifications contain a warning to prepare to stop study activities if the project is not re-approved by the expiration date. On the day the study expires, a final email is sent which states that all study activities must stop immediately.
Continuing review of research must be substantive and meaningful. Toward that end, when a completed Continuing Review Application (Appendix 50) is received at the CHS office, the application is logged into the HIRBERT database, screened by CHS Staff for completeness, and ordinarily pre-reviewed by (and in the same manner) the CHS staff member who had been responsible for the project when it was initially submitted to the CHS.
5.1. Required Continuation Submission Documentation
In addition to the requirements indicated throughout the Continuing Review Application, the following materials (if applicable) also must be submitted for continuing CHS review:
- Data Safety Monitoring Board (DSMB) reports, or adverse/unanticipated event reports with resolution from the institution where the research is taking place.
- Competing/non-competing grant submissions/annual/progress reports to funders.
- IRB approvals from any other reviewing IRB.
- Recruitment materials currently in use. If recruitment materials (such as cover letters, fliers, brochures, or email notices) have been translated into languages other than English, a current copy of the translated version(s), as well the Translation Attestation Form also must be submitted for CHS review
- Consent form(s) currently being used to enroll participants. Any revisions to the existing consent form or significant new findings that may relate to the participant's willingness to continue participation should be included in a new/revised consent form for CHS approval. If consent forms have been translated into languages other than English, a current copy of the translated version, as well the Translation Attestation Form also must be submitted for CHS review.
- All other study materials currently in use (such as data collection forms, survey instruments, and follow up materials).
- Requests for amendments of any modifications sought to the research project (such as the addition or removal of research personnel, changes in study design or study population, addition or subtraction of the number of participants to be enrolled in the study, additions or changes to recruitment or other research materials) and any supporting materials (such as revised protocols and/or revised CHS applications).
5.2. CHS Office Processing of Continuing Review Submissions
The CHS staff member who previously reviewed the study materials (either initially or as part of the prior continuing review) will be responsible whenever possible, for seeing the continuation through the re-approval process. This staff person will communicate with the Investigator (or personnel designated by the Investigator) any requests for changes or additional documentation needed for a thorough review by the CHS (see Section 5.3), or CHS member (see Section 5.4).
Incomplete submissions (lacking requisite forms, signatures, or documentation) will not be placed on the CHS monthly agenda. However, should an Investigator exercise his/her discretion not to make recommended changes as a result of the pre-review, the submission will be placed on the agenda along with a memorandum regarding the issues of concern for the CHS to consider in determining continuing approval.
5.3. Continuing Review by the Full Committee
The following materials are provided to all CHS members for review of study continuations at convened CHS meetings:
- Continuing Review Application
- The current recruitment and consent documents
- Any newly proposed recruitment and consent documents
- The initial application form, updated with any changes
- The last Continuing Review application (if applicable)
- A status report on the progress of the research (and progress reports for grants/contracts)
- New or competing and non-competing grants/contracts
- The current personnel roster
- IRB approvals from other institutions (and applications, when applicable)
- Copies of amendment requests and approvals during the past review period
- Adverse or unanticipated event or DSMB reports (if applicable)
- HIPAA patient authorizations, or waivers/waiver requests
- Citations of current findings that might affect the risk: benefit balance of the study
- Communications with the Investigator (to/from CHS staff and/or Reviewer)
- Minutes from previous year reviews, if necessary
The CHS applies the same criteria for continuing approval of research projects as it does in the initial review (i.e., acceptable risks, potential benefits, informed consent, and safeguards for research participants). Review at a full CHS meeting is required for all research studies that were previously reviewed at a full CHS meeting unless the research qualifies for expedited review under categories 8 or 9 (see Section 4.9.2.2).
If possible, the same Reviewer who previously reviewed the proposal will be sent the continuation materials in order to maintain continuity. If the original Reviewer is no longer on the CHS or is otherwise unavailable, then another CHS member with similar knowledge and expertise in the field of the research (whenever possible) will be chosen. This system applies regardless of whether the proposal meets the criteria for review by the full CHS or qualifies for expedited review. If additional expertise is required, the CHS (Chair, Associate Director, ORSP Director or IO) will determine the appropriate consultant for the review (see Section 3.3). If the study involves prisoners or is adding prisoners to the study population, then an ad hoc prisoner representative will be a Reviewer along with another member of the Committee, or the research will be ceded to an institution with a prisoner representative. While the Primary Reviewer is responsible for presenting the study at the meeting, all CHS members in attendance are expected to thoroughly review the materials sent to them for each study in order to discuss the protocol at the meeting. At least one member must review the complete protocol in-depth, including any protocol modifications previously approved by the IRB; ordinarily this is the responsibility of the Primary and Secondary Reviewers, as well as the Chair.
In some circumstances, the CHS may request verification from others (such as a Department Chair, the study or site Coordinator, or the CHS QA Coordinator) that requested changes by the CHS have occurred, or that no material changes have occurred without appropriate and prior CHS review and approval. This may happen when there is suspected non-compliance with CHS determinations, either through communications with the Investigator or study personnel, or if the materials submitted to the CHS Office are inconsistent with the Continuing Review application.
For continuing reviews at full CHS meetings, the same criteria and procedures for initial review apply (see Section 4.10).
5.4. Continuing Review of Research Meeting Expedited Categories
Research eligible for an expedited review procedure (see Section 4.9) also may undergo continuing approval through the expedited review process (see Section 4.9). The CHS staff collects and reviews the documentation listed for review of continuations via full CHS meetings (see Section 5.3), then sends it to the CHS Chair or designated member for expedited review (Section 4.9). CHS members review and approve studies according to the expedited review criteria listed in Section 4.9.2.1.
5.5. Lapse in Continuing Review Approval
Investigators are notified of study expiration dates starting 90 days prior to the expiration (see Section 5), and are encouraged to submit continuation materials 60 days in advance of the expiration date in order to avoid any lapse in approval. If there is a lapse in approval, the Investigator is automatically notified via email from the HIRBERT database that all study activities must cease until the continuation is reviewed and re-approved by the CHS (confirmed by a ROA; Appendices 51 and 52). The CHS staff will notify the Investigator’s Department Chair and SPA representative if a study has expired to make sure that the research (and funding) has been/will be stopped.
Any lapse in approval is also handled under the non-compliance policy (see Section 14). There may be issues regarding current study participants continuing on study medications or scheduled events for participation, and questions about notification of participants of the lapse in approval for the study. The CHS Chair or designee may allow current participants to continue in some or all research procedures when it finds an overriding safety concern or the ethical issues involved are such that it is in the best interest of individual participants to continue participating. The CHS will notify the investigator that new enrollment of participants may not occur after the expiration date of approval.
5.5.1. Investigator Reports for Lapsed Studies
Investigators whose studies lapse IRB approval due to late submission of continuing review applications or other required materials must include with their application a Non-Compliance Report Form (Appendix 53). The Report Form requests pertinent information required by the CHS, including a description of the event, what (if any) study procedures took place, how many participants were engaged in research activities (or specimens/data analyzed) during the lapse in approval, and a corrective action plan for prevention of future lapses in study approval.
5.5.2. Review of Lapsed Approval of an Expedited Study
Lapses of continuing approval of expedited studies may be reviewed and approved by a CHS member during the review of the study continuation, and do not require review at a convened CHS meeting. As with other expedited reviews, the Reviewer may request that the lapse be reviewed at a convened CHS meeting.
5.5.3. Review of Lapsed Approval for a Study Requiring Full-CHS Review
Lapses of continuing approval for studies requiring full CHS review are presented by the Primary Reviewer, along with the Investigator’s Non-Compliance Report Form at the full CHS meeting. At the meeting there shall be two votes: one for the continuing approval of the research; and one for the use of any data collected during the period of lapsed approval. Both votes will be documented on the ROAs.
5.5.4. Study Closure of Lapsed Studies
If a Continuing Review Application is not filed within three (3) months after expiration, the study will be closed by the CHS office and the Investigator notified in writing. The CHS staff will copy the Department Head and SPA representative on any letters indicating Study Closures or lapses in approval. SPA will notify any funding agencies or sponsors of closures or lapses in approval, as appropriate with the criteria/stipulations of the funding sponsor, and no funds will be expended for an expired study (see Section 17).
5.5.5. Reporting Study Lapses to OHRP and other Regulatory Agencies
A single lapse in continuing approval does not require reporting to institutional officials, OHRP or other regulatory agencies. However, continuous lapses in approval or serious issues of non-compliance with CHS, DHHS or FDA requirements do require notification to institutional officials, OHRP and other regulatory agencies (such as the FDA), as applicable. The serious and continuing nature of non-compliance is determined by the CHS, and notification schedules for non compliance are outlined in Section 14.
5.5.6. CHS Administrative Functions Resulting in Study Lapses
Investigators whose studies lapse approval due to CHS administrative error (i.e. materials were received in a timely manner, but the office did not review it in a timely manner) are not required to file a Non-Compliance Report Form, although all study activities must cease until re-approval by the CHS is confirmed by the ROA.
5.6. CHS Study and Study Closure
Once all research activities are complete and all data analysis is either complete, or the only remaining analysis involves data where; (i) all identifiers have been destroyed, or (ii) the investigator no longer has access to codes, links, or keys to identifiers, then the study is eligible for closure. If this is the case, the Investigator must submit the Study Closure Form (Appendix 54) and submit all appropriate information and documentation listed on the form including the Investigator’s signature.
Study Closure may also be appropriate if the jurisdiction of IRB review has been transferred to another institution. Transfer of jurisdiction occurs when an Investigator leaves the Faculty of Medicine for another institution and will be conducting his or her research at that institution, or when his or her grant is administered through or transferred to another institution and no research activities are (or are no longer) taking place at HMS or HSDM facilities and Faculty of Medicine students are not the prime participants in the research study.
6. Amendments to Research Activity
If, after the initial approval of a research project, the Investigator wishes to amend or modify the study in any way (such as: changes to the study population, research personnel roster, recruitment, consent, inclusion/exclusion criteria, medications, devices or study procedures) the requested change(s) must be submitted on an Amendment Request Form (Appendix 55) or a revised Personnel Roster form (Appendix 39), and preferably accompanied by a cover letter outlining the changes and the reasons for the them.
The most frequent example of non-compliance reviewed by the CHS is the implementation of study changes without prior CHS approval. Any changes, no matter how minor (the addition of minor study procedures, interactions or interventions with study participants, or another change that does not alter the risk:benefit analysis of the study. Minor revisions cannot affect the safety of participants, or alter in any way the scientific integrity of the study, or include a procedure for which expedited review is not permissible) must be submitted to and approved by the CHS, documented by a ROA (Appendices 56 and 57), prior to implementation of the change(s).
The federal regulations specifically require the CHS to review proposed changes in research activity and to ensure that such changes are not initiated without CHS review and approval, except when necessary to eliminate apparent immediate hazards to the participant [45 CFR § 46.103(b)(4)(iii) and 21 CFR § 56.108(a)(4). As noted in Section 5.3, in some circumstances, the CHS may request verification from others (such as a Department Chair, the study or site Coordinator, or the CHS QA Coordinator) that requested changes by the CHS have occurred, or that no material changes have occurred without appropriate and prior CHS review and approval.
6.2. Required Materials for Amendment Requests
Significant changes to the study, such as changes to the study population and study procedures, must be incorporated into the CHS Initial Application (and protocol, when appropriate), as all current study activities must be documented in one place. In addition, if changes are sought to the consent form, or if the change to the study will affect the risk:benefit analysis for participants or should otherwise be communicated to potential participants, then two consent documents (one with highlighted changes and one unmarked copy incorporating the proposed change) must be submitted to the CHS for review and approval. Incomplete submissions (lacking requisite forms, signatures, or documentation) will not be placed on the CHS monthly agenda or sent for expedited review.
6.3. CHS Procedures for Processing Amendment Requests
After an amendment request (including all relevant materials) has been received, CHS staff will date-stamp the materials, enter the appropriate information into the HIRBERT database, add the newly submitted materials to the existing study folder, and provide the appropriate CHS staff member with the folder for pre-review. As with study continuations, the CHS staff member who has been working with the Investigator and the study will be responsible for seeing the amendment(s) through the approval process.
The CHS staff will communicate with the Investigator (or personnel designated by the Investigator) any requests for changes or additional documentation needed for a thorough review by the CHS (see Section 6.5), or CHS member (see Section 6.6).
6.4. Document Distribution to CHS Members
The following documents are submitted for distribution to all CHS members to review at a full meeting (or to a CHS member for expedited review) for amendments to previously approved research:
- Amendment Request form and cover letter
- Supporting documentation (such as the revised CHS application, current findings, DSMB/adverse/unanticipated event reports, present and revised or new materials for review/approval, and other documentation as applicable and/or requested by CHS staff or members)
- Citations of current findings that might affect the risk:benefit balance of the study
- Continuing Review materials from current review period
- Personnel roster listing all current study personnel, and CVs/biosketches, training certificates and Disclosure Statements for all new personnel
6.5. Amendment Review by the Convened CHS
In accordance with 45 CFR § 46.108 (b), review of proposed (more than minor) study changes must be conducted at a full CHS meeting. The Investigator will be reminded that if the amendment is the result of new findings that may affect participants’ willingness to continue, then those new findings must be communicated to participants.
For amendments reviewed at full CHS meetings, the same criteria and procedures for initial review apply see: Research involving more than minimal risk, Proposals not involving more than minimal risk, but that require full committee review, Document distribution, Committee review procedures, Committee determinations, Committee actions and notifications, Voting validity, Participation by phone, Research requiring review more often than annually, and Research monitoring (see Section 4.10).
6.6. Amendment Review Meeting Expedited Categories
Expedited review of amendments to research that was previously approved at a full CHS meeting is permissible, providing the research meets the appropriate categories at 45 CFR § 46.110 f 8 (a-c) or 9.
For applicable procedures and criteria for amendments via expedited review, see: Research meeting expedited review categories, Reviewer determination, When there are contingencies for approval, Notification to Investigators (SPA and to the CHS), Categories of Research that may be reviewed through an expedited review procedure, Research Categories, and Expedited review criteria for CHS members (see Section 4.9).
6.7. Modifications to Research Resulting from Emergency Procedure/Process
If an Investigator has changed a study procedure or process to eliminate an immediate hazard to participants, the Investigator must notify the CHS office as soon as possible by phone or email, within 48 hours. Emergency modifications will be reviewed as unanticipated problems involving risks to participants or others and will be treated according to that policy (see Section 13). According to the policy, the Investigator should follow the immediate notification to the CHS with a formal letter describing the problem. The letter should include the following:
- A description of the reason for initiating the change without prior CHS approval;
- The provisions made to maintain the safety and privacy of participants;
- An indication of whether the hazard was (and is anticipated to be) a one time occurrence;
- A statement as to whether modifications need to be made to the study itself as well as relevant study materials (such as the consent form). If study modifications are indicated, the amendment will be reviewed according to the policies and procedures outlined above (see Section 6).
The letter is sent to the CHS Chair for immediate review; the Chair will review the change to determine whether the change is consistent with ensuring the participants’ continued welfare. The event will be reviewed by the CHS at the next convened meeting unless an emergency meeting is called to review the changes (see Section 3.7). Depending on the facts and circumstances, the Investigator may be required to halt the research (or a portion of the research) until necessary changes have been reviewed and approved, and if appropriate, notification of the study sponsor.
6.8. Amendment Review of Studies Meeting Exemption Criteria
Investigators should submit modifications to studies that have met the criteria for exempt research (see Section 4.8.3) when there is a possibility that the modification could result in a change to the risk:benefit analysis and have an impact on study participants. If the modification does not alter the risk:benefit analysis and exemption criteria, an acknowledgement letter (Appendix 58) will be sent to the Investigator. If the modification does alter the risk:benefit analysis and the study requires expedited or full CHS review, the appropriate CHS staff will notify the Investigator via email and the Investigator will be asked to complete or modify the CHS application and submit appropriate study materials for review and approval according to the policies and procedures outlined previously in this section.
Under 45 CFR § 46.114, institutions engaged in research projects involving more than one institution may enter into joint reviewing arrangements or rely on the review of one of the institutions’ IRBs. Three vehicles are available to cede review to another IRB – Cooperative Agreements, Reliance Agreements, and IRB Authorization Agreements, as defined below.
7.1.1. Cooperative Agreements and Reliance Agreements
Cooperative Agreements (CAs) and Reliance Agreements (RAs) are written between the institutions and agreed upon by the IRB Chairs and Institutional Officials, with advice from legal counsel. CAs and RAs apply to all human research studies where both institutions are involved either financially as the awardees for grants/contracts or as the study site of the research activity. Each site must hold an active FWA. The CHS currently has one CA in place – with The Forsyth Institute. It has a Reliance Agreement in place with Harvard University, Harvard School of Public Health, Brigham and Women’s Hospital, The General Hospital Corporation d/b/a Massachusetts General Hospital, Children’s Hospital Boston, Beth Israel Deaconess Medical Center, Joslin Diabetes Center, and Dana Farber Cancer Institute.
Each IRB may decide the appropriateness of ceding or accepting responsibility for the review of human studies, regardless of the presence of a CA or RA. The CHS ordinarily will not cede review to another institution if students from the Faculty of Medicine are to be recruited specifically for a study, and thus reserves the right to review and approve all such studies.
Investigators never should assume that a study is automatically approved by one or the other institution even if a CA or RA is in place. For this reason, the CHS requires Investigators to complete a Designation Request Form (Appendix 59) or the online Catalyst Cede Review Request form. These forms outline the materials required (see Required Documentation, below) for the CHS to make a determination of the appropriateness of ceding or accepting review. Once this determination is made by the CHS Associate Director, the Associate Director contacts the appropriate IRB administrative personnel at the other institution to confirm acceptance or reliance of review for a given study. The Investigator will receive formal notification of ceded review from the CHS office (see Notifications, below), which is copied to the other relying or reviewing IRB as well as the Faculty of Medicine’s SPA representative, as appropriate.
7.1.2. IRB Authorization Agreements (IAA)
IAAs are formed between institutions where there is no CA or RA, but where one institution will accept responsibility for the review of a specified study or studies. In contrast to CAs and RAs, which cover all human studies taking place at an institution for which that institution is all or partially responsible, IAAs are written between institutions generally for one specific study, though the institutions can agree that they will cover more than one study. IAAs usually are initiated by the IRB administrators of each institution, but must be approved and signed by the IOs. As is the case when there is a CA or RA, the Request Forms must be completed by the Investigator and submitted to the CHS, along with the Required Documentation (see Section 7.3). Once all documentation is in place and reviewed, the Investigator will receive formal notification of ceded review from the CHS office (see Section 7.4.1), and copied to the other IRB and the Faculty of Medicine’s SPA representative, as appropriate.
Protection of participants in research projects under Cooperative, Reliance, and IRB Authorization Agreements remains the responsibility of all institutions involved in the research. Thus, designating a relying or reviewing IRB does not absolve any institution involved in the research of such responsibility.
7.2. Conditions for Ceded Review
To avoid duplication of review, the CHS will consider accepting review responsibilities, or ceding review to another IRB, when the following conditions are met.
7.2.1. Accepting Review Responsibilities for another Institution
The CHS will accept reviewing responsibilities on a case-by-case basis, including but not limited to the following situations:
i. When the primary work involving participants takes place on Faculty of Medicine property under the jurisdiction of an Investigator from the Faculty of Medicine and the secondary institution’s involvement is primarily financial or limited to minimal risk activities, or
ii. When the study involves a secondary institution or institution’s personnel but is initiated by an Investigator from the Faculty of Medicine. Such studies may include but are not limited to: clinical rotation curriculum of students, program evaluations, surveys and questionnaires, and research conducted at international sites.
The acceptance of reviewing responsibilities will apply to all levels of risk and review categories and review level by the CHS. In all situations where a study is sponsored by a federal award, a CA, RA, or IAA must be in place with an institution holding a current FWA. When the CHS is accepting review for another institution, the CHS’ review procedures and requirements are the same as those outlined in this policy document.
7.2.2. Ceding Review to other Institutions
The CHS may cede reviewing authority to another IRB under one or more of the following conditions:
i. The Faculty of Medicine acts solely as the funding recipient of an award and no research activities will be taking place at HMS or HSDM facilities;
ii. The Faculty of Medicine is the recipient of a prime funding award and provides a subcontract for human studies work to be performed at another institution that either has or will have IRB approval for the human studies work;
iii. The involvement of the Faculty of Medicine Investigator is limited to data or specimen analysis collected through the other institution, or other minimal risk, engaged activities.
iv. The other institution’s reviewing IRB is more properly constituted to review a certain scope or topic of work, or may have knowledge of the local research context.
The CHS will ordinarily not cede review if any research activities conducted at HMS or HSDM require direct intervention or interactions with study participants.
Ceding of review to another institution’s IRB will apply to all levels of risk and review categories. In all situations where a study is sponsored by a federal award, a CA, RA, or IAA must be in place with an institution holding a current FWA, and a designation confirmation letter (Appendix 60) must be issued before funds can be released and research activities can commence.
7.2.3. Harvard Clinical and Translational Science Center (CTSC)
In 2008, the Harvard Faculty of Medicine received an award from the National Institutes of Health to establish a Clinical and Translational Science Center (“CTSC”). This award is intended to foster cooperative and collaborative research and the sharing of resources between the Faculty of Medicine and its affiliated institutions (e.g. Harvard University, Harvard School of Public Health, Brigham and Women’s Hospital, Massachusetts General Hospital, Children’s Hospital, Boston, Beth Israel Deaconess Medical Center, Joslin Diabetes Center, Dana Farber Cancer Institute). Research conducted at one or more of the CTSC sites and/or with CTSC funds will be reviewed by the appropriate institution’s IRB, with ceded review as appropriate. Each institution’s IRB may decide the appropriateness of ceding or accepting responsibility for the review of research involving human subjects, regardless of whether the project is related to the CTSC. Procedures for requesting ceded review are located in Section 7.3 and 7.4 of this policy document.
7.3. Required Documentation for Ceded Review
The following documents must be submitted to the CHS for consideration of ceding review to another IRB:
- Designation Request Form or Online Catalyst Cede Review Request Form
- Funding application (grant, contract and/or subcontract), if funding is awarded to the Faculty of Medicine
- IRB approval letter from the reviewing IRB (if ceding review is requested)
7.4. Procedures for Ceded Review
The documentation listed in Section 7.3 must be submitted to the CHS for consideration of ceded review. As with all materials submitted to the CHS office, the information is logged into the HIRBERT database and a file is generated by CHS staff and submitted to the CHS Associate Director. Once the appropriateness of ceded review is determined by the Administrators of the affected IRBs, an IAA (if applicable) will be generated and signed by the appropriate IOs, or (if applicable) agreement to use the CA or RA will be confirmed by the Administrators. Once all of the required documentation is in place, a letter will be generated by the CHS office, and, once approved by the CHS Associate Director or ORSP Director, sent to the Investigator, with a copy to the reviewing IRB, and the Faculty of Medicine’s SPA representative (as appropriate).
The designation confirmation letter (Appendix 60) specifies the Investigator, study title and number, funding source, reviewing institution, and the reviewing institution’ study number, approval and expiration dates. Copies of designation letters are sent to the representative of the IRB accepting review responsibilities for the CHS.
If it is not appropriate to cede review of the study, the CHS Associate Director will notify the Investigator of the reason for this decision and of the Investigator’s need to complete a CHS Application for initial review of the research (see Section 4).
Studies that have been ceded to another institution’s IRB must still receive continuing approval from the CHS each year, or as often as the reviewing institution’s IRB deems it appropriate. The required documentation (see Section 7.3) must be submitted to the CHS office for continuing approval of ceded review each year.
If the CHS Associate Director determines that it may no longer be appropriate to cede review of the study (if for instance, amendments have changed the study activities, engagement of Faculty of Medicine personnel, or location of activities), the Associate Director will contact the Investigator and/or the Reviewing Institution’s IRB Administrator, with any questions or concerns. If these questions/concerns are not satisfactorily resolved, the Investigator will be informed of the reasons why the study is no longer appropriate to cede review and of the Investigators need to complete a CHS application or, if appropriate submit a copy of the application from the institution that conducted the review, for CHS review.
7.4.3. Amendments, Non-Compliance, and Unanticipated Problem Reporting
If amendments to the protocol alter the engagement of the Faculty of Medicine or its investigators (e.g. relocation of activities to Faculty of Medicine property, changes in the Investigator’s role, etc.), the Investigator should contact the CHS; these amendments may either trigger CHS review, or indicate that it is appropriate to close the study with the CHS office.
Incidents resulting in a determination of serious or continuing non-compliance, or unanticipated problems involving risks to participants or others, are reported to the CHS by the reviewing institution, as outlined in the IAA and RA. However, Investigators may also report these determinations to the CHS.
If the CHS Associate Director has questions or concerns in the review of the paperwork and the Investigator’s response to the questions are not satisfactory, the Associate Director (in consultation with the IO and ORSP Director, and possibly the representative from the reviewing IRB) will determine the appropriateness of continuing ceded review. Depending on the seriousness of the events and/or activities, the CHS may contact the reviewing IRB to coordinate actions to be taken, or review minutes of meetings when the events were discussed. If ceding review is no longer appropriate, the Associate Director will notify the Investigator (with a copy to the reviewing IRB) of the reasons for this determination and the need to complete a CHS application, or if appropriate, to submit a copy of the application submitted to the reviewing IRB for CHS review.
The IRB Leadership Team may be asked to evaluate the effectiveness of ceding review to a particular institution. Additionally the management of procedures for ceding review will be evaluated regularly to assess best practices for the HRPP to insure protection of participants while decreasing unnecessary redundancies in oversight.
Studies that have been ceded to another institution’s IRB may be closed with the CHS office (even if there is continuing IRB approval at the reviewing institution), assuming one or more of the following conditions:
i. When there is no longer engagement of the Faculty of Medicine;
ii. When there is no more funding for the research activities awarded through the Faculty of Medicine;
iii. When the funding is transferred to another institution and there is continuing review at that institution; or
iv. When the study is closed by the Institution providing review responsibilities and research activities are no longer taking place. Note: if the study is closed at the reviewing institution, but there is data analysis being performed by a Faculty of Medicine Investigator, then the CHS will review the study.To request Study Closure, the Investigator must complete the CHS Study Closure form (Appendix 54) and submit it with the closure confirmation of the reviewing IRB and other documentation noted on the form, as appropriate. CHS Study Closure is confirmed with a letter to the Investigator (Appendix 61) that is copied to the reviewing IRB and the Faculty of Medicine’s SPA representative, as appropriate.
Faculty of Medicine Investigators often participate in collaborative research projects that involve multiple research sites.
8.1. Where the Faculty of Medicine is the recipient of the primary funding award (regardless of the source), and the research is conducted at HMS or HSDM (with additional sites coordinated by the HMS/HSDM Investigator)
i. The CHS is responsible for the initial and continuing reviews of the main study, the grant, all research materials and activities, and participant safety.
ii. The CHS is responsible for receiving copies of IRB approvals, approved consent documents and research materials (including language translations) from all sites and, for DHHS sponsored research, assuring that research is taking place at institutions holding a current FWA.
iii. The CHS will review plans for circulating approved protocols and data collection instruments to the sites, for communicating changes to the protocol to those sites, and for data distribution from those sites back to the Investigator and/or between sites.
iv. The CHS is responsible for reviewing unanticipated problems, and adverse events (unless there is a DSMB, in which case timely DSMB reports must be submitted to the CHS for review) and for ensuring an adequate plan of informing additional sites of these issues in a timely manner.
v. The CHS is responsible for reviewing requests for changes to the protocol and the Investigator’s plan to disseminate information about approved changes to the additional sites, and also is responsible for receiving amendment approvals (and approvals of any revised documents) from the IRBs at those sites.
vi. The CHS is responsible for reviewing any protocol deviations or issues of non-compliance with federal regulations at the HMS/HSDM site, and for reviewing any such reports to/from the additional site’s IRBs. The CHS will review the Investigator’s plans for reporting such issues to the other sites and will itself report such issues to the other site IRBs.
vii. The CHS will collaborate and communicate with other IRBs reviewing or ceding review of the research, as necessary.
8.2. Where the Faculty of Medicine is the recipient of a primary funding award and the Principal Investigator is an HMS/HSDM faculty member who is based at a Harvard-affiliated institution where the research will be taking place
i. The CHS will either confirm its use of a Cooperative Agreement (CA) or Reliance Agreement (RA) with the Institution or will ordinarily enter into an IRB Authorization Agreement (IAA) with the IRB of the Harvard-affiliated institution.
ii. If the CHS is unable to enter into an IAA with the IRB of the Harvard-affiliated institution, then the CHS remains responsible for the items in Section 8.1, above.
iii. The CHS will collaborate and communicate with other IRBs reviewing or ceding review of the research, or to whom it is ceding review, as necessary.
8.3. Where the Faculty of Medicine is the recipient of a subcontract funding award and the research is taking place at HMS or HSDM
i. The CHS is responsible for the initial and continuing reviews of the research indicated in the subcontract for the research taking place at HMS/HSDM, and for participant safety at the HMS or HSDM sites.
ii. The CHS is responsible for ensuring that the Investigator enters into a data use agreement (DUA), material transfer agreement (MTA; Appendix 62) or a clinical trial agreement (CTA; Appendix 63), as appropriate, before the research begins. The CHS is responsible for reviewing the CTA with the Office of Technology Development (OTD).
iii. The CHS is responsible for receiving a copy of the approval document from the IRB of the institution receiving the primary funding award.
iv. The CHS is responsible for reviewing unanticipated problems and adverse events (unless there is a DSMB) and the plan for (i) reporting events to the main/overall Investigator, and (ii) receiving information about events from the other research sites, and/or the DSMB reports.
v. The CHS is responsible for reviewing requests for changes to a protocol at the Faculty of Medicine site.
vi. The CHS is responsible for reviewing any reports of protocol deviations and/or non-compliance with federal regulations at the HMS/HSDM site.
vii. The CHS will collaborate and communicate with other IRBs reviewing or ceding review of the research, or to whom it is ceding review, as necessary.
8.4. Where an HMS/HSDM Investigator who is based at a Harvard-affiliated institution is the recipient of a subcontract funding award from the Faculty of Medicine and the research is taking place at the Harvard-affiliated institution
i. The CHS will either confirm its use of a CA or RA with the Institution or will ordinarily enter into an IAA with the IRB of the Harvard-affiliated institution.
ii. If the CHS is unable to enter into an IAA with the IRB of the Harvard-affiliated institution, then the CHS remains responsible for the items in Section 8.3, above.
iii. The CHS will collaborate and communicate with other IRBs reviewing or ceding review of the research, or to whom it is ceding review, as necessary.
8.5. Where there is no external funding to the Faculty of Medicine and the HMS/HSDM Investigator is the Principal Investigator and additional sites are coordinated by the Investigator
See Section 8.1, above.
8.6. Where an HMS/HSDM Investigator who is based at a Harvard-affiliated institution receives no external funding through the Faculty of Medicine and the research is taking place at the Harvard-affiliated institution
The research should be approved by the IRB of the Harvard-affiliated institution.
8.7. Where the primary research funds are awarded to the Faculty of Medicine and may or may not include a subcontract to the Institution where the research is taking place and where the HMS/HSDM Investigator has no affiliation
See Section 8.2, above.
8.8. Where the subcontract research funds are awarded to Faculty of Medicine and the research is taking place at an Institution where the Investigator has no affiliation
See Section 8.4, above.
The Leadership Team may be asked to evaluate the effectiveness of these policies to assess best practices for the HRPP to insure protection of human participants while decreasing unnecessary redundancies in oversight.
9. Research by Faculty of Medicine Students
HMS and HSDM pre-doctoral students conduct independent research projects, and thus the CHS allows these students to serve as Principal Investigators on their own studies. Student research must meet minimal risk exemption or expedited review criteria (though, as stated in Section 4.10.2, some minimal risk studies may require full CHS review depending on the research topic, activities, population and/or location). HMS and HSDM students are subject to the same policies, guidelines and regulations as the Faculty of Medicine, as documented in this Policy and Procedures manual, as well as additional requirements outlined in this section.
Each student must have at least one faculty mentor or faculty advisor and one mentor at the site where the research is taking place. The faculty mentor should be available to assist the student in developing his/her protocol, CHS application and study materials. The site mentor should be available to assist the student with any local/institutional approvals, and be available while the study is being conducted, in the event that problems or questions arise.
9.1.1. Mentor Letters/Letters of Support
9.1.1.1. HMS and HSDM Faculty Letters
Students are required to have a letter from their faculty mentor or advisor. This letter must accompany the CHS application and should include the following information:
- The mentor is assisting the student in the development of the research proposal, CHS application and research materials.
- The mentor will be available throughout the conduct of the research to answer any of the student's questions and help the student deal with any problems that may arise.
- The mentor is familiar with the ethical conduct of research and has taken a human subjects protection course or training (documentation of the mentor’s current certificate should accompany the student’s CHS application).
- Any knowledge the mentor has of the site/location where the student will be working, or with whom they will be working (i.e. on-site mentor or organization).
9.1.1.2. On-Site Mentor Letters/Letters of Support
Students performing research at institutions, organizations, or clinics not at HMS/HSDM, domestic or international, are required to also have an on-site mentor (i.e. a mentor at the institution, organization or clinic where the research will be taking place). Site mentor letters should include the following:
- The site mentor will be available to help the student set up his/her research project.
- The site mentor will be available to help the student with any questions/problems that arise with the research/materials.
- The site mentor is familiar with the ethical conduct of research and confidentiality/privacy issues.
- The site mentor is familiar with local customs, language, laws (or can assist the student in seeking such legal counsel), standards of care and practice where the research is taking place.
The HSDM Office of Research assigns students to Faculty Advisors who are responsible for working with students to ensure they are meeting their research requirements, selecting appropriate projects and mentors, and offering guidance as needed throughout their program. The HSDM Office of Research has a database of mentors that have worked with HSDM students in the past and will keep this resource on file. There is a HSDM Pre-Doctorate Advisory Committee which oversees the research advisor program.
9.2. Funding for Student Research
9.2.1. Faculty of Medicine Scholars in Medicine Office (SMO)
The SMO serves as a resource for Faculty of Medicine students interested in applying for Harvard University and other domestic or international traveling fellowships for study, community service, or research. These fellowships include, for example, the Fulbright Scholars Program, the Zuckerman Fellowships, the Howard Hughes Medical Institute fellowships, the Doris Duke/Pasteur fellowships, the Fogarty Ellison Overseas Fellowships in Global Health and Clinical Research, and the traveling fellowships available through the Harvard University Committee on General Scholarships.
The SMO and CHS offices work closely together to ensure that all student research projects have been reviewed and approved by each office/Committee before research activities commence. Students who have submitted funding applications to SMO must submit the complete SMO application with their CHS application to the CHS office. No funding may be released by SMO to the student until the CHS office confirms with SMO that the student is actively engaged in the CHS review process and likely to receive approval, or that CHS approval has been documented.
If a student will be receiving fellowship monies from the Faculty of Medicine to support his/her research project and the fellowship includes living expenses, the funding can be released with the following conditions: (a) the student may not expend any of the fellowship monies for research purposes until CHS approval has been documented, and (b) no research activities can take place until CHS approval has been documented. However, if the fellowship is only for research purposes, no money may be released until CHS approval has been documented. CHS approval is documented in the form of a ROA or exemption letter (see Sections 4.8, 4.9, 4.10).
Students receiving grants or contracts from outside the Faculty of Medicine must submit the entire grant application, along with the CHS application and all applicable materials outlined in Section 4, for CHS review and approval. No research monies will be released until CHS approval is documented in the form of a ROA or exemption letter (see Sections 4.8, 4.9, 4.10).
9.3. CHS Student Submission Requirements
Student submissions of independent research projects to the CHS should include:
- Cover letter
- CHS Application signed by student and mentor.
- A copy of the grant, contract, and/or SMO or research fellowship application.
- Informed consent forms or request for waiver (also HIPAA authorization or request for waiver of same, if applicable).
- Research materials (such as recruitment fliers, survey instruments, questionnaires, telephone scripts, and focus group questions)
- Evidence of CITI training (or equivalent training certificate) for student and mentor.
- CV or biosketch
- Personnel roster (if additional people will be working on the study with the student)
- IRB approvals from other institutions/sites.
- Mentor letters (HMS/HSDM faculty and on-site supervisor).
Students who wish to work on a research project (as a research assistant/associate) that has existing approval from an IRB other than CHS or if the project will soon to be approved by an IRB other than CHS, and who are or will receive funding from the Faculty of Medicine must submit materials to request that the CHS consider ceding review (see Section 7).
Students planning to work on a research project (as a research assistant/associate) that has CHS approval and who are or will receive funding from the Faculty of Medicine must submit materials to amend the existing project (see Section 6).
To provide all-around support for the student and information about his/her intended research project, all communications from the CHS office to the student are copied to: (a) SMO (if the student is receiving SMO funding); (b) the faculty mentor; (c) the on-site mentor, as appropriate; and (d) any other appropriate entity (such as additional IRB/ethics committee, facility manager or advisor).
Students are required to obtain all appropriate institutional and site approvals before commencing research activities.
CHS approval must be documented with an ROA or letter of exemption (or a letter or participation; Appendix 64, if the student is receiving funding from the Faculty of Medicine and joining a study as research personnel) before any research activities may commence. Approval documentation will additionally be copied to: (a) SMO (if the student is receiving SMO funding); (b) the faculty mentor; (c) the on-site mentor, as appropriate; and (d) any other appropriate entity (such as additional IRB/ethics committee, facility manager, or advisor). Final approvals for research to be undertaken at external sites may be held until formal approval documentation from that site is forwarded to the CHS.
9.5.2. Research Site Approvals
As noted in Section 4.13 of this policy document, the CHS is required to have knowledge of the local research context (whether the research site is a domestic or international research site) in order to provide a thorough review, to understand particular risks and benefits of the study population, and the relevance, customs and cultural significance of study procedures and outcomes to the community in which the research is taking place. In addition, while the CHS provides institutional approval for the student (which is required), it cannot and does not cover the responsibility or replace the need of the student to receive approval from the local reviewing authority at the site where the research will be taking place. Site approvals are required in all circumstances.
9.5.3. Ceded Review of Independent Student Research
Review and approval of independent student research projects ordinarily are not ceded to another institution. However if the research activities would require review by another Harvard IRB or the IRB of one of Harvard’s affiliated institutions, a request to cede may be granted if approved by all involved/engaged IRBs. Affiliated and other institutions, however, may cede review of student projects (where appropriate) to the CHS.
10. Policies and Criteria for IRB Approval
The mission of the CHS is to ensure that all participants are protected from any unnecessary risk when enrolled in a research study; to ensure participants make an informed decision to participate, and when possible, ensure that participant and/or society at large benefits from the knowledge gained from the research study. The CHS reviews the participation of humans in research, in accordance with applicable federal regulation (45 CFR § 46.111(a) and (b)), the Belmont Report, and University and CHS policy, as documented in the following section.
10.1.1. Equitable Selection of Participants
In assessing whether the selection of participants for a research study is equitable, in accordance with 45 CFR § 46.111(a), the CHS takes into account the purpose(s) of the research and the setting in which the research will be conducted. Equitable selection of participants is meant to ensure that a research study is: (a) as inclusive as possible of all gender, ethnicities, and racial groups, so that the risks and benefits are experienced equitably amongst the population and also are generalizable to the greater population; and (b) not overly inclusive of groups of participants that may be easy to enroll because of location or circumstance.
The CHS is particularly cognizant of the special challenges of research involving vulnerable populations (such as children, prisoners, pregnant women, and persons with cognitive impairments). When the participants of a study are likely to be vulnerable to coercion or undue influence, the CHS ensures that additional safeguards have been included in the study to protect the rights and welfare of these participants (see Section 11).
According to the Belmont Report, risk refers to the “possibility that harm may occur,” and the level of risk (i.e. minimal, moderate, severe) also pertains to the likelihood of harm and the possible/likely magnitude of harm. Benefit refers to “positive value related to health or welfare.”
As set forth in 45 CFR § 46.111(a), the CHS must determine that:
i. Risks to participants are minimized: (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose participants to risk, and (ii) whenever appropriate, by using procedures already being performed for diagnostic or treatment purposes; and
ii. Risks to participants are reasonable in relation to the anticipated benefits to participants from the research, if any, and the importance of the knowledge that may reasonably be expected to result.
The CHS evaluates all potential areas of risk including not only physical risk but also risk of psychological harm, risk of social or economic harm, and legal risk. This aspect of risk evaluation is of particular importance as the majority of the research activities covered by the CHS are social and behavioral in nature. Thus, membership of the CHS over time has included sociologists, psychologists, ethnographers, lawyers and psychiatrists who are well versed in a variety of aspects of risk assessment. Once risk in these categories have been identified, the CHS determines the level of risk, and whether the risk is outweighed by the benefit either in that particular area of research or with respect to society as a whole. Additionally the CHS may suggest ways to minimize identified risks, such as having a counselor on call for any emergent situations arising from sensitive issues, or eliminating the request for participant identifiers from a survey instrument that collects sensitive or potentially damaging information.
In evaluating risks and benefits, the CHS considers those that may result from the research, as well as the procedures participants would undergo if not participating in the research.
10.1.3. Data Safety Monitoring
The CHS follows NIH policy regarding safety oversight and monitoring of clinical studies. It is the policy of the NIH for each institution to provide appropriate oversight and monitoring of the conduct of clinical trials (http://grants.nih.gov/grants/guide/notice-files/not98-084.html) to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials. Data Safety Monitoring Boards (DSMBs) are required for all Phase III trials (for more information on trial phases, see Section 12.1). However, for Phase I and II trials, a DSMB or a Data Safety Monitoring Committee (DSMC) may be appropriate if a study has multiple sites, is blinded (masked), or if it involves particularly high-risk interventions or vulnerable populations.
Regardless of funding source/sponsorship of the study, and depending on the level of risk to participants (including non-clinical risks), the CHS may require that an Investigator form a DSMB/C before a study begins, or if risks are identified during the course of an ongoing study. These determinations or requested requirement for formation of a DSMB or DSMC are made on a case by case basis for studies involving more than minimal risk or when additional risks are identified during the course of study and presented as an unanticipated problem, adverse event, or during the review of an amendment or the continuing review process.
While DSMB/Cs operate separately from IRBs, the CHS will review all research data safety monitoring plans and reports, which must be included with the research materials submitted for review and approval of the study. All monitoring plans must include a plan for reporting adverse and unanticipated events to the CHS, the FDA, the NIH or another sponsor source, as applicable. Additionally, DSMB/C reports must be submitted to the CHS at the time the reports are available to the Investigator, regardless of the timing of the report to the continuation of the study.
10.1.3.1. Data Safety Monitoring Plans (DSMPs)
DSMPs outline how the DSMB/C will protect participants from any unnecessary harm. DSMPs are created by the Investigator and his/her DSMB/C and should include the following information:
- A list of the DSMB/C members, including the Chair, with a description of their expertise (such as drug or clinical trial, treatment expertise, and biostatisticians) and whether they are connected to the research study in any way.
- An outline of DSMB/C Chair, member and Investigator responsibilities (e.g. who is responsible for meeting scheduling, conduct of the meeting and generation reports for the CHS, the FDA and/or funding sponsor).
- The DSMB/C meeting schedule.
- A description of the potential risks and the factors that may influence them (i.e. how side effects may increase with drug escalation, or how drugs may affect a participant who may be entering a new phase of his/her medical condition)
- A description of any special information that the Investigator should include in event reports, and the timing of reporting the events to the DSMB/C Chair and members.
- The reporting schedule of events and DSMB/C reports to the CHS, the FDA and the NIH or other study sponsor, as applicable.
- For multi-site trials, a description of a central reporting entity that will be responsible for preparing timely summary reports of unanticipated problems involving risks participants or others, including adverse events, for distribution among sites and the IRBs.
Research protocols must include descriptions of how Investigators will protect participant privacy – whether related to recruitment, consent, or data collection and analysis. When designing and conducting research, Investigators must consider how the release of certain information could damage a participant’s social or family structure, employability, insurance coverage, financial security, or even legal liability. Participants must be able to choose how and when their private information will be used, withheld, or disclosed. Potential risks of a breach of confidentiality or of a participants’ right to privacy are evaluated by the CHS and considered before a study will be approved; any such breaches during the conduct of the study must be reported to the CHS and evaluated under the Organization’s policy on unanticipated problems involving risks to participants or others (see Section 13).
For information on the Health Insurance Portability and Accountability Act (HIPAA) privacy rules, please see Section 10.4.
10.1.5. Confidentiality of Data
Investigators must include in their research applications and protocols a plan for maintaining confidentiality of participant data – including how data will be collected (such as whether identifiers will be maintained or coded on data collection forms, and where codes for identifiers will be maintained to prevent unauthorized access to this information), stored (for data stored in paper form, where the paper will be kept, how unauthorized access will be prevented, how paper will be disposed and when; for data stored electronically, how unauthorized access will be prevented and distributed (electronic protections such as firewalls, encryption, locking of laptops, and storage of memory disk); and for data stored on video or audio, how and by whom the information will be transcribed, and how the tapes will be disposed of), analyzed (aggregate or raw form) and documented (stripped of personal identifiers and other information that may identify someone by circumstance) in publications. Faculty of Medicine personnel are required to abide by Harvard’s Enterprise Security and Research Data Security Policies (Appendix 4a and 4b) , and the HMS Information Security Policy (Appendix 5).
Under 45 CFR § 46.111(a)(6), before approving a study, the CHS must confirm that each research protocol contains adequate provisions for the confidentiality and maintenance of data to ensure the safety of participants. The CHS may request additional protections, if it believes the research plan is not sufficient to protect participants. In addition, depending on the type of research being conducted, the CHS may request that the Investigator secure a Certificate of Confidentiality (see Section 10.1.6).
10.1.6. Certificates of Confidentiality
In some circumstances, the CHS may require an Investigator to obtain a Certificate of Confidentiality from the NIH (or other Health and Human Services department) in order to protect research participants should they disclose activity that would likely result in legal action against them or damage to other aspects of their lives. Circumstances for such a requirement generally include research that specifically targets (or is likely to include information pertaining to) illegal activities, such as drug use or distribution, illegal sexual practices, stealing, or fraud.
The OHRP Guidance States:
Certificates of Confidentiality are issued to protect identifiable research information from forced or compelled disclosure. They allow the investigator and others who have access to research records to refuse to disclose identifying information on research participants in civil, criminal, administrative, legislative, or other proceedings, whether federal, state, or local. Certificates of Confidentiality may be granted for studies collecting information that, if disclosed, could have adverse consequences for participants, such as damage to their financial standing, employability, insurability, or reputation. By protecting researchers and institutions from being compelled to disclose information that would identify research participants, Certificates of Confidentiality help to minimize risks to participants by adding an additional level of protection for maintaining confidentiality of private information. (http://www.hhs.gov/ohrp/humansubjects/guidance/certconf.htm)
Certificates of Confidentiality protect participants from compelled disclosure of identifying information but do not prevent the voluntary disclosure of identifying characteristics of research participants. Researchers, therefore, are not prevented from voluntarily disclosing certain information about research participants, such as evidence of child abuse or a risk of harm to themselves or others. If a researcher intends to make such voluntary disclosures, the consent form must clearly indicate this intent.
For more information on certificates of confidentiality, visit: http://grants.nih.gov/grants/policy/coc/index.htm.
10.1.7. Remuneration Guidelines
Payment, compensation or remuneration to individuals who participate in research projects is an acceptable practice. The CHS reviews and must find that the amount, schedule and type of any proposed remuneration is fair, and whether the payments could be considered coercive (due to an excessive enticement of money, goods or services). Thus, remuneration:
- Should be comparable to other projects involving similar time, effort, and inconvenience.
- Should be pro-rated on the number of procedures and study visits and should not be a condition of completing the entire study, although a bonus for completing the study may be acceptable. However, any amount paid as a bonus for completion must be reasonable and not so large as to unduly induce participants to stay in the study when they would otherwise have withdrawn.
- Should ensure that confidentiality of participants is protected and participants are paid in a manner that allows them to retain privacy. Thus, cash or a money order might be acceptable, but a check that participants would have to negotiate and that might link them to the research might not.
- Must include the specifics (including the amount per visit and payment schedule) documented in the consent form under the “Compensation” section of the consent form– but not under the “Benefits” section.
- Must not include “finder fees” (referrals of prospective participants).
- Must not include a coupon from a trial sponsor for a discount on the purchase price of the product once it has been approved for marketing.
Investigators should note that payments to participants of $600 or more per year require IRS reporting on Form 1099-MISC as non-employee compensation. For more information, consult the Harvard Tax Office http://vpf-web.harvard.edu/ofs/tax_services/index.shtml, or the IRS http://www.irs.gov/. The Harvard University policy on processing payments to research participants can be found at: http://vpf-web.harvard.edu/policydocuments/alphalisting.do#H (Appendix 65).
The CHS must review and approve the procedures for recruitment and consent of research participants to ensure compliance with 45 CFR § 46.111 and 116. All materials to be used with research participants must be reviewed and approved by the CHS, including materials such as recruitment advertisements, telephone scripts, direct mailings, consent forms, assessments of understanding of consent forms, questionnaires, surveys, and payment slips for remuneration of study procedures, to be sure that accuracy, non-coercive language and confidentiality is maintained at all times.
10.2.1. Recruitment Guidelines
The CHS must ensure that recruitment methods are not coercive, do not promise what they cannot deliver, and maintain confidentiality and privacy of potential participants. Research applications submitted to the CHS office should include the following information:
- How potential participants will be identified
- How, by whom and where potential participants will be approached
- How long after recruitment consent procedures will take place
- Whether parties other than the Investigator and study personnel will recruit participants (e.g. treating clinicians or calling centers).
Recruitment of participants can take many forms, including identification though medical record review, patient databases or registries, treating clinicians, family members or friends, faculty, students, and advertisements through media, such as print, radio, television and the Internet.
Any materials to be sent to, seen or heard by research participants must be approved by the CHS. Recruitment materials should include the following information for the potential participants:
General advertisements should include:
- Name of the research project
- Purpose of the project
- Special inclusion or exclusion criteria (e.g. smoker/non-smoker, age range, medical or social condition)
- Duration of participation
- Name and contact information of study personnel for questions, or to participate
Direct mailing to potential participants should include the above information, in addition to the following:
- How the Investigator received his/her name and contact information
- Opt in or opt out information
Opt in – participants receive a letter about the study which includes a phone number to call or a post card to return if they are interested in participating or learning more about the study. The Investigator does not call potential participants if they do not indicate by letter or phone that they wish to participate or receive more information.
Opt-out - participants receive a letter about the study, which includes a phone number to call or post card to return if they are not interested in participating or learning more about the study. Not opting-out indicates to the Investigator that they can proceed with contacting the individuals.
- Letters should be signed by the Investigator and/or the treating clinician.
10.2.3. CHS Review of Recruitment Materials
When reviewing recruitment materials, the CHS must have the following:
When reviewing advertising materials, the CHS must insure that advertisements do not:
- The mode of communication from the Investigator to the potential participant (e.g. public flyers, direct email or mail, phone calls)
- The final copy of all printed materials/study advertisements;
- The final audio/video taped advertisements.
- State or imply a certainty of favorable outcome or other benefits beyond what is outlined in the consent document and the protocol.
- Make claims, either explicitly or implicitly, that the drug, biologic or device is safe or effective for purposes under investigation.
- Make claims, either explicitly or implicitly, that the test article is known to be equivalent or superior to any other drug, biologic or device.
- Use terms, such as “new treatment”, “new medication”, or “new drug” without explaining that the test article is investigational.
- Promise “free medical treatment”, when the intent is only to say participants will not be charged to take part in the study.
- Include exculpatory language.
- Emphasize the payment or the amount paid, by such means as larger or bold type.
10.3. Informed Consent Guidelines
Informed consent is a process, not a form. Thus, the CHS pays particular attention to all information given to potential participants from recruitment through enrollment. The CHS will sometimes require re-consent of participants when, for example, a study is to be carried out over long periods of time; involves participants who may need to be reminded of study activities (such as the elderly, or those with cognitive disabilities); includes numerous procedures; or has been modified in a way that could affect participants or their decision to continue to participate in the study.
Once a participant has been recruited, he or she must provide informed consent to participate in the research. Consent form content must:
- Be provided in a format understandable to the participant. Reading levels should generally be at an 8th grade level or under;
- Be provided in the primary language of the individual;
- Define medical terminology and jargon; and
- Be written in a context that is easy to follow (e.g. subject headings, short and concise sentences).
Pursuant to 45 CFR § 46.116, participants (or their legally authorized representatives) should be presented with study information in ample time to consider whether to participate, and to reduce the likelihood of their being or feeling coerced or unduly influenced. No informed consent (verbal or written) should include exculpatory language, whereby participants or their representatives are made to waive or appear to waive any of the participants’ legal rights, or release or appear to release the Investigator, the sponsor, the Institution or its agents from liability for negligence.
The Investigator is responsible for using a current, validated consent form with participants. A copy of the informed consent form must be given to the participant (or his/her legal representative) to read and sign; the original should be placed in the participant’s record (hospital/clinic, or other, as appropriate); and a copy must be maintained in the Investigator’s study file. Investigators’ study files are subject to CHS review, as well as federal audits (i.e. FDA, NIH, or OHRP).
10.3.1.1. Basic Elements of Informed Consent
Consent forms must contain the following elements, as required by 45 CFR § 46.116(a)(1-8):
(1) A statement that the study involves research
(2) The purpose of the research
(3) The expected duration of participant involvement in the study
(4) A description of the procedures to be followed
(5) Identification of the procedures which are experimental
(6) Description of any reasonably foreseeable risks or discomforts to the participant
(7) Description of any benefits to the participant or to others that may reasonably be expected from the research
(8) Disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the participant
(9) A statement describing the extent, if any, to which confidentiality of records identifying the participant will be maintained. For FDA-regulated research, a statement that notes the possibility that the FDA might inspect the records.
(10) For research involving more than minimal risk, an explanation as to whether any compensation or any medical treatments are available if injury occurs, and if so, what they consist of, or where further information may be obtained.
To address Element 10, the following statement must be in the Informed Consent:
HARVARD’S WORDING FOR DISCLOSURE OF COMPENSATION FOR INJURY –
“If physical injury resulting from participation in this research should occur, although Harvard’s policy is not to provide compensation, medical treatment will be available including first aid, emergency treatment and follow-up care as needed, and your insurance carrier may be billed for the cost of such treatment. In making such medical treatment available, or providing it, the persons conducting this research project are not admitting that your injury was their fault.”
(11) The Consent form includes the contact information of the research team for the participant to obtain answers to questions about the research and voice concern or complaints or about, or problems with the research. The consent form should also include the contact information for a person independent of the research for participants to voice complaints about the research, obtain answers to questions in the event the research staff could not be reached or if they wished to talk with someone other than the research staff, and to obtain information about their rights as a research participant.
(12) A statement that participation is voluntary and refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled; and that the participant may discontinue participation at any time without penalty or loss of benefits to which they would otherwise be entitled.
Additional Elements of Informed Consent to be used when appropriate as defined below and, as required by 45 CFR 46.116 (b)(1-6):
(1) A statement that the particular treatment or procedure may involve risks to the participant which are currently unforeseeable such as when the research involves investigational test articles or drugs or other procedures in which the risks to the participants are not well known.
(2) A statement that if the participant is or becomes pregnant, the particular treatment or procedure may involve risks to the embryo or fetus, which are currently unforeseeable. This statement must be included when the research involves pregnant women or women of child-bearing potential and the risk to the fetuses of the drugs, devices or other procedures in the research is not well known. In the majority of cases this statement would apply to clinical studies, but any social and behavioral studies involving stress may also be considered and as such this statement may be required according to the judgment of the CHS.
(3) Anticipated circumstances under which the participation may be terminated by the investigator with out regard to the participant’s consent. This statement should be considered for inclusion in the consent when there are anticipated circumstances under which the investigator may terminate participation of a participant.
(4) Any additional costs to the participant that may result from participation in the research. This statement would be appropriate when it is anticipated that participants may have additional costs.
(5) The consequences of a participant’s decision to withdraw from the research and procedures for orderly termination of participation. This statement must be included when withdrawal from the research is associated with adverse consequences.
(6) A statement that significant new findings developed during the course of the research which may relate to the willingness of a participant to continue in the study will be provided to the participant. This statement is appropriate when the research is long term and interim information is likely to be developed during the conduct of the research.
(7) The approximate number of participants involved in the study should be stated in the consent when the research involves more than minimal risk.
If the project includes remuneration for participants, the amount of remuneration, the schedule of payments, and any requirements to obtain remuneration must be included on the consent form.
If the study involves the collection of DNA for genetic analysis, a statement must be included indicating that information is being obtained for this purpose and specific options and information for the participant (such as whether participant’s biological samples may be used for other purposes, and whether any incidental finding may be determined about the participant’s condition) should be given to the participant, as well as other elements as determined by the CHS, depending on the nature of the study. On the consent form, the statements should appear as “Yes or No” options and read: (1) I wish to receive a letter with information about the study once some relevant results have been obtained. I understand that this letter cannot discuss my personal case or data related directly to my family; (2) I agree to donate genetic material for the approved study; and (3) I agree that my genetic material may be stored and used for future studies.
10.3.1.2. Documentation of Consent
According to federal regulations 45 CFR § 46.117(b) documentation of signed consent is required in the following manner (unless a waiver of consent/element of consent is granted; see waiver criteria, below):
(1) A written consent document must contain the required elements of informed consent, as outlined above. The consent form may be read to the participant or the participant's legally authorized representative, and ample time should be given to the participant / legal representative to read it before it is signed (and dated for FDA-regulated research); or
(2) A short form written consent document, stating that the elements of informed consent required by § 46.116 (or 21 CFR§ 50.27 for FDA-regulated research) have been presented orally to the subject or the subject's legally authorized representative, may be used. However, when this method is used, there must be a witness to the oral presentation. The IRB must approve the written summary of what is to be said to the participant or their representative (and dated for FDA-regulated research). Only the short form itself is to be signed by the participant or their representative. However, the witness shall sign (and date for FDA-regulated research) both the short form and a copy of the summary, and the person actually obtaining consent shall sign (and dated for FDA-regulated research) a copy of the summary. A copy of the summary shall be given to the participant or their representative, in addition to a copy of the short form.
10.3.2. Guidelines for Waiver or Alteration of Consent Requirements
Under 45 CFR § 46.116(c), the CHS may approve a consent procedure that does not include, or that alters, some or all of the elements of informed consent, or waive the requirement to obtain consent, provided the CHS finds and documents that:
(1) The research or demonstration project is to be conducted by, or subject to, the approval of state or local government officials and is designed to study, evaluate, or otherwise examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or services under those programs; (iii) possible changes in or alternatives to those programs or procedures; or (iv) possible changes in methods or levels of payment for benefits or services under those programs;
(2) The research could not practically be carried out without the waiver or alteration, and
(3) The research is not FDA-regulated.
Additionally, under 45 CFR § 46.116(d), the CHS “may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent” or waive the requirement to obtain consent all together, provided the CHS finds and documents that:
(1) The research involves no more than minimal risk to the participants;
(2) The waiver or alteration will not adversely affect the rights and welfare of the participants;
(3) The research could not practicably be carried out without the waiver or alteration;
(4) Whenever appropriate, the participants will be provided with additional pertinent information after participation, and;
(5) The research is not FDA-regulated.
According to 45 CFR § 46.117(c) the CHS may waive the requirement for the Investigator to obtain a signed consent form for some or all participants if it finds either:
(1) That the only record linking the participant and the research would be the consent document, the principal risk would be potential harm resulting from a breach of confidentiality, and the research is not FDA-regulated. In each circumstance, the participant should be asked whether they want documentation linking them with the research, and their wishes will govern; or
(2) That the research presents no more than minimal risk of harm to participants and involves no procedures for which written consent is normally required outside of the research context.
10.3.2.1. Waiver Requests to the CHS
Investigators must complete a Request for Waiver of Consent (Appendix 38) to outline/specify waiver requests. The requests must contain the criteria in 10.3.2 (as appropriate) in order for the CHS to approve the waiver of a specific element(s), to waive consent in general, or to waive documentation of informed consent. Waivers requested for written documentation of the consent process must be accompanied by a written description of the information that will be provided to participants. CHS must determine for each waiver of written consent whether the Investigator must provide participants with a written statement regarding the research. Waivers that have been granted by the CHS are noted on the ROA. In cases in which the documentation requirement is waived, the CHS may require that the Investigator provide participants with a written statement or short form explaining the research. The CHS will validate such documents with the CHS stamp and this validated document (or version of the document, if translated into another language) must be used with study participants.
Please note that consent requirements are different in research involving children (see Section 11.3).
10.4. Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule
In 1996, DHHS was obligated under federal law to create privacy regulations governing the protection of personal health information held by health care providers, insurers and others (“covered entities”). The HIPAA Privacy Rule, effective April 14, 2003, protects the privacy and confidentiality of all individually identifiable health information, such as medical history, diagnosis, treatment or payment information. This Protected Health Information (PHI) also includes demographic information that is maintained with health information (e.g., an individual's date of birth and social security number). HIPAA protection applies to all forms of PHI, both electronic and paper.
The OHRP and FDA human subject protection regulations (45 CFR § 46 and 21 CFR § 50, respectively) contain some provisions concerning protection of research participants’ confidential information that are similar to but separate from the HIPAA Privacy Rule research provisions. The HIPAA Privacy Rule built upon those pre-existing federal protections, creating a second, partly overlapping but also complementary tier of privacy protection for research participants whose PHI will be accessed or used in research.
Harvard is not a covered entity under HIPAA. It is a "hybrid entity", consisting of both covered and non-covered components. The University's covered components include the University Health Service (UHS), the Harvard Dental Center, and the Harvard University Group Health Plan (HUGHP). All other parts of the University, including Investigators whose research involves health care information, are not covered components.
An Investigator seeking data must first find out if the data exists as PHI at a HIPPA covered entity. If the entity holding the data is not a covered entity, then the Investigator does not need to be concerned with the HIPAA Privacy Rule to obtain the data, unless the entity passes along secondary restrictions in disclosing the data. However, the entity may still be bound by other laws, contractual agreements or institutional policies which restrict or condition its ability to provide the data. The Faculty of Medicine SPA office is available to help Investigators obtain these data, under appropriate restrictions and conditions.
If the data source is a HIPAA covered entity, Investigators should work with the covered entity's Privacy Officer to establish the permissible ways of accessing the PHI. Examples include: obtaining written authorizations from individuals; the Privacy Board may grant a waiver of the individual authorization requirement; or the Investigator and the HIPAA covered entity may enter into strict data use agreements (DUA) permitting the sharing of PHI with the least number of identifiers necessary for the research to proceed.
HIPAA waivers of authorization are approved by an institution’s Privacy Board. For the Faculty of Medicine, the CHS serves as the Privacy Board.
For more information on HIPAA and Harvard, please see the CHS website; the Harvard Information and Security website: http://www.security.harvard.edu/resources/references/health-insurance-portability-and-accountability-act-hipaa (Appendix 66); or the HSDM website: http://www.hsdm.harvard.edu/asp-html/research-links.html (Appendix 67).
10.5. CHS Review of HIPAA Waivers of Patient Authorization
Requests by Investigators for waivers of the individual authorization requirement under HIPAA may be reviewed via exempt or expedited procedures if a study/protocol or HIPAA waiver of authroization request meets exemption criteria under 45 CFR § 46.101 (b)(1-6), a federal category of an expedited study under 45 CFR § 46.110 and 21 CFR § 56.110, or at full CHS meetings . Requests for waivers of patient authorization (Appendix 68) under HIPAA are sent to CHS members for review/approval along with appropriate study documents (such as the CHS application, protocol, etc.). If the project meets exempt or expedited review criteria, the Chair or designee will review and approve such waiver requests, if appropriate. However, the Chair may request that the full CHS review the waiver request at its next regularly scheduled meeting.
11. Vulnerable Populations and Special Protections
The CHS is guided by 45 CFR § 46 and 21 CFR § 50 when reviewing research involving the following categories of vulnerable participants: pregnant women, neonates and fetuses [45 CFR §§ 46.201-207 (Subpart B)]; prisoners [45 CFR §§ 46.301-306 (Subpart C)]; and children (45 CFR §§ 46.401-409 (Subpart D); 21 CFR §§ 50.50-50.56 (Subpart D). Where a potential research population falls into more than one protected category, such as, for example, adolescents in a juvenile detention facility, then the CHS will apply all relevant review criteria.
Additionally, while there are no specific review criteria in the federal regulations for participants with cognitive impairments, economic or educational disadvantages, or stigmatizing health conditions, the CHS will consider in its review whether additional safeguards or protections are warranted to protect the rights and welfare of these participants, as outlined below. Similarly, the CHS will carefully review research projects which include as the primary participant population HMS or HSDM students, staff and fellows, as these populations may be subject to coercion, based on their status and accessibility to researchers at the University.
11.1. Pregnant Women, Neonates, and Fetuses
11.1.1. Pregnant Women and Fetuses
Pregnant woman can and are encouraged to participate in research studies. Research studies may recruit pregnant women for behavioral studies of minimal risk and which may offer no direct benefit to the pregnant women or fetus but may provide benefits to society. There are both Federal and Commonwealth requirements for research with pregnant women and fetuses.
11.1.1.1. Federal Regulations Involving Pregnant Women and Fetuses
Under 45 CFR § 46.204, research involving pregnant women or fetuses may be conducted if all of the following conditions are met:
(a) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
(b) The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means;
(c) Any risk is the least possible for achieving the objectives of the research;
(d) If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater that minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, the pregnant woman’s consent is obtained in accord with the informed consent provisions of Subpart A of 45 CFR § 46;
(e) If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of Subpart A of 45 CFR § 46, except that the father’s consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.
(f) Each individual providing consent under paragraph (d) or (e) above is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
(g) For children, as defined in 45 CFR § 46.402(a), who are pregnant, assent and permission are obtained in accord with the provisions of Subpart D of 45 CFR § 46;
(h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy;
(i) Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and
(j) Individuals engaged in the research will have no part in determining the viability of a neonate.
11.1.1.2. Massachusetts Law Involving Fetuses in Research
Experimentation on human fetuses is also regulated under Massachusetts law, MGL Chapter 112C, § 12J(a), which states in part:
I. No person shall use any live human fetus whether before or after expulsion from its mother’s womb, for scientific, laboratory, research or other kind of experimentation. This section shall not prohibit procedures incident to the study of a human fetus while it is in its mother’s womb, provided that in the best medical judgment of the physician, made at the time of the study, said procedures do not substantially jeopardize the life or health of the fetus, and provided said fetus is not the subject of a planned abortion. . . . This section shall not prohibit or regulate diagnostic or remedial procedures the purpose of which is to determine the life or health of the fetus involved or to preserve the life or health of the fetus involved or the mother involved.
II. No experimentation may knowingly be performed upon a dead fetus unless the consent of the mother has first been obtained, provided, however, that such consent shall not be required in the case of a routine pathological study.
III. No person shall perform or offer to perform an abortion where part or all of the consideration for said performance is that the fetal remains may be used for experimentation or other kind of research or study.
IV. No person shall knowingly sell, transfer, distribute or give away any fetus for a use which is in violation of the provisions of this section.
For the purposes of this section, a fetus is a live fetus when, in the best medical judgment of a physician, it shows evidence of life as determined by the same medical standards as are used in determining evidence of life in a spontaneously aborted fetus at approximately the same stage of gestational development… [Also,] for the purposes of this section, "fetus'' shall include a neonate and an embryo, but shall exclude a pre-implantation embryo or parthenote as defined in section 2 of chapter 111L and obtained in accordance with said chapter 111L.
The Massachusetts statute includes criminal penalties, but states that those who have performed a procedure that allegedly violates the statute’s provisions will not be held liable if: (i) the procedure received the written approval of a duly appointed IRB; and (ii) at the time the procedure was performed, there was not an outstanding court judgment that the procedure violated the statute. The IRB’s written approval must state specifically that the procedure does not violate the provisions of the statute and must set forth a reasonable basis for this conclusion. The written approval must contain a detailed description of the procedure and must be maintained as a "permanent record" of the IRB or the institution for which it acts. A copy of the written approval must be filed with the office of the District Attorney for the county in which the IRB's institution is located, and shall be available for public inspection at all times. MGL Chapter 112C, § 12J(a)(V-VII). IRB members are themselves immune from liability under the statute if they acted in good faith in concluding that the procedure was lawful. MGL Chapter 112C, § 12J(a)(VI).
45 CFR § 46.205 provides as follows:
(a) Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met:
(1) Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates;
(2) Each individual providing consent under paragraph (b)(2) or (c)(5) of 45 CFR § 46.205 is fully informed regarding the reasonably foreseeable impact of the research on the neonate;
(3) Individuals engaged in the research will have no part in determining the viability of a neonate; and
(4) The requirements of paragraph (b) or (c) of 45 CFR § 46.205 have been met as applicable.
(b) Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by 45 CFR § 46.205 unless the following additional conditions are met:
(1) The IRB determines that: (i) The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or (ii) The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and
(2) The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent’s legally authorized representative is obtained in accord with subpart A of 45 CFR § 46, except that consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.
(c) After delivery a nonviable neonate may not be involved in research covered by 45 CFR § 46.205 unless all of the following additional conditions are met:
(1) Vital functions of the neonate will not be artificially maintained;
(2) The research will not terminate the heartbeat or respiration of the neonate;
(3) There will be no added risk to the neonate resulting from the research;
(4) The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and
(5) The legally effective informed consent of both parents of the neonate is obtained in accord with Subpart A of 45 CFR § 46, except that the waiver and alteration provisions of § 46.116(c) and (d) do not apply. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the requirements of this paragraph, except that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representative of either of both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph.
(d) A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of 45 CFR § 46 Subparts A and D.
11.1.3. Research Involving, After Delivery, the Placenta, the Dead Fetus or Fetal Material
45 CFR § 46.206 provides as follows:
(a) Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accord with any applicable federal, state or local laws and regulations regarding such activities.
(b) If information associated with material described in paragraph 45 CFR § 46.205(a) is recorded for research purposes in a manner that could identify living individuals, either directly or through identifiers linked to those individuals, then those individuals are research subjects and all pertinent subparts of 45 CFR § 46 are applicable.
11.1.4. Research not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women, fetuses, or neonates
Under 45 CFR § 46.207, where the CHS does not believe that the proposed research meets the requirements of 45 CFR § 46.204 or § 46.205, but does believe that it presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of pregnant women, fetuses or neonates, it may refer the protocol to the DHHS for review. The research may proceed only if the Secretary of DHHS, after consulting with a panel of experts in pertinent disciplines (e.g., science, medicine, ethics, law) and following an opportunity for public review and comment (including a public meeting), determines either: (1) that the research in fact satisfies the conditions of 45 CFR § 46.204; or (2) the following:
a) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of pregnant women, fetuses or neonates;
b) the research will be conducted in accordance with sound ethical principles; and
c) informed consent will be obtained in accord with the informed consent provisions of 45 CFR § 46 Subpart A and any other applicable subparts.
Under 45 CFR § 46, Subpart C, prisoners who participate in research are afforded additional safeguards because their incarceration might affect their ability to make truly voluntary and un-coerced decisions. These additional protections apply not just to individuals who are prisoners at the time they are enrolled in a study, but also to those who become incarcerated during the course of a study.
A prisoner is defined as: “any individual involuntarily confined or detained in a penal institution.” The definition includes “individuals detained in other facilities by virtue of statutes or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial or sentencing.” 45 CFR § 46.303(c). The CHS interprets this definition to include individuals who are sent by court order to alcohol/drug rehabilitation facilities.
11.2.1. Additional CHS Composition Requirements
45 CFR § 46.304 (a) and (b) requires that, in addition to meeting the composition requirements set forth in 45 CFR § 46.116 and 46.117, if the CHS reviews research involving prisoners as research participants then it must also meet the requirements set forth below. These requirements apply to all aspects of review, including initial review, continuing review, review of study amendments, and review of reports of unanticipated problems involving risks to the participants:
(a) A majority of the CHS (exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership on the CHS.
(b) At least one member of the CHS must be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one IRB, only one IRB need satisfy this requirement.
11.2.2. Additional Issues for Consideration by the CHS
Under 45 CFR § 46.305(a), where prisoners are involved in potential research, the CHS may approve such research only if it finds that:
(1) The research under review represents one of the categories of research permissible under 45 CFR § 46.306(a)(2) set forth below;
(2) Any possible advantages accruing to the prisoner through his or her participation in the research, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such a magnitude that his or her ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison is impaired;
(3) The risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers;
(4) Procedures for the selection of subjects within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners. Unless the Principal Investigator provides to the IRB justification in writing for following some other procedures, control subjects must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project;
(5) The information is presented in language which is understandable to the subject population;
(6) Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on his or her parole; and
(7) Where the IRB finds there may be a need for follow-up examination or care of participants after the end of their participation, adequate provision has been made for such examination or care, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact.
The Institution responsible for the conduct of the research shall certify to the DHHS Secretary that the CHS has made the required findings. The Institution must send to OHRP a certification letter to this effect, which should also include the name and address of the institution and specifically identify the research protocol in question and any relevant HHS grant application or protocol. Research involving prisoners as participants may not proceed until OHRP issues its approval in writing to the institution on behalf of the Secretary under 45 CFR § 46.306(a)(2).
11.2.3. DHHS-Funded Research Involving Prisoners
Under 45 CFR § 46.306, biomedical or behavioral research conducted or supported by DHHS may involve prisoners as participants only if: the institution responsible for the conduct of the research has certified to the Secretary of DHHS that the CHS has approved the research under 45 CFR § 46.305; and in the judgment of the Secretary of DHHS, the proposed research involves solely the following:
(1) Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
(2) Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
(3) Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after the Secretary of DHHS has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the Secretary’s intent to approve such research; or
(4) Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary of DHHS has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the Secretary’s intent to approve such research.
Unless it meets the criteria set forth above, biomedical or behavioral research conducted or supported by DHHS shall not involve prisoners as research participants. In determining whether the proposed research meets these criteria, the CHS must apply the definition of “minimal risk” set forth in 45 CFR § 46.303(d), rather than the definition set forth in 45 CFR § 46.102(i). The applicable definition of “minimal risk” is: “the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons.” 45 CFR § 46.303(d).
11.2.4. Expedited Review Procedures
Ordinarily, the CHS will not expedite its review of research involving prisoners, however expedited review procedures are permitted under 45 CFR § 46.110 and 21 CFR § 56.110 for minor changes in approved research and for certain kinds of research involving no more than minimal risk. As noted above, with respect to research involving prisoners, the CHS must apply the definition of “minimal risk” set forth in 45 CFR § 46.303(d).
11.2.5. Exempt Research with Prisoners
The exemptions set forth in 45 CFR § 46.101(b) do not apply to research involving prisoners. 45 CFR § 46.101(i), FN1.
45 CFR § 46 Subpart D affords special protections for children involved in research to prevent any unnecessary risk or harm. Under 45 CFR § 46.402(a), children are defined as "persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted.” Massachusetts law contains a number of provisions which define minors and the limited number of circumstances under which children whom have not reached majority may consent to receive medical care, or to participate in research, and circumstances and conditions under which the child’s parents or legal guardians may consent on their behalf. These provisions are outlined below. For research conducted outside of Massachusetts, the CHS will consult the Office of the General Counsel to understand and apply the applicable law of the jurisdiction in question.
Age of majority. Eighteen is the age of majority both in Massachusetts (M.G.L. c. 231, § 85P) and under federal policy. When a person turns 18, s/he is considered to be an adult under the law. (Buying and consuming alcohol, however, are two activities that are not legal until a person turns 21 in Massachusetts.)
Massachusetts law recognizes two instances when teenagers under the age of 18 may have the legal capacity to consent to medical treatment. These are the emancipated minor and mature minor rules. Note that these rules concern individuals in their capacity as patients, not as participants in research, and also that they apply only to persons in Massachusetts. These rules would not apply, for example, to research participants living in a foreign country, although that country might have analogous rules
Emancipated minor. A patient under 18 years of age may consent to treatment of any kind, except abortion, and may authorize the release of his or her medical records if s/he is: (a) married/widowed/divorced, a parent, (b) a member of the armed forces, (c) living apart from parents and managing his or her own finances, or, in the case of a female, (d) pregnant or believes herself to be pregnant. M.G.L. c. 112 § 12F. A female under the age of 18 may consent to an abortion if she is or has been married. Otherwise, consent must be obtained from her parent(s) or the procedure must be authorized by court order. M.G.L. c. 112 § 12S. Further, patients under 18 years of age may consent to treatment and may authorize the release of their medical records relating to: diseases dangerous to the public health, drug dependency (but not alcohol dependency), and pregnancy (but not abortion, except in the case of those who had married).
Mature minor. Under Massachusetts case law, students under the age of 18 who are not emancipated under M.G.L. c. 112, § 12F, can, in certain circumstances, nevertheless consent to treatment and control access to their medical records. In such cases, the clinician proposing to provide the treatment may determine that the patient is a mature minor capable of consenting to treatment. To reach this determination, the clinician must conclude that the minor is capable of giving informed consent to the treatment; and that it is in the best interest of the minor not to notify his or her parents of the intended medical treatment. In general, where a minor has the capacity to consent to medical treatment, that minor also has the capacity to control his or her medical records, including releasing them to others, such as researchers. In addition, there is an argument that a minor who has the capacity to consent to medical treatment also should have the capacity to consent to research that may accompany that treatment. However, this argument has not been tested in a Massachusetts court.
Parents or Guardians of minor children. In general, and as more fully explained below, parents and guardians may provide consent to participation in research for their minor children or wards. The definition of who is a parent or guardian differs in some respects under federal and Massachusetts laws. The Massachusetts Uniform Statutory Will Act (the “Will Act”) indirectly defines “parent” in its definition of “child.” See M.G.L. c. 191B, § 1(1). Under this law, the “parent” is the biological or adoptive mother or father of a child. However, a father of a child who is not married to the child’s mother may not always be considered a parent; his status would depend on whether he openly treats the child as his offspring or on whether a court has made a paternity determination. Under the Will Act, the term “parent” does not include step-parents who have not formally adopted the child, foster parents, grandparents or other relatives. Id. In general, the term “guardian” is widely understood to mean a person lawfully invested with the power, and charged with the duty, of taking care of and managing the property and rights of someone who is considered incapable of administering his or her own affairs. This definition includes a person who legally has responsibility for the care and management of the person or estate or both of a child during his or her minority. Parents are usually considered the guardians of their minor children under Massachusetts law. For example, with respect to children, the Department of Mental Retardation defines “guardian” in its regulations concerning research as “a natural or adoptive parent, or the individual or agency with legal guardianship of the person.” 115 CMR 10.02.
Legal guardianship in Massachusetts usually is created through a court process, most often through the Probate Court, M.G.L. c. 201 § 2, although parents may designate another adult to be a guardian without having to invoke a court proceeding. This kind of guardian, once appointed, is also referred to as a “standby proxy,” whose authority becomes enforceable when the parent dies, becomes incapacitated or is unavailable to care for the child. M.G.L. c. 201 §§ 2B – 2D. The Department of Social Services (DSS) or other state agencies may become the legal guardian of children it takes into custody. The CHS will make a determination based on the risk/benefits to determine whether to accept DSS, or other agency consent for children in their custody.
In general, a parent or legal guardian is considered under federal policy to be the legally authorized representative of a child, and thus may consent to the child’s participation in a research project. Thus, for a child participant in research, a parent or guardian acting as a legally authorized representative can give permission (consent) on behalf of the child to participate in research. As discussed above, an exception to this general rule is where the research involves medical treatment and the child has the capacity to consent under the emancipated minor or mature minor rules.
11.3.1. Research Not Involving Greater than Minimal Risk
Under 45 CFR § 46.404, where the CHS has found that the proposed research presents no greater than minimal risk to the children, it may approve the research only if it also finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in 45 CFR § 46.408. (Note that 45 CFR § 46.408(b) the permission of both parents is required unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. The CHS may find that the permission of one parent is sufficient for research to be conducted under 45 CFR § 46.405 even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for the care and custody of the child.)
11.3.2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual child participants
Under 45 CFR § 46.405, where the CHS has found that the proposed research presents more than minimal risk to the children but involves either an intervention or procedure that holds out the prospect of direct benefit for the individual participant, or a monitoring procedure that is likely to contribute to the participant’s well being, it may approve the research only if it also finds that:
a) the risk is justified by the anticipated benefits to the subjects;
b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and
c) adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in HHS regulations at 45 CFR § 46.408.
(Note that 45 CFR § 46.408(b) the permission of both parents is required unless one parent is deceased , unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child. The CHS may find that the permission of one parent is sufficient for research to be conducted under 45 CFR § 46.405 even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for care and custody of the child.)
11.3.3. Research involving greater than minimal risk and no prospect of direct benefit to the individual child participants, but likely to yield generalizable knowledge about the participant’s disorder or condition
Under 45 CFR § 46.406, where the CHS has found that the proposed research presents more than minimal risk to the children and involves either an intervention or procedure that does not hold out the prospect of direct benefit for the individual participant, or a monitoring procedure that is not likely to contribute to the participant’s well being, it may approve the research only if it also finds that:
a) the risk of the research represents a minor increase over minimal risk;
b) the intervention or procedure presents experiences to the child subjects that are reasonably commensurate with those inherent in their actual, or expected medical, dental, psychological, social, or educational situations;
c) the intervention or procedure is likely to yield generalizable knowledge about the subject's disorder or condition which is of vital importance for the understanding or amelioration of the disorder or condition; and
d) adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians, as set forth in 45 CFR § 46.408.
(Note that, under 45 CFR § 46.408(b), where research to be conducted under 45 CFR § 46.406, and permission is to be obtained from parents, both parents must give their permission unless either: one parent is deceased, unknown, incompetent, or not reasonably available, deceased; or only one parent has legal responsibility for the care and custody of the child.)
11.3.4. Research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
Under 45 CFR § 46.407, where the CHS does not believe that the proposed research meets the requirements of 45 CFR §§ 46.404, 46.405, or 46.406, but does believe that it presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, it may refer the protocol to DHHS for review. The research may proceed only if the Secretary of DHHS, after consulting with a panel of experts in pertinent disciplines (e.g., science, medicine, education, ethics, law) and following an opportunity for public review and comment, determines either: (1) that the research in fact satisfies the conditions of 45 CFR § 46.404, § 46.405, or § 46.406, or (2) the following:
a) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
b) the research will be conducted in accordance with sound ethical principles; and
c) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth at 45 CFR 46.408.
(Note that, under 45 CFR § 46.408(b), where research to be conducted under 45 CFR § 46.407, and permission is to be obtained from parents, both parents must give their permission unless either: one parent is deceased, unknown, incompetent, or not reasonably available, deceased; or only one parent has legal responsibility for the care and custody of the child.)
11.3.5. Requirements for Permission by Parents or Guardians
Under 45 CFR § 46.408(b), for research involving children, the CHS must determine, in accordance with and to the extent required by 45 CFR § 46.116, that adequate provisions are made for soliciting the permission of each child’s parents or guardian. As noted above, for research conducted under 45 CFR §§ 46.404-405 (minimal risk), the CHS may find that the permission of one parent is sufficient. Where research is to be conducted under 45 CFR §§ 46.406-407 (greater than minimal risk), and permission is to be obtained from parents, both parents must give their permission unless either: one parent is deceased, unknown, incompetent or not reasonably available; or only one parent has legal responsibility for the care and custody of the child.
Under 45 CFR § 46.408(c), in addition to the provisions for waiver set forth in 45 CFR § 46.116, if the CHS finds that a study is designed for conditions or for a participant population for which parental or guardian permission is not a reasonable requirement to protect the participants (for example, neglected or abused children), then it may waive consent, provided an appropriate mechanism for protecting the children is substituted, and provided further that the research is not FDA-regulated and the waiver is not inconsistent with federal, state or local law. The choice of an appropriate mechanism depends on the nature and purpose of the proposed activities, the risk and anticipated benefit to the research participants, and their age, maturity, status and condition.
Under 45 CFR § 46.408(d), permission of parents or guardians for their children to participate in research must be documented by a signature on the consent/permission form, unless a waiver of consent/permission or documentation is approved by the CHS. The CHS will determine whether parental permission is required of both parents, of one parent, or if a waiver of parental permission or permission documentation, is warranted.
11.3.6. Requirements for Assent by Children
“Assent” means agreement – specifically, in this context, a child’s agreement to participate in research. Assent, like consent, is a process that should be documented.
Under 45 CFR § 46.408(a), when, in the CHS’s judgment, children are capable of providing assent, the CHS must determine that adequate provisions are made for soliciting their assent. The CHS will additionally determine how assent will be solicited, obtained and documented. In determining whether children are capable of assenting, the CHS takes into account their ages, maturity, and psychological state. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the CHS deems appropriate. If the CHS determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, then the assent of the children is not a necessary condition for proceeding with the research. Even where the CHS determines that the participants are capable of assenting, the CHS still may waive the assent requirement in accord with 45 CFR § 46.116.
Under 45 CFR § 46.408(e), when the CHS determines that assent is required it shall also determine whether and how assent must be documented. Assent forms are designed similarly to consent forms and should include the purpose, procedures, risks and benefits of participating in a particular research study. The assent should be written at the age level of the children, with jargon and technical terms explained or removed.
For children ages seven and under, the CHS recommends that the Investigators verbally explain the study to the child, including its purpose, procedures, and potential risks and benefits (if appropriate, depending on the child’s age, maturity and development). For children ages seven through 17 years, the CHS typically requires written assent from the child, although this may be waived by the CHS. Depending on the study, its procedures, risk and benefits, the CHS may also approve verbal assent. Assent (written and verbal) should be obtained in the presence of a parent or legal guardian, unless the study procedures are taking place in a setting (such as a school) where parents are not usually present. However, in nearly all cases, a child’s assent must be accompanied by the permission or consent of the child’s parent or guardian.
11.3.7. Additional Requirements for Wards and Foster Children
Under 45 CFR § 46.409(a), children who are wards of the state or any other agency, institution, or entity can be included in research approved under § 46.406 or § 46.407 only if such research is: (1) related to their status as wards; or (2) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as participants are not wards.
Even if such research is approved under 45 CFR § 46.409(a), 45 CFR § 46.409(b) requires the appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way (except in the role as advocate or member of the CHS) with the research, the Investigator(s), or the guardian organization.
Massachusetts law (MGL Chapter 119, et. seq.) allows the Department of Social Services (DSS) to remove children from their parents’ custody in certain circumstances, but the placement of a child in foster care does not automatically terminate all parental rights. Because these situations are complicated, investigators who wish to use foster children as participants in their research are urged to consult in advance with the CHS.
Research proposals involving children ordinarily must include a plan for reporting suspected abuse of children to DSS. Additionally, consent and assent forms for children and parents ordinarily must include a statement that suspected child abuse or neglect may be reported to DSS.
Certain people, as a function of their professions or provisions, are deemed to be mandated reporters. Under Massachusetts law, (MGL Chapter 119, § 51A), mandated reporters include any: “physician, medical intern, hospital personnel engaged in the examination, care or treatment of persons, medical examiner, psychologist, emergency medical technician, dentist, nurse, chiropractor, podiatrist, optometrist, osteopath, public or private school teacher, educational administrator, guidance or family counselor, day care worker or any person paid to care for or work with a child in any public or private facility, or home or program funded by the commonwealth or licensed pursuant to the provisions of chapter twenty-eight A, which provides day care or residential services to children or which provides the services of child care resource and referral agencies, voucher management agencies, family day care systems and child care food programs, probation officer, clerk/magistrate of the district courts, parole officer, social worker, foster parent, firefighter or policeman, licensor of the office of child care services or any successor agency, school attendance officer, allied mental health and human services professional as licensed pursuant to the provisions of section one hundred and sixty-five of chapter one hundred and twelve, drug and alcoholism counselor, psychiatrist, and clinical social worker, priest, rabbi, clergy member, ordained or licensed minister, leader of any church or religious body, accredited Christian Science practitioner, person performing official duties on behalf of a church or religious body that are recognized as the duties of a priest, rabbi, clergy, ordained or licensed minister, leader of any church or religious body, or accredited Christian Science practitioner, or person employed by a church or religious body to supervise, educate, coach, train or counsel a child on a regular basis.”
Reports must be made where the mandated reporter, in his or her professional capacity, has reasonable cause to believe that a child under the age of 18 is suffering physical or emotional injury resulting from abuse inflicted upon him or her which causes harm or substantial risk of harm to the child's health or welfare, including sexual abuse, or from neglect, including malnutrition, or who is determined to be physically dependent upon an addictive drug at birth. A mandated reporter must immediately make a verbal report to DSS and must make a written report within 48 hours.
11.3.9. Confidential Birth Information
MGL Chapter 111, § 67E requires physicians to report diagnoses of congenital anomalies and birth defects to the Department of Public Health (DPH). 105 CMR § 302.070 provides a mechanism by which researchers may access and use this confidential birth information. Researchers must submit an application that includes: the purpose and design of the study, its public health benefits, its relationship to the DPH’s goal of reducing morbidity and mortality, the data requested, a justification for the data request, a description of the extent to which the study involves “contact with the data subjects,” a description of the extent to which informed consent will be obtained from the participants, information regarding CHS review and approval of the project, proposed measures to preserve the confidentiality of the data, and the names and titles of all persons who will access the data requested. Investigators also must also submit to DPH copies of consent forms, questionnaires or telephone interview scripts, their filings with an IRB, the IRB’s written determinations, and their CVs. 105 CMR § 302.070(B) and (C). Investigators’ use of confidential birth information released by the DPH is subject to the terms and restrictions set forth in 105 CMR § 302.080. Thus, in addition to following CHS policies, investigators also must comply with DPH IRB requirements.
11.4. Embryonic Stem Cell Research
Chapter 27 of the Acts of 2005, referred to hereinafter as the “MA Stem Cell Law” which, among other things, authorized with some restrictions the use of human Embryonic Stem Cells (hESCs) in research, also imposed certain IRB approval requirements on institutions conducting such research. Activities that the law specifically authorizes include “research and clinical applications involving the derivation and use of [hESCs], including somatic cell nuclear transfer, human adult stem cells from any source, umbilical cord cells, parthenotes and placental cells”. The MA Stem Cell Law also specifically prohibits certain research activities, including those involving “human reproductive cloning,” and those involving the creation of an embryo by the means of fertilization “solely for the purpose of donating the embryo for research”. The law also requires that all research “involving the derivation of human embryonic stem cells” must be reviewed and approved by a duly constituted IRB, regardless of whether IRB approval may or may not also be required under federal law, and to report such projects to the Massachusetts Department of Public Health (DPH) on an annual basis. The statute describes the IRB’s required role as follows:
Research involving the derivation of human embryonic stem cells through the use of human genetic material, including somatic cell nuclear transfer, parthenogenesis and other asexual means . . . shall only be conducted upon the written approval of a duly authorized institutional review board. The written approval of the institutional review board shall include a detailed description of the research, experimentation or study to be conducted and a detailed description of the research or a copy of the protocol, all of which shall be maintained as a permanent record by the board or by the hospital or institution for which the board acts.
All research with embryonic stem cells must first be reviewed by the Embryonic Stem Cell Research Oversight (ESCRO) Committee. Once approved by ESCRO, such studies must be submitted to the CHS for review and approval or exemption.
11.5. Participants with Cognitive Impairments
The CHS respects the autonomy of each individual and his or her decision-making. Those with cognitive impairments or less of a capacity of understanding (as a result of, for example, age, illness or genetic impairment) deserve respect when participating in research activities. The difficulty lies in establishing when, and to what degree, a person has the capacity to understand and to make an informed decision about participation in research.
11.5.1. Research outside the jurisdiction of the Massachusetts Department of Mental Health (DMH)
Research involving potential participants who are under the jurisdiction of the Massachusetts Department of Mental Health (DMH) is governed by state regulation as described below. Even where the DMH regulations do not apply, however, the CHS review process incorporates special protections when people who have a limited capacity to understand research or research concepts are potential research participants.
11.5.2. Research within the Jurisdiction of the DMH
Under 104 C.M.R. § 31.00, et. seq., DMH has the jurisdiction to review and approve any human research “related to” the Department, its facilities or programs in which its “clients” are proposed participants. HMS or HSDM Investigators whose research proposals fall within the DMH’s jurisdiction must submit them to the DMH IRB, the Central Office Research Review Committee (CORRC), for approval.
DMH regulations (104 CMR § 31.01 et seq.) describe information Investigators must submit to the agency concerning such studies, and the standards governing review and approval of studies by the agency, which are very similar to the standards of review utilized by IRBs operating under the 45 CFR § 46. However, the regulations impose a few additional content requirements for informed consent forms for these studies, beyond those included in the 45 CFR § 46, such as: statements describing “the basis for selection of the subject”, and a statement indicating that participation in the study is not required of participants in order to obtain continued access to DMH services. Please see DMH regulations (available through http://www.mass.gov/dmh) for specific information.
11.5.3. Research Protocol Considerations
For any research protocol that may involve persons with decisional or cognitive impairments:
1) Where applicable, the Investigator must describe the reasons why recruiting this vulnerable population is necessary.
2) The Investigator must consider whether and which of the following safeguards would be appropriate for the research and must document the decision process in his or her application to the CHS. The CHS may, at its discretion require additional safeguards. Where appropriate, for example, the CHS may require the Investigator to assess participants’ comprehension at various stages in the protocol.
a) Use of a party independent of the research team with appropriate expertise to assess the capacity of a potential participant. Investigators may conduct a preliminary competency assessment whenever there is a possibility of either impaired cognitive status or decision-making capacity in prospective participants, however, a final determination that the prospective research participant is incompetent or has an impaired decision-making capacity must be made and documented by a physician after appropriate medical evaluation. Consultation with a psychiatrist or licensed psychologist must be obtained when the physician’s determination that the prospective research participant lacks decision-making capacity is based on a diagnosis of mental illness.
b) Use of a standardized assessment of cognition and/or decisional capacity.
c) Use of methods that could enhance participants’ ability to decide for themselves whether to participate in the proposed research, such as, for example, reading the consent form aloud to the participant, showing a video recording to the participant, or communicating with the participant by some other method that is aimed at the participant’s level of understanding.
d) Use of other informational or educational techniques for the potential participants and/or their legal representatives. Tools to aid in this effort may include single sheet summaries of important information about key elements of the studies, regular opportunities for participants and their legal representatives to ask questions, and other educational tools to enhance understanding, including use of videos demonstrating study interventions or use of post-test assessments documenting comprehension.
e) Use of a party independent of the Investigators to monitor the consent process and verify what information was conveyed.
f) Use of waiting periods to allow potential participants additional time to consider information about the research protocol. Planning waiting periods into the informed consent process may be useful to increase comprehension in decisionally impaired populations and to allow involvement, where appropriate, of participants’ legal representatives.
g) Obtaining informed consent by proxy from a participant’s legally authorized representative. If feasible, the Investigator must explain the proposed research to the prospective participant even when his or her legal representative gives consent.
h) Where informed consent is obtained by proxy, also obtaining assent from participants. Under no circumstances may a person be forced or coerced to participate in a research study.
11.5.4. Assent, Consent, and Legally Authorized Representatives and Proxy Consent
Respect for the autonomy of individuals requires that, regardless of diagnosis or condition, all adults generally should be presumed competent to consent to participate in research unless there is evidence of a serious disability that would impair the individual’s ability to comprehend either the voluntary nature of research participation, the nature of the research procedures, the potential risks and benefits of the study, and/or his or her ability to make a personal judgment about the value of participation.
Thus, ordinarily, an Investigator must obtain informed consent directly from prospective research participants. However, when the prospective participant is an adult whose own consent would not be legally effective because s/he lacks the capacity to comprehend or communicate informed consent, then research may be conducted only with the consent of the potential participant’s legally authorized representative (the “LAR”), also known as “surrogate consent.” This policy is designed to protect persons from exploitation and harm and, at the same time, make it possible to conduct essential research on issues that are unique to persons who are not competent, or who have an impaired decision-making capacity. The federal regulations define “legally authorized representative” as “an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the participant's participation in the procedure(s) involved in the research.” 45 CFR 46.102(c). Under Massachusetts law, this means the consent must come either from the legal guardian of the participant, or, in the case of research that is part of medical treatment, from the participant’s health care agent (either as appointed under the Massachusetts health care proxy law, or as designated by a health care provider under the common law for obtaining consent to the provision of medical care and associated procedures). If the participant is able to give assent (affirmative agreement) this is required, but the CHS may waive the requirement if the participant is not competent to assent.
The Massachusetts Department of Mental Retardation (DMR) regulations concerning research are useful in understanding how Massachusetts defines “guardian.” Those regulations state that “with respect to persons 18 years of age and older,” a guardian is the “individual, organization or agency, if any, that has been appointed legal guardian of the person found to be incompetent by a court of competent jurisdiction.” 115 CMR 10.02. Massachusetts law allows for guardianships to be created for persons who are judged to be mentally ill or mentally retarded, or for persons judged unable to communicate informed decisions. M.G.L. c. 201 §§ 6, 6A, 6B. The guardianship law does not enumerate all of the guardian’s authority, except to say that the guardian “shall have the care and custody of his ward . . . and the management of all his estate.” As this authority is generally accepted to mean that the guardian may take all actions for the ward that the ward might have taken if competent, there is no reason to believe that the ability to consent to research is not within the guardian’s authority. Indeed, this view is consistent with the manner in which the DMR conducts its research using consent from guardians. See 115 CMR 10.00.
Massachusetts law provides for proxy consent for medical decisions to be given on behalf of a patient who does not have the capacity to consent. The law allows a competent adult to appoint a designated person as his or her “health care agent.” M.G.L. c. 201D. If the person then becomes incapacitated, and is in need of medical care, the health care proxy becomes empowered to make medical decisions on his or her behalf. If no health care agent has been appointed in advance, then medical care providers are authorized by the law to accept consent from “responsible parties,” under common law principles, usually meaning the patient’s next-of-kin. M.G.L. c. 201D, §16. It is generally accepted in Massachusetts that if research involves the provision of medical care, a health care agent, whether appointed or holding that status by virtue of being a “responsible party,” may consent to that treatment and to the accompanying research.
In light of Massachusetts law, federal policy, and existing judicial opinions on the interrelationships of the two, it is unclear whether an IRB may approve a study that involves consent by an LAR for a cognitively-impaired adult to participate in non-medical research in the Commonwealth with more than minimal risk to that participant. In such situations, the CHS will not approve research in which cognitively impaired adults participates in non-medical research in the Commonwealth with more than minimal risk to that participant until legal counsel determines that the individual proposed to serve as legally authorized representatives meet the federal definition of “legally authorized representative”.
11.5.4.1. Additional Policies Relating to Proxy Consent
In cases where a protocol approved by the CHS contemplates proxy consent, all of the following conditions apply:
1) Consent by proxy is not acceptable for research that presents an increase over minimal risk and does not have the potential for direct individual benefit.
2) Consent by proxy may be given only by the potential participants legally authorized representative (as discussed above).
3) Where informed consent is sought by proxy, the Investigator must fully inform the LAR about the risks, benefits and alternatives to the research. The LAR also must be informed that his or her decision should be made (i) in accordance with his or her assessment of the potential subject’s wishes, including the potential subject’s religious and moral beliefs, or (ii) if the potential participant’s wishes are unknown, in accordance with the LAR’s assessment of the potential participant’s best interests. See M.G.L. Chapter 201D, § 5.
4) If a potential participant with decisional impairment is capable of exercising some judgment concerning the nature of the research and his or her participation in it, then the investigator should obtain the participant's assent in addition to the consent of his/her health care agent.
5) A potential participant’s objection to participation in research, in whatever form, shall be binding. If the participant, at any time, objects to continuing in the research study, such objection must be respected and his or her participation shall cease.
6) Where the condition causing a participant’s decisional impairment is of an intermittent or temporary nature, then the informed consent process should include a mechanism for obtaining the participant’s subsequent direct informed consent to participate in the research. If the participant, upon regaining decisional capacity, declines to continue participation in the research, his or her decision must be respected and his or her participation shall cease.
11.6. Participants with Limited Capacity to Speak English
The CHS requires that research information and materials be presented to potential research participants in language understandable to them, which means that, where the potential participant has limited capacity to speak or understand English, all informed consent information, written and verbal, must be translated into the language of the potential participant. Written consent documents, regardless of the language in which they are written, must contain all of the elements of consent, as noted in Section 10.3.1.1.
45 CFR § 46.117(b)(2) permits an Investigator to verbally present the information required to allow a participant to make an informed judgment about participation in research, provided that there is a witness to the verbal presentation and the participant is given a written summary of the presentation (approved by the CHS), as well as a copy of the short form written consent document (stating that the elements of consent have been presented verbally). When this procedure is used with potential participants who do not speak English:
(i) the verbal presentation and the short form written document should be in a language understandable to the potential participants;
(ii) the CHS-approved English language informed consent document may serve as the summary; and
(iii) the witness should be fluent in both English and the language of the participant.
At the time of consent,
(i) the short form document should be signed by the participant (or the participant’s legally authorized representative);
(ii) the summary (i.e., the English language informed consent document) should be signed by the person obtaining consent as authorized under the protocol; and
(iii) the short form document and the summary should be signed by the witness. When the person obtaining consent is assisted by a translator, the translator may serve as the witness.
The CHS “must receive all foreign language versions of the short form document as a condition of approval” under the provisions of § 46.117(b)(2). Expedited review of these versions is acceptable if the CHS application/protocol, the full English language informed consent document, and the English version of the short form document have already been approved by the CHS.
If research is taking place in settings where the primary language spoken is not English, and the Investigator and study staff are fluent in that language, then the witness need only be fluent in the language of the potential participant (for example, if the research is taking place in Mexico and the Investigator, study staff, potential subjects and witnesses all are fluent in Spanish, then there is no need for the witness to speak English).
When study materials are translated into languages other than English, the English and other language (e.g. Spanish) versions of all materials to be used with potential participants (such as recruitment notices, consent forms and survey instruments) must be submitted to the CHS accompanied by the dual-signed Translation Attestation Form.
11.7. Participants with Economic Disadvantages
HMS/HSDM faculty and students at times perform research, both in the US and abroad, with people who have limited resources in terms of finances, health, goods, and/or access to services. The CHS pays particular attention to remuneration and other inducements that might encourage people with limited resources to participate in research projects in which they might not otherwise participate. Money, goods and/or services should not be the sole grounds for participation in a research project and these inducements should not cause participants to assume risks that they would not ordinarily find acceptable.
The CHS considers persons with limited resources to be vulnerable to the extent that inducements to participate in research may result in their acting against their own best interests. Where the population from which participants will be recruited primarily consists of people with limited resources, the CHS will look carefully at recruitment procedures, the potential risks in relation to the compensation being offered and the potential benefits irrespective of compensation. The Investigator will be asked to justify the compensation being offered. If the CHS finds it to be coercive, the CHS will ask the Investigator to provide alternative compensation so as not to impede the participants’ decision about whether they should participate in the research project.
11.8. Participants with Educational Disadvantages
Research may involve participants who have limited education and either cannot read or write, or may do so at a lower level than the general population of a given community. Of course, the ability to read or write may not be an indication of a person’s ability to understand the research, the procedures involved, the risks and benefits associated with the research, or the ability to make an informed decision about whether to participate in the research. When research is likely to involve persons who cannot read or write or who do so at a low level, the CHS is likely to require the use of materials (pictures, demonstrations, videos, etc.) that aid in understanding the risks, benefits and procedures involved in the research. In addition, the CHS may require an assessment of the participant’s understanding (e.g. a short quiz) after the consent is read and explained, as well as a witness to the consent process who will also be required to sign the consent form. Consent requirements are the same as required by 45 CFR § 46.116 and 117.
11.9. Participants with Stigmatizing Conditions
The CHS is particularly mindful of the privacy and confidentiality needs of person who has a stigmatized condition, such as HIV or AIDS, sexually transmitted diseases or mental health issues. Investigators working with people with such conditions must incorporate special protections into the recruitment, consent, study and follow-up procedures, form of remuneration, data storage, data analysis, data destruction and study publications. While the CHS understands that there may be public health reporting requirements for some conditions, the privacy of research participants must always be maintained.
Suggested practices:
Recruitment - Direct mailings should not indicate that a person has a certain condition; if the potential participant is required to call to inquire about the study, a person knowledgeable about the study should answer the phone, and only study personnel should have access to the phone messages. When the Investigator or study personnel return a potential participant’s call, s/he should only leave their name and contact information – not information about the study or condition being studied.
Consent – Consent should take place in a private setting where the discussion is unlikely to be overheard by others. Consent materials should contain a tear-off sheet with the name and contact information of the Investigator, in case the participant does not wish to carry a copy of the entire consent form. Participants should always be advised that while the Investigator and study personnel will do his/her best to maintain their privacy and confidentiality, it is always possible that a breach in confidentiality could happen, or that others close to them may guess their condition or participation in a study.
Study/follow-up Procedures – study and follow-up procedures should take place in a private setting, whenever possible. While some research may take place in a participant’s home, the Investigator should take measures not to obviously identify themselves to family and neighbors. Investigators working in international settings may have more difficulty not being obvious, therefore alternative settings for research procedures should be considered.
Form of Remuneration – Remuneration pay slips or checks should not contain the name of the study, nor should they include the social security number of the participant.
Data Storage – Data should be stored according to current data security policies and in physically secure settings. Hard copies of study documents (such as medical histories and questionnaires) should not contain the name of participants and codes/keys to any participant IDs should never be kept with study documents. Data stored on laptop, transportable device, or desktop computers must conform to the Harvard Enterprise Security and Harvard Research Data Security Policies.
Data Destruction – Investigators must have a plan for when and how they will strip data of participant’s personal identifiers and should notify participants of this practice.
Publications – No publications should contain a participant’s personal identifiers or scenarios that could identify a participant by someone close to them. In certain situations, however, the participant may want to be identified – if this case arises, it should be discussed with the CHS and a special permission for the use of the participant’s name and or image may be used.
11.10. Participants who are Students, Fellows, or Employees of Harvard University
University employees, fellows and students may participate in any study for which they are eligible. However, in order to prevent any coercion (or perception of coercion) or undue pressure to participate, Investigators should not specifically recruit individuals who work directly or indirectly for them, nor should they recruit fellows or students who work with or for them, or for whom they have any educational oversight.
Participation in a research study may never be a condition of employment, insurance, grades, promotion, or any other benefits or bonuses. The CHS is particularly mindful of situations that may put undue pressure on employees, fellows or students to participate in research projects, and thus recommends that Investigators refrain from directly soliciting participants from these populations. Instead, all recruitment should take place via public forums, such as bulletin boards and school notices where those interested in participating may contact the Investigator.
The Faculty Council of the Harvard Faculty of Medicine in 1986 set forth the Rules Governing the Participation of Medical Students as Experimental Subjects in Research Studies (Appendix 69) which apply to research projects specifically recruiting (or conducted with) Faculty of Medicine students in biomedical research.
11.10.1. Curriculum Studies and Studies Specifically Recruiting Students
11.10.1.1. Harvard Medical School
Research involving HMS curriculum or specifically recruiting/targeting HMS students must be reviewed and approved by The Academy at Harvard Medical School (The Academy) Research Review Committee (RRC). The Academy will perform its own review of the research to make sure it is in keeping with the values and direction of the University and the curriculum, where appropriate. When The Academy has approved the study, the CHS application, study materials and The Academy approval letter will be forwarded to the Dean for Medical Education (or the Dean of Students, if the project does not involve curriculum) for further approval and signature on the CHS application. The Dean for Medical Education’s (or Dean of Students) office will forward the CHS application and all related materials (including The Academy RRC approval letter) to the CHS office for its review. No curriculum study or study specifically recruiting or targeting students at HMS can take place without all three (The Academy, Dean for Medical Education/Dean of Students, and CHS) approvals.
Amendments to these studies must first be submitted to the CHS Office. If the CHS determines that the change is minor, the CHS will review the amendment and copy The Academy on the approval notice. If the CHS determines that the change is major, it will send the amendment materials to The Academy for review and approval first, and once The Academy has approved the changes, it will send the materials to the CHS office for final review and approval.
11.10.1.2. Harvard School of Dental Medicine
Research involving HSDM curriculum or specifically recruiting/targeting HSDM students must be reviewed and approved by the HSDM Office of Dental Education (ODE) and HSDM Office of Research. The ODE will perform its own review of the research to make sure it is in keeping with the values and direction of the University and the curriculum, where appropriate. When the ODE has approved the study, the CHS application and all study materials will be forwarded to the HSDM Dean for Research for further approval and signature on the CHS application. The HSDM Dean for Research will forward the CHS application and all related materials back to the Investigator, who will then be required to submit all materials and approvals to the CHS for its review and approval. No curriculum study or study specifically involving students at HSDM can take place without all three (ODE, Dean for Research, and CHS) approvals.
11.11. Investigator Self-Experimentation
The Faculty of Medicine does not prohibit Investigator self-experimentation. However, as it would with any proposed research, the CHS will review each protocol and determine the appropriateness of the research. The CHS will consider as part of its review the level of self-experimentation and the potential risks and benefits to the Investigator as a research participant.
One of the main concerns of the CHS is that the enthusiasm for a novel concept may outweigh the Investigator’s concern for his/her own welfare. For this reason, the CHS may require that a Department Chair or even a CHS member obtain informed consent from the Investigator. The CHS also may institute additional safeguards for the research project, such as shorter review periods and monthly progress reports.
Although the majority of studies reviewed by the CHS are social-behavioral in nature, some clinical research involving FDA approved drugs and devices, as well as clinical research involving the use of investigational new drugs or devices are undertaken at Harvard Medical School or Harvard School of Dental Medicine facilities or elsewhere where review by the CHS is necessary. Emergency use of test articles in a life-threatening situation does not occur nor is it allowed at HMS or HSDM.
Clinical Research. NIH defines human clinical research as: (1) Patient-oriented research, that is research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes: (a) study of mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies. (2) Epidemiologic and behavioral studies. (3) Outcomes research and health services research.
Clinical Trial. The NIH defines a clinical trial as a prospective biomedical or behavioral research study of human subjects that is designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective. Behavioral human subjects research involving an intervention to modify behavior (diet, physical activity, cognitive therapy, etc.) fits this definition of a clinical trial. Human subjects research to develop or evaluate clinical laboratory tests (e.g. imaging or molecular diagnostic tests) might be considered to be a clinical trial if the test will be used for medical decision making for the subject or the test itself imposes more than minimal risk for subjects. Biomedical clinical trials of experimental drug, treatment, device or behavioral intervention may proceed through four phases:
- Phase I clinical trials test a new biomedical intervention in a small group of people (e.g., 20-80) for the first time to evaluate safety (e.g., to determine a safe dosage range and to identify side effects).
- Phase II clinical trials study the biomedical or behavioral intervention in a larger group of people (several hundred) to determine efficacy and to further evaluate its safety.
- Phase III studies investigate the efficacy of the biomedical or behavioral intervention in large groups of human subjects (from several hundred to several thousand) by comparing the intervention to other standard or experimental interventions as well as to monitor adverse effects, and to collect information that will allow the intervention to be used safely.
- Phase IV studies are conducted after the intervention has been marketed. These studies are designed to monitor effectiveness of the approved intervention in the general population and to collect information about any adverse effects associated with widespread use.
In such cases where FDA regulated investigational drugs and devices are being studied:
1. If the research is to be conducted anywhere other than the Veteran’s Affairs-Boston Healthcare System (VA-Boston), then the CHS will rely on the review of the Partners Healthcare IRB (Partners IRB), or the IRB of the medical facility where the research will take place.
2. If research is to be conducted at the VA-Boston, then the CHS will not review the research unless and until it has been approved by the VA-Boston IRB. Once the VA-Boston IRB has approved the research, the CHS will review the research for compliance with DHHS regulations and will rely on the VA-Boston IRB for compliance with FDA requirements.
For studies involving approved drugs/biologics and devices the following additional state and federal regulations, and CHS policies and procedures apply:
12.1. Studies Involving Drugs in Research
12.1.1. Massachusetts Requirements
Studies Involving Schedule II Narcotics. The Massachusetts Controlled Substances Act (M.G.L. c. 94C) and the regulations of the Massachusetts Department of Public Health (DPH) implementing that Act (105 CMR 700.001 et seq), contain provisions relating to “research projects and studies” involving controlled substances. Those provisions (M.G.L. c. 94C, § 8, and 105 CMR 700.009) impose certain requirements on individual researchers planning to conduct any “research project or study involving any narcotic drug in Schedule II or the investigational use of any ‘new drug’ as defined in [21 USC § 321(p)]” (hereinafter “covered studies”). Specifically, researchers planning to conduct covered studies must register with the DPH and provide the agency with information relating to the study drug, including descriptions of how the drug will be used in the study and how it will be stored and secured. The researcher is also required to provide DPH with copies of the IRB approval letter for the study, and in appropriate cases the FDA Form 1572 (for IND studies) and the researcher’s DEA Researcher Registration. [Note: any use of investigational new drugs in research must follow the policy as outlined in Section 12 (above) regarding the review of such research.]
The Investigator may also be required to submit, upon the specific request of the DPH, a copy of the study protocol and such further related information that DPH may reasonably require. Requests for additional information by the DPH should be reviewed and approved by the CHS Chair and Associate Director, and ORSP Director. The Director should be copied on all correspondence to the Commissioner of DPH, and the correspondence will remain in the study file.
The statute and the DPH implementing regulations also impose the following substantive requirements in addition to what is required by 45 CFR§ 46 and the FDA regulations:
- A parent or guardian may not, under any circumstance, “override a minor’s refusal of consent.”
- The IRB must document how it will monitor the Investigator on the project and how it will notify the Commissioner about proposed protocol changes or “emergent problems” (e.g. unexpected side effects of the drug) that arise in the course of the research.
- At least one-third of IRB members approving the study “must be independent of the research institution and must not be health care professionals.”
The statute also authorizes the Commissioner of Public Health to order that a study within Massachusetts be “terminated” when, after giving Investigators notice and an opportunity to be heard, he or she concludes that: (1) the drug is unsafe under the conditions of use, (2) the Investigators lack the knowledge and experience to conduct or complete the study, or (3) the Investigators made a material misstatement in the materials they furnished to the DPH. A further provision authorizes the Commissioner to “discontinue” a study if s/he finds (1) that the Investigators are not maintaining an adequate reporting system or (2) the study methodology does not adequately insure against “diversion” of the subject drug. Any suspension or termination of the study by the MA DPH must be reported to the CHS Office, reviewed by the convened CHS, and be reported to the FDA and OHRP as outlined in Section 15 of this policy document.
In order to comply with the federal and state regulations pertaining to the use of controlled substances, the University has developed the Harvard University Researchers’ Guide for Use of Controlled Substances (Appendix 70).
12.1.2. Use of FDA-Approved Drugs in Research
When the research activities involve the administration of an FDA-approved drug or biologic, dietary supplement or food additive (hereafter, “Drug”), Investigators are required to complete CHS Form C (Appendix 35) to provide the CHS with information about the Drug, how it will be used in the research, and to confirm the FDA approval status of the Drug. We don’t use investigational drugs at HMS.
The CHS does not review the use of Investigational drugs. If the Drug requires an IND the research must be reviewed as indicated in Section 12 above, and stated again below:
1. If the research is to be conducted anywhere other than the Veteran’s Affairs-Boston Healthcare System (VA-Boston), then the CHS will rely on the review of the Partners Healthcare IRB, or the IRB of the medical facility where the research will take place.
2. If research is to be conducted at the VA-Boston, then the CHS will not review the research unless and until it has been approved by the VA-Boston IRB. Once the VA-Boston IRB has approved the research, the CHS will review the research for compliance with DHHS regulations and will rely on the VA-Boston IRB for compliance with FDA requirements.
The CHS may review and approve research involving approved drugs, as long as the Drug meets the following criteria, which confirm that an IND is not required:
(i) the drug is lawfully marketed in the United States;
(ii) it is not intended to be reported to FDA in support of a new indication for use or to support any other significant change in the labeling;
(iii) it is not intended to support a significant change in the advertising;
(iv) it does not involve a route of administration or dosage level, use in a participant population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with its use;
(v) it is conducted in compliance with the requirements for IRB review and informed consent [21 CFR §§ 56 and 50, respectively];
(vi) it is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR § 312.7]; and
(vii) it does not intend to invoke 21 CFR § 50.24 (Exception from informed consent requirements for emergency research).
In addition to providing information about the Drug and its use, the CHS must determine whether the Investigator has the appropriate expertise and knowledge to conduct the research. The CHS may require one or more of the following:
- A meeting with the CHS Associate Director and/or ORSP Director to assess the knowledge of the Investigator in terms of the requirements to conduct the research, document informed consent, has the appropriate facilities for the research (including Drug storage), and record keeping, prior to CHS approval;
- A department mentor or advisor to help oversee the research activities and requirements;
- Regular monitoring (which could involve verification of study records and control of the Drug, as well as monitoring of informed consent) by a member of the CHS, the CHS staff, or the QA Coordinator; and
- Regular progress reports submitted to the CHS.
For CHS reviews of studies involving Drugs, the composition of the Committee will include reviewers with experience in reviewing such research, and may also include consultants with appropriate expertise in the field of research under review. The confirmation that an IND is not required will be recorded in the minutes of the convened CHS meeting in which the study is reviewed.
12.2. Use of Devices in Research
When the research activities involve the use of a device, Investigators are required to complete CHS Form D (Appendix 36) to provide the CHS with information about the device, how it will be used in the research, its FDA approval status, and whether the FDA considered it a Significant Risk (SR) or a Non-Significant Risk (NSR) device.
When a medical device is being evaluated for safety or effectiveness, the device is considered “investigational” and is subject to the requirements of the IDE regulations (21 CFR § 812). If the device requires an IDE from the FDA (meaning it is not exempt from the IDE regulations and does not qualify for an abbreviated IDE), then the study involving its use will be reviewed as noted above in Section 12 above, and stated again below:
1. If the research is to be conducted anywhere other than the Veteran’s Affairs-Boston Healthcare System (VA-Boston), then the CHS will rely on the review of the Partners Healthcare IRB, or the IRB of the medical facility where the research will take place.
2. If research is to be conducted at the VA-Boston, then the CHS will not review the research unless and until it has been approved by the VA-Boston IRB. Once the VA-Boston IRB has approved the research, the CHS will review the research for compliance with DHHS regulations and will rely on the VA-Boston IRB for compliance with FDA requirements.
If the device is deemed a non significant risk (NSR) device, which is considered to have an abbreviated IDE or is exempt from the requirements for an IDE, then the study involving its use will be reviewed by the CHS.
In addition to reviewing information about an FDA determined NSR device and its proposed use, prior to any study protocol approval, the CHS may require one or more of the following:
- A meeting with the CHS Associate Director and/or ORSP Director to assess the knowledge of the Investigator in terms of the requirements to conduct the research, document informed consent, has the appropriate facilities for the research (including Drug storage), and record keeping, prior to CHS approval;
- A department mentor or advisor to help oversee the research activities and requirements;
- Regular monitoring (which could involve verification of study records and control of the device, as well as monitoring of informed consent) by a member of the CHS, the CHS staff, or the QA Coordinator; and
- Regular progress reports submitted to the CHS.
The determination that a device is a non-significant risk and does not require an IDE will be recorded in the minutes of the convened CHS meeting in which it is reviewed.
12.2.1. Significant/Non-Significant Device Determinations by the CHS
a) A study involving an NSR device may be submitted directly to the CHS with documentation from the FDA supporting the NSR status. The study is then reviewed by the CHS with the FDA NSR status noted, and the study evaluated as per CHS review processes for participant safety.
b) If a study involving a device comes before the CHS and there is no risk status documentation from the FDA about the device, then the CHS will evaluate the risk status of the device based on the regulations noted below in (c). If the CHS determines that the study device is in fact a significant risk device, it notifies the Investigator and, where appropriate, the sponsor (21 CFR § 812.66), ordinarily within 5 business days of the CHS meeting, that an IDE is required by the FDA and therefore, the CHS cannot further review or approve the study, and the review must take place in accordance with the policy outlined in Section 12.
c) If the convened CHS makes an independent determination based on the criteria set forth below that the device is NSR, the investigation may proceed only when approved by the CHS. In order to find that the device is NSR, the CHS must find that it does not fall into any of the following categories:
i. Is intended as an implant and presents a potential for serious risk to the health, safety, or welfare of a participant (21 CFR § 812.3(m)(1).
ii. Is purported or represented to be for a use in supporting or sustaining human life and presents a potential for serious risk to the health, safety, or welfare of a participant (21 CFR § 812.3(m)(2).
iii. Is for a use of substantial importance in diagnosing, curing, mitigating, or treating disease, or otherwise preventing impairment of human health and presents a potential for serious risk to the health, safety, or welfare of a participant (21 CFR §812.3(m)(3).
iv. Otherwise presents a potential for serious risk to the health, safety, or welfare of a participant (21 CFR § 812.3(m)(4).
If the device does fall into any of the above categories, then the CHS must determine that an investigation in fact involves a significant risk device. In such cases, it notifies the Investigator and, where appropriate, the sponsor (21 CFR § 812.66), ordinarily within 5 business days of the CHS meeting, that an IDE is required by the FDA and therefore, the CHS cannot further review or approve the study, and the review must take place in accordance with the policy outlined in Section 12.
If the device does not fall into any of the above categories, then CHS may make an NSR determination. If the risk to participants is determined to be minimal in accordance with 21 CFR § 56.102(i), then the CHS may vote to conduct continuing review through the expedited review procedure (21 CFR § 56.110).
12.2.2. Exemption from the Requirement for an IDE
Research that falls into one or more of the following categories is exempt from the requirement for an IND: [21 CFR 812.2(b)]
- Exemption #1: A device, other than a transitional device, in commercial distribution immediately before May 28, 1976, when used or investigated in accordance with the indications in labeling in effect at that time.
- Exemption #2: A device, other than a transitional device, introduced into commercial distribution on or after May 28, 1976, that FDA has determined to be substantially equivalent to a device in commercial distribution immediately before May 28, 1976, and that is used or investigated in accordance with the indications in the labeling FDA reviewed under subpart E of 21 CFR §807 in determining substantial equivalence. (I.e., “FDA-approved device”)
- Exemption #3: (All must be true)
3.1. A device is a diagnostic device.
3.2. The sponsor complies with applicable requirements in 21 CFR §809.10(c).
3.3. The testing is noninvasive.
3.4. The testing does not require an invasive sampling procedure that presents significant risk.
3.5. The testing does not by design or intention introduce energy into a subject.
3.6. The testing is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.- Exemption #4: A device undergoing consumer preference testing, testing of a modification, or testing of a combination of two or more devices in commercial distribution, if the testing is not for the purpose of determining safety or effectiveness and does not put subjects at risk.
- Exemption #5: A device intended solely for veterinary use.
- Exemption #6: A device shipped solely for research on or with laboratory animals and labeled in accordance with 21 CFR §812.5(c).
- Exemption #7: A custom device as defined in 21 CFR §812.3(b), unless the device is being used to determine safety or effectiveness for commercial distribution.
12.2.3. Requirements for Investigators using Drugs or Devices in Research
Whether FDA regulated or not, Investigators using Drugs and Devices in research are responsible for:
i. Ensuring that the study is conducted according to the safety indications of administering the drug/device in manner outlined in the drug/device brochure, the grant and the research protocol;
ii. Protecting the rights, safety, and welfare of participants under the Investigator’s care;
iii. Obtaining informed consent from all participants, as outlined in section 10.3 of this policy document;
iv. The control of the drugs/devices, including appropriate storage, quantity released to study participants, returning or destroying any unused drugs/devices at the end of the study, for drugs - maintaining and dispensing only non-expired drugs, destroying any expired drugs, and. If the drug is a controlled substance, the Investigator will comply with the Harvard University Researchers’ Guide for Use of Controlled Substances (Appendix 70);
v. Administering the drugs/devices only to participants in the study only by authorized study personnel approved for such administration by the CHS;
vi. Maintaining accurate records and case histories of all participants receiving the drug/device, including any benefits they have experienced as well as side effects or adverse reactions. The records should be kept for a minimum of 5 years, as recommended by the Faculty of Medicine Guidelines for Investigators in Clinical Research (Appendix 71);
vii. Reporting any serious adverse events and unanticipated problems to the CHS as outlined in Section 13 of this policy document, or DSMB reports as outlined in section 10.1.3;
viii. Assuring that timely and thorough continuing review applications are conducted as outlined in Section 5 of this policy document;
ix. Assuring that any changes in the research are reviewed and approved by the CHS as outlined in Section 6 of this policy document.
12.2.4. Clinical Research Requirements for Sponsored Programs Administrators (including Grant and Contract Officers and CHS Administrators)
Written Agreements with Sponsors shall clearly address:
i. The responsibility of Faculty of Medicine Investigators to abide by applicable institutional policies, CHS policies, ethical standards, and applicable federal and state laws.
ii. The responsibility of Faculty of Medicine Investigators to conduct the research in accordance with the CHS-approved protocol.
iii. The publishing rights of the Faculty of Medicine Investigator, within Faculty of Medicine guidelines.
iv. What medical care, if any, will be provided to participants in the event of a study related injury and how a participant will receive or be reimbursed for such care.
v. What compensation or payments, if any, will be provided to participants who incur a study related injury.
vi. The responsibility of the Investigator and Sponsor to submit reports of any unanticipated problems or adverse events, or Data Safety Monitoring reports, in accordance with CHS policies.
vii. The responsibility of the Sponsor to promptly report to the Investigator any findings that could:
a. Affect the safety of participants
b. Affect the willingness of participants to continue with the research
c. Influence the conduct of the study
d. Alter the CHS approval
viii. Mechanisms to communicate to participants any study results which may affect their safety or medical care.
13. Adverse Events and Unanticipated Problems
In the course of a research project, various problems arise some of which may affect the research participants in varying degrees of severity. It is important that the CHS be aware of any problems that arise so that a determination can be made by the CHS whether such problems are anticipated or unanticipated and involve risks to participants or others with resultant corrective actions. Investigators must contact the CHS office via phone or email as soon as possible but not more than 48 hours after learning of a problem within their research project. All calls and emails are handled confidentially by CHS staff. The convened CHS will decide, as described below, which of the problems are anticipated or unanticipated involving risks to participants or others and subsequently determine whether any corrective actions need to be taken including, in extreme cases, suspension of the research with notification to participants.
Definitions and examples are provided below. However, the Investigator must report the following to the CHS as soon as possible, but in all cases not more than 48 hours:
- Any adverse event (any harm experienced by a participant regardless of whether the event was internal (on-site) or external (off-site) and regardless of whether the event meets the FDA definition of “serious adverse event”) which in the opinion of the Investigator are both unexpected and related.
- “Unexpected” is defined as an event whose specificity and severity are not accurately reflected in the human studies application, protocol, consent form, current investigational brochure or medical device/medication package insert.
- “Related to the research procedures” is defined as an event which in the opinion of the Investigator, was more likely than not to be caused by the research procedures or if it more likely than not affects the right and welfare of current participants.
- Information that indicates a change to the risk or potential benefits of the research , such as
- An interim analysis or safety monitoring report indicates that frequency or magnitude of harms or benefits might be different from those initially presented to the CHS;
- A paper is published from another study that shows that the risks or potential benefits of the research might be different from those initially presented to the CHS.
- Breach of confidentiality.
- Change in FDA labeling or withdrawal from marketing of a drug, device, or biologic used in a research protocol.
- Change to the protocol taken without prior CHS review to eliminate an apparent immediate hazard to a research participant.
- Incarceration of a participant in a protocol not approved to enroll prisoners.
- Any event that requires prompt reporting to the sponsor
- Sponsor imposed suspension for risk.
- Complaint of a participant when the complaint indicates unexpected risks or which cannot be resolved by the research team.
- Protocol violation (meaning an accidental or unintentional change to the CHS approved protocol) that harmed participants or others or that indicates participants or others may be at risk of increased harm.
- Unanticipated Adverse Device effect: any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with a device, if that effect, problem , or death was not previously identified in nature, severity ,or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of participants.
- Serious Adverse Event (SAE): (used interchangeably with Adverse Event (AE) in many settings) is defined as any adverse event occurring that results in any of the following outcomes:
- Death;
- A life threatening adverse drug experience;
- In-patient hospitalization or prolongation of existing hospitalization;
- Persistent or significant disability/incapacity;
- Prolonged hospitalization;
- Congenital anomaly/birth defect;
- Any important medical event that may not result in death, be life-threatening, or require hospitalization may still be considered a serious adverse event when , based upon appropriate medical judgment, they may jeopardize the patient or participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
- Unanticipated Problem involving Risks to Participant or Others is defined as a problem that is (1) unforeseen and (2) indicates that participants or others are at increased risk of harm. The majority of the studies reviewed by CHS involve social and behavioral research and thus, these events may be sometimes difficult to determine. As stated above, all problems should be reported to the CHS office for evaluation by the CHS staff, CHS Chair or CHS.
13.1. When and How to Report Events to the CHS
The CHS adheres to 45 CFR § 46.103(b)(5)(i) and 21 CFR § 56.108(b)(1), which require IRBs to have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the federal department or agency head of any unanticipated problems involving risks to research participants or others.
Investigators should report any research problems involving human participants or research staff via telephone or email immediately but not more than 48 hours after learning of the problem (as defined above). After the initial contact with the CHS Office, Investigators are required to file an Unanticipated Problem/Adverse Event form (Appendix 72) and/or a separate written report to the CHS office, as well as to study sponsor or FDA (if applicable), within five working days of the event unless otherwise specified (depending on the severity of the event) by the CHS office.
13.1.1. When there is a Data Safety Monitoring Board or Committee (DSMB/C)
DSMB/Cs (see Section 10.1.3) can be relied upon by the CHS to review SAEs happening at other study sites in a clinical trial, but the CHS must still receive and review reports of local adverse events. If a study has a DSMB/C, the Investigator must submit the data safety monitoring report to the CHS office as soon as it is available. DSMB/C reports should include a statement indicating that the data have been reviewed, the date of review and a summary of specific findings of the research study.
13.2. CHS Review of Reported Problems
The CHS Staff will consult with the CHS Chair and work with the Investigator upon notification of a reported problem (Appendix 72). The CHS Chair will review the report and determine whether the problem 1) is unforeseen; and 2) indicates that participants or others are at increased risk of harm. If both criteria are met, then the problem is considered an unanticipated problem involving risks to participants or others and requires review by the convened CHS. If the CHS Chair believes that the situation is urgent, the CHS staff or Chair will contact the Investigator and suspend study activity while the CHS Chair reviews the problem more thoroughly and determines whether the problem can wait until the next convened CHS meeting, or whether it requires an emergency CHS meeting.
If the problem is anticipated, or does not involve increased risk of harm to participants or others, the Chair will review the event and indicate whether any action is required of the Investigator, or to the protocol, consent process or documents. In these circumstances, if the study is reviewed via expedited procedures, the Chair or his/her designee may review these changes via expedited procedures, or, if the changes require convened CHS review, procedures will be followed as outlined in Section 6.
The Chair may:
- Determine whether the problem: is unanticipated; and involves risks to participants and/or others.
- Require additional information from the Investigator;
- Require additional information from any additional reviewing IRBs;
- Contact other CHS members or experts in the field for consultation as to the degree or level of risk;
- Request review of the unanticipated problem at the next convened meeting (if the risk upon discovery is considered not an immediate significant risk to other participants);
- Call an emergency meeting, if the problem and risk is such that a study and/or study procedures need to be suspended. In such cases, the CHS office may handle all communication to the Investigator, the Institutional Official and federal agencies; funding sponsors will be notified by SPA or OTD, as appropriate and as outlined below in section 13.3.1.
If an event is reviewed by the convened CHS, the CHS shall determine appropriate action in response to the report including one or more of the following:
- Decide that no further action is necessary and that the research may continue as designed (whether previously temporarily halted or not).
- Require further investigation by a member or outside expert designated by the Chair prior to the next convened CHS meeting.
- Require modification to the study/protocol and/or procedures necessary to minimize risks to participants.
- Require that additional information regarding risks be given to past participants and determining when this information should be given.
- Require notification of current participants when such information might relate to the participants willingness to continue to take part in the research.
- Require modification to the consent process and/or form to accurately reflect the nature, frequency or severity of the event.
- Require re-consenting current participants in the study.
- Require modification of the continuing review schedule.
- Require assessment by Quality Assurance Coordinator including monitoring of research procedures and consent process.
- Suspend the study procedures including any new enrollment of participants, or suspend the study approval altogether.
- Terminate the study approval.
- Referral to other institutional office as appropriate.
The following documents are provided to the CHS prior to review of an unanticipated problem involving risks to participants or others:
- Event report(s) – including any previous events related to the study
- CHS Application and protocol, if separate documents
- Continuing Review Application from current review period, including progress report and CHS initial applications, if necessary
- DSMB report, if applicable
- The associated grant is provided to the Chair and is brought to the CHS meeting.
- Any other materials of relevance or requested by the CHS
13.3.1. Notification of CHS Determinations to Investigator, Institutional Officials, and Regulatory Agencies
The CHS staff will notify the Investigator as soon as possible (ordinarily within three working days of report receipt) of the level of review required for the reported problem, as well as any additional information that may be needed by the Chair or convened CHS to perform a thorough review.
The CHS staff shall send the Investigator written notice of any action taken by the Chair or CHS and the reasons for that action, ordinarily within five working days of the CHS meeting but notification may be sooner depending on the severity of the event or the specifics of the CHS determination. However,
- If the CHS determines that a study needs to be suspended or terminated immediately, the Investigator will be notified by phone or email immediately after the meeting.
- In cases where enrollment in the study had been temporarily halted and the halt has been lifted, the Investigator will be notified immediately after the meeting by phone or email. Email messages will be sent with a “receipt confirmation” affixed to the message so that the CHS staff will know that the Investigator received the message.
The CHS is required to report to OHRP “any unanticipated problems involving risks to subjects or to others”, and thus the ORSP Director will forward decisions of the CHS within five working days to the Director of Compliance at OHRP and to the following other agencies or institutional officials, as appropriate:
- The Investigator’s Faculty of Medicine Department Head (and any additional Department Heads where the Investigator holds multiple professional appointments)
- The Faculty of Medicine Institutional Official. The IO will contact any additional institutional authorities, such as the Dean of the Faculty of Medicine, the President of the University, the Associate Provost for Research, the representative from the Office of the General Council, and Risk Management and Audit Services;
- The Sponsored Research Administration representative (where grants are supporting the research), and the Office of Technology Development (where corporate/company contracts are supporting the research). SPA or OTD will notify the study sponsor.
- Any additional University departments involved in the conduct of the research;
- Any additional IRBs and institutions involved in the research (for multi-site studies, subcontracts, IRBs and institutions relying on CHS review);
- The FDA, when the research is FDA-regulated; and
- Any additional federal agencies involved when the research is subject to those agencies.
Suspensions and terminations of research will be handled and managed as outlined in Section 15 of this policy document.
14. Non-compliance with 45 CFR § 46, HU or CHS Policies/Procedures
The CHS reviews all allegations of non-compliance with federal regulations, University and CHS policies, and CHS determinations (such as approvals and contingencies) relating to research with human participants. Any individual or organization may submit a complaint or allegation of non-compliance to the CHS. The CHS may also initiate a complaint based on information available (e.g., deficiencies noted in CHS files, media or scholarly reports of research activity subject to CHS jurisdiction).
Non-compliance means conducting research in a manner that disregards or violates federal regulations governing human studies research, Harvard University policies, Faculty of Medicine policies, accepted ethical guidelines, CHS policies, and/or CHS requirements and determinations.
- Research Activity includes all aspects of the research study, e.g., recruitment methods, consent process, invasive or non-invasive procedures used with the participants, means used to protect privacy and confidentiality (both electronic and traditional), and use of survey or study instruments. In other words, all of the information outlined in the study submission and reviewed and approved by the CHS is considered the “research activity.”
- Non-Compliance is a failure to follow the regulations or the requirements or determinations of the CHS.
- Serious Non-Compliance is non-compliance that adversely affects the rights and welfare of participants or places participants at increased risk of harm.
- Continuing Non-Compliance is a pattern of non-compliance that indicates an unwillingness to comply or a lack of knowledge that may lead to an adverse effect on the rights and welfare of participants or may place participants at an increased risk of harm,. Examples of continuing non-compliance include:
- Repeated instances of allowing a study to expire before it is re-approved;
- Repeated failure to respond to CHS inquiries or requests for documentation;
- Repeated failure to respond to and resolve any study contingencies; or
- Repeated instances of failures to respond to CHS inquiries and contingencies
14.2. Investigator Reports of Protocol Deviations and Non-Compliance
It is the responsibility of the Investigator to ensure proper and prompt reporting of protocol deviations and other non-compliance events to the CHS and to consult with the CHS staff regarding the nature of the deviation and the potential the impact, if any, on study participants.
14.2.1. What to Report to the CHS
Investigators are required to report to the CHS any minor or major protocol deviations or other non-compliance events, and anything they believe to be serious or continuing non-compliance (even if unintended), as outlined above.
Investigators are required to file a Non-Compliance Report Form (Appendix 53) and/or a separate written report to the CHS office including the following information:
- A complete description of the protocol deviation(s);
- The procedures and/or documents involved;
- A timeline of when the deviation began, was discovered and stopped (and if not stopped, a justification for such action);
- The number of participants and/or data affected;
- A reason or justification for not seeking CHS approval prior to implementation of any new procedures or documents;
- A description of any unanticipated problems involving risks to participants or others, or adverse events as a result of the deviations should be fully described;
- A plan for notification to any other sites or Investigators involved (if a multi-site project).
- A plan to prevent future similar incidents.
14.2.2. When to Report to the CHS
All deviations and non-compliance events must be reported by the Investigator or his/her staff to the CHS office upon discovery if possible, but in any case not more than 48 hours after discovery. Initial notifications to the CHS office may be provided by phone or email, but must be reported in writing to the CHS office within five working days (unless otherwise specified by CHS staff, depending on the nature of the event). Any study activities or materials not approved by the CHS should be stopped immediately and not re-initiated until the CHS has reviewed and approved the event, activity or material.
14.2.3. Other Allegations or Reports of Non-Compliance
The CHS prefers that Investigators report their own deviations. However, there are times when allegations of non-compliance are reported to the CHS from sources within the research team, the Investigator’s department, the CHS office, or by study participants or others with knowledge of a particular situation. Generally, when protocol deviations are reported to the CHS office or discovered by CHS staff, the deviations are treated as allegations of non-compliance. Any allegations of non-compliance may be submitted directly to the CHS office, the Institutional Official’s office, or to the Office of Research Compliance. All allegations of non-compliance (including anonymous allegations) will be investigated promptly.
Whenever an allegation or complaint of non-compliance is received, the ORSP Director and/or CHS Associate Director will review the allegation/complaint with the project file. The Director or Associate Director may re-contact the person filing the allegation or complaint (if known; some reports may be anonymous) for more information. Depending on the nature and seriousness of the allegations and the information or evidence available, the Associate Director or Director may find it necessary to assess the validity of the report by speaking with the Investigator, meeting with the Investigator and research personnel at the CHS office or the study site, or to review the Investigator’s study files. No allegations or complaints will be dismissed until the validity of the report/complaint is determined by the CHS office.
Upon confirmation of a valid allegation or complaint, the Associate Director or Director will forward the allegation to the Chair. The Chair may consult with a member of the CHS with expertise in the area of study or a member who is familiar with the reviews of the particular study, or may refer the allegation back to the appropriate CHS staff with a request to provide or obtain more information. Thereafter, the following actions ordinarily will take place:
i. The CHS Chair or staff (as directed by the Chair) will send written notice of the allegations to the Investigator and request a response specifically addressing the allegations.
ii. The Chair and/or designee will review the allegation/complaint, the response from the Investigator and any other relevant information (such as the initial or continuing review application and related materials, copies of amendment requests, unanticipated/adverse event/DSMB reports, consent forms, communications with the Investigator and any other pertinent information) in order to determine whether the allegation is serious or continuing, and if so, provide a recommendation to the CHS concerning appropriate action. If the non-compliance is not serious or continuing the Chair may determine the following corrective actions, which will be forwarded to the Investigator by the Chair, or the CHS staff (if so requested by the Chair):
- Resolution through corrective or educational measures.
- Require changes to the protocol, consent form or process, or study procedures or processes to avoid future incidents of non-compliance.
- Referral to a convened CHS meeting to review and recommend appropriate actions.
- Referral to other organizational entities (e.g., Office for Research Issues for allegations of research misconduct (for example fabrication, falsification, or plagiarism).
- In some situations, especially those involving allegations of continuing non-compliance, the CHS may require verification from someone other than a researcher (for example, a Department Head, Department Administrator, CHS member or staff) that changes to documents or procedures, required by the CHS, have been made. Although not typical, this external verification may be required by the CHS if it has made more than one unsuccessful attempt to receive documentation of changes from the researcher, or if it has received a report from study personnel, study participants, or others, that the changes required by the CHS were not implemented.
iii. All incidents determined by the Chair to be serious or continuing non-compliance are reviewed by the convened CHS. The Chair acts as the primary reviewer, and all of the documents the Chair reviewed in order to make the determination of serious or continuing (see ii., above) will be sent to the CHS members who will be present at the convened meeting via the same procedures outlined in Section 4.10.3.
iv. The allegation of serious or continuing non-compliance (including all of the materials reviewed by the Chair in (ii), above) is reviewed at a convened CHS meeting where one of the following determinations will be made:
- Modification of the protocol.
- Modification of the information disclosed during the consent process.
- Providing additional information to past participants.
- Notification to current participants when such information might relate to participants’ willingness to continue to take part in the research.
- Requiring current participants to re-consent to participation.
- Modification of the continuing review schedule.
- Monitoring of the research.
- Monitoring of the consent.
- Suspension of the research.
- Termination of the research.
- Referral to other organizational entities.
At any time during the inquiry process, the Investigator may request a meeting with the CHS staff, chair, or time at a convened CHS meeting to discuss the report/allegation.
14.3. Further Investigation by the CHS
Where the Initial Inquiry has resulted in a decision by the CHS that an investigation is warranted, a sub-committee of the CHS ordinarily will be formed for this purpose. The subcommittee will conduct an appropriate investigation, which may include, for example:
- Meeting with the Investigator;
- Visiting the study site;
- Consulting with appropriate experts;
- Reviewing the study files;
- Meeting with members of the research team, the Investigator’s Department Head, study participants, or others;
- Consulting with the Institutional Official and/or other University and Faculty of Medicine officials.
Ordinarily, the sub-committee investigation will result in a report detailing their findings and recommendations, which is sent to the CHS Chair and Associate Director, ORSP Director and Institutional Official upon completion, and reviewed at the next convened CHS meeting for further determination of actions.
The CHS shares information relating to an open inquiry or investigation only with others at the University who have a need to know, those who are involved in or necessary to the investigative process, and with federal agencies as required.
14.5. Coordination with Other Investigative Process
As appropriate, the CHS will cooperate with other Harvard offices or committees, or with federal agencies such as OHRP or the FDA, which may be conducting an inquiry, investigation, review or audit involving a researcher about whom the CHS has knowledge or documentation. Where the CHS and another University committee are conducting inquiries, investigations, reviews or audits involving the same or related allegations, the CHS will work to coordinate with the other committee to avoid duplication of effort.
14.6. Action Prior to Decision
At any time during an inquiry or investigation, the CHS may determine that it is necessary to suspend accrual of research participants or to suspend approval of research project(s) to ensure the protection of research participants, to preserve the integrity of the study, or to preserve the integrity of the Faculty of Medicine’s human research protection program. Ordinarily, the CHS will not suspend approval of research studies until the Investigator has had an opportunity to respond to the allegation of non-compliance, but such opportunity may occur after the suspension where there is an immediate risk to participants.
14.7. Decision (including suspension or termination of approval)
The CHS will review all reports from the sub-committee’s investigation and any information provided by the Investigator before reaching its final decision. Actions the CHS may take with respect to the investigation include, but are not limited to:
- Dismissal of the complaint;
- Imposition of remedial education for the Investigator and/or other personnel working on the study;
- Monitoring of research activities;
- Increased reporting to the CHS by the Investigator of his/her human studies activities;
- Restrictions on research practice, such as limiting the Investigator to conducting studies with only minimal risk or conducting research under supervision;
- Suspension of approval for one or more of the Investigator’s studies;
- Termination of approval for one or more of the Investigator’s studies;
- Referral to other Harvard officials or committees for possible further review.
14.8. Notification of CHS Determinations to Investigator, Institutional Officials, and Regulatory Agencies
The CHS Associate Director or ORSP Director will notify the Investigator in writing of CHS determinations or actions and the reasons for the determinations and actions, ordinarily within two working days of the CHS meeting, although notification may be sooner depending on the severity of the event or the specifics of the CHS determination. However,
- If the CHS determines that a study needs to be suspended or terminated immediately, it will follow the procedures outlined in Section 15, and will notify the Investigator by phone or email immediately after the meeting.
- In cases where enrollment in the study had been temporarily suspended and the suspension has been lifted, the Investigator will be notified immediately after the meeting by phone or email. Email messages will be sent with a “receipt confirmation” affixed to the message so that the CHS staff will know that the Investigator received the message.
The CHS is required to report to OHRP “any serious or continuing noncompliance with this policy [45 CFR § 46 and its subparts B, C and D] or the requirements or determinations of the IRB”, and thus the ORSP Director will forward decisions of the CHS within five working days to the Director of Compliance at OHRP and to the following other agencies or institutional officials, as appropriate:
- The Investigator’s Faculty of Medicine Department Head (and any additional Department Heads where the Investigator holds multiple professional appointments)
- The Faculty of Medicine Institutional Official. The IO will contact any additional institutional authorities, such as the Dean of the Faculty of Medicine, the President of the University, the Associate Provost for Research, the representative from the Office of the General Council, and Risk Management and Audit Services;
- The Sponsored Research Administration representative (where grants are supporting the research), and the Office of Technology Development (where corporate/company contracts are supporting the research). SPA or OTD will notify the study sponsor.
- Any additional University departments involved in the conduct of the research;
- Any additional IRBs and institutions involved in the research (for multi-site studies, subcontracts, IRBs and institutions relying on CHS review);
- The FDA, when the research is FDA-regulated; and
- Any additional federal agencies involved when the research is subject to those agencies.
Suspensions and terminations of research will be handled and managed as outlined in Section 15 of this policy document.
The CHS will inform Investigators that, in accordance with University policy and the law, they are prohibited from engaging in any kind of retaliatory action following allegations of research non-compliance or misconduct.
15. Suspension or Termination of Research
The CHS is authorized to suspend or terminate the approval of research that:
- Is not being conducted in accordance with the CHS’s requirements; and/or
- Has been associated with unexpected or serious harm to participants.
Suspension of research approval means a halt in all research activities until the CHS determines whether the research may commence (with or without modifications to the research), or whether it shall be terminated.
Termination of research approval means a permanent stop to the research and all related activities.
Suspensions or terminations of approval of research are determined at a convened CHS meeting. When the CHS votes to suspend or terminate the CHS approval of a research study based on a serious adverse event, unanticipated problem or serious or continuing non-compliance, it must consider whether the suspension or termination requires that current participants be withdrawn from the study and/or whether other measures must be taken to protect them.
If the CHS determines that participants must be withdrawn from a clinical study involving a drug, test article or treatment of any kind, the CHS must determine the necessary steps to be taken to ensure the safety, welfare and rights of those participants, e.g., drug taper, final visit, lab tests, continuation of treatment, other follow-up. Additionally the Investigators will be reminded that arrangements will need to be made for continued care by the participant’s physician, another Investigator, or through appropriate referrals.
If the CHS determines that the suspension or termination of the research will place participants at risk of harm, the CHS must determine what participants are to be told, by whom, the manner in which they are to be notified (e.g., in writing or by telephone), and the timing of notifications.
In addition to the CHS, the study DSMB, the Dean of the Faculty of Medicine, the President or Provost of Harvard, and the Committee on Biological Safety (COMS) may suspend or terminate research; all such suspensions and terminations must be reported to the CHS Office within 24 hours by the Investigator, and may additionally be reported to the CHS by the official or Committee suspending or terminating the research; the person or committee terminating or suspending the research will have any adverse events or outcomes reported to the CHS. The suspension or termination must be evaluated by the convened CHS. Additionally, in the event of an extreme or immediate emergency, the CHS Chair or IO may suspend the research until it can be further evaluated by the convened CHS, and any other appropriate entity responsible to review the research or activities of the Investigator. These suspensions must also be reported to the CHS Office within 24 hours by the Investigator, and evaluated by the convened CHS.
15.1. Notification to Participants
Depending upon the reasons for the suspension or termination and the design of the protocol, the CHS may require that participants who have been consented or enrolled in the study be notified of the suspension or termination.
Ordinarily, participants will be notified by the Investigator of a study termination and reason for the termination, however depending on the reasons of the termination, the notification may come from another party (such as a Co-Investigator or the Department Chair). Participant notification will be given in a manner so as not to arouse concern but to fully inform them of the situation. Letters will ordinarily:
- Be written by the Investigator and reviewed and approved by one or more of the following, as determined in the CHS meeting: a convened CHS meeting, the Chair, CHS subcommittee, IO, or representative from OGC.
- Be signed by the Investigator, and may also be signed by the CHS Chair and/or the ORSP Director, before being sent by the Investigator to participants;
- Contain the contact information of the Investigator, ORSP Director, and the study sponsor for the participant to contact for further information;
- Inform the participants of any follow-up procedures that are needed or required for their safety and a recommendation made as to how this follow-up can be done and by whom.
- Direct participants to notify the ORSP Director, the Investigator or the Sponsor of any adverse event or problem that occurs during the follow-up period.
15.2. Notification of CHS Determinations to Investigator, Institutional Officials, and Regulatory Agencies
Whenever the CHS suspends or terminates the approval of a study due to serious or continuing non-compliance or an unanticipated problem involving risks to participants or others, the ORSP Director will draft a report of the suspension/termination. The report will include the circumstances surrounding the suspension or termination, the findings of the CHS in making the determination to suspend or terminate the research, any necessary steps to be taken to ensure the safety, welfare and rights of past or present study participants (e.g., drug tapers, continuation of treatment, notification to participants, etc.), and any corrective actions for the Investigator. The report is reviewed and approved by the CHS Chair (and other CHS members, as the Chair determines) prior to distribution.
The following individuals and entities receive a copy of the suspension or termination report, ordinarily the next business day (and not later than 5 business days) after the CHS determination to suspend or terminate the research, by the ORSP Director:
- The Investigator and Co-Investigator;
- The Investigator’s Faculty of Medicine Department Head (and any additional Department Heads where the Investigator holds multiple professional appointments)
- The Faculty of Medicine Institutional Official. The IO will contact any additional institutional authorities, such as the Dean of the Faculty of Medicine, the President of the University, the Associate Provost for Research, the representative from the Office of the General Council, and Risk Management and Audit Services;
- The Sponsored Research Administration representative (where grants are supporting the research), and the Office of Technology Development (where corporate/company contracts are supporting the research). SPA or OTD will notify the study sponsor.
- Any additional University departments involved in the conduct of the research;
- Any additional IRBs and institutions involved in the research (for multi-site studies, subcontracts, IRBs and institutions relying on CHS review);
- FDA, when the research is FDA-regulated;
- Any additional federal agencies involved when the research is subject to those agencies; and
- OHRP, as appropriate.
Investigators shall have the opportunity to respond to the suspension or termination and offer new procedures or a new research plan to protect the rights and welfare of the participants.
The CHS maintains the following documentation in its office: (1) discussions and decisions of reviews by the convened CHS; (2) discussions and decisions that take place by an expedited review procedure; (3) discussions and decisions that take place by an exempt review procedure; (4) communications between CHS members or CHS staff and Investigators and/or their staff; (5) study files; (6) CHS Membership Rosters; and (7) Policies and Procedures of the CHS.
The CHS’ record-keeping practices comply with 45 CFR § 46.115, which are as follows:
(a) An institution, or when appropriate an IRB, shall prepare and maintain adequate documentation of IRB activities, including the following:
(1) Copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents, progress reports submitted by investigators, and reports of injuries to subjects.
(2) Minutes of IRB meetings which shall be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controverted issues and their resolution.
(3) Records of continuing review activities.
(4) Copies of all correspondence between the IRB and the investigators.
(5) A list of IRB members in the same detail as described in § 46.103(b)(3).
(6) Written procedures for the IRB in the same detail as described in § 46.103(b)(4) and § 46.103(b)(5).
(7) Statements of significant new findings provided to subjects, as required by § 46.116(b)(5).
(b) The records required by this policy shall be retained for *at least three years, and records relating to research which is conducted shall be retained for at least three years after completion of the research. All records shall be accessible for inspection and copying by authorized representatives of the department or agency at reasonable times and in a reasonable manner.
The CHS records also contain the following documentation:
- Copies of the DHHS-approved sample consent documents.
- The description of action taken by the Reviewer
- The specific permissible categories for expedited and exempt reviews.
- The frequency of reviews for full CHS and expedited studies, for initial and continuing reviews.
- Documentation of determinations required by the regulations along with protocol-specific findings justifying those determinations.
- For exemption determinations and expedited reviews, the specific category for the determination or approval of the research.
- Protocols that were cancelled without participant involvement and those that were withdrawn without receiving initial approval.
Study files are kept in the CHS office for all active studies requiring full CHS and expedited reviews. The files are organized such that the CHS or others could construct a complete history of the study and all CHS actions pertaining to the review and approval of the study.
CHS study files contain the following documentation, as appropriate:
- CHS applications (new, continuing, and supplemental forms), signed by the Investigator and Department Head (or mentor, if student).
- Complete protocol, if not embedded within the application.
- Complete grant applications, subcontracts and contracts (including budget pages and appendices).
- All study materials (such as recruitment letters/emails/phone scripts, surveys, questionnaires, other data collection instruments, and payment forms).
- Approved consent documents (see Section 10.3), containing the CHS stamp. Please note – where another IRB has already stamped a consent form, the CHS will not additionally stamp the form, unless it is requested.
- DHHS-approved sample consent documents.
- Yearly progress reports, including any significant new findings that have been reported to study participants.
- All unanticipated problems, adverse event forms, and DSMB reports, as well as resolutions and/or acknowledgement of review by the convened CHS, or CHS Chair, as appropriate.
- All completed reviewer sheets noting any additional findings and safeguards for research involving populations protected under subparts B, C and D of 45 CFR § 46 and other vulnerable populations as noted elsewhere in these policies.
- Any additional scientific or consultant reviews.
- Communications between the CHS staff or CHS members with the Investigator (or designated research personnel).
- All approvals from additional IRBs reviewing the project, and at times, complete applications and materials approved (such as consent forms, recruitment and data collection tools) from additional IRBs.
- The ROA for each CHS review (including initial, continuing, and amendments).
Study materials are organized in reverse chronological order, with the first approved record last in the file, and the last approved record (or most recent), first. All records pertaining to a study are kept together in the file cabinet until the study is closed. Convened CHS meeting minutes are stored separately.
Exempt studies and studies not meeting the definition of research or research with human subjects are scanned in their entirety, made into a .pdf document, and kept on the CHS shared-drive (listed by Investigator last name and protocol number). The original paper copies are sent to the Harvard Depository.
16.2. Study Record Retention Policy
16.2.1. Investigator’s Study Records
In accordance with the Faculty of Medicine policy on retention of research records and Harvard University Retention of Research Data and Materials(Appendices 71 and 71a), Investigators should keep all records pertaining to clinical studies for a minimum of seven years after the study is complete. The CHS recommends this retention policy for all studies, regardless of risk or type of CHS review. At a minimum standard set by DHHS (45 CFR § 46.115(b) and the FDA (21 CFR § 56.115(b), Investigators must keep complete study records for three years. Records must be kept in a secure location that allows for maintaining participant confidentiality. The study records must be available for inspection by the CHS, DHHS, FDA, or the funding source, as applicable, and if requested.
The CHS maintains all study records (containing the above noted materials, as appropriate to the study) at the Harvard Depository. The records stored at the Depository are saved for a minimum of 7 years from when the study is complete (note: this differs from OHRP policy requiring records to be maintained for a minimum of 3 years), and may be held indefinitely, depending on the study. Records are also maintained for studies that were cancelled without participant enrollment for a minimum of 3 years.
Records may be recalled from the Depository when needed, however only the CHS Associate Director, ORSP Director, and CHS Administrative Coordinator have the authority to request recall and pick-up of boxes to/from the depository. All records are stored in an archive box and listed in alphabetical order; each box contains a bar code assigned by the Depository.
The CHS Administrative Coordinator keeps a paper copy of the list of boxes, study records and bar codes for easy recall, and this list is also accessible on the Harvard Depository folder on the CHS shared-drive.
Some studies either close before any research activities take place or are never completed for various reasons (such as when an Investigator changes institutions or if funding is not awarded). However, any file of a study that received approval from the CHS is organized, maintained and archived in the same manner as other study files noted in this section.
In addition to maintaining all study files at the Depository, complete meeting packets of studies that received convened CHS review are stored at the Countway Library, dating back to 2004.
16.3. Minutes of a Convened CHS Meeting
Convened CHS meetings are recorded via tape or digital recorder by CHS staff and each study section is transcribed by the CHS staff responsible for pre-reviewing the study. The meeting recordings are destroyed (or taped-over) within a year of the meeting. The CHS Associate Director is responsible for transcribing any agenda items that are not study-related, or when the responsible CHS staff is unavailable to transcribe his/her section of the minutes. Minutes are entered by CHS staff into the HIRBERT database and then exported into a word document, reviewed and edited by the CHS Associate Director.
Minutes of CHS meetings include:
The complete/edited minutes are circulated by the CHS Associate Director or Administrative Coordinator to the full CHS via email for approval. The minutes are ordinarily sent to the CHS for review with the meeting packet each month and accepted formally at the next convened meeting (e.g. June minutes are sent with the July meeting packet and accepted at the July meeting).
- The names of all members present
- When an alternate replaces a primary member, and the name of the alternate and primary member
- The names of all non-members present
- Date of meeting
- Time of meeting commencement and conclusion
- Time of members entering or leaving the room after the meeting has begun
- Documentation of and for each project under review:
- Members voting for, against or abstaining.
- The names of the members who absent themselves from the meeting due to a conflict of interest, along with the fact that a conflicting interest is the reason for the absence.
- Review status (initial, continuing, amendment, adverse/unexpected event, or non-compliance)
- CHS action (approval, contingent approval, deferral, disapproval)
- Separate deliberations for each action
- Justification for actions
- A written summary of the discussion of controverted issues and their resolution
- Any unresolved questions for the Investigator
- Any required changes to the study
- The basis for requiring changes to research
- Any questions or suggestions for the Investigator that do and do not have bearing on the approval of the study.
- Degree of risk
- Determinations required by the regulations and protocol-specific findings justifying those determinations for:
- Waiver or alteration of the consent process.
- Research involving pregnant women, human fetuses and neonates.
- Research involving prisoners
- Research involving children
- Special criteria under Massachusetts law
- The rationale for significant and non-significant risk device determinations.
- Approval of documents, such as consent forms, recruitment materials, questionnaires, and assessments.
- Justification of any deletion or substantive modification of information concerning risks or alternative procedures contained in the DHHS-approved sample consent document.
- Confirmation that the CHS reviewed the protocol material in relation to the following: the risks to participants are minimized and reasonable in relation to anticipated benefit to the participants, if any; the importance of the knowledge that may reasonably be expected to result; the selection of participants is equitable; the procedures for securing and documenting informed consent are appropriate; the privacy of the participants and the confidentiality of the data are secured, and when appropriate, data monitoring is performed to ensure the safety of participants.
- The basis for disapproval of research
- Approval period for initial and continuing reviews.
A copy of the CHS accepted minutes are kept in the ‘Minutes’ folder on the CHS Office shared-drive, and in the meeting packets sent to Countway for archiving and kept in perpetuity. The meeting packets are archived at the Countway Library at the completion of each year. Additionally, minutes dating back three years are kept in a binder and brought to each CHS meeting.
CHS membership rosters are kept in the ‘IRB Membership Lists’ folder on the CHS office shared-drive. All changes in membership are approved by the Institutional Official (IO) and submitted by the CHS Associate Director to OHRP via their electronic submission system each time a change in membership occurs. Paper copies are also available in the CHS Associate Director’s office and are distributed to the CHS membership and staff, the IO and Office of General Counsel (OGC) each year and/or each time a change is made.
Policies and procedures of the CHS are updated as necessary and posted in entirety on the CHS website. Changes to the policies are reviewed and approved by the CHS Leadership Team and the CHS, before being posted. The CHS policies and procedures indicate the date on which they were last updated. The most recent/approved version of the document is available on the CHS website for Investigators, administrators, CHS staff and members, and the general public. Changes in regulations, policies or procedures that require immediate action or significant effort on the part of the Investigators (or their staff) are sent via email to the affected parties, are listed in the HMS weekly ‘Quad Bulletin’ and are noted via banner on the CHS website, as appropriate.
17.1. Organizational Structure
The HMS Sponsored Programs Administration (SPA) Office provides services to the Faculty of Medicine and oversight and stewardship of sponsored awards. SPA works closely with other offices within the overall research administration infrastructure at Harvard, and has signatory authority for purposes of proposing and accepting awards for the Faculty of Medicine. The funding portfolio at the Faculty of Medicine is comprised largely of federally funded awards for basic science along with a smaller proportion of federal awards for clinical research, non-federal grants, donations, trust or gifts and agreements with pharmaceutical companies.
The proposal review process serves complementary functions of assuring a complete and accurate proposal and compliance with sponsor and institutional policies. The review process is a collaboration between the faculty member, Department Head, Department Administrator, SPA staff and other offices that assure compliance with policies and regulations, including regulations related to human studies research and CHS policies. Each party in the review process assumes an important responsibility to assure that all aspects of the proposal have been thoroughly addressed.
The CHS works closely with SPA to ensure compliance with all regulatory requirements for protection of human research participants. To this end, the senior grants administrators in SPA have access to the HIRBERT database. In this way the grants administrators can confirm that all human research protocols associated with a grant have received CHS approval, and can access details such as CHS approval and renewal dates, involvement of other IRBs, and current CHS certifications for personnel working with human research participants.
The SPA staff is keenly aware of the NIH requirement for certification of training in human subject research for all key personnel on a federal grant who are working with research participants (including participant data and biological specimens). Whenever there is a question of certification, the SPA grant administrators confirm training status on the HIRBERT database, or check with the CHS office if no documentation appears in the database.
In compliance with specific training grant requirements, additional training in the Program in Responsible Conduct of Research is made available to post doctoral fellows and others through the HMS Course on Medical Ethics. The Program in the Practice of Scientific Investigation (PPSI) was established in 1990 by the Division of Medical Ethics to provide education in the responsible conduct of research for post-doctoral research fellows. In 1999, the Dean of the Faculty of Medicine mandated completion of the PPSI for all post-doctoral fellows working in laboratories in the Harvard Medical School Quadrangle, regardless of funding source. The PPSI offers education in the responsible conduct of research to all post-doctoral fellows working in HMS labs. Five sessions for post-doctoral fellows are presented concerning issues such as authorship, data sharing and material transfer agreements, peer review of manuscripts and grants, scientific fraud, and conflicts of interest. The sessions are designed to encourage discussion and to examine the academic policies in place at HMS for the responsible conduct of science.
The SPA and CHS offices work closely with each other allowing effective working relationships. The Office of Technology Development (OTD) similarly supports communication and sharing of information. Any issues of potential non-compliance discovered in conjunction with the work of any of these offices are quickly communicated between them, as necessary. The CHS office copies SPA and OTD on official notices when a study has been suspended or terminated. The SPA office or OTD, as appropriate, will notify the funding agency of this occurrence.
17.3. Additional Requirements for Clinical Trials
See Section 12.1.7.
17.4. Requirements for Social/Behavioral Research
Although much of the human studies research taking place at HMS is more social or behavioral in nature, the commitment to the protection of human participants in these studies is no different from that of clinical studies or trials. The funding for these studies may be federal or non-federal, but the requirements for proper training and the ethical conduct of research in human studies research are the same. Any issues involving non-compliance of non-exempt human studies research will be dealt with in a similar fashion as described above regarding notification of funding entities.
The Faculty of Medicine encourages, when appropriate, that study populations and community members be included in the design, conduct, and evaluation of research. The inclusion of study populations and community members in the design, conduct and oversight of studies often adds more depth to the research, better understanding of the research results, as well as additional protections for the research participants. Study populations and community members may also be better able to disseminate the results of research, having better knowledge of the community and how information is best passed along and understood by community members.
Aside from participation in the design/conduct of research, it is essential that community members and other potential research participants have pertinent information about any research in which they are eligible and wish or agree to take part and that they have information about their rights as a research participant. The Leadership Team will assist in the further development and evaluation of the effectiveness of HRPP participant outreach activities and assess best practices to insure the protection of and information for participants.
18.1. Consent form Requirements
In accordance with regulations at 45 CFR § 46.116 (a)(6-7) and 21 CFR § 50.25 (a)(6-7), each consent form is required to contain:
- Contact information of the Investigator (or his/her staff) for any questions, concerns or problems the participant may have about the research.
- Where to go and whom to contact (and contact information) in the event of a research-related injury when medical interventions or treatments are involved in the research.
- Contact information of the CHS (or other appropriate IRB or ethics committee) for any questions the participant may have about their rights as a participant in research or any complaints or concerns about the research.
18.2. CHS Contact Information and Procedures
The contact for research participants in the CHS office is the ORSP Director (617-432-0651), who handles all calls in a confidential manner. The ORSP Director may take down the caller’s name and contact information, or if the caller does not wish to provide that information the call will be treated in the same respectful and serious manner as with an identified caller. The ORSP Director will take notes on the call and will follow-up with the Investigator, especially regarding any complaints or to confirm understanding of the research project (or parts of it, as pertinent to the question of the participant) as it was approved by the CHS.
Depending on the nature of the call, the ORSP Director may advise the participant to call the Investigator or his/her research personnel directly, or may act as the liaison between the two parties. If a serious allegation is made against the Investigator or his/her research personnel, the ORSP Director will treat the allegation in the same manner as noted regarding non-compliance investigations noted in Section 14 of these policies.
Information for research participants, such as participants’ rights and whom to contact with any pertinent questions about the research, is available on the CHS website in English and in Spanish; participants may submit research questions or comments online. The HMS website includes a section entitled “Consumer Information” which links to a consumer health information site and the Longwood Seminar series, the latter of which encompasses various aspects of research and research topics for the community.
Print-Ready Policies and Procedures 
Appendices to the Policies and Procedures
Updated: 19-Dec-2011