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Ethical Foundation for Human Subject Protections

The University of Pittsburgh is committed to ensuring that all human subject research¹ in which it is engaged² is conducted in accordance with the ethical principles stated in the Belmont Report http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm. The Belmont Report, published in 1979 by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, provides the ethical foundation for the federal regulations for the protection of human research subjects. All University personnel involved in the conduct and oversight of human subject research must abide by the fundamental principles set forth in the Belmont Report which include:

Regulatory mandates

The IRB and the research community adhere to the following regulations and policies for human subject research activities:

1. The Federal Policy regulations for the protection of human research subjects (45 CFR Part 46 ; Subpart A also known as the “Common Rule”).
2. When research involves articles subject to regulation by the FDA, the FDA regulations for the protection of human subjects (21 CFR Parts 50 ) and Institutional Review Boards (21 CFR Parts 56 ).
3. Where applicable, other federal, state and local regulations regarding research involving human subjects.
4. The provisions of the Federal Wide Assurance Agreements (FWA) for the University of Pittsburgh (FWA #00006790), UPMC (FWA #00006735), UPMC Cancer Centers (FWA #00003338), UPMC Children’s Hospital of Pittsburgh (FWA #00000600), and Magee Women’s Research Institute (FWA #00003567).

When making determinations concerning the rights and welfare of human subjects participating in research studies, the IRB will also refer to current versions of the OHRP’s (formerly OPRR’s) Protecting Human Research Subjects, Institutional Review Board Guidebook; the FDA’s Information Sheets for IRBs and Clinical Investigators; and to other interpretative directives, information documents and guidance materials disseminated by OHRP, DHHS, the National Institutes of Health (NIH) the FDA and other federal agencies (e.g., Office of Civil Rights).

The primary purpose of the IRB is to protect the rights and welfare of human subjects involved in research activities being conducted under its authority. In so doing, the IRB shall ensure adherence to the criteria for IRB approval as listed in 45 CFR 46.111 and 21 CFR 56.111 i.e., that:

• The risks to human research subjects are minimized by using procedures that are consistent with sound research design and that do not unnecessarily expose the research participants to risk, and whenever appropriate, by using procedures already being performed on subjects for diagnosis or treatment purposes.
• The risks to human research subjects are reasonable in relation to the anticipated benefits (if any) to the individual, and the importance of the knowledge that may be expected to result.
  • For the purpose of IRB consideration, "benefit" is defined as a valued or desired outcome; an advantage.
  • For the purpose of IRB consideration, "risk" is defined as the probability of harm or injury (physical, psychological, social, or economic) occurring as a result of participation in a research study.
  • In evaluating risk, the IRB is to consider the conditions that make the situation dangerous, per se (i.e., as opposed to those chances that specific individuals are willing to undertake for some desired goals). In evaluating risks and benefits, the IRB considers only those risks and benefits that may result from the research (i.e., as distinguished from risks and benefits of treatments or procedures that the patient would undergo if not participating in the research).
  • In evaluating risks and benefits, the IRB does not consider possible long-range effects of applying knowledge gained in the research (e.g., the possible effects of research on public policy).
• The selection of human subjects for research participation is equitable.
• Human research subjects are adequately informed of the risks and benefits of research participation and the procedures that will be involved in the research; and that informed consent is obtained from each prospective human research subject, or his/her legally authorized representative, in accordance with, and to the extent required by federal regulations and IRB policies.
• Informed consent of human research subjects is obtained in advance of research participation and appropriately documented in accordance with, and to the extent required by federal regulations and IRB policies.
• The research plan, when appropriate, makes adequate provisions for monitoring the data collected to ensure the safety of human research subjects.
• There are adequate provisions to protect the privacy of human research subjects and to maintain the confidentiality of research data.
• Appropriate additional safeguards have been included in the study to protect the rights and welfare of human research subjects who are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, pregnant women, decisionally impaired persons, or economically or educationally disadvantaged persons).

As a secondary purpose, the IRB must seek to ensure that the University, affiliate institutions, and the investigators that it serves are compliant with the ethical standards and regulations governing human subject research. The IRB and IRB Office also serve to assist investigators in the design of ethical and regulatory compliant human subject research studies.

The University of Pittsburgh IRB is required to review and approve all research activities, within its jurisdiction, involving human subject research prior to its implementation.

Definitions:

Research (DHHS): A systematic investigation, including research development, testing and evaluations, designed to develop or contribute to generalizable knowledge [45 CFR 46.102(d)].

• Systematic Investigation: An activity that involves a prospective plan which incorporates data collection, either quantitative or qualitative, and data analysis to answer a question.
• Generalizable: Knowledge that may be justifiably transferred or extrapolated to a broader population or situation than from which it was initially derived.

Research (FDA): Any experiment that involves a test article and one or more human subjects and that is either subject to requirements for prior submission to the FDA under section 505(i) or 520(g) of the Act, or is not subject to requirements for prior submission to the FDA under these sections of the Act, but the results of which are intended to be submitted later to, or held for inspection by, the FDA as part of an application for research or marketing permit. The terms "research," "clinical research," "clinical study," "study," and "clinical investigations" are deemed to be synonymous for purposes of this part (21 CFR 50.3(c) and 21 CFR 56.102(c)

Human Subject (DHHS): A living individual about whom an investigator (whether professional or student) conducting research obtains (1) data through intervention or interaction with the individual, or (2) identifiable private information. Intervention includes both physical procedures by which data are gathered (for example venipuncture) and manipulation of the subject or the subject’s environment that are performed for research purposes. Interaction includes communication or interpersonal contact between investigator and subject. Private information includes information about behavior that occurs in a context in which an individual can 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. 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 ([45 CFR 46.102(f)].

Human Subject (FDA): An individual who is or becomes a participant in research, either as a recipient of a test article or as a control. A subject may be either a healthy individual or a patient (21 CFR 50.3(g) and 21 CFR 56.102(e)). For clinical investigations involving medical devices, the results of which are intended to be submitted later to, or held for inspection, by the Food and Drug Administration as part of an application for a research or marketing permit, human subject also means a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease.

Guidance concerning activities that may or may not be overseen by the human research protection program such as classroom research, quality assurance/improvement, case reports, program evaluation, and innovative practice is located on the IRB website http://www.irb.pitt.edu/Guidance.

Authority Granted to the IRB through the Institution

The University Chancellor has delegated authority, through the Vice Chancellor for Research Conduct and Compliance (the designated Institutional Official), to the University of Pittsburgh Institutional Review Board (IRB) to oversee all research activities falling under the Human Research Protection Program (HRPP) of the University of Pittsburgh.

Authorities Granted to the IRB by Federal Regulation

The Institutional Review Board (IRB) of the University of Pittsburgh (FWA00006790) is an appropriately constituted administrative body established to protect the rights and welfare of human subjects (including patients) recruited to participate in research activities. In accordance with the Federal Policy regulations (45 CFR 46) of the Department of Health and Human Services (DHHS) and the applicable regulations (21 CFR 50, 56) of the Food and Drug Administration (FDA), the IRB has the authority to approve, require modifications to, or disapprove all research activities involving human subjects that fall under its authority.

• Research activities approved by the IRB are subject to further appropriate review and approval or disapproval by the Institutional Official of the University of Pittsburgh and by officials of the UPMC. However, those officials may not approve human subject research to be conducted within their institution if such research has not received prior approval from the IRB.
• Unresolved questions or issues between the IRB and investigators will be referred to the Institutional Official for additional discussion. Comments and recommendations of the Institutional Official will be considered by the IRB in its subsequent decision to approve or disapprove the proposed research protocol.

The IRB has the authority to determine that a project submitted by an investigator does not meet the regulatory definition of human subject research under 45 CFR 46.102(f) and 21 CFR 56.102(f).

The IRB has the authority to require progress reports from investigators and to conduct continuing reviews of approved human subject research studies at intervals appropriate to the degree of risk, but not less than once per year. Research studies qualifying for “exempt” status in accordance with 45 CFR 46.101(b) will not be subject to continuing review.

The IRB has the authority to approve prospectively all modifications to previously approved research protocols and/or informed consent documents; the only exception being a protocol deviation that may be necessary to eliminate an apparent immediate hazard to a given research subject.

The IRB has the authority to observe or have a third party observe the conduct of approved human subject research studies, including the informed consent process.

The IRB has the authority to suspend or terminate the approval of, human subject research activities that are not being conducted in accordance with the IRB’s requirements or have been associated with unexpected serious harm to subjects.

The IRB has the authority to place restrictions on human subject research activities.

Jurisdiction of the University of Pittsburgh IRB

The University of Pittsburgh’s HRPP has jurisdiction over human subject research projects that meet the following criteria:

• Conducted by University of Pittsburgh faculty, staff, or students regardless of funding source and/or the location at which the research will be conducted.
• Conducted within the facilities of the University of Pittsburgh by outside investigators. Note that the University of Pittsburgh does not permit an individual outside of the institution to be named as the principal investigator of a study.
• Conducted utilizing the private records of the University of Pittsburgh.
• Conducted in any UPMC owned, operated, or controlled domestic facility or program and/or by any UPP member and/or by any UPMC employee of any UPMC nonprofit corporations, program or facility.

Research not falling under the jurisdiction of the IRB is outlined in points 1, 2, and 4 below.

1. VA Pittsburgh Healthcare System (VAPHS)

   The University of Pittsburgh executed (May 2005) a revised Memorandum of Understanding (MOU) with the VAPHS which outlines the IRB review and approval requirements for human subject research studies that are jointly subject to oversight by the IRBs of these institutions.

   In brief, the VAPHS IRB serves as the IRB-of-Record for all human subject research studies in which:

   • a VAPHS staff member or University faculty member is the principal investigator or a co-investigator of the study; the research is conducted using only VAPHS records and/or research subjects are recruited through the VAPHS;
   • no University or UPMC facilities are engaged in the conduct of the research; and
   • no University funds are expended in direct support of the research.

   All other instances of research involving University of Pittsburgh and VAPHS resources is subject to review by both institutions’ respective IRBs. Additional details can be found in the MOU http://www.irb.pitt.edu/FWA/VA%20Agreement.pdf.

2. UPMC Office of Sponsored Programs and Research Support (OSPARS)

   Effective August 24, 2004, as amended November 1, 2008, the University of Pittsburgh and the University of Pittsburgh Medical Center (UPMC) entered into an agreement whereby, with certain limited exceptions, all industry-initiated and sponsored clinical trials conducted within the facilities of UPMC or University of Pittsburgh Physicians (UPP) by University faculty or staff, who are also UPMC or UPP staff members, became the responsibility of UPMC, and will be processed through the UPMC OSPARS. Therefore, industry-initiated and sponsored clinical trials conducted by University faculty and staff and subject to the terms of this agreement are not part of the University of Pittsburgh’s HRPP.

3. Affiliated Institutions

   UPMC Institutions

   Through an IRB Designation agreement dated December 15, 2003, as amended August 24, 2004, the UPMC has delegated authority to the University of Pittsburgh IRB to review initially and periodically and to approve, require modifications to , and/or disapprove all human subject research conducted at domestic UPMC or UPP facilities, by UPMC or UPP staff and/or with the private records of the UPMC or UPP with the exception of industry-sponsored clinical trials processed through the UPMC OSPARS.

   Magee Women’s Research Institute (MWRI)

   Through a collaborative agreement dated April 1, 2004, the MWRI has delegated authority to the University of Pittsburgh IRB to review initially and periodically and to approve, require modifications to and/or disapprove all human subject research conducted in MWRI facilities, by MWRI staff, or with the private records of the MWRI.

4. NCI Central IRBs

   Effective July 2006, the University of Pittsburgh designated the National Cancer Institute (NCI) Central Institutional Review Board (CIRB) as the IRB of Record for:

   • Adult Cancer Cooperative Group Phase III Trials
   • Pediatric Cancer Cooperative Group Phase II and III Trials

   For details surrounding this review process, please refer to Section XXII.

The Principal Investigator (PI) is ultimately responsible for assuring compliance with applicable University IRB policies and procedures, DHHS Federal Policy Regulations, and FDA regulations and for the oversight of the research study and the informed consent process. Although the PI may delegate tasks to members of his/her research team, s/he retains the ultimate responsibility for the conduct of the study.

Who May Serve as a Principal Investigator

Because PI responsibilities involve direct interaction and supervision of the research team, the PI must be a current employee or student of the University and/or UPMC who is operating within their University or UPMC role to oversee the conduct of the study. PIs leaving the institution are responsible for notifying the IRB well in advance of their departure so that they can make arrangements to either close the study or name another appropriately qualified individual currently at the institution to serve as the PI.

The following individuals may serve as PI:

• Faculty members: All categories of faculty members may serve as PI if their School allows them to serve as Principal Investigator on applications for sponsored funding administered through the University. Adjunct faculty of the University, including lecturers and instructors, are not permitted to serve as a PI or Faculty Mentor but may serve as co-investigator.
• Staff: Other University, UPMC, or UPP staff may serve in this role if they have appropriate qualifications to conduct the research and if they have obtained approval to conduct the research from their immediate supervisor.
• Students: Students may serve as principal investigators for their own research projects and are responsible for submitting the IRB application. However, when a student is listed as the PI, a faculty mentor must be listed on the protocol submission.
  
  Note:The IRB reviews and holds student research projects to the same standards as human subject research conducted by faculty or staff. IRB approval or exemption must be obtained prior to initiating any research activity under IRB oversight. “Retroactive” IRB approval or exemption is not permitted under federal regulations and University policy. Failure to obtain IRB approval for research with human subjects may preclude the use of the previously collected data and could result in other institutional sanctions.

General Responsibilities of Principal Investigators

As a general condition for the approval of a research study, the IRB holds the principal investigator of the study mutually responsible for ensuring that:

• risks to research subjects are minimized by using procedures which are consistent with sound research design and which do not unnecessarily expose the subjects to risk; and, whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes;
• risks to human research subjects are reasonable in relation to the anticipated benefits (if any) to the individual, and the importance of the knowledge that may be expected to result;
• selection of human subjects and patients for research participation is equitable;
• individuals are adequately informed of the risks and benefits of research participation and the procedures that will be involved in the research, and that informed consent will be obtained from each prospective human research subject, or his/her legally authorized representative, in accordance with, and to the extent required, by University policies and federal regulations;
• informed consent of human research subjects will be obtained in advance of research participation and appropriately documented in accordance with, and to the extent required, by University policies and federal regulations;
• where appropriate, there is routine monitoring of the data collected to the ensure the safety of human research subjects;
• the privacy of human research subjects is protected and the confidentiality of data is maintained;
• appropriate additional safeguards are included in the study to protect the rights and welfare of human research subjects who are likely to be vulnerable to coercion or undue influence (e.g., children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons).

Specific Responsibilities of Principal Investigators

The IRB holds the principal investigator and co-investigators of an approved research study responsible for:

• promptly responding to all requests for information or materials solicited by the IRB Office, including the timely submission of the research study for IRB renewal;
• ensuring that adequate resources and facilities are available to carry out the proposed research study;
• abstaining from enrolling any individual in a research study (i) until such study is approved in writing, by the IRB; (ii) during any period when the IRB or sponsor/principal investigator has suspended study activities; or (iii) following IRB- or sponsor/principal investigator-directed termination of the study;
• ensuring that all associates, colleagues, and other personnel assisting in the conduct of the research study are appropriately informed of (i) the study procedures; (ii) informed consent requirements; (iii) the potential adverse events associated with study participation and the steps to be taken to reduce potential risks; (iv) adverse event reporting requirements; and (v) data collection and record-keeping criteria;
• conducting the study in strict accordance with the current IRB-approved research protocol except where a change may be necessary to eliminate an apparent immediate hazard to a given human research subject;
• reporting promptly to the IRB Office any deviations from the currently approved research protocol;
• requesting IRB approval of any proposed modification to the research protocol or informed consent documents prior to implementing such modifications;
• obtaining prospectively and documenting informed consent in accordance with the current IRB-approved informed consent documents (i.e., unless the IRB has granted a waiver of the consent process) maintaining adequate, current, and accurate records of research data, outcomes, and adverse events to permit an ongoing assessment of the risk/benefit ratio of study participation;
• reporting promptly to the IRB (and, if applicable, the sponsor and FDA) any internal or external adverse event that is considered to be 1) unexpected; 2) serious) and 3) possibly or definitely related to the study;
• reporting promptly to the IRB any significant changes in the risk/benefit of study participation;
• ensuring that, in the event a research subject experiences a significant adverse event, every reasonable effort is made to provide the subject with adequate care to correct or alleviate the consequences of the adverse event to the extent possible;
• ensuring that human research subjects are kept fully informed of any new information that may affect their willingness to continue to participate in the research study;
• ensuring that all listed investigators have the appropriate credentials to conduct the portion of the study in which they are involved;
• ensuring that conduct of the research study adheres to Good Clinical Practice guidelines, if applicable. If the study is regulated by the FDA, ensuring that all research investigators and coordinators have completed the Good Clinical Practices training required by the University IRB.

Institutional Official

The Chancellor, University of Pittsburgh, has delegated authority and responsibility for the University’s human research protection program to the Vice Chancellor for Research Conduct and Compliance (i.e., the Institutional Official).

The IRB and IRB Office are managed as determined by the Institutional Official. Management on a day-to-day basis is carried out under the direction of the IRB Chair, Director of the IRB Office, and administrative/management staff operating under broad delegated authority from the Institutional Official.

The Institutional Official ensures that adequate facilities, equipment, and resources are available to support the IRB-related activities of the IRB Chair, IRB Vice Chairs, Director of the IRB Office, and IRB Office staff. The Institutional Official is also responsible for approving organizational relationships with other institutions or sites (e.g., hospitals) wherein the human subject research activities of University faculty, students or staff or UPMC staff may or will be conducted.

The IRB reports to the Institutional Official through the IRB Chair. The IRB Office reports to the Institutional Official through the Research Conduct and Compliance Office.

Appointment of IRB Chair, Vice Chairs and IRB Director

The IRB Chair, IRB Vice Chairs, and Director of the IRB Office will be appointed by the Institutional Official.

1. In appointing the IRB Chair, IRB Vice Chairs, and Director of the IRB Office; primary consideration will be given to current or past members of the IRB.
2. The IRB Chair and IRB Director should be highly respected individuals fully capable of managing the IRB and the matters brought before it with fairness and impartiality. The task of making the IRB a respected part of the institutional community will fall primarily on the shoulders of these individuals.
3. Vice Chairs are appointed based on previous experience as an IRB member and/or past experience in the conduct of human subject research.
4. The terms of appointment of the IRB Chair, IRB Vice Chairs, and Director of the IRB Office are indefinite.

Responsibilities of the IRB Chair

The IRB Chair will hold leadership responsibility for IRB review and approval of human subject research in accordance with current guidelines, institutional policies, and federal and state regulations governing human subject protections. In addition, the IRB Chair will:

• oversee the recruitment, orientation, continuing education and retention of IRB members;
• oversee the development and implementation of appropriate policies, procedures and guidelines directed at human subject protections and the functions and activities of the IRB. The IRB Chair is responsible for reviewing the IRB’s policies and procedures for currency, accuracy and consistency on an ongoing basis but not less than every three years. Ad hoc committees will be formed to review guidance issued by regulatory agencies to determine whether updates to the policies and procedures are required;
• reside over IRB Executive Committee (Committee F) meetings;
• communicate IRB Executive Committee (Committee F) decisions, directives, and sanctions relating to known or suspected problems in the conduct of human subject research to involved investigators;
• have authority to request audits of human subject research activities;
• have the authority to suspend some or all research activities if exceptional human subject safety issues are identified. (Note that this authority is only exercised if an action is required prior to a convened meeting and it is not feasible to assemble an emergency meeting) When this authority is exercised, it will be reported at the next convened University IRB meeting;
• represent the IRB in interactions related to issues surrounding the ethical and regulation-compliant conduct of human subject research; such interactions involving:
  • University and UPMC investigators
  • University and UPMC administrators
  • University deans, department chairs, division or center directors
  • other University and UPMC committees and offices involved in the oversight of human research studies
  • applicable federal and state regulatory agencies.
• approve written correspondence to state and federal regulatory agencies having jurisdiction over human subject research prior to final approval and signature of the Institutional Official;
• represent the IRB at national and local meetings related to institutional review board activities and human subject protections.

All deans, department chairs, program directors, and/or other unit administrators of the institutional sites that fall under the authority of the IRB are responsible for ensuring that the human subject research activities of faculty, staff and students under their span of responsibility are carried out in compliance with IRB guidelines and directives. These individuals take direction from the IRB Chair in fulfilling these responsibilities.

All research investigators involved in the conduct of human subject research that falls under the authority of the IRB take direction from the IRB Chair.

The IRB Chair receives support in the performance of his/her responsibilities from the IRB Vice Chairs, the Director of the IRB Office, legal counsel to the IRB, the IRB Office staff and the Co-Director of the RCCO.

Responsibilities of the IRB Vice Chairs

A sufficient number of IRB Vice Chairs will be appointed to provide adequate support to the IRB Chair. The number of IRB Vice Chairs will be determined by the IRB Chair and Institutional Official based on the current number of IRB committees and volume of IRB submissions qualifying for administrative (i.e., expedited) IRB review versus full board consideration.

The primary responsibilities of the IRB Vice Chairs are to the assist the IRB Chair in the:

• leadership responsibility for IRB review and approval of human subject research studies in accordance with current guidelines, institutional polices, and federal and state regulations governing human subject protections;
• recruitment, orientation, continuing education and retention of IRB members;
• development and implementation of appropriate policies, procedures and guidelines directed at human subject protections and the functions and activities of the IRB.

In addition, vice chairs are to serve as voting members of the IRB. They are also expected to represent the University of Pittsburgh at national and local meetings related to IRB activities and human subject protections.

Responsibilities of the IRB Director

The IRB Office Director provides day to day oversight of the operations of the IRB Office. In addition, the IRB Director is also responsible for assisting the IRB Chair in:

• the development and implementation of appropriate policies, procedures and guidelines directed at human subject protections and the functions and activities of the IRB;
• interactions related to issues surrounding the ethical and regulatory-compliant conduct of human subject research; such interactions involving:
  • University and UPMC investigators
  • University and UPMC administrators
  • University deans, department chairs, division or center directors
  • other University and UPMC committees and offices involved in the oversight of human research studies
• the drafting of written correspondence to state and federal regulatory agencies having jurisdiction over human subject research activities.

The IRB Director serves as a member of the IRB Executive Committee (Committee F) and is also expected to represent the University of Pittsburgh at national and local meetings related to IRB activities and human subject protections.

The Director of the IRB Office is also responsible for the employment and termination of IRB Office staff.

Evaluation of Chair

The IRB Chair is evaluated on an annual basis by the Institutional Official. The basis for this evaluation includes, but is not limited to, the Chair’s knowledge and consistent application of the ethical principles of the Belmont Report and the federal regulations and IRB policies governing human subject protections; the Chair’s responsiveness to the concerns of IRB committee members; the Chair’s ability to interact constructively with and to manage the activities of the IRB Vice Chairs; the Chair’s ability to manage the efficient and effective conduct of IRB committee meetings; and the Chair’s ability to interact with and achieve the respect of human subject investigators.

Evaluation of Vice Chairs

The IRB Vice Chairs are evaluated on an annual basis by the IRB Chair. The basis for this evaluation includes, but is not limited to, the Vice Chair’s knowledge and consistent application of the ethical principles of the Belmont Report and the federal regulations and IRB policies governing human subject protections; the Vice Chair’s responsiveness to the concerns of IRB committee members; the Vice Chair’s ability to manage the efficient and effective conduct of IRB committee meetings and post meeting activities; and the Vice Chair’s ability to interact with and achieve the respect of human subject investigators.

Evaluation of IRB Director

The IRB Director will be evaluated on an annual basis by the Institutional Official and the Co-Director of the Research Conduct and Compliance Office. The basis for this evaluation includes, but is not limited to the Director’s knowledge and consistent application of the ethical principles of the Belmont Report and the federal regulations and IRB policies governing human subject protections; the Director’s responsiveness to the concerns of investigators, management of the IRB office and ability to meet annual goals established for the IRB Office.

Evaluation of IRB Staff

The IRB Office staff will be evaluated per polices of the University of Pittsburgh Department of Human Resources.

Compensation of the IRB Leadership

The IRB Chair, IRB Vice Chairs, and Director of the IRB Office will be compensated for their IRB duties and responsibilities. The rate of compensation is at the discretion of the Institutional Official and will take into account the professional background of the individual and the expected time commitment of the appointed position to IRB activities.

The compensation of IRB Office staff is determined by the IRB Chair and Director of the IRB Office in accordance with University policies.

Indemnification

University Policy 07-06-06 sets forth the conditions under which indemnification and legal defense may be available to faculty and staff. Indemnification may be afforded to the IRB Chair, IRB Vice Chairs, Director of the IRB Office, and IRB Office staff as set forth in that policy.

Termination of IRB Chair, Vice Chairs and IRB Director

Only the Institutional Official has the authority to terminate the appointment of the IRB Chair, IRB Vice Chairs, or Director of the IRB Office.

Termination of appointment (i.e., by the Institutional Official) or resignation of appointment by the IRB Chair, IRB Vice Chairs, or Director of the IRB Office shall be subject to a minimum of 3 months advanced notice unless extenuating circumstances exist.

Sufficient Number

The IRB is comprised of a sufficient number of standing IRB committees so as to permit the adequate, appropriate and timely review of human subject research activities that fall under its authority.

There will be a minimum of one IRB committee meeting each week of each month with the exception of those weeks that the University is closed due to a holiday. IRB members and investigators are provided, in advance, with a schedule of the dates of IRB committee meetings for the calendar year.

Each IRB committee has delegated legal authority to function as a separate IRB under common administration and direction of the IRB Chair, IRB Vice Chairs, Director of the IRB Office, and legal counsel to the IRB.

Should exigent circumstances arise, the IRB Chair may request the formation of a special IRB committee. The special IRB committee must be comprised of a minimum of 10 members or alternate members of the standing IRB committees and must meet all of the requirements for IRB committee membership as addressed under Section VII of these policies.

The IRB Executive Committee (Committee F)

The IRB Executive Committee (Committee F) is a fully constituted IRB comprised of the following voting members: the IRB Chair, the IRB Vice Chairs, the Director of the IRB Office, Assistant Director of the IRB (nonscientific member), IRB Adverse Event Coordinator, one Full Board Research Review Coordinator, and at least one nonscientific member and one non-affiliated member. Consultants to the Committee include: Legal Counsel of the University of Pittsburgh and the UPMC, representatives from the Education and Compliance Office for Human Subject Research and the Co-Director of the Research Conduct and Compliance Office.

The IRB Executive Committee is responsible for decisions, directives and sanctions related to known or suspected problems in the conduct of human subject research. This body is also responsible for the development and implementation of appropriate policies, procedures and guidelines directed at human subject protections and the functions and activities of the IRB.

Subcommittees and Task Forces

The IRB, IRB Chair, or an IRB Committee may form subcommittees/task forces on an ad hoc basis to address various specific issues related to the use of human subjects in research and human subject protections.

Psychosocial Advisory Committee

The Psychosocial Advisory Committee was formed to serve as a liaison between the IRB and investigators in the Provost’s area schools as well as others engaged in psychosocial research. The Committee is comprised of five to seven members selected jointly by the Vice Provost for Research and the Vice Chancellor for Research Conduct and Compliance. Members should be faculty or staff actively engaged in psychosocial research and in good standing with the IRB and RCCO. This Committee will meet at the discretion of the Committee chair.

Composition of IRB

1. Each University of Pittsburgh (UOP) IRB Committee will be comprised of at least ten (10) members, with varying background and expertise to provide complete and thorough review of research activities commonly conducted by the Institution.
2. The membership of the IRB will be sufficiently qualified through the experience and expertise of its members and the diversity of its members, including consideration of race, gender, and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of human research subjects.
3. Each IRB committee includes persons able to ascertain the acceptability of the proposed research in terms of institutional commitments and regulations, applicable law, and standards of professional conduct and practice.
4. Each IRB committee includes both men and women.
5. Each IRB committee includes members of more than one profession.
6. Each IRB committee includes at least one member who represents the perspective of research participants.
7. Each IRB committee includes at least one member whose background is primarily related to the biomedical sciences, at least one member whose background is primarily related to the psychosocial sciences, and at least one member whose concerns are of a nonscientific nature (i.e., “non-scientific member”).
8. Each IRB committee includes at least one member who is not otherwise affiliated with the University of Pittsburgh, UPMC, CHP, UPMC Cancer Centers, or Magee, and who is not part of the immediate family of a person with such affiliation (i.e., “unaffiliated member”).
9. Regardless of the risk level associated with the protocol, research funded by the National Institute on Disability and Rehabilitation that purposefully requires inclusion of children with disabilities or individuals with mental disabilities will be reviewed by at least one individual who is primarily concerned with the welfare of these research subjects. This representative will have the appropriate scientific or scholarly expertise to serve in this capacity. If this is full board review, a member of the committee will serve in this capacity as a primary or secondary reviewer. In the absence of an appropriate reviewer, the IRB will identify a consultant to serve in this role. This will be documented in the minutes generated by the Full Board RRC. If the study meets an expedited review category, an appropriate consultant will review the protocol. This will be documented on the Documentation Form generated by the EERRC.

Alternates

The UOP IRB maintains an OHRP roster of trained alternates who may vote in place of an absent voting member. In addition, all active members listed on the OHRP rosters may be utilized as alternates for other active members as long as all applicable regulatory requirements and IRB policies are met. OHRP has been notified of this policy through correspondence sent on June 30, 2005.

1. The alternate member will have similar expertise as the regular committee member for whom s/he is serving as a replacement (physician to physician; other scientific to other scientific; and non-scientific to non-scientific).
2. The alternate member will assume all of the responsibilities of the committee member for whom s/he is serving as a replacement.
3. Alternate members may attend IRB meetings without serving as a replacement for a regular committee member; however, in this capacity, the alternate member may not participate in any of the final approval decisions of the committee.
4. IRB minutes will document if a member present at the meeting is an alternate as well as the IRB member for whom the alternate is substituting.

Consultants

During initial review (at the time of meeting assignment, RRC review, vice chair review, or primary reviewer review) of a proposed research study, an IRB committee member or an IRB staff member may determine that the current membership of the IRB does not include appropriate expertise to conduct an adequate study evaluation and may defer to another IRB committee or may invite individuals with competence in special areas to assist in the review.

1. Consultants may be chosen from past IRB members or by contacting the department chair or division chief of the area from which the research is being submitted.
2. Consultants will be provided with a copy of the IRB protocol and consent document as well as any attachments (investigator brochures, multicenter protocols, etc.) prior to the IRB meeting.
3. Consultants are held to the same standards as regular members of the IRB Committee.
4. Consultants may attend the meeting to participate in the review and discussion of the research study; however, s/he may not vote or count towards quorum.
5. If the consultant is unable to attend the meeting, his/her written comments will be taken into consideration by the Committee during its review of the respective research protocol and will be documented in the IRB meeting minutes.
6. During the review of a proposed research study, an IRB committee member may obtain consultations by directly contacting colleagues for information related to a research study. Before obtaining advice from a consultant in this manner, the IRB committee member should ensure that the colleague does not have a conflict of interest with the research study (Conflict of Interest Policies are addressed in Section XVIII).

Appointment of IRB Members

Appointments of voting IRB Committee members are made by the Institutional Official (IO). Recommendations for board members can be made to the IO by either the IRB Chair or IRB Membership Coordinator based on the specific needs of the IRB Committee (e.g. medical specialty, diversity, non-scientific, non-affiliated, etc.).

• The IRB Chair or his designee requests recommendations for faculty volunteers from the Division Chiefs and Department Chairs as needed based on considerations including, but not limited to, required committee composition, expertise and experience; knowledge of the individual’s interest; recommendations of institutional leadership; and/or investigators involved in research studies currently or previously approved by the IRB.
• The IRB Chair or his designee reviews the membership rosters and recommends appointment by the Institutional Official of potential non-scientific and/or non-affiliated members to the IRB based on considerations including, but not limited to: required committee composition, expertise and experience, knowledge of the individual’s interest; recommendations of current or past non-scientific and/or non-affiliated members; and individuals recruited from disease-related organizations or groups.
• The IRB Chair and membership coordinator will review each new member’s CV and demographic sheet for educational background, work history, as well as his/her current vocation to determine the member’s status (i.e., scientific versus non-scientific, affiliated vs. non-affiliated) on the IRB rosters. Refer to Section XIX – Record Keeping and Retention.

Term of Service

Committee members are initially appointed to a term of three years. Committee members may be requested to accept reappointment to the IRB for an additional term of three years at the discretion of the Chair. At the end of the six year term, a determination will be made about an additional reappointment period. If a member declines full membership, s/he may be asked to become an alternate member. Reappointed members will be asked for an updated CV and demographic sheet.

Compensation of IRB Members

Affiliated IRB Committee members do not receive any direct monetary compensation for participation on the board. Unaffiliated IRB Committee members will be reimbursed at an amount not to exceed $50 per month to pay for internet access. Reimbursement payments will be issued quarterly.

Indemnification

University Policy 07-06-06 sets forth the conditions under which indemnification and legal defense may be available to faculty and staff. University Policy 07-06-07 sets forth the conditions under which indemnification and legal defense may be available to volunteers at the University. Indemnification may be afforded to the IRB members as set forth in these policies.

Responsibilities of IRB Members

General Responsibilities of all IRB Members include:

• Reviewing research study proposals and evaluating them from the perspective of the regulatory criteria for approval addressed under 45 CFR 46.111, 21 CFR 56.111 (if applicable); and any other relevant ethical, scientific or compliance considerations;
• Reviewing informed consent documents and evaluating them from the perspective of addressing the required and additional elements of informed consent addressed under 45 CFR 46.116, 21 CFR 50.20 (if applicable) and any other relevant ethical or compliance considerations;
• Attending at least 70% of IRB meetings in person, unless exigent circumstances prevent such attendance on an occasional basis; reporting promptly at the designated time that the meeting convenes; and remaining in attendance at the meeting until the full agenda has been addressed;
• Participating in IRB deliberations concerning issues inherent to proposed research studies and related informed consent documents, and making recommendations for reducing risk and improving the informed consent process and otherwise for improving human subject protections;
• Voting for full approval, approval subject to modification(s), reconsideration, or disapproval of the human subject research as outlined in Section XII;
• Evaluating the risk level (i.e., minimal or greater than minimal) of the proposed research. In performing this evaluation, IRB members will use the following absolute definition for "minimal risk" at 45 CFR 46.102(i) unless the research is directed at prisoner-subjects:
  "Minimal risk means that 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 (i.e., of the general population) or during the performance of routine physical or psychological examinations or tests."
• Deciding, for research studies of greater than minimal risk, if IRB continuing review of the research is warranted on a more frequent basis than the requisite annual review. In making this determination, IRB members will follow the procedure outlined in Section XII;
• Deciding, for research studies involving greater than minimal risk, complexity, or conflict-of-interest concerns, if the informed consent process and/or other aspects of the research study should be audited by the Education and Compliance Office of the University of Pittsburgh’s RCCO;
• Deciding, for research studies involving an unapproved device, if the device and its proposed use constitute a non-significant or significant risk to research subjects;
• Deciding, for research studies subject to IRB continuation approval, if verification is required from sources other than the investigator that no material changes have occurred since previous IRB review using the criteria outlined in Section XII;.
• Recommending improvements to IRB policies and procedures so as to enhance the IRB review process and/or human subject protections;
• Informing the IRB Chair or an IRB Vice Chair of human subject research noncompliance problems or ethical issues of which they become aware;
• Conforming, at all times, their behavior to be within legal and ethical principles accepted by the IRB; including, but not limited to, maintaining confidentiality/non-disclosure of human subject research submitted for IRB review and approval, and good faith participation in IRB deliberations without appearance of discrimination or conflict-of-interest.

Responsibilities of IRB Members Designated Reviewers

In addition to the responsibilities outlined above, responsibilities of those assigned as reviewers include:

• Providing written evaluations of the research protocol and informed consent document(s) to the IRB Office staff either on paper or through the OSIRIS system in advance of the IRB meeting;
• Utilizing the IRB Reviewer Checklist as a guide when reviewing protocol submissions;
• Basing their review and approval decisions for industry-sponsored clinical trials on the information presented in the sponsor’s clinical protocol and investigator’s brochure and IRB research application;
• Ensuring that for federally-supported research requiring full board IRB review that the IRB research application is essentially consistent with the corresponding federal grant application.

IRB Roster

The IRB membership roster will include the following information and will be used to determine relevant expertise in making protocol assignments at convened meetings:

• Names of members;
• Earned degrees;
• Representative capacities;
• Scientific/nonscientific status
• Affiliation status (whether the IRB member or an immediate family member of the IRB member is affiliated with the organization)Indications of experience sufficient to describe each IRB member’s chief anticipated contributions;
• Employment or other relationship between each IRB member and the organization;
• Alternate members including the primary members or class of primary members for whom each alternate can substitute.

The IRB Membership Coordinator is responsible for submitting an updated membership roster to OHRP at the beginning of each month or more often based on necessity. The IRB Membership Rosters are posted on the IRB website at www.irb.pitt.edu/committees.

Evaluation of Committee Members

The IRB Chair, Vice Chairs and senior IRB staff meet monthly to discuss the conduct of IRB Committee meetings and the performance of IRB membership.

• The performance of committee members is discussed with respect to their awareness and understanding of relevant ethical issues, regulations, and institutional policies. If concerns are identified, the IRB Chair and/or Vice Chairs will address these with the individual committee member and then provide necessary guidance materials or educational sessions.
• IRB coordinators will interact with the Vice Chair to provide feedback on member performances. If concerns are identified, the IRB Chair and/or Vice Chairs will address these with the individual committee member and then provide necessary guidance materials or educational sessions.
• Attendance of the members will be monitored by the membership coordinator. Any issues that arise related to non-attendance will be discussed with the IRB Chair to determine whether action is necessary. Attendance reports will be sent to the members’ responsible department chairs or center/institute director at their request.

Resignation and Termination of IRB Members

Resignation of IRB membership status, based on the wishes of the IRB member, will be submitted, in writing, to the Institutional Official and copied to the IRB Chair and, where applicable, the member’s department chair or center/institute director.

IRB Membership status may be terminated by the IRB Chair due to failure to attend and/or otherwise actively participate in IRB functions. Termination of any individual from IRB membership will be reported to the Institutional Official to include a written justification for the termination.

Assignment of IRB Number

New Protocols

All new protocols are required to be submitted through the OSIRIS system. IRB numbers are assigned by the system with the prefix “PRO.” The number assigned reflects the year and month of submission with consecutive numbers thereafter (e.g., PRO10060008 would mean the protocol was submitted in June 2010 and was the 8th protocol submitted in the month).

Renewals

Renewals that are currently being reviewed in a paper format will retain the number originally assigned with the addition of a four digit suffix to indicate the most recent date (i.e., year/month) of IRB continuation approval (e.g., 0603107-1003 for IRB continuation approval of this research granted in March 2010).

Renewals that are eligible to be submitted through the OSIRIS system will be assigned a different IRB number with the prefix “REN.” The number assigned reflects the year and month of submission with consecutive numbers thereafter (e.g., REN10050003 would mean that the renewal was submitted in May 2010 and was the 3rd renewal of the month). The original number assigned will also remain with the submission and will be reflected on all correspondence generated for the renewal.

Modifications

Modifications that are currently being reviewed in a paper format will retain the number originally assigned to the study.

Modifications that are submitted through the OSIRIS system will be assigned the same IRB number as the original study but with the prefix “MOD.” This is because the modification is a copy of the original study. In addition, a suffix will be assigned to the modifications to indicate the sequential number of the modification (MOD0706008-01; MOD0706008-02, etc.) which would indicate that there have been two modifications submitted.

Required Ancillary Reviews

The OSIRIS system is constructed to automatically forward submissions to required ancillary reviews prior to submission to the IRB based on responses from the principal investigator to a series of "smart forms."

Scientific Review

All proposed human subject research are required to undergo scientific review prior to submission for IRB review, with the exception of (i) research qualifying for “exempt” review status; and; and (ii) research reviewed by a peer scientific review committee as a condition of research funding (e.g., NIH/NSF sponsored research).

Regardless of the exceptions cited above, the following types of human research studies MUST undergo unit-specific scientific review prior to the initiation of IRB review:

• Research involving oncology patients or the use of University of Pittsburgh Cancer Institute (UPCI) resources must be approved by the UPCI Protocol Review Committee.
• Research involving psychiatric patients or the use of Western Psychiatric Institute and Clinic (WPIC) resources must be approved by the WPIC Research Committee.
• Research funded by, or using the resources of, the Magee Women’s Research Institute (MWRI) must be approved by the Clinical Research Use Committee of the MWH Clinical Translational Research Center.
• Research funded by the Department of Defense.

Proposed modifications that substantially or materially impact the specific aims and/or design of an IRB-approved study must undergo scientific re-review prior to submission of the modifications for IRB approval.

If the proposed modifications to an IRB approved research study are substantial and numerous, the IRB may require that the research be resubmitted for review as a new research study.

Radioactive Drug Research Committee/Human Use Subcommittee

All proposed human subject research involving the experimental use of procedures that include exposure to ionizing radiation must be reviewed and approved by the Human Use Subcommittee of the University of Pittsburgh Radiation Safety Committee (HUSC), and as applicable, by the University of Pittsburgh Radioactive Drug Research Committee (RDRC) prior to submission for IRB review.

• Modifications to IRB- and RDRC/HUSC-approved research protocols must be submitted for RDRC/HUSC review and approval if the modification involves a change in the number of research subjects or a change that affects the radioactive drug, if applicable, or the subject’s exposure to ionizing radiation.

Institutional Biosafety Committee

All proposed human subject research involving a gene transfer intervention must be reviewed and approved by the Institutional Biosafety (rDNA) Committee (IBC-rDNA) prior to their submission for IRB review.

• Modifications to IRB- and IBC-rDNA-approved research protocols must be submitted for IBC-rDNA review and approval if the modification involves a change in the gene transfer (i.e., rDNA) intervention.

Human Stem Cell Research Oversight Committee (hSCRO)

All proposed human subject research involving stem cell research will be submitted to hSCRO. There are two categories of hSCRO Committee review, i.e. an administrative review and a review by the convened hSCRO Committee. Protocols qualifying for an administrative review are to be submitted to the hSCRO after review and approval by other relevant committees (e.g., IRB, IACUC or rDNA). Protocols not meeting one of the administrative review categories must be submitted for review and approval by the convened hSCRO Committee prior to submission to the IRB.

Conflict of Interest

The Conflict of Interest (COI) Office is required to review and approve through OSIRIS any study that is submitted for IRB review where the investigator indicates that any member of the study team who participates in the design, conduct, or reporting of the research protocol has a reportable conflict. COI management is also required if any researcher’s spouse, registered domestic partner, dependent, or other household members have a reportable conflict. If necessary, the standard Conflict of Interest Management Plan will be implemented to address the conflict (refer to Section XVIII for more information).

Notifications to Other Offices

In addition to the requirements for approval by the Ancillary Review groups described above, the OSIRIS system will provide notifications to the following offices:

Investigational Drug Service (IDS)

The IDS of the UPMC Department of Pharmacy is notified of all proposed human subject research that involves the evaluation of an investigational or approved drug.

Office of Sponsored Programs and Research Support (OSPARS)

All proposed human subject research at UPMC facilities or with UPMC patients involving any of the following will be reviewed and approved by the UPMC Fiscal Review Committee consistent with their policy and procedures:

• the performance of potentially billable procedures or tests;
• the provision of services or hands on care;
• the collection of biological specimens.

If required, OSPARS approval must be in place before research activities may commence within a UPMC facility. The IRB approval letter contains standard language indicating this requirement.

Office for Investigator Sponsored IND and IDE Support (O3IS)

For research studies where there is an investigator-sponsored Investigational New Drug (IND) application or Investigational Device (IDE) application associated with the research, O3IS is notified. This office was established for the purpose of providing assistance to University researchers involved in the development and submission of investigator-sponsored Investigational New Drug (IND) applications and Investigational Device Exemptions (IDEs) for acceptance by the U.S. Food and Drug Administration (FDA) and the conduct of clinical research studies under such FDA-accepted applications and exemptions.

Clinical and Translational Research Center (CTRC)

For research studies where investigators indicate that CTRC resources will be utilized for research study procedures, the staff at the CTRC receives a notification from the OSIRIS system.

Exceptions to Ancillary Review Approvals

Exceptions to ancillary review approvals/notifications may be granted by the IRB Chair or his/her designee. If an exception is granted, final IRB approval will not be granted until approvals/notifications from all applicable committees are submitted.

Verification of Training Requirements

All investigators and key personnel involved in Human Subject Research (including Faculty Mentors) are required to complete specific research ethic courses using the CITI training program. Only those individuals who have completed the required training are permitted to conduct human subject research or to access OSIRIS (IRB on-line application). The courses are designed for three user groups: biomedical researcher (includes all health science students), social and behavioral researcher, and undergraduate student researcher. At a minimum, all users must completed courses in Human Subjects Protections and Responsible Conduct of Research. Go to www.citi.pitt.edu for more information and to access the courses. If you have any questions, email us at irb@pitt.edu.

Good Clinical Practice Module

All principal investigators, listed co-investigators and study coordinators will be required to complete the Good Clinical Practice module if the study that is being conducted is FDA-regulated. The principal investigator is required to maintain documentation that all members of the research team have completed the GCP module. At the time of audit or a monitoring visit, investigators may be asked to produce the documentation. If documentation is not provided at that time, this may result in a finding of serious or continuing non-compliance by the IRB.

The IRB considers research to be FDA regulated if it falls under sections 505 (New Drug Application) or 520 (Devices intended for human use) of the Federal Food, Drug, and Cosmetic Act (the Act), as well as clinical investigations that support applications for research or marketing permits for products regulated by the FDA, including food and color additives, drugs for human use, medical devices for human use, biological products for human use, and electronic products.

Research involving the "off-label" use of FDA-approved drugs is also considered FDA regulated if any of the following three conditions exists:

• The research is intended to be reported to the FDA in support of a new labeling indication for the drug or to support any other significant change in the labeling of the drug, or
• the research is intended to support a significant change in the advertising for the drug, or
• the research involves a route of administration or dosage level, use in a subject population, or other factor that significantly increases (i.e., compared to the FDA-approved indication for use of the drug) the risks (or decreases the acceptability of the risks) associated with the use of the drug.

If the off-label use of a marketed device is intended to be solely the practice of medicine and no research is being done, IRB review is not required. If, however, the off-label use of a medical device is part of a research project involving human subjects, the investigator must provide an IDE number or a justification as to why the use of the device constitutes a non-significant risk to the involved research subjects.

Historical Review

For renewals and modifications submitted in paper format, the IRB file for research will be reviewed by an IRB member designated by the IRB Chair to ensure that the most current version of the research protocol with all modifications included and informed consent documents were submitted and that no outstanding issues or deficiencies exist. This review will be documented on the Checklist – IRB Office Review of Protocol Files.

For renewals and modifications submitted through the OSIRIS system, only the most current version is available and therefore a historical review will only be conducted on the consent documents uploaded into the system as a Word document.

Maintenance of IRB Database

For paper submissions, the IRB Office staff maintains a database that includes, at a minimum the following fields: the IRB number assigned to the submission, principal investigator’s name, co-investigators names, title of the research, contact information, and IRB approval dates.

The OSIRIS system serves as a database and includes all information related to the individual projects submitted through the system.

Calculation of Initial Approval Date

The IRB calculates the date of initial IRB approval in the following manner:

• When a research study is approved at a convened meeting, the date of the convened meeting is the date of IRB approval.
• When the research study is approved subject to modifications at a convened meeting, the date of IRB approval is the date that the requested changes are verified by the Chair, Vice Chair, or his/her designee.
• When a research study is reviewed and approved through an expedited review process, the date that approval is extended by the Chair, Vice Chair, or his/her designee is the date of IRB approval.

Calculation of Expiration Date

Initial Approval

The IRB calculates the date of expiration in the following manner:

• When a research study is fully approved at a convened meeting, the date of expiration is based on the date of the convened meeting (minus one day). For example, if the committee meeting date is 10/17/10, then the date of IRB expiration is 10/16/11 for an annual approval or 4/16/11 for a six month approval.
• When a research study is approved subject to modifications, the date of expiration is one year from the date of the convened meeting (minus one day). It is not calculated from the date that the Chair, Vice Chair, or his/her designee verifies the requested changes and grants final approval. For example, if the committee approves a research study subject to modifications on 10/17/10 and the response is verified by the Chair, Vice Chair, or his/her designee on 10/20/10, then the date of IRB approval is 10/20/10 and the expiration is 10/16/11 for an annual approval or 4/16/11 for a six month approval.
• When a research study is reviewed and approved by expedited review, the date of expiration is based on the date that the Chair, Vice Chair, or his/her designee verifies any requested changes and grants final approval (minus one day).

The approval period expires at 11:59 p.m. on the date set forth in the IRB approval letter.

Modification Dates

The IRB calculates the date of modification approval in the following manner:

• When a modification is approved through an expedited review mechanism, the modification approval date is the date that the Chair, Vice Chair or his/her designee reviews and approves the modification.
• When a modification is reviewed at a full board meeting and is approved at the meeting, the modification approval date is the date of the IRB meeting.
• When a modification is reviewed at a full board meeting and is approved subject to modifications, the modification approval date is the date that the response is verified by the Chair, Vice Chair, or his/her designee.

Expiration dates are maintained as the date assigned upon initial or continuing review unless the IRB determines that there has been a significant change to the risk/benefit ratio which would require a more frequent continuing review. If this change occurs, the IRB will notify the principal investigator of the study of the new expiration date. The new date must never exceed the original expiration date.

Maintenance of Anniversary Date (Expedited Submissions Only)

OHRP recognizes the logistical advantages of keeping the IRB approval period constant from year to year throughout the life of each project. When continuing review occurs annually and the IRB performs continuing review within 30 days before the IRB approval period expires, the IRB may retain the anniversary date as the date by which the continuing review must occur.

New Information

Throughout the life span of a research protocol, the IRB may determine that currently enrolled subjects need to be notified of new information or significant new findings that alter the risk benefit ratio and may affect their willingness to continue study participation. New information may be presented to research participants via an addendum consent form or a modified consent form (See Section XIII).

Verification from Other Sources

Protecting the rights and welfare of participants sometimes requires that the IRB verify independently, utilizing sources other than the investigator, that no material changes occur during the IRB designated approval period. Additional sources may include: audit by the Education and Compliance Office for Human Subject Research, investigational pharmacy records, incident reports, radiation safety or source documents, as well as information from staff, research participants, families, sponsors or others.

Criteria for determining if verification is required includes, but is not limited to:

• Complex protocols involving unusual levels or types of risks to subjects;
• Protocols conducted by PIs who previously have failed to comply with Federal regulations or the requirements or determinations of the IRB;
• Protocols where concern about possible material changes occurring without IRB approval have been raised based on information provided in continuing review reports or from other sources.

Investigator Communications

Initial Comments from the IRB – General Information

The principal investigator will be notified, in writing, of the IRB’s decision to approve, reconsider, or disapprove the proposed research, or of the modifications required to secure IRB approval of the research study. Comments will be issued to investigators once either the minutes from the full board meeting have been accepted by the IRB Vice Chair, or the comments have been finalized for expedited or exempt submissions. Correspondence will contain, at a minimum:

• the name of the principal investigator;
• the title of the project;
• the IRB number assigned to the submission;
• the decision of the IRB.

Full Board Decisions

The IRB full board decisions will be outlined in the investigator communications as follows:

• Full Approval - If a convened IRB determines that the study can be approved as submitted, the investigator will be issued a full approval letter.
• Approved subject to minor modifications (comments must be directive) - If the IRB decides to approve a research study subject to modifications, the written notification will include the specific revisions stipulated by the IRB in order to obtain full approval to conduct the research.
  • The written notification provides instruction to the investigators to revise the research and informed consent document(s) in accordance with the specific revisions stipulated by the IRB and to resubmit for final IRB approval.
• Reconsideration - If a convened IRB decides to reconsider a research activity, the written notification to the investigator will include:
  • a statement of the primary reason(s) for the IRB’s decision to reconsider the research;
  • a listing of additional problems and/or deficiencies identified by the IRB;
  • instructions relating to resubmission of the research for full-board IRB review, including statements that the principal investigator should address in writing the comments and concerns of the first IRB review and that s/he may appear in person to address additional questions or concerns related to full-board IRB review of the resubmitted protocol.
• Disapproval – If a convened IRB decides to disapprove a research activity, the written notification to the investigator will include:
  • a statement of the primary reason(s) for the IRB’s decision to reconsider the research;
  • a listing of additional problems and/or deficiencies identified by the IRB;
  • instructions relating to resubmission of the research for full-board IRB review, including statements that the principal investigator should address in writing the comments and concerns of the first IRB review and that s/he may appear in person to address additional questions or concerns related to full-board IRB review of the resubmitted protocol.

Exempt/Expedited Submissions

Submissions that are reviewed by the Exempt/Expedited Team can either receive full approval or approval subject to minor modifications. In the event that directive comments cannot be provided or if the study does not meet a regulatory category which would permit an expedited review, the investigator will be notified that the study will be reviewed by the convened IRB.

Investigator Responses

Responses of the principal investigator are returned to the IRB reviewer who conducted the initial review (i.e., or to another IRB reviewer if the initial reviewer will be unavailable for an extended period) for final approval.

In the event of a failure to resolve problems or concerns related to the investigator’s response(s), the IRB submission (to include prior correspondence between the IRB reviewer and investigator) will be reviewed at a convened meeting of an IRB committee (i.e., full-board IRB review).

Response Deadline

The communication to the principal investigator specifies that s/he must respond to the comments or concerns of the IRB reviewer within 6 weeks of the date of the communication, and that failure to respond within this 6-week period may result in withdrawal of the project by the IRB.

Content of IRB Concurrence/Approval

The principal investigator is notified of IRB concurrence/approval through written correspondence prepared and discharged by the IRB Office. All correspondence contains:

• the name of the principal investigator;
• the title of the project;
• the IRB number assigned to the submission;
• the name of the non-conflicted IRB Chair or Vice Chair granting final concurrence/approval;
• the date of IRB approval/concurrence;
• the date of IRB expiration (for expedited and full board studies only) the date of IRB modifications (for modification requests only);
• a statement that modifications to the IRB approved research study will require either notification to the IRB (for no human subjects research or exempt determinations) or approval by the IRB (for expedited or full board studies).

For studies that are designated as “not human subject research” the correspondence will indicate a concurrence that the project does not meet either the definition of "research" at 45 CFR 46.102(d) or "clinical investigation" at 21 CFR 56.102(c), or the definition of "human subject" at 45 CFR 46.102(f) or 21 CFR 56.102(e).

For activities determined by the IRB Reviewer to meet either the DHHS or FDA definition of “human subject research,” the principal investigator will be advised to resubmit the project for exempt, expedited or full-board IRB review as appropriate.

For studies that are designated as "exempt" the correspondence includes the basis for granting exempt status (i.e., 45 CFR 46.101(b)(1-6) and/or 21 CFR 56.104(d)). For research activities that involve human subjects but are determined to not qualify for exempt status, the principal investigator will be advised to resubmit the research for expedited or full-board IRB review as appropriate.

For studies that are approved as "expedited" the correspondence includes the basis for granting expedited approval of the research. This would not only include the minimal risk status of the research, but the applicable category or categories of research activities listed in the OHRP and FDA document, "Categories of Research That May Be Reviewed by the Institutional Review Board through an Expedited Review Procedure". That information is documented, with justification, within the IRB Research Protocol and/or review materials. For research activities that are determined to not qualify for expedited review status, the principal investigator will be advised to resubmit the research for full-board IRB review.

For studies involving the use of a Humanitarian Use Device the correspondence must include the following statement:

"Clinical use of the HUD must be limited to the manufacturer’s product labeling and the clinical protocol approved by the IRB."

Renewal Reminder Notices

For renewals that have been approved in a paper format, the IRB Office will send a reminder notice to the principal investigator and, if applicable, the study coordinator, 60 days and 30 days in advance of the expiration date of IRB approved research studies.

For renewals that have been approved in the OSIRIS system, the system automatically generates an e-mail notification to the principal investigator and, if applicable, the study coordinator, 90, 60 and 30 days in advance of the expiration date of the IRB.

Study Expiration

If the study is not reviewed and approved by the IRB prior to the expiration date of the previous IRB approval, the principal investigator will be required to cease all research activities described in the IRB protocol (including data analysis) until notification of final IRB approval for continuation of the research has been issued. The approval period expires at 11:59 p.m. on the date set forth in the IRB approval letter. The notification sent to the investigator will indicate that: 1) enrollment of new participants must stop; 2) all research activities must stop; and 3) any continuation of research activity is a violation of Federal regulations. The letter also indicates that the investigator may petition the IRB Chair for permission to continue certain research activities if there is an overriding safety concern or ethical issue. However, under no circumstances can new subjects be enrolled into a research study after expiration of IRB approval. In order to preserve the historical integrity of a research study, investigators who want to continue research activities must submit a renewal to the IRB. Research activities may not resume until a new IRB approval has been issued.

Investigator/Sponsor-Initiated Termination or Suspension of a Research Protocol

An investigator may choose to voluntarily suspend or terminate some or all activities of an approved protocol. This should be reported to the IRB and is not considered to be a reportable event unless the IRB independently determines that suspension or termination has occurred because there was an unanticipated problem involving risks to subjects or others or there was a incident of serious or continuing non-compliance.

If a research project is being terminated or suspended by the principal investigator and/or the sponsor based on a change in the risk-to-benefit ratio of study participation, a report should be submitted through OSIRIS within 1 working day of the receipt of the notice.

If the reason for the termination or suspension is for administrative reasons, a report should be submitted through OSIRIS within 10 working days of receipt of the notice. The termination report in OSIRIS requests information including:

• the primary reason for the termination;
• the number of subjects enrolled to date;
• the plan for notifying currently enrolled subjects, if necessary;
• the procedures that will be undertaken to ensure the orderly and safe withdrawal of currently enrolled subjects, if necessary;
• whether there were any unanticipated problems involving risks to subjects or others that were not previously reported;
• whether subjects will be notified of the study results;
• whether the study had been monitored/reviewed/audited by an outside monitor, sponsor, or agency;
• whether the report has been sent to other agencies.

The suspension report in OSIRIS requests information including:

• the primary reason for the suspension;
• the type of suspension (intervention only; all research activities)the number of subjects currently enrolled in the study;
• the procedure that will be undertaken to ensure the safe withdrawal of currently enrolled research subjects, if necessary;
• whether permission is being requested to continue research activities during the suspension period for the safety of currently enrolled subjects;
• whether subjects will be notified of the study suspension;
• whether the report has been sent to other agencies;
• a description of what must occur in order for a request for re-initiation of study activities can be submitted.

When a study is suspended in OSIRIS, all listed investigators and research personnel are notified through the system. In addition, the informed consent documents are no longer displayed on the project page. This is to ensure that new subjects are not enrolled into the study during the suspension.

Investigators who have protocols approved in paper format should follow the format noted above and e-mail the information to askirb@pitt.edu. All reports of termination/suspension are reviewed by the IRB Adverse Events Coordinator within two business days of receipt in the IRB Office. The IRB Chair is responsible for the final disposition of study suspensions/terminations.

For research protocols suspended due to serious adverse events, IRB approval is required to re-initiate the research study. A modification should be submitted in order to request re-initiation. The information submitted should include:

• the outcome of investigations on the causality of the serious adverse event;
• the frequency of occurrence of the serious adverse event at the University or UPMC sites or external sites, if applicable;
• changes to the protocol and/or informed consent document.

Human subjects currently participating in a research study may need to be notified of its termination or suspension. Upon review of the suspension or termination report, the IRB will make a determination about whether this is required as well as the best mechanism for the research team to utilize to make the notification.

In order for the principal investigator to request re-initiation of a suspended study, a modification request must be submitted. For research protocols suspended due to serious adverse events, the modification must address: i) the outcome of investigations on the causality of the serious adverse event; ii) the frequency of the occurrence of the serious adverse event at the University of UPMC sites or external sites, if applicable; and iii) the modifications that are being requested as a result of the serious adverse event.

Reviewer Designation

All such requests are reviewed by the IRB Exempt/Expedited Vice Chairs or a designated IRB member (including Exempt and Expedited Research Review Coordinators).

Provision of Review Materials

The reviewer has access to the complete submission. Submission forms are available at www.osiris.pitt.edu

Criteria for Determination of No Human Subject Research

The IRB Reviewer can make the following determinations:

• The activity does not meet either the definition of research as specified under 45 CFR 46.102 (d) or the definition of clinical investigation as specified in 21 CFR 56.102 (c).
• The activity is research but does not involve human subjects 45 CFR 102 (f) or 21 CFR 56.102 (e).

In making this determination, the following are used as references:

OHRP Decision Chart

The IRB reviewer refers to the OHRP’s decision Chart #1 "Is An Activity Research Involving Human Subjects?"(http://www.hhs.gov/ohrp/policy/checklists/decisioncharts.html.)

FDA Regulations

The IRB reviewer refers to 21 CFR 50.1 (a) for a definition of the scope of clinical investigations regulated by the U.S. Food and Drug Administration. Activities that meet any of the following criteria do not qualify for the "No Human Subject Research Designation."

• Any use of a drug or medical device not approved by the FDA, regardless of the presence of an IND or IDE.
• Any use of a drug in any manner (even if approved and even if used in an activity which does not meet the DHHS definition of research) other than the use of an FDA approved drug in the course of medical practice.
• Any use of a medical device in any manner (even if approved and even if used in an activity which does not meet the DHHS definition of research) other than the use of an FDA approved medical device in the course of medical practice.
• Any use of an FDA regulated item in which the data will be submitted to or held for inspection by FDA.

Investigator Communications

Comments or concerns of the IRB reviewer with regard to a designation of “no human subject research” are documented and communicated via OSIRIS or e-mail to the principal investigator, consistent with the procedures described in Section VIII.

Responses of the principal investigator are returned to the IRB reviewer who conducted the initial review (or to another IRB reviewer if the initial reviewer is not available for an extended time).

Determination that an activity IS NOT Human Subject Research

After reviewing the protocol submission, the IRB reviewer documents his/her determination in OSIRIS. The chair or vice chair reviews the protocol submission along with the IRB reviewer's determination and then makes the final determination surrounding the protocol submission.

The principal investigator of the activity is notified of IRB designation of “no human subject research” in OSIRIS or via email.

The determination letter specifies at a minimum:

• the IRB number assigned to the submission;
• concurrence that the project does not meet either the definition of “research” as defined in 45 CFR 46.102(d) or 21 CFR 56.102(c); or the definition of “human subject” at 45 CFR 46.102(f) or 21 CFR 56.102(e); and
• that the IRB should be notified in advance of any proposed substantive modifications of the activity.

Determination that an activity IS Human Subject Research

The IRB Reviewer may determine that the proposed activity is human subject research because it meets the DHHS definition of research (45 CFR 46.102(d)); and involves individuals who meet the definition of human subject (45 CFR 46.102(f); or meets the FDA definition of clinical investigation as described above.

For activities determined by the IRB Reviewer to meet either the DHHS or FDA definition of “human subject research,” the principal investigator is advised to resubmit the research for exempt, expedited or full-board IRB review, as appropriate.

Reviewer Designation

Research specified by the investigator as qualifying for “exempt” status is reviewed by the IRB Exempt/Expedited Vice Chair and/or a designated IRB member (including Exempt and Expedited Research Review Coordinators). No one may serve as a reviewer if they have a conflict of interest as outlined in Section XVIII.

Provision of Review Materials

The IRB reviewer has access to the complete IRB submission including the following (as applicable):

• OSIRIS protocol application;
• Recruitment materials (e.g., advertisements, flyers, phone screening procedures, scripts, and/or screening questions, etc.);
• measures that will be utilized in the study (e.g. survey instruments, questionnaires, interview scripts, recruitment material, etc. – unless referenced on the IRB website as a standard measure;
• grant application;
• verification of approval from site(s) outside of the University of Pittsburgh or UPMC;
• Other materials specific to the proposed study.

IRB reviewers are expected to conduct an in-depth review of all materials and are provided access to Reviewer Checklists found in OSIRIS as a guide to ensure inclusion of the regulatory criteria (if applicable).

Criteria for Exemption

The IRB reviewer determines if the proposed research is exempt from federal policies governing human subject protections. This determination is made in accordance with:

• The OHRP Decision Chart # 2- "Is the Research Involving Human Subjects Eligible for Exemption under 45 CFR 46.101 (b)?"
• The criteria for exemption as specified under 45 CFR 46.101 (b)(1), (b)(2) and (b)(4) and 21 CFR 56.104(c) and (d). If an investigator wishes to request an exemption under 45 CFR 46.101(b)(3), (b)(5) or (b)(6), s/he is instructed to contact the IRB Office for guidance.
• If subjects are under the age of 18 years, the exemption criteria described in 45 CFR 46.101(b)(2), are not applicable with the exception of research limited to (a) the use of educational tests or (b) to observations of public behavior when the investigator does not participate in the activities being observed.
• For protocols that meet the criteria for an exemption under 45 CFR 46.101(b)(2), investigators are required to provide an introductory script that includes key elements of consent and is consistent with the principles of the Belmont Report.
  • NOTE: The exemption criteria in 45 CFR 46.101 (b) do not apply to studies involving prisoners.
  • The exemption criteria [with the exception of 45 CFR 46.101(b)(6) / 21 CFR 56.104(d)]do not apply to FDA-regulated research studies.

Review of Grant Application

For Federally-supported research, the IRB reviewer will ensure that the research application is essentially consistent with the grant application. This determination is documented as a note in OSIRIS.

Investigator Communications

Comments or concerns of the IRB reviewer with regard to the exempt status of the research activity are documented and communicated in OSIRIS to the principal investigator, as described in Section VIII.

Responses of the principal investigator are returned for review by the IRB reviewer who conducted the initial review (or to another IRB reviewer if the initial reviewer is unavailable for an extended time).

Documentation of Determination

After reviewing the protocol submission, the IRB reviewer documents his/her determination in OSIRIS. The chair or vice chair reviews the protocol submission along with the IRB reviewer's determination and then makes the final determination surrounding the protocol submission.

Determination that Activity Meets the Exempt Criteria

The principal investigator of the research activity is notified of IRB concurrence of exempt status through OSIRIS. This notification letter specifies, at a minimum:

• The IRB number assigned to the submission;
• The regulatory basis for granting exempt status (i.e., 45 CFR 46.101 (b) (1-6) and/or 21 CFR 56.104(d));
• That the IRB should be notified in advance of any proposed substantive modifications of the exempt research activity.

Determination that Activity Does NOT Meet the Exempt Criteria

For research activities that involve human subjects but are determined to not qualify for exempt status, the principal investigator is advised to resubmit the research for expedited or full-board IRB review.

Waiver of HIPAA Authorization and Exempt Review

The IRB may grant a waiver of HIPAA Authorization for an exempt study for the following: Recording of Medical Information, Without Identifiers, by or Under the Oversight of a Principal Investigator Who Would Normally Have Access to this information by Virtue of his/her Patient Care Responsibilities.

To grant this waiver, the IRB reviewer utilizes the Exempt with HIPAA Waiver checklist.

Frequency of Review

Protocols designated for exempt are not required to be submitted for annual renewal.

This section applies to initial IRB review, modifications, renewals, renewals with modifications, and approval of research that qualifies for expedited review.

Reviewer Designation

Research studies submitted for “expedited” review status are reviewed by the IRB Exempt/Expedited Vice Chair or an IRB member (including Exempt/Expedited Research Review Coordinators).

For research that purposefully requires the inclusion of children with disabilities or individuals with mental disabilities and is funded by the National Institute on Disability and Rehabilitation, the protocol will be reviewed by at least one individual who is primarily concerned with the welfare of these research subjects and who has the appropriate scientific or scholarly expertise to serve in this capacity. In the absence of an appropriate reviewer, the IRB will identify a consultant to serve in this role. This will be documented on the Documentation Form generated by the Exempt/Expedited Research Review Coordinator.

No one may serve as a reviewer if they have a conflict of interest as outlined in Section XVIII.

Provision of Review Materials

The IRB Reviewer has access to the complete IRB submission including the following (as applicable):

• OSIRIS protocol application;
• Renewal Report Form;
• Modification Cover Sheet;
• Investigator- or sponsor-provided protocol informed consent documents;
• Recruitment materials (e.g., advertisements, flyers, phone screening procedures, scripts, and/or screening questions, etc.);
• measures that will be utilized in the study (e.g. survey instruments, questionnaires, interview scripts, recruitment material, etc. – unless referenced on the IRB website as a standard measure;
• Confirmation of scientific review;
• Grant application;
• Other materials specific to the proposed study (e.g. Investigator’s Brochure or relevant investigator correspondence with regulatory agencies. etc.) .

IRB reviewers are expected to conduct an in-depth review of all materials and are provided access to Reviewer Checklists found in OSIRIS as a guide to ensure inclusion of the regulatory criteria and informed consent requirements that must be met as per 45 CFR 46.111 and 21 CFR 56.111 (if applicable). In addition, assigned reviewers are expected to evaluate informed consent documents from the perspective of addressing the required and additional elements of informed consent addressed under 45 CFR 46.116, 21 CFR 50.20 (if applicable) and any other relevant ethical or compliance considerations(if applicable).

The IRB reviewer completes applicable documentation forms to ensure that all regulatory issues are addressed as part of the review.

Categories of Expedited Review

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

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

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

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

Initial expedited review is not applicable to research studies where the subjects are known to be prisoners (see XIV for additional information).

Review of Grant Application

For Federally-supported research, the IRB reviewer ensures that the research application is essentially consistent with the grant application. This determination is documented as a note in OSIRIS.

Industry Sponsored Research

For industry sponsored research, the IRB reviewer bases his/her review and approval decisions on the information presented in the sponsor’s clinical protocol and the IRB protocol submission.

Investigator Communications

Comments or concerns of the IRB reviewer are documented and provided to the investigator. This is done through OSIRIS for electronic submissions and via email for paper submissions. Procedures for investigator communications are outlined in Section VIII.

Responses of the principal investigator are reviewed by the IRB reviewer who conducted the expedited review (or to another non-conflicted IRB reviewer if the initial reviewer is unavailable for an extended time).

In the event of a failure to resolve problems or concerns related to the investigator’s response(s), the IRB submission (including prior correspondence between the IRB reviewer and investigator) will be reviewed at a convened meeting of an IRB committee (i.e., full-board IRB review).

• Expedited reviewers cannot disapprove an IRB submission or modification. In the event that an expedited reviewer cannot make a determination, the study will be referred to a convened meeting for discussion by a committee.

Documentation of Determination

After reviewing the protocol submission, the IRB reviewer documents his/her determination in OSIRIS using the Documentation of Expedited Review Form. The chair or vice chair reviews the protocol submission along with the IRB reviewer's determination and then makes the final determination surrounding the protocol submission.

Final expedited approval of the research study and corresponding informed consent document(s) is granted by a non-conflicted IRB Chair or Vice Chair.

If an IRB submission is determined to not meet the criteria for an expedited review, the principal investigator will be advised by the IRB that their submission has been referred for full-board IRB review.

Basis for Approval

The minimal risk status of the research and the applicable category or categories of research activities listed “Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure” will be documented, with justification, within the IRB Research Protocol and/or review materials.

Expedited Approval Notification

The principal investigator is notified of IRB approval for initial or continuing review via an electronic letter sent from OSIRIS (or via email for paper submissions) indicating the name of the IRB Chair or Vice Chair who granted the final expedited approval. This letter specifies, at a minimum:

• The IRB number assigned to the submission
• The basis for granting expedited review and approval, including identification of the applicable category or categories
• the date of IRB approval and the date the IRB approval expires

Studies originally reviewed via full board meeting

For renewals or modification, the IRB reviewer determines if research that was initially approved by the full-board IRB, may now qualify for expedited review. This determination is made based on the risk level or status of the research and in accordance with the "Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure."

Studies originally approved via expedited review

For renewals or modifications, IRB protocols originally approved by the expedited process are re-evaluated to ensure that the submission continues to qualify for expedited review as specified in "Categories of Research That May Be Reviewed by the Institutional Review Board (IRB) through an Expedited Review Procedure." If the research no longer meets these requirements, it will be forwarded for review by a convened IRB Committee and the principal investigator so informed.

New Information and Significant New Findings

The IRB reviewer evaluates whether any new information/significant new findings obtained during continuing review should be provided to subjects when this information might relate to the subjects’ willingness to continue to take part in the research.

These procedures are specific to those protocols undergoing review by the convened IRB. Please refer to Section VIII for those procedures that are relevant for review of all protocol submissions.

Meeting Assignment

1. Human subject research requiring full-board IRB review and approval will be assigned by the IRB Office staff to the next scheduled full-board IRB meeting (i.e., subject to the availability of IRB committee members with appropriate expertise as determined by review of IRB Member Rosters). Meeting agendas will typically be limited to no more than 30 protocols with a maximum of 6 to 7 new applications. In rare circumstances, exceptions can be made to these limits by senior IRB staff.
2. Research submissions will be assigned to a committee where there is sufficient expertise. The schedule for IRB meetings can be found on the IRB website.
3. Protocols previously voted by the IRB for reconsideration will generally be assigned to the same IRB committee that previously reviewed the initial submission. As necessitated by time constraints, the principal investigator of the research may request reconsideration of the research submission at the next scheduled full-board IRB meeting. If the next available meeting involves a committee which was not involved in the previous review of the submission, the primary IRB reviewers involved in the previous review of the research submission will be given the opportunity to provide written comments regarding the resubmission. The principal investigator will be invited to attend the full-board IRB meeting at which the protocol is being reconsidered.
4. Protocols previously voted by the IRB for disapproval are required to be submitted as a new protocol and will be assigned to the first available committee with appropriate expertise to review the study.
5. Audit reports (including modification submissions related to auditing findings), unanticipated problems involving risks to human subjects or others and issues related to serious or continuing non-compliance are assigned to Committee F. All other research submissions will be assigned to one of the general IRB committees. If appropriate, an UP or audit report may be reviewed by an alternative IRB committee with appropriate expertise.

Reviewer Assignment

1. For initial review, three IRB members serve as reviewers (i.e., a primary, secondary, and tertiary reviewer).
2. For subsequent reviews, studies will be assigned to primary and secondary reviewers. If deemed necessary, a tertiary reviewer will also be assigned.
3. For research involving primarily biomedical intervention(s), the primary reviewer will be a physician or health care practitioner with adequate expertise in the area of the research; the secondary reviewer will be a scientific member of the committee; and the tertiary reviewer, if applicable, will be a member whose primary responsibility will be review of the consent document to ensure readability.
4. For research involving primarily psychosocial interventions, the primary reviewer will be a scientific member with adequate expertise in the area of the research; the secondary reviewer will be a scientific member of the committee; and the tertiary reviewer, if applicable, will be a member whose primary responsibility will be review of the consent document to ensure readability.
5. For research that purposefully requires the inclusion of children with disabilities or individuals with mental disabilities and is funded by the National Institute on Disability and Rehabilitation, the protocol, regardless of level of risk, will be reviewed by at least one individual who is primarily concerned with the welfare of these research subjects. This representative will have the appropriate scientific or scholarly expertise to serve in this capacity and will serve as either a primary or secondary reviewer. In the absence of an appropriate reviewer, the IRB will identify a consultant to serve in this role. This will be documented in the minutes generated by the Full Board RRC.

Distribution of Meeting Materials

1. The committee meeting agenda and review materials for both paper and electronic submissions will be distributed to the IRB committee members at a minimum of five days prior to the scheduled IRB committee meeting. Due to the nature of the information reviewed by Committee F, which may require immediate attention, the five day minimum will not apply to this committee.
2. The agenda indicates:
   • the meeting date, time and location;
   • educational topics for discussion;
   • conflict of interest disclosure;
   • previous meeting minutes for review and approval;
   • previously approved exempt/expedited research proposals, full board studies and full board; modifications for review;
   • adverse event information to be reviewed;
   • new proposals, modifications, renewals, and other unanticipated problems.
3. Electronic Submissions (New Projects, Reconsidered Projects, Renewals, Renewals with Modifications and Modifications for studies initially submitted through the OSIRIS system)
   
   All members will have access via laptop to the complete submission for IRB review which includes the following, when applicable:
   • OSIRIS protocol application;
   • Renewal Report Form;
   • Modification Cover Sheet;
   • investigator written or sponsor-provided protocol;
   • informed consent documents;
   • recruitment materials to include advertisements, flyers, phone screening procedures, scripts, and/or screening questions;
   • measures that will be utilized in the study, e.g. survey instruments, questionnaires, interview scripts, recruitment material, etc.;
   • scientific evaluation ;
   • DHHS approved grant; DHHS approved-sample consent; DHHS-approved protocol;
   • information relevant to humanitarian use devices;
   • other materials specific to the proposed study (e.g. investigator’s brochure or investigator correspondence with applicable regulatory agencies. etc.).
4. Paper Submissions (Renewals, Renewals with Modifications, and Modifications for studies in existence prior to inception of OSIRIS)
   
   Paper submissions will be scanned into the OSIRIS system so that all members will have access to a copy of the complete submission which includes the information listed in #3 above.

Review of Materials Prior to the Meeting

1. Vice Chairs and assigned reviewers are expected to conduct an in-depth review of all materials in advance of the meeting. Reviewers are provided with access to the IRB Reviewer Checklists as a guide to ensure inclusion of the regulatory criteria and informed consent requirements that must be met as per 45 CFR 46.111 and 21 CFR 56.111 (if applicable). In addition, assigned reviewers are expected to evaluate informed consent documents from the perspective of addressing the required and additional elements of informed consent addressed under 45 CFR 46.116, 21 CFR 50.20 (if applicable) and any other relevant ethical or compliance considerations.
2. For electronic submissions, reviewers are expected to document concerns through the use of the Reviewer Note tab. For paper submissions, reviews are expected to be documented by submitting the IRB Reviewer Report Form to IRB staff prior to the convened meeting.
3. In addition to reviewing the above material, the primary reviewer will also be responsible for ensuring general consistency between (where applicable) the federal grant application, sponsored protocol and/or investigator brochure.
4. Committee members who are not assigned as reviewers are expected to review the provided materials in advance of the meeting in enough depth to be familiar with the materials and prepared to discuss them at the meeting.

Verification and Maintenance of Quorum

1. Except when an expedited review procedure is authorized and used, the IRB will review proposed research at full board convened meetings at which a majority (i.e., > 50%) of the IRB members are present. A quorum will also require at least one non scientific member.
2. In order to ensure the presence of a quorum, alternate IRB members and members of a different standing IRB committee may be requested to participate as members of an IRB committee scheduled to review proposed research. IRB minutes will indicate if the members present at the meeting is an alternate as well as the IRB member for whom the alternate is substituting.
   • With the exception of the IRB Executive Committee (Committee F), at no time may the voting membership of an IRB committee include more than four members who are also an IRB Chair or Vice Chair or a member of the IRB Office staff.
   • A consultant may attend the meeting to participate in the review and discussion of the research study; however, s/he may not vote or count towards quorum. His/her comments are recorded either in memo format or on a reviewer report form.
3. Quorum includes those participating in the meeting via teleconference. Members present via teleconference are noted as such in the meeting minutes. Such members must receive all pertinent information prior to the meeting and be able to actively and equally participate in all discussions.
4. The Research Review Coordinator assigned to the meeting will be responsible for ensuring that quorum is maintained. If at any time during the conduct of a convened IRB committee meeting the quorum is not maintained, proceedings of the meeting will be suspended until the quorum is re-established. If quorum is not realized, the meeting will be adjourned.

Education

The IRB membership coordinator is responsible (in conjunction with the IRB Chair) for preparing monthly educational topics for review at all convened IRB meetings. In order to ensure consistency in the presentation of material, it is the IRB membership coordinator’s responsibility to review the material at all meetings and to encourage discussion regarding the topic.

IRB members will receive continuing education credit for preparation and participation in the IRB meeting. This is further discussed in Section XX.

Conflict of Interest

Potential conflicts of interest are assessed at every meeting as outlined in Section XVIII.

Notification of Protocols Reviewed Via Expedited Process

All IRB Committee members are provided with a list of protocols approved through an expedited review mechanism since the last meeting. This includes exempt and expedited submissions as well as full board studies that required a response to comments. Reviewers raising concerns about protocols approved in this manner should contact the IRB Office for access to the submission.

Review of Meeting Minutes from Prior Meeting

Before each meeting, the Vice Chair will poll the members to determine if the meeting minutes from the prior meeting are approvable as submitted or if any modifications to the prior meeting minutes are warranted. A vote will be taken for this action and documented in the minutes. The Research Review Coordinator assigned to the meeting will be responsible for making any corrections to the previous minutes. If requested changes affect the correspondence that was forwarded to the principal investigator, a correction will be issued.

Presentation of IRB Materials

Each research study requiring review and approval by the full board IRB will be addressed separately at the convened meeting of the IRB committee.

The primary reviewer leads the discussion of the study at the IRB meeting and will provide a brief summary of the proposed research followed by:

• a presentation of significant concerns related to the research and informed consent document(s);
• recommendations regarding the risk level (i.e., minimal, greater than minimal) of the research;
• recommendations for full approval, approval subject to modifications, reconsideration, or disapproval of the conduct of the proposed research.

The secondary reviewer and non-scientific reviewers will subsequently provide any additional comments or concerns.

Following the reviewer presentations, the research protocol and informed consent document(s) will be discussed by all IRB committee members.

Pertinent comments and concerns of the IRB committee members will be recorded by the Research Review Coordinator assigned to the meeting for inclusion in the minutes of the committee meeting.

Absence of Primary Reviewers

When the primary reviewer is absent the IRB Chair or Vice Chair will be responsible for ensuring that at least one IRB member or consultant with adequate expertise in the areas of the research is in attendance at the convened meeting and has conducted an in-depth review of all submitted materials. The IRB Committee will consider the written comments of an absent primary reviewer in its review of the research. However if there is not at least one IRB member or consultant with adequate expertise in the areas of the research in attendance at the convened meeting who has conducted an in-depth review of all submitted materials, the IRB will table consideration of the research.

IRB Determinations

At the conclusion of the primary reviewer presentations, the IRB will deliberate on the following items, which will be included in the IRB minutes.

Applicable Regulatory Issues

For all research studies, a determination will be made and the minutes documented as to whether the criteria under 45 CFR 46.111 or 21 CFR 56.111 (if applicable) are met. A poster outlining these criteria is posted in the conference room where the meetings take place. In addition, research involving the following subject matter, the IRB Chair or Vice Chair will review with the IRB members a checklist of requisite additional criteria for approval of the research and, if applicable, additional consent form requirements. Regulatory checklists are available on the IRB website:

• Vulnerable Subjects Documentation Forms
  • Child Documentation Form
  • Fetal Tissue Documentation Form
  • Neonate Documentation Form
  • Pregnancy Documentation Form
  • Prisoner Documentation Form
  • Proxy Documentation Form
• Waiver Forms
  • Waiver of Consent & HIPAA
  • Waiver of Consent to Identify Subjects
  • Waiver of Informed Consent
  • Waiver to Obtain a Signed Consent
  • Waiver of HIPAA Authorization
  • Waiver of HIPAA for Recruitment
  • Waiver of HIPPA Exempt
  • Waiver for Emergency Research Documentation Form
• Non – local research Forms
• Non significant risk devices Forms
• IND checklist
• Department of Defense

The Vice Chair of the meeting should ensure that all points are discussed during committee deliberations. The Research Review Coordinator is responsible for documenting the applicable points during preparation of the meeting minutes for final concurrence by the vice chair.

Level of Risk

When considering risks, the IRB considers physical, psychological, social, economic and legal risks. IRB members will be polled to determine the risk level (minimal, greater than minimal) of the proposed research. The basis for this determination will be documented, with justification, in the IRB Research Protocol and/or the meeting minutes.

Frequency of IRB Continuing Review

For research studies involving greater than minimal risk or other significant human subject protection concerns, the IRB determines if IRB continuing review is warranted on a more frequent basis than the requisite annual review and, if so, establishes the parameters for an appropriate continuing review interval. In making this determination, the following may be taken into consideration by an IRB Committee:

• Phase I and II clinical trials involving use of an unapproved investigational drug or device
• Involvement of recombinant DNA or other types of gene transfer protocols;
• Research activities that pose a significant likelihood of a life-threatening or serious adverse event to involved subjects;
• Research where multiple adverse events have been observed during the conduct of the study
• Previously raised concerns about an investigator during an audit;
• Recommendations from other institutional committees (e.g., RDRC, IBC,CTRC);
• Any other concern raised by an IRB member.

New Information

Throughout the life span of a research protocol, the IRB may determine that currently enrolled subjects need to be notified of new information or significant new findings that alter the risk benefit ratio and may affect their willingness to continue study participation. New information may be presented to research participants via an addendum consent form or a modified consent form (See Section XII).

Verification from Other Sources

Protecting the rights and welfare of participants sometimes requires that the IRB verify independently, utilizing sources other than the investigator, that no material changes occur during the IRB designated approval period. Additional sources may include: audit by the Education and Compliance Office for Human Subject Research, investigational pharmacy records, incident reports, radiation safety or source documents, as well as information from staff, research participants, families, sponsors or others.

Criteria for determining if verification is required will include, but not be limited to:

• Complex protocols involving unusual levels or types of risks to subjects;
• Protocols conducted by investigators who previously have failed to comply with Federal regulations or the requirements or determinations of the IRB;
• Protocols where concern about possible material changes occurring without IRB approval have been raised based on information provided in continuing review reports or from other sources.

Monitoring of Informed Consent

For research determined to be of greater than minimal risk or if potential conflict -of-interest or coercion concerns exist, the IRB members may request that random monitoring of the informed consent process be undertaken by a representative of the University’s Education and Compliance Office for Human Subject Research (ECO-HSR). The Research Review Coordinator assigned to the IRB meeting will notify the ECO-HSR of this request.

Possible IRB Committee Actions for Research Studies

The following are actions that may be taken by the IRB during the review of protocol submissions. In addition to the actions noted below, there are also actions in Section XVII that are utilized by the IRB Executive Committee (Committee F) when reviewing unanticipated problems involving risk to human subject, as well as serious, or continuing noncompliance:

• require that a study be submitted for continuing review at an interval less than annually;
• request an audit of the informed consent process;
• request a complete audit of the study;
• request that the investigator appear before the Committee to provide information related to the submission;
• request review of a federally funded research study by the Secretary, DHHS if designated for approval under 45 CFR 46.407 (Subpart D – Additional Protections for Research Involving Children). If the study is not federally funded, review by an independent expert panel will be sought;
• request review of a federally funded research study by the Secretary, DHHS if designated for approval under 45 CFR 46.207 (Subpart B – Additional Protections for Pregnant Women, Human Fetuses and Neonates involved in research). If a study is not federally funded, review by an independent expert panel will be sought;
• terminate or suspend any or all research activities or University IRB approval of the research study.

When terminating or suspending some or all research activities, the University IRB will consider what additional actions the principal investigator or institution should take in order to protect the rights and welfare of current human subjects. These additional actions may include but are not limited to:

• Transferring the human subjects to another research study (i.e., based on equivalent inclusion/exclusion criteria);
• Making arrangements for clinical care outside the research;
• Allowing continuation of some research activities under the supervision of an independent monitor;
• Requiring or permitting follow-up of the human subjects for safety reasons;
• Requiring adverse events or outcomes to be reported to the University IRB and the sponsor;
• Notifying current human subjects of the University IRB’s decision to terminate or suspend the research study;
• Notifying former human subjects of the University IRB’s decision to terminate or suspend the research study;
• Recommending suspension of the PI’s privileges to serve as a PI or requiring a replacement of the PI for the research study in question. This recommendation will be placed on the agenda for a Committee F (Executive Committee) meeting for final disposition.

Types of Motions

Based on its review of initial or ongoing review of research, the IRB decides to approve, reconsider, disapprove or stipulates specific modifications of the proposed research and/or consent document(s) as required to secure IRB approval of the research. Following is a brief description of each of the possible motions.

Full Approval: No changes to the research or informed consent document(s) required. The investigator may initiate the research immediately upon receipt of the written notification of full approval to conduct the research.

Approval Subject to Modifications: Conduct of the research can be granted full approval by the IRB Chair or IRB Vice Chair pending principal investigator concurrence with specific revisions stipulated by the IRB with directive comments. The principal investigator may not initiate the research until such time that s/he has modified the research protocol and/or informed consent document(s) to comply with the specific revisions stipulated by the IRB; such revisions have been reviewed and approved by the IRB Chair or IRB Vice Chair; and the principal investigator has received written notification of full approval to conduct the research.

Reconsideration: Approval to conduct the research requires substantive clarifications or modifications of the research design or procedures or substantive revisions of the informed consent document(s). The principal investigator must respond to the identified concerns, clarifications, modifications or revisions and resubmit the revised research and/or informed consent document(s) for full-board IRB review.

Disapproval: The proposed research has fundamental design problems and/or presents significant ethical or safety concerns to involved human subjects. The principal investigator must undertake a major revision of the research before it can be resubmitted for full-board IRB review.

Tabled: Insufficient information is available to review the proposed research in an adequate manner. The principal investigator must provide this information before it can be resubmitted for full-board IRB review. The proposed research may also be tabled due to loss of quorum or lack of appropriate expertise present at the meeting.

Call for Vote

Following open discussion of the above applicable referenced items, the IRB Chair or Vice Chair will call for a vote of the committee to grant full approval, approval subject to modifications, reconsideration, or disapproval of the proposed research.

• IRB members in attendance at the full meeting, but absent from the meeting during the discussion of the research protocol and the vote will not be counted in the committee vote.
• The absence of members due to a conflict (i.e., a listed investigator, financial or other conflict) during the discussion of the research protocol and the vote will be documented in the minutes of the full board IRB meeting to include the reason for their absence (e.g., listed investigator on research study under consideration, financial interest in sponsor of the research or the technology being evaluated).
• IRB members who provide written comments regarding the proposed research and informed consent documents, but who are not present at the meeting, will not be counted in the committee vote.
• The vote of the majority of the IRB members present at the meeting will determine the final approval status (i.e., full approval, approval subject to modifications, reconsideration, disapproval) of the conduct of the proposed research.

Generation of Meeting Minutes

Attendance

The minutes of the IRB meetings will specify the members of the committee who were present at the meeting; members who were absent, but provided written comments, and members who were absent. IRB Office staff (i.e., not serving as members of the committee), consultants to the committee, and guests will be listed separately.

Protocol Specific Information

Each research submission reviewed by the IRB will be listed separately by IRB number, principal investigator name, and protocol title. For each research submission, the minutes address:

• the action (i.e., full approval, approval subject to modifications, reconsideration, disapproval) taken by the committee and the corresponding numerical vote;
  • Documentation of the numerical vote will address the number of IRB members voting for or against the action taken by the committee; the number of IRB members abstaining from the vote; and any IRB members listed as being present at the committee meeting, but who were absent during the discussion of the research submission and subsequent vote. The vote will be reflected as the number for the action, the number against the action and abstentions (e.g., 13 members for the action; 0 members against the action; 1 abstention).
• the risk level of the research as determined by the committee;
• the IRB approval interval designated by the committee;
• pertinent comments and concerns of the primary IRB reviewers and pertinent comments and concerns expressed during open discussion of the research submission, to include significant new findings to be communicated to research subjects and a summary of controverted issues and their resolution (when the IRB reached consensus).
  • In order to ensure that human subject protection issues are fully addressed at the IRB meeting, many times housekeeping problems (i.e., grammatical and typographical errors) are not presented for committee discussion. However, in preparing the meeting minutes, which are used directly to generate IRB response letters to the involved investigators, these housekeeping problems are included; especially as they relate to the consent form and ensuring its understanding by potential research subjects.
• Reconsideration or Disapproval of Protocols
  
  For research submissions voted for reconsideration or disapproval, the following information should be recorded in the minutes:
  • a summary of the primary reason(s) for such determination by the full-board IRB;
  • where applicable (i.e., wherein there was a vote for reconsideration or disapproval in the face of majority vote for approval), a summary of the unresolved controverted issues.
• Regulatory Forms
  
  The research review coordinator will ensure that all criteria outlined on the regulatory forms are included in the meeting minutes.

Additional Documentation Requirements

• Reconsideration or Disapproval of Protocols
  
  For research submissions voted for reconsideration or disapproval, the following information should be recorded in the minutes:
  • a summary of the primary reason(s) for such determination by the full-board IRB ;
  • where applicable (i.e., wherein there was a vote for reconsideration or disapproval in the face of majority vote for approval), a summary of the unresolved controverted issues.
• Regulatory Forms
  
  The research review coordinator will ensure that all criteria outlined on the regulatory forms are included in the meeting minutes.

Approval and Utilization of Minutes

Minutes of the IRB committee meeting will be reviewed and accepted by the IRB Vice Chair overseeing the meeting and/or, if present at the meeting, by the IRB Chair or another IRB Vice Chair. Following their acceptance by an IRB Vice Chair or IRB Chair, the minutes of the IRB committee meeting will be directly used to generate written notifications of IRB decisions regarding the approval status of the research submission for dissemination to the listed principal investigator.

The minutes of the IRB committee meeting will be included with the materials prepared for review at the next convened meeting of the IRB committee, and will be voted for approval at the convened meeting. The minutes will be modified as necessary to obtain approval of the IRB committee. If modifications to the minutes affect the approval status of a research study, the Principal Investigator will be notified.

The Institutional Official has access to all approved IRB minutes through the OSIRIS system, including a listing of research studies granted final approval by the IRB.

General Overview of Informed Consent

Informed consent is one of the primary ethical requirements underpinning research involving humans; it reflects the basic principle of respect for persons. It should always be remembered that informed consent is an ongoing process, not a single event, designed to provide potential research subjects with all of the relevant information they need to make a fully informed, autonomous decision as to whether they wish to participate in a research study.

To assist investigators and coordinators who are conducting research, information regarding the informed consent process is provided on the IRB website. Examples and instructions are available, including guidelines for the informed consent process and sample language for the informed consent document.

IRB Review of Informed Consent Process

During its review of the informed consent process as described in the protocol, the IRB requires that:

• Adequate opportunity is provided to the subject or the subject’s legally authorized representative to read the consent document and ask questions regarding the study before the informed consent document is signed.
• The consent process minimizes the possibility of coercion or undue influence. The consent discussion is in language understandable to the subject or the subject’s legally authorized representative.
• The information communicated to the subject or the subject’s legally authorized representative during the consent process does not include any exculpatory language that waives or appears to waive any legal rights that the subject may have, or releases or appears to release the investigator, the sponsor, the institution or its agents from liability for harm caused by their negligence.

In addition, the IRB requires that the consent document include all of the basic elements of consent set forth in 45 CFR 46.116 and, if applicable, 21 CFR 50.25, except those which can be waived, or altered, according to regulation. The IRB may also require that additional elements or information be given to the prospective subjects when, in the IRB’s judgment, the information would meaningfully add to the protection of the rights and welfare of the research subject.

Basic Elements of Informed Consent – 45 CFR 46.116 (a) or 21 CFR 50.25(a) include:

• A statement that the study involves research;
• A description of any reasonably foreseeable risks or discomforts to the subject;
• A description of benefits to the subject or others that may be reasonably expected from the research;
• The disclosure of appropriate alternative procedures or course of treatment, if any, that might be advantageous to the subject;
• A statement describing the extent to which confidentiality of records identifying the subject will be maintained;
• For medical research involving more than minimal risk, an explanation as to whether or not any compensation or any medical treatments are available if injury occurs during study participation;
• The identification of an individual who can be contacted by the subject for answers to questions related to the research, research-related injury, or their rights as a research subject;
• A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which s/he is otherwise entitled.

Additional Elements of Informed Consent – 45 CFR 46.116 (b) or 21 CFR 50.25(b) that should be addressed as appropriate include:

• A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable;
• Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent;
• Any additional costs to the subject that may result from participation in the research;
• The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject;
• A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject;
• The approximate number of subjects involved in the study.

Consent Form Addendum

When subjects need to be informed of specific changes in the risk or benefit of study participation, an addendum consent, which focuses on the new information, may be more appropriate than a modified consent document. A consent form addendum may also be used to inform enrolled subjects about significant new findings that may have a bearing on their willingness to continue participation in the study.

Waiver of the Requirement to Obtain a Signed Informed Consent (45 CFR 46.117)

Regulatory Requirements

Following expedited or full-board review, the IRB may waive the requirement to obtain a signed consent form for some or all subjects if it finds that either:

1. the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context (i.e., see 45 CFR 46.117 (c) (2); 21 CFR 56.109 (c) (1)) or
2. the only record linking the subject and the research would be the informed consent document and the principal risk would be potential harm resulting from a breach of confidentiality (i.e., see 45 CFR 46.117 (c) (1))
   • Subject to granting a waiver of the requirement to obtain a signed informed consent based on this criterion, the IRB will require the principal investigator to ask each subject whether s/he wants documentation linking him/her to the research, and the subject’s wishes will govern.

The IRB will not waive the requirement to document informed consent based on criterion #2 if the research study is subject to the FDA regulations (21 CFR Parts 50, 56) governing human subject protections.

Upon granting a waiver of the requirement for obtaining a signed informed consent, the IRB reviews and approves the information that will be provided to potential subjects to obtain their verbal consent for study participation, and the procedure(s) that will be used by the investigators to document obtaining verbal consent.

IRB Documentation of Concurrence

Documentation of concurrence that a request for waiver to obtain written informed consent meets with the applicable regulatory requirements (45 CFR 46.117 (c), 21 CFR 56.109 (c)) is required of the IRB reviewer(s). The IRB reviewer utilizes the "Waiver of Consent" form found on the IRB website. For full board protocols, the Full Board Research Review Coordinator documents that the applicable criteria have been met in the minutes. For expedited reviews, the Exempt/Expedite Research Review Coordinator documents that the applicable criteria have been met via electronic notification to the vice chair.

Waiver or Alteration of Consent

Regulatory Requirements

The IRB requires that informed consent be sought from each prospective subject or the subject’s legally authorized representative prior to participation in research activities, with the following exceptions.

1. The IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent, or
2. The IRB may waive the requirement to obtain informed consent if it finds and documents that the research activity meets the criteria for a waiver of consent as addressed under 45 CFR 46.116(d) as follows:
   • The research involves no more than minimal risk to the subjects;
   • The waiver or alteration will not adversely affect the rights and welfare of the subjects;
   • The research could not practicably be carried out without the waiver or alteration; and
   • Whenever appropriate, the subjects will be provided with additional pertinent information after participation.
3. The IRB may also waive the requirement to obtain informed consent if it finds and documents that the research activity meets the criteria for a waiver of consent as addressed under 45 CFR 46.116 (c) This IRB does not typically receive requests of this type. If investigators wish to request this waiver, they should contact the IRB for further guidance.

The IRB does not waive the requirement to obtain informed consent if the research study is subject to the FDA regulations (21 CFR Parts 50, 56) governing human subject protections except for planned emergency research 21 CFR 50.24 see Section XVI.

IRB Documentation of Concurrence

Documentation of concurrence that a request for waiver of informed consent meets with the applicable regulatory requirements (45 CFR 46.116) is required of the IRB reviewer(s). The IRB reviewer utilizes the "Waiver of Consent" form. For full board protocols, the FBRRC documents that the applicable criteria have been met in the minutes. For expedited reviews, the EERRC documents that the applicable criteria have been met via electronic notification to the vice chair.

Waiver of Consent for Planned Emergency Research

The IRB (subsequent to full-board review) may approve a research study without requiring that informed consent of all research subjects be obtained if it finds and documents that the research activity meets the criteria for an exception to the requirement to obtain informed consent for emergency research as addressed under planned emergency research regulations found at 21 CFR 50.24. See Section XIV.

Waiver of Parental Consent for Abused or Neglected Children

The IRB may waive the requirement for parental consent if it determines that the research study is designated for conditions or for a subject population (e.g., neglected or abused children) for which parental or guardian permission is not a reasonable requirement to protect the subjects (see Section XIV and also refer to 45 CFR 46.408).

Assent

For information on assent, please refer to Section XIV.

Proxy Consent

For research involving subjects who are or may be decisionally impaired such that the subject is not capable of giving informed consent, the IRB approves the research only if it finds that proxy consent is appropriate. For more information on how this is handled in this subject population, see Section XIV.

Non-English Speaking Participants

Federal regulations require that informed consent information must be presented in a language understandable to the subject and, in most situations, that informed consent be documented in writing (45 CFR 46.116 and 46.117). All required elements necessary for legally effective informed consent must be present in the consent document in the language spoken by the research subjects. Investigators should submit the proposed consent document in English, with a certified translation in the language which will be used with subjects. This process should be utilized any time a research study is actively recruiting non-English speaking participants.

There is an alternative approach available to investigators in the event that the study is not designed to recruit non-English speaking participants. If a potential subject otherwise meets inclusion criteria, a short form written consent document can be utilized. Guidance on this approach as well as translations of the short form in several different languages are available on the IRB website.

Responsibility for Obtaining Consent

The principal investigator of the research study is ultimately accountable for assuring that all aspects of the study are at all times in compliance with applicable research regulations and IRB policies. This includes the entire informed consent process and the instruction and oversight of individuals who may be involved in this process. The IRB application must include a detailed plan for informed consent process and include the individuals who will actually be conducting the consent process.

Studies Involving Drug, Device, or Surgical Procedures

The University requires that the PI or a Co-Investigator who is a licensed physician obtain informed consent. This does not mean the study coordinator cannot introduce the study and answer preliminary questions about the research. The final process of obtaining the written informed consent must be conducted by a physician investigator who must sign the Investigator's Certification statement at the time of this involvement.

There are circumstances when the IRB may permit, with an appropriate justification, that the consent process to be conducted by a licensed health care professional who is listed as a Co-Investigator. This individual must have the appropriate expertise and credentials to perform this duty.

Greater Than Minimal Risk Study

For greater than minimal risk research studies which do not involve the use of a drug, device, or surgical procedure; the PI or listed Co-Investigator must be involved in the informed consent process and must sign the Investigator's Certification statement at the time of this involvement.

Minimal Risk Study

The IRB may approve an exception to the rule requiring the PI or Co-Investigator’s to obtain consent with appropriate justification. If a waiver is requested, the individual who will be involved in the informed consent process and who will sign the Investigator’s Certification must be identified by name or position.

Note that verbal or telephone consent is not acceptable unless the IRB has specifically waived the requirement for a signed consent form. Deferred consent (i.e., obtaining consent after the initiation of study procedures) is also prohibited.

The investigator must seek informed consent under circumstances that give the individual sufficient opportunity to consider whether to participate in the research study, and that minimize possible coercion or undue influence.

Informed consent to participate in a research study should be sought at a time separate from obtaining informed consent for procedures performed for the medical management of the patient (i.e., non-research procedures).For certain research studies (e.g., studies involving questionnaires, surveys) it may be practical and acceptable to mail the informed consent document to the potential subject and to have the signed document returned by mail. If this approach is taken, there must also be provisions for a telephone interaction between the potential subject and investigators so as to ensure that the informed consent process has been appropriately addressed. The cover letter accompanying the mailed informed consent document and survey or questionnaire materials must clearly address this telephone interaction. The procedures for ensuring an appropriate informed consent process when the consent form is mailed to potential research subjects should be addressed in the recruitment section of the corresponding IRB research protocol.

The Principal Investigator must retain the original signed informed consent document in his/her research records. A copy of the informed consent document must be provided to the subject. For hospital inpatients, a separate copy of the informed consent document should be incorporated into the patient’s medical record.

In addition to obtaining the signed, written informed consent document, it is recommended that a narrative note be written in the subject’s research records documenting the informed consent process. This documentation may depend on the risk of the study and could include information such as:

• Who was present during the informed consent discussion;
• The fact that risks were presented;
• A notation, if applicable, that significant issues of concern to the subject were addressed;
• A statement that all questions were answered to the satisfaction of the subject.

The narrative note should also indicate the date and time that the subject signed the informed consent document and be signed by individual responsible for the documentation. Noting the time of consent, in addition to the date, is especially important if any research procedures will be performed on the same day that informed consent was obtained. Note that this is a requirement for any research study involving the evaluation of a research intervention which falls under the jurisdiction of the FDA.

HIPAA Authorization

The IRB requires that written HIPAA autho rization be sought from each subject or the subject’s authorized representative prior to participation in any research activity that involves the use of the subject’s protected health information (i.e., identifiable medical record information) maintained by a covered entity (i.e., health care provider, health care plan, health care clearinghouse). See sample HIPAA authorization, found on the IRB website. HIPAA authorization must also be obtained for the placement of research data into the subject’s medical record information maintained by the covered entity.

When protected health information (PHI) will be accessed, used and/or disclosed for research purposes, the research consent may include all the necessary elements under HIPAA thereby alleviating the need for a separate HIPAA Authorization.

Regulatory Requirements

The necessary HIPAA elements include the following:

• A specific description of PHI that will be collected for research and the purpose of collecting this information;
• A specific description of any research-derived information that will be placed in the individual’s medical record;
• The person or class of persons who may use or disclose the PHI collected for research;
• The person or class of persons to whom PHI collected for research may be re-disclosed and the purpose of such re-disclosure;
• The expiration date of the authorization;
• Consequences to the individual of a refusal to sign the authorization;
• The individual’s right to revoke authorization and consequences of such revocation.

Waiver of HIPAA Authorization - For UPMC Facilities Only

The IRB also serves as the Privacy Board for UPMC facilities and may approve a HIPAA authorization process for studies taking place in UPMC facilities which does not include, or which alters some or all of the elements of a valid written authorization (as specified under 45 CFR 164.508(c)), or waives the requirement for written HIPAA authorization if the IRB finds and documents that the use of the subjects’ protected health information meets the criteria for a waiver as addressed under 45 CFR 164.512 (i)(2)(ii). In granting an alteration or waiver of HIPAA authorization, the IRB must determine that the alteration or waiver, in whole or in part satisfies each of the following criteria:

1. The use or disclosure of protected health information involves no more than minimal risk to the privacy of individuals, based on, at least, the presence of the following elements:
   • an adequate plan to protect the identifiers from improper use and disclosure;
   • an adequate plan to destroy the identifiers at the earliest opportunity consistent with the conduct of the research, unless there is a health or research justification for retaining the identifiers or such retention is otherwise required by law; and
   • an adequate written assurance that the protected health information will not be reused or disclosed to any other person or entity, except as required by law, for authorized oversight of the research study, or for other research for which the use or disclosure of protected health information would be permitted (i.e., under the HIPAA regulations).The research could not practicably be conducted without the waiver or alteration.
2. The research could not practicably be conducted without access to the use of the protected health information.

Documentation of Approval Concurrence

Documentation of the IRB’s approval of an alteration or waiver of HIPAA authorization must include:

• a statement that the alteration or waiver of authorization has been reviewed under either full-board or expedited review procedures;
• a statement that the IRB has determined that the alteration or waiver, in whole or in part, of the authorization satisfies each of the waiver criteria under 45 CFR 164.512(i)(2)(ii);
• a statement identifying the date on which the alteration or waiver of authorization was approved;
• a brief description of the protected health information for which use or access has been determined to be necessary by the IRB; and the documentation of the alternation or waiver of authorization must be signed by the IRB Chair or other IRB member, as designated by the IRB Chair.

The IRB reviewer utilizes the Waiver of HIPAA Authorization form and documents in the minutes (if full board) or in a note to vice chair (if expedited) that the applicable criteria have been met. Note that the IRB cannot approve alteration or waiver of HIPAA authorization for protected health information from covered entities other than UPMC.

Use Preparatory to Research Within UPMC

UPMC has established a policy whereby researchers may access protected health information held by UPMC solely for use preparatory to research. Following is an excerpt from the policy. The policy in its entirety can be found on the IRB website, and researchers should directly contact the appropriate offices within UPMC for further information.

For reviews of PHI preparatory to research (hypothesis/protocol work), HIPAA permits UPMC to make available the PHI to a researcher based solely on the researchers written representations that no PHI shall be recorded for the purpose of research and/or removed from the provider entity and that the PHI reviewed by the researcher shall be limited to that necessary to prepare a research protocol. UPMC shall permit researchers to review PHI, held by a UPMC entity, for the purpose of preparing a research hypothesis and research protocol. UPMC has a template agreement that is available to the researcher (from the IRB or UPMC) for this HIPAA-permitted activity. The researcher must provide requested information and attest/sign and submit this agreement to the director of the entity’s health information management department or an individual designated by the entity to receive such information in order to access the records/PHI.

Research on Deceased Individuals

Research involving deceased individuals is not human subjects research according to 45 CFR 46.102(f) and does not require IRB oversight unless the research involves both living and deceased individuals. At the University of Pittsburgh, the Committee for Oversight in Research Involving Decedents (CORID), under the Office of Oversight of Anatomic Specimens, conducts reviews of projects that involve deceased individuals exclusively.

UPMC polices address access to the PHI of deceased individuals as outlined below and found on the IRB website.

Consent for HIV Testing

For studies involving HIV testing a separate consent can be used by investigators to address unique issues under state law. This consent notifies subjects that their information will be handled in compliance with the Pennsylvania law on HIV-related confidential information, that they will be notified of the testing results and that counseling will be available to them prior to and after HIV testing.

Consistency of Informed Consent Language with Sponsor Contract: Subject Injury

The University of Pittsburgh Office of Research will provide the IRB with the sponsor’s contract language related to subject injury. The language will be reviewed for consistency with the IRB application and informed consent document. If the language is not consistent, the IRB will contact the research team through OSIRIS and request that a modification be submitted.

Research Involving Children

The University of Pittsburgh adheres to the regulatory requirements for research with children as outlined in 45 CFR 46 Subpart D and 21 CFR 50 Subpart D. When reviewing research with children, the IRB membership includes at least one member who is knowledgeable about or experienced in working with children.

Definitions

Children – Federal law defines “children” as persons who have not attained the legal age for consent to treatment for procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. Under Pennsylvania law, persons under the age of eighteen (18) generally meet this definition of "children" with the exceptions noted below. As a result, permission of the child’s parent(s) or guardian(s) must generally be obtained prior to the participation of that child in research.

• The provisions that permit a minor to be considered emancipated vary depending upon the circumstance. In the Commonwealth of Pennsylvania, a minor can be considered emancipated for one purpose (for example, obtaining birth control) but not for others. Unless a minor has been emancipated by court order, which should be confirmed by requesting a copy of the order, a minor should NOT be considered emancipated for purposes of consenting to participation in research.

Guardian – Under federal law, guardian means an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care.

• A child’s "guardian" may provide legally effective informed consent for participation in research. If a guardian provides consent, the court order or legal authorization to consent to general medical care should be copied and included in the research records with the consent document. It is important to note that physical custody and legal guardianship may not be the same for some children, and that courts may only grant partial or joint custody in some cases. Review of the court order or other legal documentation establishing the guardianship is necessary to determine who may provide consent for participation in research on behalf of the child.
• Under the laws of the Commonwealth of Pennsylvania, foster parents or Children and Youth Services cannot consent to general medical care on behalf of a child, unless a court order or the consent of the parent has been obtained. Therefore, such persons do not meet the federal definition of “guardian” and cannot provide consent for the participation of a foster child in a research study. Only the birth or adoptive parent(s) can provide the legally authorized consent to participation in research. In addition, a child who is in the custody of Children and Youth Services is considered a ward of the state, and the procedures set forth below for enrolling wards must be followed.

Permission – The agreement of parent(s) or guardian to the participation of the child in research.

Assent – An affirmative agreement by the child to participate in research. Mere failure to object should not be construed as assent without an affirmative agreement.

Parent – A child’s biological or adoptive parent.

Applicable Categories of Research

The IRB reviews all research involving children as participants and approves only research that satisfies all of the conditions of applicable federal regulatory subpart sections. The IRB assesses the potential risks and benefits for each research proposal, and the provisions for permission and assent, to determine if the activity satisfies the conditions for a category of research permitted for children, as specified in DHHS 45 CFR 46.404, 46.405, 46.406, 46.407 and 46.409 and FDA 21 CFR 50.51, 50.52, 50.53, 50.54 and 50.56.

The research categories are described as follows:

(45 CFRF 46.404 and 21 CFR 50.51) Research that does not involve greater than minimal risk may be approved if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

(45 CFR 46.405 and 21 CFR 50.52)Research involving greater than minimal risk, but presenting the prospect of direct benefit to an individual participant, or a monitoring procedure that is likely to contribute to the participant’s well-being may be approved if the IRB finds that:

• The risk is justified by the anticipated benefit to the participant;
• The relationship of anticipated benefit to risk is at least as favorable as that presented by available alternative approaches; and
• Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.

(45 CFR 46.406 and 21 CFR 50.53)Research involving greater than minimal risk with no prospect of direct benefit to individual participants, but likely to yield generalizable knowledge about the participant’s disorder or condition may be approved if the IRB finds that:

• the risk represents a minor increase over minimal risk;
• the intervention or procedure presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or educational situations;
• the intervention or procedure is likely to yield generalizable knowledge about the participant’s disorder or condition which is of vital importance for the understanding or amelioration of the participant’s disorder or condition; and
• adequate provisions are made for soliciting assent of the children or permission of their parents or guardians.

(45 CFR 46.407 and 21 CFR 50.54)Research that is not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health of welfare of children may be approved if the IRB and the Secretary of Health and Human Services (DHHS), after consultation with a panel of experts in pertinent disciplines and following an opportunity for public review and comment, find that the research in fact satisfies one of the above three categories; or satisfies all of the following requirements:

• the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health and welfare of children;
• the research will be conducted in accordance with sound ethical principles; and
• adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.

If the research study is not Federally-supported or subject to FDA regulation, the IRB Office will request review by a panel of pediatric experts to determine the applicability of approval under Section 45 CFR 46.407.

Wards of the State

Children who are wards of the state or any other agency, institution, or entity can be included in research approved under 45 CFR 46.406 and 45 CFR 46.407 or 21 CFR 50.53 and 21 CFR 50.54 only if such research is:

• related to their status as wards; or
• conducted in schools, camps, hospitals, institutions or similar settings in which the majority of children involved as participants are not wards (45 CFR 46.409 or 21 CFR 50.56).

Where the proposed research involves Wards of the Commonwealth of Pennsylvania or any other agency, institution, or entity; an advocate will be appointed 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 (i.e., see 45 CFR 46.409 (b) and, if applicable, 21 CFR 50.56).

• One individual may serve as an advocate for more than one child-Ward.
• The advocate will 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 of advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.

Consent Requirements

If a research study is designated as meeting the criteria for (45 CFR 46.404 or 21 CFR 50.51); or (45 CFR 46.405 or 21 CFR 50.52), the IRB will determine whether adequate provisions have been made to solicit the permission of each child’s parents or guardians, unless one parent is deceased, unknown, incompetent, or not reasonably available, or unless one parent has sole legal responsibility for the care and custody of the child. Where parent permission must be obtained, the IRB may determine that the permission of one parent is sufficient.

If a research study is designated as meeting the criteria for (45 CFR 406 or 21 CFR 50.53); or (45 CFR 46.407 or 21 CFR 50.54), the IRB requires the permission of both parents, unless one parent is deceased, unknown, incompetent, or not reasonably available, or unless one parent has sole legal responsibility for the care and custody of the child.

The permission of the child’s parent(s) must be documented by the inclusion of a signature on the consent form indicating that the child is under the age of 18 and therefore cannot provide direct consent.

Waiver of Parental Consent for Abused or Neglected Children

The IRB may waive the requirement for parental consent if it determines that the research study is designated for conditions or for a subject population (e.g., neglected or abused children) for which parental or guardian permission is not a reasonable requirement to protect the subjects (see 45 CFR 46.408). If the IRB grants this type of waiver based on this criterion, it must substitute an appropriate mechanism for protecting the children-subjects. The choice of such mechanism will depend on the nature and purposes of the proposed research activities; the risk and anticipate benefit to the children-subjects; and the age, maturity, status, and condition of the proposed subject population.

The IRB will not waive the requirement to obtain parent or guardian permission based on the above-stated criterion if the research study is subject to FDA regulations (21 CFR Parts 50 and 56) governing human subject protections (i.e., the research study involves an evaluation of any article regulated by the FDA).

Consent for Continued Participation

If the research study involves children (age < 18 years old) who will continue to undergo research interventions (including the collection of identifiable private information) after they become adults, the IRB research protocol should address a mechanism (e.g., addendum informed consent document with copy of originally signed consent form attached; new consent form) whereby direct consent for continued participation in the research study will be obtained from these individuals at the time they reach adult status.

Consent for Children Participating in Non-Local Research

If the research includes enrollment of participants in other states or countries, the principal investigator is responsible for providing the IRB with sufficient information to verify the age at which participants in other jurisdictions have the ability to consent to participation in research, including any medical treatments or procedures if applicable. The IRB may, if it appears advisable, require the submission of an opinion rendered by an attorney from any applicable jurisdiction on age at which an individual can consent to participation in research. Non local research is addressed in Section XXIII.

Child Abuse Statement

The following statement should appear under the Confidentiality section of all informed consent documents involving research studies conducted with children: "If the researchers learn that you or someone with whom you are involved is in serious danger of harm they will need to inform the appropriate agencies as required by Pennsylvania law." There may be instances where alternate language is appropriate.

Assent Requirements

Adequate provisions must be made for soliciting the assent of the children-subjects when, in the judgment of the IRB, the children-subjects are capable of providing assent. In determining whether children-subjects are capable of providing assent, the IRB will take into account the ages, maturity, and psychological state of the involved children. This judgment may be made for all children to be involved in given research study, or for each child, as the IRB deems appropriate. The assent of a child-subject will not be a necessary condition for proceeding with the child’s research participation if the IRB determines:

• that the capability of some or all of the children-subjects is so limited that they cannot reasonably be consulted;
• 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-subjects and is available only in the context of the research; or
• the IRB finds and documents that:
  • the research involves no more than minimal risk to the children-subjects;
  • the waiver of assent will not adversely affect the rights and welfare of the children-subjects;
  • the research could not practicably be carried out without the waiver; and
  • whenever appropriate, the children-subjects will be provided with additional pertinent information after participation.

Children who are developmentally able to provide written assent will sign the consent document in addition to the parent(s). For children who are not determined to be developmentally able to sign the consent document, the investigator must certify that the purpose and nature of the research was explained in age appropriate language and that the child provided positive affirmation to participate.

Research Involving Prisoners

The University of Pittsburgh IRB adheres to the regulatory requirements for research which involves a prisoner as outlined in 45 CFR 46 Subpart C.

Definitions

Prisoner – A prisoner is defined as “an individual involuntarily confined or detained in a penal institution” and encompasses individuals sentenced to such an institution under criminal or civil statute, 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.

Prisoner Representative – An individual who is currently or formerly a prisoner or an individual who has a close working knowledge, understanding and appreciation of prison conditions from the perspective of the prisoner (e.g., prison chaplain, prison social worker, prison health care worker.)

Minimal Risk – For research involving prisoners, the IRB will use the following definition for "minimal risk": "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 (emphasis added)."

Regulatory Requirements

Research involving prisoners will be reviewed by a convened IRB committee which includes at least one member who is a prisoner or a prisoner representative with appropriate background and experience to serve in that capacity. This includes initial review, continuing review, full-board modifications, and reportable unexpected or unanticipated problems.

• Modifications that would otherwise be approvable by expedited review can be expedited as long as the prisoner representative receives a copy of the modification and concurs that it does not adversely affect the prisoners.

The IRB will approve the research only if it finds and documents that:

1. the research meets one of the regulatory criteria for approval addressed under 45 CFR 46.306 (a)(2); that is the research is a 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;
     
   • 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;
   • 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 has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the FEDERAL REGISTER, of his intent to approve such research; or
   • 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 has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the FEDERAL REGISTER, of the intent to approve such research.
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, and quality of food, amenities and opportunity for earnings in the prison, are not of such 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 research project;
5. the information is presented in a 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;
7. where the IRB finds there may be a need for follow-up examination or care of subjects 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 subjects of this fact.

Note: An IRB finding that follow-up examination or care of the prisoner-subjects may be needed after the end of their study participation will necessitate a change in the standard Compensation for Injury section of the informed consent document. The change will need to address the provision of long-term care for this subject population and must be prior approved by legal counsel to the IRB.

Note: An IRB finding that follow-up examination or care of the prisoner-subjects may be needed after the end of their study participation will necessitate a change in the standard Compensation for Injury section of the informed consent document. The change will need to address the provision of long-term care for this subject population and must be prior approved by legal counsel to the IRB.

If a study utilizing prisoners as research participants is federally funded, the IRB must send a letter to the Office for Human Research Protections (OHRP) indicating it has approved a study that will include prisoners, the category the study fits into as well as how the study satisfies the six criteria noted under the regulations. A research study is not permitted to commence for DHHS supported research until written approval is received from OHRP on behalf of the DHHS Secretary under the provisions of 45 CFR 46.306(a)(2).

Research Conducted in Pennsylvania State Department of Corrections

In Pennsylvania, the Department of Corrections has issued Policy Statement 2.1.2 which effectively bans the use of state prisoners in any medical experiments, cosmetic experiments, or pharmaceutical testing, with the exception for some testing involving treatment for AIDS and HIV infection. If a study utilizes prisoners from a state prison in Pennsylvania, approval from the Research Review Committee of the Commonwealth of Pennsylvania, Department of Corrections is required.

Research Conducted in the Federal Bureau of Prisons

The Federal Bureau of Prisons has adopted extensive regulations for researchers seeking to use federal prisoners as research subjects. Among other things, these regulations prohibit use of prisoners within federal facilities for “medical experimentation, cosmetic research, or pharmaceutical testing.” 28 C.F.R. 512.11(a)(3). In addition, strict limitations are imposed on incentives to prisoner/participants, and researchers may not promise confidentiality to subjects who reveal a future intent to engage in criminal behavior. For additional requirements related to the Department of Justice regulations, see Section XXIV.

Research Involving Pregnant Women

Definitions

Dead fetus means a fetus that exhibits neither heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, nor pulsation of the umbilical cord.

Delivery means complete separation of the fetus from the woman by expulsion or extraction or any other means.

Fetus means the product of conception from implantation until delivery.

Neonate means a newborn.

Nonviable neonate means a neonate after delivery that, although living, is not viable.

Pregnancy encompasses the period of time from implantation until delivery. A woman will be assumed to be pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, until the results of a pregnancy test are negative or until delivery.

Viable, as it pertains to the neonate, means being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration. The Secretary may from time to time, taking into account medical advances, publish in the Federal Register guidelines to assist in determining whether a neonate is viable for purposes of this subpart. If a neonate is viable then it may be included in research only to the extent permitted and in accordance with the requirements of subparts A and D of this part.

Regulatory Requirements

For research involving pregnant women, fetuses, or neonates the IRB will approve the conduct of the research only if it finds that the research meets the regulatory criteria for approval addressed under the federal regulations at 45 CFR 46 Subpart B (45 CFR 46.204, "Research involving pregnant women or fetuses prior to delivery"; 45 CFR 46.205, "Research involving neonates"; 45 CFR 46.206, "Research involving, after delivery, the placenta, the dead fetus, or fetal material").

For research that does not meet the criteria for approval addressed under 45 CFR 46.204, "Research involving pregnant women or fetuses prior to delivery"; 45 CFR 46.205, "Research involving fetuses after delivery"; or 45 CFR 46.206, "Research involving, after delivery, the placenta, the dead fetus, or fetal material," the IRB must find that:

• the research presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women or fetuses; and
• the research, if federally supported, will be submitted for review and approval by the Secretary, DHHS, in accordance with the provisions of 45 CFR 46.207, "Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women or fetuses". If the research study is not federally-supported and not conducted in the Clinical Translational Research Center (CTRC), the IRB Office will use a review by a panel of obstetrician/ gynecology experts (2 members of the CTRC who are not currently IRB members) and an ethicist to recommend whether to approve the study as research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of pregnant women or fetuses.

Consent

Pregnant Women/Fetus Prior to Delivery

For research involving pregnant women or the fetus prior to delivery, the documented, written informed consent of the pregnant women or her authorized representative will be obtained in accordance with the provisions of 45 CFR 46.204; unless the IRB grants either a waiver of informed consent in accordance with 45 CFR 46.116(d) or a waiver of the requirement to document informed consent in accordance with 45 CFR 46.117(c).

Neonates of Uncertain Viability

For research involving neonates of uncertain viability, the documented, written informed consent of either parent or the authorized representative of either parent will be obtained in accordance with the provisions of 45 CFR 46.205; unless the IRB grants either a waiver of informed consent in accordance with 45 CFR 46.116(d) or a waiver of the requirement to document informed consent in accordance with 45 CFR 46.117(c).

Nonviable Neonates

For research involving nonviable neonates (i.e., neonates determined to be unable, after delivery, to survive to the point of independently maintaining heartbeat and respiration), the documented, written informed consent of both parents will be obtained in accordance with the provisions of 45 CFR 46.205.

• If either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the IRB may approve the research based on the consent of one parent. (Note: the consent of the father need not be obtained if the pregnancy resulted from rape or incest.)
• Note: the IRB may not grant approval for authorized representative (i.e., proxy) consent or a waiver of the requirement to obtain consent (i.e., 45 CFR 46.116 (c) or 45 CFR 46.116 (d)) for research involving nonviable neonates.

Fetal Material Derived from Abortion

For research involving the dead fetus or fetal material derived from an induced abortion, the documented written informed consent of the mother must be obtained in accordance with the Pennsylvania Abortion Control Act.

• The research protocol must specify that informed consent for use of the fetal tissue for research will be obtained separately from, and after, the consent is obtained for the abortion.
• No remuneration, compensation or other consideration of any kind may be offered to a woman to consent to the use of fetal tissues for research.
• The donor may not designate the recipient of fetal tissue.

All persons who participate in the procurement, use or transplantation of fetal tissue must be informed as to the source of the tissue (e.g., abortion, miscarriage, still birth, ectopic pregnancy). Any protocol that involves an intervention derived from fetal tissue must include the information as part of the informed consent document and/or process.

Under Pennsylvania law, any nontherapeutic medical procedure performed upon a fetus may be considered to be a third degree felony. 18 Pa.Con.Stat Section 3216(a).

If researchers are obtaining fetal tissues or organs from sources outside of the University of Pittsburgh, confirmation must be provided from the outside source that the material was collected with appropriately obtained consent under applicable laws.

Research Involving Decisionally Impaired Individuals

Definitions

Decisionally impaired persons are those who have a diminished capacity to understand the risks and benefits for participation in research and to autonomously provide informed consent. This decisional impairment may result from a psychiatric, organic, developmental or other disorder that affects cognitive or emotional functions, or may result from the effect of drugs or alcohol. The impairment may be temporary, permanent or may fluctuate.

Legally Authorized Representative: An individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research.

Internal Review Requirements

Although not specifically addressed in the regulations as a vulnerable population, the University of Pittsburgh IRB requires additional safeguards for research involving persons with decisional impairment. The IRB will approve the research only if it finds that:

1. the research bears a direct relationship to the decisionally impaired subject’s condition or circumstance;
2. the research meets one of the following criteria:
   • presenting no greater than minimal risk to the involved subjects;
   • presents an increase over minimal risk to involved subjects, but which offers the potential for direct individual benefit to the subject;
   • presents a minor increase over minimal risk to involved subjects and which does not have the potential for direct individual benefit; provided that the knowledge sought has direct relevance for understanding or eventually alleviating the subjects' disorder or condition.

In evaluating a protocol involving the enrollment of persons with decisional impairment, The IRB may consider requiring additional safeguards, as appropriate, for a given protocol. Such safeguards may include any of the following:

• use of an independent party (independent of the study investigator with appropriate expertise) to assess the capacity of the potential subject;
• use of standardized assessment of cognition and/or decisional capacity;
• use of informational or educational techniques;
• use of an independent person to monitor the consent process;
• use of waiting periods to allow for additional time to consider information about the research study;
• use of proxy consent;
• use of assent in addition to proxy consent in order to respect the autonomy of individuals with decisional impairment.

Consent

In general, all adults, regardless of diagnosis or condition, should be presumed competent to consent to participation in research unless there is evidence of serious disability that would impair reasoning or judgment. In making the determination about whether it is appropriate for investigator’s to utilize proxy consent, the IRB will take into consideration the following:

• the rationale for the need to obtain proxy consent;
• the criteria that will be used in determining whether a potential subject has decisional impairment sufficient to require the use of proxy consent, including any use of standardized assessment tools;
• whether any additional methods are proposed to enhance subjects’ ability to achieve decisional capacity with regard to the proposed study (e.g., reading of the consent form may not be sufficient and use of other tools such as videos, educational materials, post-test, etc. might be considered to assist potential subjects in understanding what is involved with the research);
• who will be approached, and in what order, to provide proxy consent.

The following are specific procedures that must be followed if proxy consent is utilized:

• Persons with decision impairment may also have been adjudicated legally incapacitated by a court decision. If such persons are considered for enrollment in a research protocol, the only party who may provide proxy consent is the court-appointed guardian. The guardian may only provide proxy consent if the court order, appointing them guardian, specifically states that they have the authority to enroll the incapacitated person into a research protocol. For this category of subjects, a copy of the court order appointing the guardian and granting the guardian authority to enroll the person into a research study should be attached to the informed consent document.
• Persons may also, through a health care proxy appointed by a power of attorney, designate a person to make decisions for them in the event that they are subsequently incapacitated. This person may give proxy consent for enrollment of a subject in research.
• If a potential subject has neither a guardian, nor a health care proxy designated, the investigator may obtain the informed consent of the subject’s legally authorized representative. Where neither a court-appointed guardian, nor a health care proxy exists, investigators may seek informed consent from the following individuals, in the order listed below:
  • Spouse;
  • natural or adoptive parent;
  • adult child;
  • adult brother or sister;
  • any other available adult relative related through blood or marriage known and documented to have made decisions for the subject in prior health care settings.

When a person is giving proxy consent, the proxy should be informed that, where possible, s/he should base the decision on substituted judgment, reflecting the views that the subject expressed while decisionally capable. The proxy should be fully informed on the risks, benefits and alternatives to the research. If the values of the subject are not known with respect to a proposed research study, the proxy should act in the best interest of the subject.

If a person with decisional impairment is capable of exercising some judgment concerning the nature of the research and participation in it, the investigator should obtain the subject’s assent in addition to the consent of his/her legally authorized representative.

The verbal objection of an adult with decisional impairment to participation in the research should be binding. If the subject, at any time, objects to continuing in the research study, such objection should be respected.

Where the condition causing the subject’s decisional impairment is of an intermittent or temporary nature, the informed consent process should include a mechanism for obtaining the subject’s subsequent direct informed consent to participate in the research. If a subject regains decision making capacity and declines to continue in the research, the decision must be respected.

Documentation of Consent and Assent: Informed Consent Document

Adult subjects, not deemed to have decisional impairment, should read and sign the informed consent document in the standard manner.

For adult persons with decisional impairment, the investigator should document the following before obtaining the consent and signature of the subject’s legally authorized representative or guardian and the signature of the witness to this consent:

• the conclusion that the subject is incapable of understanding the information presented regarding the research, to appreciate the consequences of acting (or not acting) on that information, and to make a choice;
• the information provided to the subject’s legally authorized representative regarding the cognitive and health status of the subject, the risks and benefits of the research, and the role of the proxy.

To document obtaining the assent of a subject with decisional impairment, a Verification of Explanation statement should appear on the consent document and be signed and dated by the Principal Investigator, listed co-investigator, or other research staff when authorized by the IRB.

Documentation of Consent and Assent: Research Record

In studies in which some or all participants may have decisional impairment, it is recommended that at the time of obtaining consent the following be documented in a note to file for the subject’s research record:

• whether the subject demonstrated the ability to understand the nature of the research procedures, the potential risks and benefits, the voluntary nature of the participation and to make a personal judgment about participation;
• use of any supplemental methods to enhance or evaluate decisional capacity;
• a summary of the matters discussed with the subject’s legally authorized representative.

Research Involving Subjects in Long Term Facilities

Commonwealth of Pennsylvania law specifies under 28 PA Code Section 201.29 (o): "Experimental research or treatment in a nursing home may not be carried out without the approval of the Department (i.e., PA Department of Health) and without the written approval of the resident after full disclosure.” For the purposes of this subsection, "experimental research" means an experimental treatment or procedure that is one of the following:

• Not a generally accepted practice in the medical community;
• Exposes the resident to pain, injury, invasion of privacy or asks the resident to surrender autonomy, such as a drug study.

The IRB will ensure that PA Department of Health approval is included in any submission which meets these criteria.

Research Being Conducted in Pennsylvania In-Patient Mental Health Facilities

According to the Pennsylvania Patient Bill of Rights, 55 Pa. Code 5100.54 (Article VI.2(d)):No patient can be the subject of any research, unless conducted in strict compliance with Federal regulations on the protection of human subjects. Patients considered for research approved by the facility will receive and understand a full explanation of the nature of the research, the expected benefit, and the potential risk involved. Copies of the Federal regulations will be made available to patients involved in, or considering becoming involved in, research or their advocates. Patient research conducted in State facilities or funded by State monies requires prior approval of the Deputy Secretary of Mental Health.

Researchers proposing to conduct research in such facilities should detail in their protocols how they will comply with these requirements and will include a copy of any necessary approvals from the state.

Research Involving Terminally Ill Patients

Research involving terminally ill patients presents additional concerns in that potential subjects tend to be more vulnerable to coercion or undue influence, and the research is likely to present greater than minimal risk. As a result, special attention should be given to the informed consent process. The following elements must be emphasized:

• Accurate information concerning eligibility for participation and risks and benefits should be conveyed clearly and in a manner that will not either engender false hope or eliminate all hope;
• Patients should be fully informed of the availability of treatment alternatives, including at what point their participation in the research study should or may be terminated to permit a treatment alternative, and that an alternative may include no additional treatment;
• Any costs to the patient associated with research study participation should be stated explicitly.

Research Involving Emergency Medical Services

For research involving Emergency Medical Service (EMS) operations in the Commonwealth of Pennsylvania, the IRB will require that investigators obtain prior approval of the Pennsylvania Department of Health if the research involves direct patient care provided by EMS workers.

Students as Research Participants

Students, including University of Pittsburgh students (e.g., undergraduates, graduate students, medical students, residents, fellows, doctoral students, etc.) may be recruited for research participation; however, a student may not be required to participate in research (without a comparable non-research alternative offered) as a course requirement. Students (individuals or groups) should not be selected solely on the basis of convenience when they would not otherwise be appropriate for inclusion.

Recruitment

Recruitment of students as research participants must be designed to minimize the possibility of undue influence. In general, potential participants should be solicited from a “broad base” of individuals meeting the conditions for study, rather than by personal solicitation of specific students. Strategies to minimize the potential influence of an investigator when recruiting his/her own students include recruitment by general announcements, postings or sign-up sheets, or other methods that require a student interested in participation to initiate contact with the investigator(s).

Investigators and IRBs must consider strategies to ensure voluntary participation when the subjects of research include students who receive instruction directly from the investigator(s). Young students, particularly, may volunteer to participate in research in an effort to please a teacher (e.g., as when credit is given for participation in class) or because they fear that failure to participate will negatively affect their relationship with the teacher-investigator or faculty in general (i.e., by seeming uncooperative or unaware of scholarly research). Students’ cultural or religious backgrounds (e.g., requiring deference to authority figures) may also influence their choices. A student’s decision about research participation may not affect (favorably or unfavorably) grades, potential letters of recommendation, or other opportunities or decisions made by teacher-investigators.

Except in unusual circumstances, investigators should not enroll students from their own classes when the research involves greater than minimal risk without the prospect of direct benefit. Such studies should proceed only where the IRB determines that adequate provisions have been made to minimize the possibility of coercion, and the research is of significant importance and cannot be conducted without the enrollment of these students.

Safeguards for Privacy

Additional safeguards may be needed to protect the privacy interests of research participants when the participants are students. Classroom conditions may make it difficult for investigators to keep an individual’s participation confidential, which could pose risks to participants, e.g., when stigma is associated with the condition or question under study or when peer pressure is a component of the research. In such situations, consideration should be given to whether conducting the research off-site and/or outside of regular school hours may minimize potential risks. Protecting the confidentiality of research participants’ personal information when the participants are students may also present additional challenges. The extent to which personal information and/or research data may be accessible to parents, teachers, or others not directly involved in the research must be considered and disclosed to potential participants and their parents/guardians (as applicable) in the informed consent and assent processes.

In cases where regular classroom activities are also the topic of research, investigators must clarify for potential research participants (and/or their parents, as applicable) those activities that are optional and distinct from required classroom activities that would take place even without the research. When access to students or educational records is needed for recruitment and/or research activities, a letter of support from an individual authorized to speak on behalf of the institution (e.g., department chair, dean, etc.) may be required.

Family Educational and Rights Privacy Act (FERPA)

Certain additional protections for students and parents are provided by federal regulations. The proposed use of student education records for research must comply with the requirements of the Family Educational and Rights Privacy Act (FERPA). The University of Pittsburgh has a FERPA policy that is applicable in part for researchers who are conducting research on students at this institution. For researchers conducting research at other institutions, please note that FERPA restricts researchers’ access to student records without written permission from parents of minor children, or permission of students over the age of 18. While some exceptions to FERPA may be available in a particular case, investigators must contact each institution in which they will be conducting research and follow that institution’s FERPA policy, in addition to the requirements of the IRB.

Protection of Pupil Rights Amendment (PPRA)

Research involving surveys with students in elementary and secondary schools that receive funding from the Department of Education must also comply with the Protection of Pupil Rights Amendment (PPRA). Guidance on PPRA requirements can be obtained at http://www.irb.pitt.edu/Guidance/.

• Per the Department of Education, research or experimental program or project means any program or project in any research that is designed to explore or develop new or unproven teaching methods or techniques.

Medical Students as Participants

Given the heavy curriculum burden on Medical students, the School of Medicine specifically developed a policy for the enrollment of University of Pittsburgh Medical Students into research protocols.

For research studies in which medical students are being recruited as subjects, including surveys of medical students, the School of Medicine’s Research on Medical Students (ROMS) Review Committee must review the proposed research plan before it can be submitted to the University of Pittsburgh Institutional Review Board (IRB). This review includes examination of how medical students will be recruited, and be involved, in the study, and how the study will fit within the conduct of the medical school curriculum. The goal of this requirement is to balance the needs of researchers with the interests and availability of the medical students being solicited as research subjects.

For this review, investigators are asked to submit their draft IRB proposal along with any supporting documents that will shed light on what any one medical student would experience as being part of the project. The submission is then reviewed by the ROMS Review Committee. Reviews are typically conducted within 2-3 weeks. The result of an approval from the ROMS Review Committee is a letter to the primary investigator which must be submitted to the IRB together with the other IRB documents in the OSIRIS electronic submission system.

To submit a study for review by the ROMS Review Committee, please e-mail the review request to John Mahoney MD, Associate Dean for Medical Education at mahoney@medschool.pitt.edu. Dr. Mahoney can also be reached at 412-648-8714.

Psychology Subject Pool

University of Pittsburgh students are offered the opportunity to participate in research (as participants) in various ways. Examples include participation for credit as part of a course requirement (e.g., Psychology Subject Pool), for credit in a course, or in exchange for payment. A Pitt student may not be required to participate in research for course credit. In all cases, a comparable non-research alternative must be offered.

To minimize the potential for coercion, alternatives to participating in research for course credit that are offered must be comparable in terms of time, effort, and fulfillment of course requirements.

All research participants, including students, must be free to withdraw from participation at any point in a study without penalty. Students who withdraw from a research study for course credit must receive full course credit for participation. When payment is offered, credit for payment accrues as the study progresses (as appropriate to the research) and is not contingent upon the student completing the entire study.

Study-specific informed consent is required as described by federal regulations and University of Pittsburgh policies. Parental permission and assent are required for University of Pittsburgh students (including high school students taking Pitt courses) who meet the regulatory definition of children.

Research Involving Employees as Research Participants

University of Pittsburgh employees may enroll in research protocols approved by the IRB. However, additional considerations and safeguards should be considered.

Employees, including University of Pittsburgh and UPMC employees (e.g., full-time, part-time, temporary, visiting, student employee appointments, etc.) may be recruited for research participation; however, an employee may not be required to participate in research as a condition of employment. Employees (individuals or groups) should not be selected solely on the basis of convenience when they would not otherwise be appropriate for inclusion.

Recruitment of potential participants who are employees must be designed to minimize the possibility of coercion or undue influence. In general, potential participants should be solicited from a “broad base” of individuals meeting the conditions for study, rather than from individuals who report directly to the investigator(s). Strategies to minimize the potential influence of an investigator when recruiting his/her own employees include recruitment through a third party unassociated in a supervisory relationship with the employee, postings or sign-up sheets, or other methods that require an employee interested in participation to initiate contact with the investigator(s).

Investigators and IRBs must consider strategies to ensure voluntary participation when the subjects of research include employees who are directly supervised by the investigator(s). An employee’s decision about research participation may not affect (favorably or unfavorably) performance evaluations, career advancement, or other employment-related decisions made by peers or supervisors. Investigators may act as participants in their own studies if they meet the inclusion/exclusion criteria and all procedures including consent are completed by a Co-Investigator or Coordinator.

Except in unusual circumstances, investigators should not enroll employees under their direct supervision into research studies that involve greater than minimal risk without the prospect of direct benefit. Such studies should proceed only where the IRB determines that adequate provisions have been made to minimize the possibility of coercion, and the research is of significant importance and cannot be conducted without the enrollment of these employees.

Additional safeguards may be needed to protect the privacy interests of employees who are also research participants. Workplace conditions may make it difficult for investigators to keep an individual’s participation confidential, which could pose risks to participants, e.g., when stigma is associated with the condition or question under study or when peer pressure is a component of the research. In such situations, research should be conducted off-site and/or outside of regular work hours when possible to minimize potential risks.

Protecting the confidentiality of research participants’ personal information when the participants are employees may also present additional challenges. The extent to which medical information and/or research data may be accessible to supervisors or others not directly involved in the research must be considered and disclosed to potential participants in the informed consent process.

In cases where regular workplace activities are also the topic of research, investigators must clarify for potential research participants those activities that are optional and distinct from any mandatory workplace activities that would take place even without the research. When access to individuals or the facilities of the site is needed for recruitment and/or research activities, a letter of support from someone authorized to speak on behalf of the employees/site may be required.

General Recruitment Policies

Recruitment plans for research projects should be designed to fully encompass racial, ethnic, and gender diversity. Efforts to identify and recruit potential human research subjects should be designed to respect personal rights to privacy and confidentiality. Everything possible should be done to avoid coercion of subjects in their recruitment for research study participation. Recruitment of vulnerable subjects should be done with respect to the regulations at 45 CFR 46, Subparts B, C or D, as appropriate. The IRB will evaluate the recruitment methods to ensure compliance with federal regulations as well as HIPAA Privacy rules. All print, video, and audio advertisements used to solicit prospective research subjects (‘directed advertising’) must be reviewed and approved by the IRB prior to dissemination.

The IRB prohibits cold-calling of potential research subjects. "Cold-calling" is the practice of investigators or research staff, unknown to the potential research subject, initiating contact with the potential subject based on their prior knowledge of private information. To avoid a cold-calling scenario, the research study should be introduced to the potential research subject by an individual who, by virtue of his/her position, would normally have access to the potential subject’s confidential information (e.g., the personal physician of the potential subject or a member of the clinic or practice staff). If the potential research subject indicates an interest in study participation, s/he should be instructed to either (a) contact the investigators directly or (b) permit the individual who initiated this contact to share with the research team the person’s interest in study participation so that the researchers can subsequently contact the potential subject and provide more information about the study.

The individual who initially introduced the study to the potential subject should document this permission in his/her records. As per the HIPAA privacy regulations, a health care provider may not share individually identifiable health information with research investigators without the written authorization of the patient. Hence, whenever there is the possibility that the potential subject’s health information and identity will be shared with members of the research team, a valid HIPAA authorization may be required from the potential subject. There are exceptions, however. For example, when a UPMC clinician refers a potential subject to a UPMC researcher a written HIPAA authorization is not required. The referring UPMC clinician must document in the clinical record the potential subject’s permission for his/her contact information to be shared with the UPMC researcher. More discussion of this, with model HIPAA authorizations for sharing health information is available in the IRB HIPAA Guidance Web page.

Examples of acceptable methods of contacting and/or recruiting potential research subjects include:

• Direct discussion of the study during a face-to-face interaction with a potential research subject.
• Mailings sent to the prospective subject from their provider, clinic, or program representative. Mailings can describe the purpose of the study and request that the subject return a postcard or make a telephone call indicating his/her agreement to participate. A less preferable option is to request the person send back a postcard (or call a designated phone number) only if s/he does not wish to participate. If no response is made within a specified time period, the subject may then be contacted by the investigator or a member of the research team. A drawback to this approach is that individuals so contacted may feel harassed by the researchers if, for example, they never receive the letter, can't read the letter, or are confused by the instructions. For studies involving children, the letter introducing the study should be sent to the child’s parents and parental permission obtained prior to enrolling the child in the research study.
• Random digit dialing and reverse directories. This differs from “cold calling” in that the call is being initiated on publicly available information rather than prior knowledge of private information.
• Public advertisements or notices posted in public places.

Directed Advertising

Directed advertising includes, but is not limited to, newspaper, radio, TV, Internet ads, audio/video tapes, bulletin boards, posters, and flyers that are intended for prospective subjects.

The following are not considered to be 'direct advertising' and do not require prospective IRB review:

• Communications intended to be seen or heard by health professions, such as “dear doctor” letters and doctor-to-doctor letters (even when soliciting for study subjects);
• News stories, so long as information is not provided regarding recruitment;
• Publicity intended for other audiences, such as financial page advertisements directed toward prospective investors;
• Directories of clinical trials on the internet when the system format limits the information provided to the most basic trial information, such as the title, basic eligibility criteria, and how to contact the study site for additional information.
  Examples of clinical trial listing services that do not need IRB review and approval include the National Institutes of Health (NIH) ClinicalTrial.gov website, the NIH National Cancer Institute’s cancer clinical trials listing (Physician Data Query [PDQ]), FDA Clinical Trials, and the government-sponsored AIDS Clinical Trials Information Service (ACTIS).
  
  When information posted on a clinical trial website goes beyond directory listings, such information is considered part of the recruitment and informed consent process and requires IRB review and approval. Examples of information which would exceed basic listing information include descriptions of clinical trial risks and potential benefits or solicitation of identifiable information (e.g., name and contact information).

Submission of Advertisements Directed at Potential Research Subjects

Advertisements directed at potential research subjects should be reviewed at the time of initial IRB review of the protocol. Advertisements directed at potential research subjects not reviewed at the time of initial IRB review must be submitted as a modification through the OSIRIS system and reviewed in an expedited manner by the IRB Chair, his/her designee, or the IRB Vice Chairs.

• The IRB will review a final formatted version of printed advertisements to evaluate the relative size of type used and other visual effects.
• When advertisements are to be taped for broadcast, the IRB will, at a minimum, review and approve the wording of the advertisement prior to taping, and, if made available review the final audio or videotape.

Approval Criteria

The following criteria must be met in order to gain IRB approval:

• Advertisements cannot state or imply a certainty of favorable outcome or other benefits beyond what is outlined in the protocol and consent document.
• Advertisements cannot state or imply that the drug, biologic, device or other type of intervention is safe or effective for the purposes under investigation.
• Advertisements cannot state or imply that the test article or other research intervention is known to be superior or equivalent to any other drug, biologic, device or intervention.
• Advertisements for recruitment into a research study involving an investigational drug, biologic, or device should not use terms such as "new treatment", "new medication", or "new drug" without explaining that the test article is investigational.
• Advertisements cannot promise “free medical treatment” when the intent is only to state that subjects will not be charged for taking part in the investigation.
• Advertisements may state that subjects will be paid, but should not emphasize the payment or the amount to be paid by such means as larger or bold type. Advertisements aimed at recruitment of children cannot contain the dollar amount of the compensation.
• Advertisements cannot include exculpatory language through which the participant or their legally authorized representative waive legal rights or releases the investigator, the sponsor or institution from liability for negligence.
• Advertisements cannot include compensation for participation in a trial offered by a Sponsor to include a coupon good for a discount on the purchase price of the product once it has been approved for marketing.

The advertisement should generally be limited to the information that potential subjects need to determine their eligibility and interest in the research. When appropriately worded, the following items may be included in advertisements, but are not required:

• The name and address of the clinical investigator and / or research facility;
• The condition under study and/or the purpose of the research;
• In summary form, the criteria that will be used to determine eligibility for study participation;
• A brief list of participation benefits, if any;
• The time or other commitment required of the subjects;
• The location of the research and the person or office to contact for further information.

Investigator Notifications

Investigators will be notified in writing of IRB approval of advertisements directed at potential research subjects. The written notification of IRB approval of the research will include a statement that the advertisement was approved by the IRB. In addition, the correspondence will specify that any substantive modification of the advertisement requires re-approval by the IRB prior to dissemination.

Incentives for Participation in Research Studies

General Policies for Incentives for Participation in Research Studies

Subjects may be paid or otherwise rewarded (e.g., gift card) for participating in a research study. Note, however, that remuneration is a recruitment incentive; it is not a benefit of study participation. Incentives are frequently used when the benefit of study participation is otherwise remote or non-existent.

• The amount of payment, if any, should be reasonable, based on the complexities and inconveniences of the study. The amount of payment should NOT be based on the risk of study participation.
• The magnitude of the incentive and the proposed method and timing of its disbursement must not be coercive or present undue influence for initial or continued participation in the study.
• It is acceptable for students to be offered course credits for their participation in a research study. However, the student must be provided with alternate, equitable ways to earn these credits if they decide not to participate in the research study. (See Policy XIV for more information on students in research).

Payment Disbursement Guidelines

Any payment or reward should accrue as the study progresses and not be contingent upon the human research subject completing the entire study. Disbursement of a proportion of the total payment or reward contingent upon study completion is acceptable, provided that the amount of this incentive is not so large as to unduly induce subjects to remain in the study when they might otherwise withdraw voluntarily.

IRB Review and Approval of Incentives for Participation in Research Studies

Information concerning the remuneration of human research subjects, including its amount or nature and the schedule of its disbursement, is subject to initial and continuing review by the IRB. This information must appear in the Costs and Payments section of the OSIRIS application and informed consent document(s). It cannot be included as a benefit of study participation.

Finder’s Fees and Bonus Payments

It is not permissible for researchers to pay or receive finder’s fees for referral of research subjects. Physicians who refer a potential subject for participation in a research study are permitted to be paid, at a reasonable amount, for any services (e.g., obtaining a medical history, performing screening examinations, conducting medical record reviews, etc.) that they perform in support of the research study. It is not permissible to pay or receive bonuses with respect to subject recruitment goals or completion of a study.

IRB Review of Studies Utilizing Drugs, Biologics and Devices

The US Food and Drug Administration (FDA) regulates clinical studies conducted on drugs, biologics, devices, diagnostics, and in some cases dietary supplements and food additives. All such research studies must be conducted in accordance with FDA requirements for the protection of human subjects and IRBs, regardless of source of funding (21 CFR Parts 50 and 56).

When FDA regulated test articles are used in research conducted at the University of Pittsburgh and funded by another agency, more than one set of regulations may apply. For example, clinical trials involving FDA regulated test articles that are supported by the Department of Health and Human Services (DHHS) fall under the jurisdiction of both the FDA and the DHHS Office for Human Research Protections (OHRP). Such trials must comply with the FDA and the DHHS human participant regulations. Where regulations differ, the University of Pittsburgh IRB will apply the stricter regulation.

In addition to the other applicable requirements outlined in this document, for studies involving drugs, biologics or devices the IRB shall follow the procedures outlined below. As specified in Section XII, reviewers are provided with the sponsor protocol as well as other materials specific to the study, e.g. the investigator brochure and correspondence with the applicable regulatory agencies.

Considerations for FDA Regulated Research – Drugs, Biological Products, and Dietary Supplements

Research Involving Drugs and Biological Products

For studies that involve FDA regulated drugs and biological products the UOP IRB will comply with the requirements of 21 CFR Parts 312 and 600.

Research Involving Unapproved / Investigational Drugs and Biological Products

In general, the submission of an Investigational New Drug (IND) application is required for any clinical research study that proposes the use (e.g., as a research tool to explore a biological phenomena or disease process) or evaluation (i.e. for safety and/or effectiveness) of an unapproved drug or biological product.

For studies that involve investigational drugs or biological products, the IRB shall require evidence that the FDA has issued an Investigational New Drug (IND) number. This confirmation will be made by determining if the IND number provided on the IRB coversheet or the OSIRIS submission matches that recorded on the sponsor protocol, communication from the sponsor, or communication from the FDA.

Research Involving Approved Drugs or Biological Products

For research using an approved drug or biologic, where the investigator has not provided a valid IND number, the IRB shall evaluate the protocol to determine if an IND is required. In general, the submission of an IND is not required for any clinical research study that proposes the use or evaluation (i.e., for safety and/or effectiveness) of an approved drug, provided that:

• The results of the study are not intended to be reported to the FDA in support of a new indication for the use of the drug or to support any other significant change in the labeling of the product;
• The results of the study are not intended to support a significant change in the advertising for the product;
• The study does not involve a route of administration or dosage level, or use in a subject population or other factor that significantly increases the risks (or decreases the acceptability of risks) associated with the use of the product; and
• The study is conducted in compliance with the requirements for IRB review and informed consent.

Dietary Supplements

Dietary supplements are exempt from FDA regulation as “drugs” provided that they are being evaluated and/or are labeled for intended use in affecting the structure or function of the body (i.e., a structure/function claim).¹ Considerations for FDA Regulated Research – Devices However, the evaluation of a dietary supplement for the diagnosis, prevention, mitigation, treatment or cure of a specific disease or condition (i.e., a disease claim) requires the prior submission of an IND application.

Considerations for FDA Regulated Research – Devices

Research Involving the Use of Medical Devices

A medical device is defined, in part, as any health care product that does not achieve its primary intended purpose by chemical action or by being metabolized. Examples of medical devices include, but are not limited to, surgical lasers, wheelchairs, sutures, pacemakers, vascular grafts or stents, intraocular lenses, orthopedic pins, and radiographic imaging equipment. Medical devices also include diagnostic aids such as reagents and test kits for in vitro diagnosis of disease or other medical conditions such as pregnancy.

For research involving medical devices, the UOP IRB will comply with the requirements set forth in 21 CFR Part 812. These regulations describe two types of investigational device studies, "significant risk" and "non-significant risk."

• A "significant risk device study" is defined by FDA regulations as a study of a device that presents a potential for serious risk to the health, safety, or welfare of a subject and/or a) is intended as an implant² Dietary Supplement Health and Education Act. ; b) is used in supporting or sustaining human life; c) is of substantial importance in diagnosing, curing, mitigating or treating disease, or otherwise preventing impairment of human health or d) otherwise presents a potential for serious risk to the health, safety, or welfare of a subject.
• A "non-significant risk device study" is a study of a device that does not meet the FDA’s definition for a "significant risk device study."

The determination that a device study presents a “significant risk” or a “non-significant risk” is initially made by the sponsor/investigator. If the sponsor/investigator considers the device study to be of “non-significant risk”, the sponsor/investigator must provide the IRB with an explanation of this determination and copies of the respective research protocol and informed consent document. The sponsor should inform the IRB of the FDA’s assessment of the risk status of the proposed device study, if such an assessment has been made. The IRB may question whether other IRBs have reviewed the proposed device study and what determination they made or the IRB may consult with the FDA for its opinion.

In making the risk determination, the IRB considers both the device as well as the nature of harm that may result from the use of the device. The IRB may agree or disagree with the determination of the sponsor/investigator.

If the IRB determines that the device study presents “non-significant risk”, and approves the research study and informed consent document(s), the study may proceed without further notification of the FDA.

If the IRB determines that the device study presents a “significant risk”, the sponsor must notify the FDA that the device study has been determined to be of “significant risk” and if electing to proceed with the study, must submit an IDE application. The device study may not commence until the FDA approves the IDE and the IRB approves the device risk designation, the study protocol and informed consent document(s).

The IRB will utilize the device checklist in making this determination and the determination will be recorded in the IRB meeting minutes.

Considerations for FDA Regulated Research – Humanitarian Use Devices (HUDs)

IRB Review and Approval of Humanitarian Use Devices (HUDs)

For proposals involving Humanitarian Use Devices, the UOP IRB will comply with the requirements set forth in 21 CFR Part 814.Subpart H.

A humanitarian use device (HUD) is a device that the FDA has determined is intended to benefit patients in the treatment and/or diagnosis of diseases or conditions that affect or are manifested in fewer than 4,000 individuals in the United States per year. The use of an HUD within its approved labeling does not constitute research. However, the FDA requires IRB review and approval before a HUD is used.

The processing and review of HUDs shall be handled in accordance with the other applicable sections of this policy, in particular Sections VIII and XII. Following are some requirements and procedures unique to studies involving HUDs.

Initial IRB Approval

The clinical use of a HUD within any institution that falls under the jurisdiction of the University of Pittsburgh IRB must be approved by a convened (i.e., full board) IRB for the initial approval. Investigators are required to provide the following information to the IRB for review:

• A copy of the FDA approval for the Humanitarian Use Device Exemption (HDE) for the HUD and its proposed use.
• A written statement from the responsible UPMC physician specifying the clinical indication for which the HUD will be used, where and by whom the HUD will be used within the UPMC environment. NOTE: This statement must specify that the use of the HUD will be limited to the clinical indications listed in the FDA-approved product labeling.
• A copy of the manufacturer’s product labeling, clinical brochure, and/or other pertinent manufacturer informational materials.
• A consent document as required by the Commonwealth of Pennsylvania for all invasive clinical procedures. This is separate from the clinical consent required by the hospital. Since the HUD is approved for clinical use by the FDA, words such as “research” or “study” should be avoided in this clinical consent form. There are specific requirements for information that must be contained in the consent document. Please see the guidance on this topic as well as a template consent document that can be utilized on the IRB Website.

Continuation of IRB Approval

The clinical use of a HUD must be reviewed at least annually. The IRB will review HUDs through an expedited review mechanism as permitted by guidance issued by the FDA. IRB approval for continuation of an HUD will be reviewed and approved by a physician vice chair. The following material must be submitted to the IRB at the time of continuing review.

• A cover letter, signed by the responsible physician, requesting continuation of IRB approval of the HUD. The cover letter should identify the HUD and describe for what indications the HUD has been used as well as where and by whom it was used within the UPMC environment.
• A copy of the current FDA-approved product labeling for the HUD.
• A copy of the current IRB-approved consent document and manufacturer’s patient information sheet.
• For each patient in whom the HUD has been used during the previous year, a summary of the following:
  • The clinical indication for the use of the HUD;
  • Adverse events associated with the clinical use of the HUD are commensurate with the expected risks as addressed in the product labeling;
  • The clinical outcome of the use of the HUD.

Modifications to the Device or Clinical Use of the Device

IRB approval is required for any modifications of the device and/or the proposed clinical use of the device. Investigators must submit the following information in order to request a modification:

• A cover letter, signed by the responsible physician, describing the modifications to the device and/or the proposed clinical use of the device and the rationale for such modifications.
• A copy of the HUD manufacturer’s amendment to the HUD product labeling, clinical brochure, and/or other pertinent manufacturer informational materials corresponding to the requested modifications.
• A copy of the revised clinical use statement and clinical consent form with the modifications highlighted.

Dependent on the nature of the modifications, review by either a convened IRB committee or an expedited review mechanism will be utilized. In the event that an expedited review mechanism is utilized, a physician vice chair will review and approve the modifications.

"Clinical use of the HUD must be limited to the manufacturer’s product labeling and the clinical protocol approved by the IRB."

Investigator Communications

In addition to the requirements outlined in Section VIII, the correspondence to the investigator should also include the following statement:

Considerations for FDA Regulated Research – Waiver of Consent for Planned Emergency Research

Criteria for Approval

In accordance with 21 CFR 50.24 or 45 CFR 46.101 (i), the IRB may approve planned research in an emergency setting without the informed consent of the participants or their legally authorized representatives in a limited class of emergency situations when the following criteria are met and documented:

• Potential subjects are in a life-threatening situation, and
  • available treatments are unproven or unsatisfactory and
  • collection of scientific data is required to determine the safety and effectiveness of the experimental intervention
• Obtaining informed consent is not feasible because:
  • the potential subject is not able to consent due to his/her medical condition
  • the intervention must be administered before consent from the potential subject’s authorized representative is feasible and
  • there is no reasonable way to prospectively identify potential eligible subjects
• Participation in the research study holds out the prospect of direct benefit to the subjects because:
  • the subjects are facing a life-threatening situation
  • appropriate pre-clinical and prior clinical research studies support the potential for direct benefit and
  • the risks associated with the research are reasonable relative to the risks of the subjects’ condition and the risk/benefit ratio of standard therapy for the condition
• The research could not be practicably carried out without the waiver.

Submission Requirements

The IRB recognizes the loss of the research subject’s autonomy when this waiver is granted and requires the following additional measures to be addressed by the Principal Investigator in the research protocol. These requirements include:

• A defined therapeutic window, based on scientific evidence, of the maximum length of time for which the intervention(s) must be initiated.
• A commitment to contact or attempt to contact, within this “therapeutic window”, a legally authorized representative for each subject and, if feasible, to ask this representative for consent for the subject’s participation. These efforts must be summarized by the investigator for all subjects enrolled at the time of continuing review.
• In the event of the unavailability of a legally authorized representative of the subject, a description of what attempts will be made, if feasible, to contact, within this “therapeutic window”, a member of the subject’s family to determine whether s/he objects to the subject’s participation.
• An informed consent document inclusive of the basic and applicable additional elements along with an outline of procedures to address subject enrollment with direct consent, if applicable, or with consent of the subject’s authorized representative, if available.
• Procedures to inform, at the earliest feasible opportunity, the subject (i.e., if his/her condition improves), a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member of the subject, of the subject’s inclusion in research, the details of the research, and the right to discontinue the subject’s participation at any time without penalty or a loss of entitled benefits.
• Appropriate procedures and information to be used in providing an opportunity for a family member to object to a subject’s participation in the research.
• Procedures to provide information about the research to the subject’s legally authorized representative or family member should a subject enrolled into the study without consent die before such individuals can be contacted.
• An independent data monitoring committee to exercise oversight of the research. See guidance on data and safety monitoring plans on the IRB website for additional requirements related to data and safety monitoring committees/plans.
• Prior specific IND or IDE approval from the FDA for research involving investigational or approved drugs or devices for which the IND/IDE submission clearly indicates that the protocol(s) may include subjects who are unable to consent.
• A plan for consultation with representatives of the community (communities) in which the research will be conducted and from which the subjects will be drawn. The University of Pittsburgh currently utilizes the Pittsburgh Human Relations Commission as its community consultation committee. A summary of comments/concerns raised by the community must be presented to the IRB prior to final approval being granted.
• A plan, including draft copy, for public disclosure/notification of the research to the community (communities) in which the research will be conducted and from which the subjects will be drawn. This could include meetings with focus groups, church or community organizations, newspaper articles, etc.
• A summary of comments/concerns raised during public disclosure/notification must be presented to the IRB prior to final approval being granted.

Note that public disclosure following the completion of the study to apprise the community and researchers of the study results is also required.

A licensed physician “who is a member of, or consultant to, the IRB and who is not otherwise participating in the clinical investigation” must concur that the waiver of consent is allowable. Review of the above requirements is documented by the IRB on the checklist titled “Documentation of IRB Review and Approval: Emergency Acute Care Research Involving a Waiver of Informed Consent.” Please refer to the IRB Forms page.

Special Additional Considerations

Research involving certain protected populations, including fetuses, pregnant women, prisoners and human in vitro fertilization, are explicitly excluded from eligibility for this waiver. If the research study does not involve an article regulated by the FDA and the IRB determines that it can approve an exception to the requirement for informed consent for emergency research as per the criteria addressed under 45 CFR 46.101 (i) (i.e., OHRP’s “Emergency Consent Waiver”), the IRB shall notify the OHRP of such approval.

If the IRB determines that the protocol does not meet the criteria outlined in 45 CFR 46.101 (i) [OHRP’s “Emergency Research Consent Waiver” to 45 CFR 46] or if applicable, 21 CFR 50.24, or because of other relevant ethical concerns disapproves the research, the IRB must promptly provide a summary of its findings to both the clinical investigator and the sponsor of the trial. The IRB recognizes that it is the sponsors’ responsibility to notify the FDA of the IRBs’ findings.

Investigators involved in the development or implementation of such research studies, wherein an exception to the requirement to obtain informed consent is an anticipated necessity, are advised to engage the assistance of the IRB Office as early as possible in the protocol development process. The Assistant Director of the IRB should be contacted for assistance with this matter.

Considerations for FDA Regulated Research – Emergency Use of Unapproved Drugs, Biologics, or Devices

Emergency Use of Unapproved Drugs, Biologics, or Devices

Note that the term device for the purpose of this section of the policy includes emergency use of an unapproved device as well as the emergency use of a humanitarian use device for an off-label indication.

Under the emergency use provisions in the FDA regulations (21 CFR 56.104(c)), the emergency use of an unapproved drug, biologic or device is an exemption from prior review and approval by the IRB. Due to the fact that the University of Pittsburgh’s Federal Wide Assurance with DHHS is limited to federally-supported research and the emergency use of an unapproved drug, biologic or device would be outside of a federally funded research study; the request for emergency use is handled as an exemption under the FDA regulations (in compliance with 21 CFR 56.104(c)). The resulting data may be collected as research data and included in any report to the FDA and the sponsor. However, the use of data from an emergency use of a test article for a retrospective research study is subject to prior review and approval by the IRB. Successive requests for an emergency use exemption cannot be used to conduct a prospective research study.

Notification of IRB Chair or Vice Chair (physician Vice Chairs only)

The IRB shall require that the IRB Chair or an IRB Vice Chair (physician Vice Chairs only) be notified, in advance, of the proposed emergency use of an unapproved drug, biologic, or device.

During non-routine working hours, the IRB Office telephone audix shall inform physicians with emergency use requests of the telephone number of the IRB Chair or in his/her absence the telephone number of the responsible physician Vice Chair.

Procedures for Emergency Use Requests (IRB Chair or Vice Chair Review)

The IRB Chair or Vice Chair notified of the intended emergency use of an unapproved drug, biologic, or device will do the following :

• Verify that the intended use meets the criteria for an emergency use; i.e.,
  • the patient has a life-threatening condition that requires immediate treatment;
  • no generally accepted alternative for treating the patient is available;
  • because of the immediate need to use the unapproved drug, biologic, or device, there is not sufficient time to obtain full-board IRB approval of a research protocol addressing this use; and
  • there has been no prior emergency use of the unapproved drug, biologic, or device; or a compassionate use protocol for the unapproved drug, biologic, or device has been submitted for pending IRB review and approval. If exceptional circumstances exist, a second emergency use may be granted.
• Document (via email) the notification of Emergency Use, to include the name, department affiliation and contact information of the requesting physician; the name of the patient; the identity of the unapproved drug, biologic, or device; the nature of its intended use and the date of notification
• Confirm that the required Investigational New Drug exemption (IND#) for an unapproved drug or biologic has been obtained for the emergency use
• Confirm for an unapproved device or humanitarian use device for an off- label indication that:
  • the manufacturer of the device has been informed of the intended emergency use and will document, if available (i.e., not required) the Investigation Device Exemption (IDE) number under which the emergency use will be conducted
  • the requesting physician will notify the Food and Drug Administration of the emergency use of the unapproved device within one day, if s/he has not already done so
• Forward the email documenting the notification of Emergency Use to the Assistant Director of the IRB or designee

In the event of a waiver of informed consent for an emergency use, the IRB Chair or Vice Chair will confirm that both the investigator and a physician who is not otherwise participating in the clinical investigation have certified in writing all of the following:

• the subject is confronted by a life-threatening situation necessitating use of the test article;
• informed consent cannot be obtained because of an inability to communicate with, or obtain legally effective consent from, the subject;
• time is not sufficient to obtain consent from the subject’s legal representative;
• no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life;

If, in the investigator’s opinion, there is not sufficient time to obtain an independent physician’s determination that the four criteria are met, the investigator should make the determination and subsequently obtain (i.e., within five working days) a review of his/her determination by a physician not participating in the investigation.

Procedures for Processing Notification of Emergency Use (Assistant Director of the IRB) or their designee

• Upon receipt of the email notification of Emergency Use, the Assistant Director of the IRB will record the following information on the Emergency Use Notification Procedure Form:
  • record the date the notification was received at the IRB Office;
  • the name and department of the physician;
  • the name of the drug, biologic or device;
  • the IND or IDE number;
  • the patient’s initials;
  • the name of the Chair or Vice Chair who was notified of the intended use.
• Assign an IRB number, to include an “EU” prefix.
• Ascertain that written informed consent of the patient, or the patient’s legally authorized representative, will be obtained prior to the emergency use of the unapproved drug, biologic or device.
• Submit a letter to the requesting physician acknowledging the notification of Emergency Use and outlining subsequent reporting requirements.
• Inform the requesting physician that s/he must comply with the IRB guidelines for documenting the emergency use of the unapproved drug, biologic, or device and for reporting outcomes to the IRB, manufacturer, and the Food and Drug Administration.

Review of Materials Submitted in Support of the Emergency Use

Requested materials submitted in support of the emergency use of an unapproved drug, biologic, or device will be reviewed by the IRB Chair or an IRB Vice-Chair. The IRB Chair or IRB Vice Chair will address with the involved physician any problems or deficiencies identified in the review. Failure to submit the requested materials within five working days will be brought to the attention of the IRB Chair who will subsequently contact the involved physician to address the delinquency.

Considerations for FDA Regulated Research – Request for an Exception to Informed Consent Requirements: Studies Using In Vitro Diagnostic Devices with Specimens that are Not Individually Identifiable

In Vitro Diagnostics (IVDs) are reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, to cure, mitigate, treat, or prevent disease. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.

IVDs that are being tested for possible future marketing are devices, and may also be biological products. They are test articles under Food and Drug Administration regulations and are subject to FDA regulations governing investigational devices (IDE regulations). When IVDs are used in research involving human subjects (or human samples), FDA’s regulations for the protection of human subjects (informed consent and IRB review) generally also apply.

IDE Exempt Studies

Studies may be exempt from FDA’s IDE regulations when the research meets all of the following criteria:

• The sponsor has labeled the device properly;
• The testing is non-invasive;
• The testing does not require an invasive sampling procedure that presents significant risk;
• The testing does not by design or intention introduce energy into a participant; and
• The testing is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically-established diagnostic product or procedure.

IRB Review

Unlike DHHS regulations, FDA regulations do not provide for exemption from IRB review when research involves existing specimens and the investigator records information without identifiers or linking codes. Nor do FDA regulations define “human subjects” with reference to the identifiability of the subject or of the subject’s private information (i.e., the donors of specimens/samples remain “human subjects” even when the specimens/samples are de-identified). Current FDA guidance indicates that IRB review is required for any IVD study involving human specimens/samples, even when the research involves no identifiers and the biological materials cannot be linked to any identifying information.

Informed Consent

With a few narrow exceptions (emergency and some DOD research), FDA regulations do not permit waiver of consent, even when studies are minimal risk and would meet criteria for waiver of consent under DHHS regulations. Under FDA regulations, informed consent is required for IVD studies involving samples that are identifiable (i.e., are labeled with identifiers or accompanied by the patient’s identifiable clinical information), as well as for studies in which the samples are not identifiable but are coded or linked to identifiable information.

Current FDA guidance (4/25/06), however, indicates that under some circumstances, when samples taken from excess clinical or research specimens cannot be identified (e.g., all linking codes and identifiers have been removed, or the investigator has no access to the code keys or identifying information), the agency will exercise “enforcement discretion” and permit the IRB to approve the study without requiring informed consent of the sample sources.

To be eligible for approval without a requirement for informed consent, FDA indicates that IVD research must meet the following criteria:

• The research must be conducted under an IRB-approved protocol;
• The research must meet criteria for an IDE exemption (see above);
• The research must use specimens left over from clinical care, specimen repositories, or other research (i.e., the specimens may not be collected specifically for the proposed research, and no additional specimen may be collected for the purpose of research);
• Individuals caring for the patients are different from and do not share information about the patient with those conducting the investigation;
• The specimens are provided for research without identifiers (codes are permissible only if neither the investigator nor anyone associated with the study has access to the code key or can identify the person who was the source of the specimen);
• Any clinical information supplied with the specimen must not be individually identifiable;
• No test results from the research may be reported to any subject or that subject’s health care provider; and
• The supplier of the specimens must have established policies and procedures to prevent the release of identifying information.

FDA recommends that the IRB review the policies and procedures that are in place to determine (1) that identifiers will not be released to investigators, and (2) whether there is the potential for test results to be needed for clinical patient management (e.g., FDA suggests that if the research involves a public health threat such as anthrax, it may be necessary to report positive results; therefore informed consent might be required).

References

Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable http://www.fda.gov/cdrh/oivd/guidance/1588.pdf

John Hopkins University Organization on Review of In Vitro Diagnostic Device Protocols (with or without Commercial Sponsors) (Policy No. FDA 50.1) September 2006 http://irb.jhmi.edu/Policies/FDA50_1.html

Considerations for FDA Regulated Research – Procedures for FDA Inspections of Investigator Sites

Procedures for FDA Inspections of Investigator Sites

This policy applies to all principal investigators who conduct clinical investigations that are regulated by the FDA and clinical investigations that support applications for research or marketing permits for products regulated by the FDA. The purpose of this policy is to outline the specific procedures that should be followed when principal investigators conducting human subject research that is subject to FDA regulations are notified of an FDA inspection.

Responsibilities of Principal Investigator

Principal investigators conducting human subject research that is subject to FDA regulations are responsible for promptly notifying the Institutional Review Board (IRB) about inspections being conducted by the FDA for the purpose of either surveillance³ or compliance⁴

Investigators must also notify the IRB immediately of any FDA correspondence requesting that a clinical hold be placed on any human subject research.

Notifications must be made in writing and sent to the Assistant Director of the IRB. The notice should include reference to the IRB protocol number, the date and location of the planned inspection, any information available as to whether the inspection is for surveillance or compliance.

Investigators should facilitate arrangements to ensure that a member of the RCCO is present for the FDA exit interview.

Investigators must provide the IRB with copies of any written correspondence received from the FDA as a result of the inspection, in particular any Form 483.

Investigators must submit all written responses prepared as a result of the FDA Inspection to the IRB Committee F for review and comment PRIOR to sending the final response to the FDA. Such responses shall be forwarded to the IRB within 10 working days of receipt of the final FDA report.

Responsibilities of the RCCO Staff

The Assistant Director of the IRB Office shall notify appropriate parties of the upcoming inspection. This includes the IRB Chair, IRB Director, Co-Director of the Research Conduct and Compliance Office, University or UPMC Legal Counsel, the Authorized Institutional Official and the Education and Compliance Office for Human Subject Research. If applicable, O3IS will be notified as well.

On a case by case basis, the Education and Compliance Office will conduct a comprehensive review of the IRB file to ensure that the file is complete and in order. Any findings of non-compliance observed from this review will be reported to the Chair of the IRB, Director of the IRB, Assistant Director of the IRB and Co-Director of the RCCO, who will assess the findings and develop a plan of corrective actions as deemed appropriate.

The Education and Compliance Office shall contact the Principal Investigator and make arrangements (if time permits) to conduct a review of the research subject records and regulatory files in advance of the FDA inspection to ensure compliance with IRB policies, FDA regulations and Good Clinical Practices.

All requests for information surrounding the FDA inspection shall be treated as a priority by all involved parties.

The Authorized Institutional Official and/or his/her designee must be included in the exit interview.

Any Form 483 issued as a result of the inspection shall be reviewed by the IRB Committee F for determination of whether any observations contained therein constitute serious or continuing non-compliance with the federal regulations governing human subject research as outlined in Section XVII of this document.

In the event that an IRB Committee F meeting is not scheduled within 5 working days of receipt of the investigator’s response, a special meeting of the Committee may be convened for purposes of reviewing the response.

During the conduct of human subjects research, unanticipated events may occur. These events must be reported to the IRB using the “Reportable Events” mechanism in OSIRIS. While the smart form questions within the OSIRIS application will assist investigators in determining the type of report required, a general summary is provided in the paragraphs below and in figure 1.

Events involving risk to human subjects or others must be reported as an “Unanticipated Problem Involving Risk to Human Subjects or Others”. This category includes some types of adverse events meeting the definition of an unanticipated problem involving risk to human subjects or others. This category can also include protocol deviations, non-compliance, or other unanticipated problems that place subjects at risk of harm. Examples include but are not limited to: missed safety labs, medication or dosing errors, potential breaches of confidentiality, etc.

Protocol deviations and incidents of non-compliance, which do NOT involve risk to human subjects or others must be reported as “Non-compliance”. Examples include but are not limited to performing research procedures outside the protocol specified window, deviating from the protocol without risk to the subject, obtaining consent using an outdated consent form with no other substantive differences other that the date, etc.

Figure 2 illustrates several key points:

• The vast majority of adverse events occurring in human subjects are not unanticipated problems (area A) and do not need to be reported to the IRB.
• Only a small proportion of adverse events are unanticipated problems (area B).
• Unanticipated problems include other incidents, experiences, and outcomes that are not adverse events (area C).
• Deviations or non-compliance can also be unanticipated problems involving risk to subjects or others.
• Events meeting criteria for an Unanticipated Problem Involving Risk to Subjects or Others, or Non-compliance (Areas B, C D and E) must be reported to the IRB.

Management and Reporting of Unanticipated Problems Involving Risks to Human Subjects and Others and Non-compliance

It is the policy of the University of Pittsburgh Institutional Review Board (University IRB) to:

• Require the reporting of adverse events and other unanticipated events which meet the definition of an “unanticipated problem involving risks to human subjects or others” and/or Non-compliance
• Review reports of adverse events, unanticipated problems and ECO-HSR compliance activity reports that have been designated for review by the IRB as outlined in the ECO-HSR policy (SOP-I-A-15) , and determine which meet the OHRP criteria for “unanticipated problems involving risks to human subjects or others”
• Review reports of non-compliance and determine which constitute serious or continuing non-compliance and/or an unanticipated problem involving risk to human subjects or others
• Fulfill reporting requirements to the appropriate entities (institutional officials, federal departments or agencies)

Definitions

Adverse event: An unfavorable medical occurrence, which may include abnormal signs (for example, abnormal physical exam or laboratory finding), symptoms, or disease, temporally associated with, but not necessarily considered related to, the subject’s participation in the research study.

Continuing non-compliance: Repeated failure to understand and consistently comply with federal regulations and University IRB policies governing human subject protections and that, in the judgment of the University IRB, seriously compromises the protection of human research subjects or adversely affects the integrity of the University’s human research protection program.

External adverse event: An adverse event that occurs at a site external to the authority of the University IRB and is reported to the University or UPMC investigator.

Internal adverse event: An adverse event that occurs at a site that falls directly under the authority of the University IRB.

IRB-Initiated suspension of approval: IRB-initiated suspension of approval refers to a determination made by the University IRB to temporarily withdraw University IRB approval for some or all activities of a currently approved research study.

IRB-Initiated termination of approval: IRB-initiated termination of approval refers to a determination made by the University IRB to permanently withdraw University IRB approval for some or all activities of a currently approved research study.
Non-compliance: Failure on the part of the investigator or any member of the study team to follow the terms of University of Pittsburgh IRB approved protocol or to abide by applicable laws or regulations, or University of Pittsburgh IRB policies. This includes protocol deviations. This also includes ECO-HSR compliance activity reports that have been designated for review by the IRB as outlined in the ECO-HSR policy (SOP-I-A-15). The IRB will determine whether reports meet the definition of serious or continuing non-compliance.
Incidents of noncompliance on the part of research participants which do not involve risk need not be reported to the IRB.
Possibly Related to the Research Intervention: In the opinion of the principal investigator, there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research.

Related to the Research Intervention: In the opinion of the principal investigator, the incident, experience or outcome more likely than not was caused by the procedures involved in the research.

Serious non-compliance: Failure to comply with any of the federal or state regulations or institutional policies governing human subject research that, in the judgment of the University IRB, significantly compromises human research subject protection or the integrity of the University’s human research protection program. Examples of non-compliance that are considered to meet the definition of serious non-compliance include, but are not limited to:

1. performing non-exempt human subject research without obtaining prospective University IRB approval
2. implementing substantial modifications to a research study without obtaining prospective University IRB approval
3. failing to systematically obtain research subjects’ informed consent as required by the IRB approved protocol
4. failing to comply with federal regulations governing human subject protections (this includes activities of the University IRB and/or University IRB Office staff)

Unanticipated: Unforeseeable at the time of its occurrence.

Unanticipated Problem Involving Risks to Human Subjects or Others: Any accident, experience, or outcome that meets all of the following criteria:

1. unexpected in terms of nature, severity, or frequency;
2. related, or possibly related, to a subject’s participation in the research;
3. places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

Unexpected Adverse Event: Not identified by nature, severity or frequency in the investigator’s brochure, sponsor protocol or current University IRB-approved research protocol or informed consent document, taking into account the characteristics of the subject population being studied.

Reporting Responsibilities of the Investigator

Adverse Events That Are Unanticipated Problems Involving Risk To Subjects Or Others - General Reporting Requirements

Outlined below are the requirements for reporting to the IRB. Note that investigators may have additional reporting obligations as specified by the study sponsor or oversight agency. Investigators who serve as sponsor-investigators of an IND or IDE also have additional reporting obligations to the FDA.

Unless subject to different IRB reporting requirements by a federal agency, investigators must report to the IRB:

1. Internal Adverse Events that are (i) Unexpected, (ii) Related or Possibly Related to the Research Intervention, and (iii)serious or otherwise suggests that the research places the subject or others at a greater risk of harm (including physical, psychological, economic or social harm) than was previously known or recognized.
2. External Adverse Events that are (i) Unexpected; (ii) Related to the Research Intervention and (iii) Serious or otherwise suggests that the research places subjects or others at greater risk than was previously recognized.

Please note that the vast majority of Adverse Events will not meet the definition of an Unanticipated Problem Involving Risk to Subjects or Others, and need not be reported to the IRB. Expected Adverse Events or Adverse Events which are determined by the investigator to be unrelated to the Research Intervention will not be reviewed by the IRB. The flow chart below provides an algorithm for determining whether an adverse event meets the definition of an unanticipated problem involving risk to subjects or others.

General IRB Reporting Timelines

Adverse Events that meet the University IRB’s reporting requirements must be reported to the IRB office as follows:

1. Internal Adverse Events which are unexpected, fatal or life-threatening, and related or possibly Related to the Research Intervention must be reported to the IRB within 24 hours of learning of the event. (Note: It is recognized that the information available during this 24 hour period may not be sufficient to permit accurate completion of the required adverse event reporting forms. However, the IRB should, at a minimum, be notified of the fatal or life-threatening internal adverse event during this time frame, with subsequent followup submission of a more detailed written report.)
2. All other internal Adverse Events will be reported to the IRB within 10 working days of the investigator learning of the event.
3. External Adverse Events which are Unexpected, Serious AND suggest that the research places subjects or others at greater risk than was previously recognized, and Related to the Research Intervention will be reported to the IRB within 30 working days of their receipt by the University/UPMC investigator. (Note: only sponsor-generated safety reports that meet the Adverse Event reporting of the IRB should be submitted to the IRB.)

Special Reporting Requirements - Gene Transfer Interventions

All Unexpected, Serious Internal Adverse Events related to the gene transfer intervention must be reported to the external sponsor of the research study (if applicable) and to the IRB, Institutional Biosafety (rDNA) Committee, NIH Office of Biotechnology Activities (OBA), and Food and Drug Administration using the following criteria:

1. Unexpected, fatal or life-threatening internal Adverse Events related or possibly related to the gene transfer intervention must be reported to the external sponsor (if applicable), IRB and Institutional Biosafety (rDNA) Committee within 24 hours of learning of the event. If the sponsor of the human gene transfer research study is a University investigator, reporting of the adverse event to the OBA and FDA should occur as soon as possible but no later than 7 working days following the sponsor’s initial receipt of the information. (If the human gene transfer research study is externally sponsored, it is the responsibility of the external sponsor to report the adverse event to the OBA and FDA.)
2. Unexpected, Serious (but not fatal or life-threatening) Internal Adverse Events Related or Possibly Related to the gene transfer intervention, must be reported to the external sponsor (if applicable), IRB and Institutional Biosafety (rDNA) Committee as soon as possible but no later than 5 calendar days of the reaction. If the sponsor of the human gene transfer research study is a University investigator, reporting of the adverse event to the OBA and FDA should occur as soon as possible but no later than 15 working days following the sponsor’s initial receipt of the information. (If the human gene transfer research study is externally sponsored, it is the responsibility of the external sponsor to report the adverse event to the OBA and FDA.)
3. Any follow up information related to an Unexpected, Serious Adverse Event Related or Possibly Related to a gene transfer intervention should be reported promptly to the external sponsor (if applicable), IRB, and Institutional Biosafety (rDNA) Committee. If the sponsor of the human gene transfer research study is a University investigator, reporting of the follow up information to the OBA and FDA should occur as soon as possible but no later than 15 working days following the sponsor’s receipt of the information. (If the human gene transfer research study is externally sponsored, it is the responsibility of the external sponsor to report the follow up information to the OBA and FDA.)
4. If an Unexpected, Serious Adverse Event occurs after the end of the clinical trial and it is determined to be related or possibly related to the gene transfer intervention, the reaction should be reported promptly to the external sponsor (if applicable), IRB, and Institutional Biosafety (rDNA) Committee. If the sponsor of the human gene transfer research study is a University investigator, reporting of this Adverse Event information to the OBA and FDA should occur as soon as possible but no later than 15 working days following the sponsor’s receipt of the information. (If the human gene transfer research study is externally sponsored, it is the responsibility of the external sponsor to report this adverse event information to the OBA and FDA.)
5. If, after further evaluation, an Unexpected, Serious Internal Adverse Event initially considered not to be related to the gene transfer intervention is determined to be Related, then the Unexpected, Serious Internal Adverse Event should be reported promptly to the external sponsor (if applicable), IRB, and Institutional Biosafety (rDNA) Committee. If the sponsor of the human gene transfer research study is a University investigator, reporting of the adverse event to the OBA and FDA should occur as soon as possible but no later than 15 working days of this determination. (If the human gene transfer research study is externally sponsored, it is the responsibility of the external sponsor to report this determination to the OBA and FDA.)

The above reporting requirements apply to all research studies involving gene transfer interventions regardless of the source of the research funding.

Procedure for Submission

OSIRIS SUBMISSIONS: For studies approved through the electronic submission system, the “Reportable Event” online submission process must be utilized in order to submit a report. The smart form questions will prompt a response to questions related to the adverse event.

PAPER SUBMISSIONS:

Adverse Events for paper studies will also be individually reviewed by the full-board IRB. Submit the following by email to askirb@pitt.edu:

• IRB Cover Sheet marked “Adverse Event Report” and, if applicable, “Modification;”
• Completed IRB Adverse Event Form and a narrative summary of the event;
• Completed sponsor adverse event reporting form or FDA MedWatch report form (For gene transfer interventions, the completed NIH Office of Biotechnology Activities (OBA) Serious Adverse Event Report Form);
• Modification request form (if applicable);
• IRB Approved Protocol, with modifications highlighted;
• IRB approved informed consent document, with modifications highlighted;
• Consent Form Addendum to provide new information to currently enrolled subjects (if applicable).

"Other" Unanticipated Problems Involving Risk to Subjects or Others and Non-compliance

Unanticipated problems which meet the following definition of “any accident, experience or outcome” that meets the following criteria must be reported:

• unexpected in terms of nature, severity, or frequency;
• related, or possibly related, to a subject’s participation in the research;
• places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized;

Examples of types of unanticipated problems that must be reported to the IRB include:

• any accidental or intentional deviation from the IRB-approved protocol that involves risks (e.g., missed safety labs, incorrect dosing or labeling);
• any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a given research subject;
• any publication in the literature, safety monitoring report, interim result, or other finding that indicates an unexpected increase in the risk to benefit ratio of the research;
• any complaint of a subject that indicates an unanticipated risk or which cannot be resolved by the research staff;
• any other untoward event that affects the welfare or the privacy, confidentiality or other rights of research subjects or members of their family (e.g. lost or stolen research data) ;
• any other untoward event that presents a risk to investigators and research staff involved in the conduct of the research.

Incidents of non-compliance, which meet the following must be reported: Failure on the part of the investigator or any member of the study team to follow the terms of University of Pittsburgh IRB approval or to abide by applicable laws or regulations, or University of Pittsburgh IRB policies. This includes protocol deviations. Incidents of noncompliance on the part of research participants which do not involve risk need not be reported to the IRB (i.e., failure to turn in medication diary)
Examples of non-compliance that must be reported to the IRB include:

• Performing non-exempt human subject research without obtaining prospective University IRB approval;
• Implementing protocol modifications without obtaining prospective IRB approval;
• Altering from the informed consent process as described in the IRB approved protocol;
• Obtaining consent using an outdated consent form;
• Conducting research during a lapse in IRB approval;
• Failing to adhere to the IRB approved protocol due to action (or inaction) of the investigator or staff (i.e., protocol deviations)Not -adhering to inclusion/exclusion criteria;
• Enrolling more subjects that approved in the protocol;
• Performing research procedures outside the protocol specified window;

Failure on the part of any individual involved in research review or oversight to abide by applicable laws or regulations, or University of Pittsburgh IRB policies.

General Reporting Requirements

Investigators are to submit all Unanticipated Problems Involving Risks to Human Subjects or Others that are Possibly or Definitely Related to the research and incidents of Non-compliance within 10 working days of the investigator becoming aware of the event.

Submission Format for Reporting Other Unanticipated Problems Involving Risks to Human Subjects or Others and incidents of Non-Compliance

OSIRIS SUBMISSIONS: For studies approved through the electronic submission system, the Reportable Event online submission process must be utilized in order to submit a report. The smart form questions will prompt a response to questions related to the Unanticipated Problem or Non-compliance.

PAPER SUBMISSIONS: Investigators are required to submit reports utilizing the form entitled “Report of Unanticipated Problems Involving Risks to Subjects or Others and Non-compliance,” which is available on the IRB website.

Responsibilities of the Education and Compliance Office for Human Subject Research

The Education and Compliance Office for Human Subject Research is responsible for reporting to the IRB Chair and Adverse Events Coordinator any compliance activity report that may represent serious non-compliance, continuing non-compliance or an unanticipated problem involving risks to human subjects or others as outlined in ECO-HSR SOP = I-A-15.

Responsibilities of the IRB

Internal and External Adverse Events

Internal Adverse Events (IAE) and External Adverse Events (EAE) reported to the University IRB are received and processed promptly by the University IRB Adverse Events Research Review Coordinator (AEC), or in his/her absence, by a designated University IRB research review coordinator.

Adverse events that meet the University IRB’s definition of an “unanticipated problem involving risk to human subjects or others” may be brought to the attention of the University IRB Chair or, in his/her absence, a University IRB Vice Chair by the University IRB AEC. In processing adverse events that appear to meet the University’s definition of an unanticipated problem involving risks to human subjects or others, the AEC will:

• Place the events on the agenda for review at the next convened University IRB meeting where there is a member with appropriate expertise. If there are potential risks to subjects which require action prior to a convened meeting, an emergency meeting may be convened (with the members attending either in person or via teleconference) or in exceptional safety circumstances, the chair has the authority to suspend some or all of the research activities. When this authority is exercised by the Chair, it will be reported at the next convened University IRB meeting.
• Perform a retrospective review of adverse events reported for the research protocol. If the adverse event was reported by the investigator as being related to a research intervention, then an assessment of the adverse events across other research protocols involving the same experimental intervention will be performed.
• Make an initial determination as to whether protocol and/or consent form modifications are required to address the reported adverse event. In making this determination, the AEC will take into consideration the severity of the event, the number of reports describing the same or similar event, and the current consent form and research protocol risk statements.

"Other" Unanticipated Problems Involving Risk to Subjects or Others

• Unanticipated problems received or identified by the University IRB Office are brought to the attention of the University IRB Chair, or in his absence, a University IRB Vice Chair.
• The University IRB Chair (or Vice Chair) will determine if the report of an unanticipated problem contains complete information that will allow an adequate review for human subject protections. If, in the opinion of University IRB Chair (or Vice Chair), the information is incomplete, s/he may request appropriate additional information from the individual submitting the report.
• The University IRB Chair (or Vice Chair) will determine if the reported unanticipated problem may involve a risk to human subjects or others or non-compliance with the federal regulations or the requirements or determinations of the University IRB.
• Unanticipated problems that may represent an “unanticipated problem involving risks to human subjects or others,” “serious noncompliance” or “continuing non-compliance” as defined above, will be referred to a convened University IRB committee.
• For those reports that clearly do not represent either i) an unanticipated problem involving risks to human subjects or others, ii) serious non-compliance, or iii) continuing non-compliance, the University IRB Chair or designee will determine if any additional actions are warranted and, if applicable, will communicate that in writing to the individual who initiated the report.
• The unanticipated problem report, the determination of the University IRB Chair (or Vice Chair), and a record of the requested actions, if applicable, will be documented in the IRB file.
• Failure to comply with actions requested by the University IRB Chair (or Vice Chair), in the absence of a suitable justification, constitutes an unanticipated problem of non-compliance and be brought to the attention of a convened University IRB committee.

Management of Research Participant Complaints

It is the policy of the University of Pittsburgh IRB to investigate all complaints or concerns reported by study participants to the IRB.

All consent documents must include telephone numbers for the principal investigator and the Human Subject Protection Advocate so that participants can call if they have questions, concerns or complaints.

The IRB will investigate all participant complaints received and will complete the Documentation of Patient/Subject Complaint Form. Actions taken to resolve complaints might include referring the complaint to:

• the Human Subject Protection Advocate;
• the Principle Investigator;
• completion of “reportable event;”
• the IRB Committee F.

The IRB Office maintains files of research subject complaints and the actions taken by the IRB Office staff, IRB Committee(s), or investigators to resolve such complaints. Such files are maintained until 3 years following termination of IRB approval of the research study.

Non-compliance with the protocol

• Reports of non-compliance with the protocol received or identified by the University IRB Office will be reviewed by the Adverse Events Coordinator, who will triage the reports.
• The University Adverse Events Coordinator determines if the report of non-compliance with the protocol contains complete information that will allow an adequate review for human subject protections. If, in the opinion of University Adverse Events Coordinator, the information is incomplete, s/he may request appropriate additional information from the individual submitting the report.
• The IRB Adverse Events Coordinator refer to the IRB Chair all reports where the reported non-compliance with the protocol that may involve a risk to human subjects or others or serious or continuing non-compliance with the federal regulations or the requirements or determinations of the University IRB.
• The University IRB Chair (or Vice Chair) determines if the reported non-compliance with the protocol may involve a risk to human subjects or others or non-compliance with the federal regulations or the requirements or determinations of the University IRB.
• Reports of non-compliance with the protocol that may represent an “unanticipated problem involving risks to human subjects or others,” “serious noncompliance” or “continuing non-compliance” as defined above, will be referred to a convened University IRB committee.
• For those reports of non-compliance with the protocol that clearly do not represent either i) an unanticipated problem involving risks to human subjects or others, ii) serious non-compliance, or iii) continuing non-compliance, the University IRB Chair or designee determines if any additional actions are warranted and, if applicable, communicates that in writing to the individual who initiated the report.
• The report of non-compliance with the protocol, the determination of the University IRB Chair (or designee), and a record of the requested actions, if applicable, will be documented in the IRB file.
• Failure to comply with actions requested by the University IRB Chair (or designee), in the absence of a suitable justification, constitutes a report of non-compliance and be brought to the attention of a convened University IRB committee.

Distribution of Information, Reviewer Assignment and Presentation to a Convened IRB Committee

Adverse Events that are Unanticipated Problems

All members of the convened committee will have access to the following:

• the adverse event report;
• the IRB-approved research protocol and consent documents;
• the recommendations of the AEC.

Each adverse event will be assigned to two primary reviewers with relevant scientific expertise.

The primary reviewers will summarize the adverse event and their decision regarding concurrence with the actions recommended by the AEC or, in the event of disagreement, propose alternate actions. After the presentation from the primary reviewers, all members of the convened committee will be given the opportunity to comment on the recommendations.

Other Unanticipated Problems and Non-compliance

All members of the convened Committee will have access to the following:

• all available documentation regarding the reported unanticipated problem;
• the IRB-approved research protocol and consent documents, if necessary;
• the ECO-HSR compliance activity report, the investigator’s response to the report and the unanticipated problem reports submitted to the IRB as a result of the ECO-HSR review of the protocol as applicable.

No primary reviewer system will be utilized for reviewing "Other" unanticipated problems or Non-compliance.

The Education and Compliance Office will summarize ECO-HSR compliance activity reports for the Committee. All other cases of non-compliance will be summarized by the IRB Chair or Vice Chair. All members of the convened committee will be given the opportunity to comment on the recommendations.

Possible IRB Committee Actions

The reviewing Committee takes whatever actions are deemed necessary to address the unanticipated problem(s). Examples of actions that might be taken include, but are not limited to:

1. Investigating the Event by:
   • requesting additional records or information about the event and its outcome;
   • interviewing the involved investigators, research staff, and/or research subjects;
   • interviewing other individuals who may have knowledge of the event;
   • requesting an independent audit of the event/protocol or of other related protocols.
2. Implementing Administrative Actions, such as:
   • requesting the IRB Chair (or Vice Chair) to meet with the involved investigator and/or research staff, and the appropriate department chair and/or dean to discuss the event/problem;
   • requesting a corrective plan of action and/or written standard operating procedures from the involved investigator and/or his/her department chair or dean;
   • requiring members of the research team to participate in pertinent training and education programs;
   • notifying other organizational entities (e.g., legal counsel, institutional risk management, the Authorized Institutional Official, the Research Integrity Officer, the UPMC Clinical Trials Office, UPMC Privacy Officer) as warranted;
   • suspending the PI’s privilege to serve as a PI or requiring a replacement of the PI for the protocol(s) in question.
3. Requiring Modifications of the Associated Protocol, such as
   • instructing the investigator to develop an addendum consent form to provide information concerning the event to subjects currently enrolled in the study;
   • requiring the investigator to perform additional follow-up or monitoring of the enrolled subjects;
   • revising the timeframe for continuing University IRB review.
   For multi-center studies - if the IRB or the local investigator proposes changes to the protocol or informed consent document/process, in addition to those proposed by the study sponsor or the coordinating center, the IRB should request in writing that the local investigator discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB.
4. Terminating or Suspending University IRB Approval of the Research Study
   
   When terminating or suspending some or all research activities, the University IRB will consider what additional actions the principal investigator or institution should take in order to protect the rights and welfare of current human subjects. These additional actions may include but are not limited to:
   • Transferring the human subjects to another research study (i.e., based on equivalent inclusion/exclusion criteria);
   • Making arrangements for clinical care outside the research;
   • Allowing continuation of some research activities under the supervision of an independent monitor;
   • Requiring or permitting follow-up of the human subjects for safety reasons;
   • Requiring adverse events or outcomes to be reported to the University IRB and the sponsor;
   • Notifying current human subjects of the University IRB’s decision to terminate or suspend the research study;
   • Notifying former human subjects of the University IRB’s decision to terminate or suspend the research study;
5. Requiring other action as determined to be appropriate by the University IRB committee.
6. Requiring no further action.

IRB Vote and Documentation in the Meeting Minutes

The University IRB will determine the recommended actions, call for a vote and document the outcome in the Committee minutes. The University IRB votes as to whether the event represents an unanticipated problem involving risks to human subjects or others, serious non-compliance and/or continuing non-compliance. This vote will be recorded in the meeting minutes. If the University IRB votes to suspend or terminate the research study, the reasons for the suspension or termination will be documented.

Communication of IRB decisions

Please see Reporting of IRB Findings

Reporting of IRB Findings

It is the policy of the University of Pittsburgh Institutional Review Board (University IRB) to comply with all applicable local, state, and federal regulations that require the following to be reported:

• Unanticipated problems involving risks to human subjects or others;
• Suspension or termination of University of Pittsburgh IRB approval;
• Serious or continuing noncompliance with federal regulations or the policies of the University of Pittsburgh IRB.

Time Frame for Communicating IRB Decisions

Reports are issued within 10 working days of the receipt of the final written report by the reviewing University IRB committee to the applicable parties as outlined below. Please refer to the policy above for studies involving gene transfer intervention.

Contents of the Report of IRB Findings

At a minimum, the following information should be included in the report of IRB findings:

• Name of the institution conducting the research;
• Title of the associated research project and/or grant proposal;
• Name of the principal investigator on the corresponding research protocol;
• Number assigned by the University IRB to the research project and the number of any applicable federal award(s) (grant, contract, or cooperative agreement)A detailed description of the reason for the report;
• Actions taken by the institution to address the reported issue.

Parties Responsible for Preparation and Distribution of Correspondence

Internal Adverse Events

Correspondence surrounding adverse events reviewed at the IRB meeting will be drafted by the AEC and approved by the IRB Chair or Vice Chair. The IRB Chair or Vice Chair will ensure the report is distributed to all applicable parties.

Study Termination or Suspension

For studies in OSIRIS, the IRB Chair or his designee will suspend or terminate the study within the system. Correspondence is sent to the Principal Investigator as well as to all listed co-investigators and research staff. The study moves to a “suspended” or “terminated” state and the consent documents are no longer accessible. For paper studies, reports surrounding study termination or suspension will be drafted by the IRB staff and approved by the IRB Chair or Vice Chair. The IRB Chair or Vice Chair will ensure the report is distributed to all applicable parties.

Serious or Continuing Non-Compliance and Unanticipated Problems Involving Risks to Human Subjects or Others

Correspondence related to determinations of serious or continuing non-compliance or that involve risk to subjects related to ECO-HSR compliance report activities will be prepared by the Co-Director of the RCCO or his/her designee for approval by the IRB Chair and Associate Legal Counsel.

Correspondence related to determinations of serious or continuing non-compliance or that involve risks to human subjects or others related to unanticipated problems will be drafted by the Research Review Coordinator (RRC) for review and approval by the Co-Director of the RCCO, the IRB Chair and Legal Counsel.
After review and comment by the above parties, the Authorized Institutional Official will review, approve and sign the report and ensure the report is distributed to all applicable parties.

Compliance Activity Reports

Correspondence related to Compliance Activity Reports where the study remains active and no serious or continuing non-compliance were identified or protocol modifications were required will be prepared by the Education and Compliance Office staff for signature of the Co-Director of the Research Conduct and Compliance Office.

Correspondence related to a Compliance Activity Report which resulted in a determination of serious or continuing non-compliance; an unanticipated problem involving risks to human subjects or others; or study termination or suspension will be performed in the same manner as other determinations of this kind.

When a protocol modification is necessary as the Compliance Activity Report, the correspondence associated with the protocol modification will be drafted by the IRB staff with input from the Education and Compliance Office for signature by the IRB Chair or Vice Chair.

Recipients of the IRB Correspondence / Reports

Investigator Correspondence

The University IRB Chair or Vice Chair communicates the IRB’s determinations to the principal investigator. If the IRB’s decision requires immediate action on the part of the principal investigator, the decision will be communicated verbally to the principal investigator as soon as possible and followed up with written notification by the IRB Chair or Vice Chair within 10 working days of the decision.

A date for the investigator response is specified in the written notification. Failure to comply with this date, in the absence of a suitable justification, will be handled in accordance with University IRB policies involving the reporting and handling of other unanticipated problems.

Compliance of the principal investigator with the directed actions specified by the reviewing University IRB committee are reviewed and approved by the IRB Chair or an IRB Vice Chair unless full board review of the principal investigator’s response/actions is determined to be required by the reviewing University IRB committee.

If the principal investigator has additional information that may be relevant to the situation at hand, it will be brought to the attention of the reviewing University IRB committee for consideration.

Institutional Official, Regulatory Agencies, Sponsors and Others

In addition to the IRB correspondence sent to the investigator, reports of any unanticipated problems involving risks to human subjects or others, any serious or continuing non-compliance, any suspension or termination of IRB approval will be sent to all applicable parties, which may include:

• The Office for Human Research Protections – for research funded by any agency that is a signatory to the “Common Rule” at 45 CFR 46;
• The Food and Drug Administration – for research that is subject to the FDA regulations at 21 CFR 50 and 56;
• The federal or non-federal external funding agency For DOD funded research, the letter will be sent to the attention of the Director, Defense Research and Engineering;
• The VAMC R&D Committee and the regional VA Office of Research Oversight;
• The UPMC Office for Sponsored Programs and Research Support;
• Other University offices (e.g., Office of Research, Conflict of Interest, Risk Management);
• The principal investigator;
• The department chair;
• University or UPMC legal counsel;
• University or UPMC risk management;
• UPMC Institutional Officials.

References

• 45 CFR 46.103(b)(5)
• 21 CFR 56.108(b) (1), 312.53 (c) (vii) and 312.66 – Investigators are required to report promptly to the IRB all unanticipated problems involving risks to human subjects or others
• OHRP - Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events (http://www.hhs.gov/ohrp/policy/advevntguid.html)
• Appendix M – NIH Guidelines for Research Involving Recombinant DNA Molecules
• Standard Operating Procedures for the Education and Compliance Office for Human Subject Research http://www.ecohsr.pitt.edu/regulatory-information/ECO_SOP.pdf.

Disclosure

The IRB leadership, staff and affiliated IRB members are required to disclose significant financial interests (SFI) in accordance with University of Pittsburgh Conflict of Interest policies http://www.coi.pitt.edu/index.htm.

Consistent with University policies and applicable laws, an SFI includes an interest owned by the individual, the individual’s spouse, dependent children or other members of his/her household and means anything of monetary value, including, but not limited to, current or contingent salary or other payments for services (e.g., consulting fees or honoraria); equity interests (e.g., stocks, stock options, bonds); and intellectual property rights (e.g., patents, copyrights and royalties from such rights).
The term SFI includes:

1. an equity interest in the entity that either sponsors this research or owns the technology being evaluated that when aggregated for the individual, individual’s spouse, dependent children and other members of the household exceeds 5% ownership interest or a current value of $10,000, as determined through reference to public prices or other reasonable measures of fair market value;
2. salary, royalty or other payments from the entity that either sponsors this research or owns the technology being evaluated that when aggregated for the individual, individual’s spouse, dependent children and other members of the household is expected to exceed $10,000 per year;
3. an agreement with the University or an external entity that would entitle sharing current or future commercial proceeds related to the technology being evaluated (e.g., royalties through a license agreement); and
4. a financial relationship with a start-up company (which is being monitored by the Entrepreneurial oversight Committee) that has an option or license to utilize the technology being evaluated. An SFI exists under these circumstances regardless of the individual’s ownership percentage in and/or remuneration received from the start-up company.

The term SFI does not include:

1. salary from the University of Pittsburgh, UPMC, or VA;
2. income from seminars, lectures, or teaching engagements sponsored by governmental or nonprofit entities; and

income from service on advisory committees or review panels for governmental or nonprofit entities.

IRB Members

IRB members who are considered unaffiliated with the institution will not be required to complete the standard conflict of interest form. These members will be required to sign a statement at the time of their orientation indicating that the conflict of interest policy has been provided to them.
To ensure understanding of Conflict of Interest (COI) issues, all members will be provided with the University definitions of COI at the time of their orientation. In addition, the IRB COI Policy will be reviewed on an annual basis with all committee members to ensure they are aware of acceptable COI thresholds.

Potential conflicts of interest (COI) include but are not limited to:

• being a listed investigator (or having an immediate family member including the spouse, dependents, and all members of the employee’s household including domestic partners listed as an investigator);
• having a significant financial interest (or having an immediate family member with such an interest) in the sponsor of the research or the technology being evaluated; or
• having any other conflict that might be perceived to inhibit a fair and unbiased review of the research.

Reviewer Assignment

The IRB Exempt/Expedited Vice Chairs will not review or approve a research study in which s/he has a conflict of interest.

No IRB reviewer will be assigned to review a research study in which s/he has a conflict of interest.

Consultants

Consultants to the IRB will be asked, at the time they are contacted to review a research study, if they (or a member of their immediate family) have a conflict with the study on which they are being asked to consult. No consultants will be assigned to review a research study in which s/he has a conflict of interest.

Investigators

• Research investigators are not be permitted to participate in decisions relating to the selection of IRB members responsible for performing the review of their research studies.
• Investigators must disclose if they have a significant financial interest in a sponsor of the research or the technology being evaluated.
• As outlined in Section VIII, for research studies submitted for initial and continuing IRB review, the Conflict of Interest Office is notified if the investigator indicates that there is a conflict of interest.
• Investigators possessing a significant financial interest in the sponsor of the research or the technology being evaluated are generally prohibited from serving as principal investigators of a human subject research study if they have a SFI that may be affected, or perceived to be affected, by the outcome of the research study. Any exception to this policy must be approved by the authorized institutional official for human subject research, the Vice Chancellor for Research Conduct and Compliance.

Individuals with an SFI that may be affected, or perceived to be affected, by the outcome of a human subject research study may be permitted to serve as a co-investigator with the implementation of the Standard Conflict of Interest Management Plan for Human Subject Research. If the Institutional Review Board (IRB) and/or the investigator with the SFI wishes to request an exception to the standard plan (e.g., to add/remove elements to/from the plan), such request should be communicated to the director of the COI Office. The request will then be forwarded to a subcommittee of the Conflict of Interest Committee for deliberation. The results of these deliberations will be reported to the IRB and the investigator with the SFI within two weeks of receiving the request.

In the unlikely event that the IRB is not in agreement with the proposed COI management plan and an agreement cannot be reached following the above procedures, the decision to grant IRB approval of the protocol remains with the IRB. This includes an assessment (for the purpose of protecting the rights and welfare of the human subjects) of the COI provisions under which the research would be conducted.

Placement of Study on Agenda

No IRB reviewer or consultant will be assigned to review a research study in which s/he has a conflict of interest.

Research submissions will not be placed on the agenda of an IRB committee meeting if the IRB Vice Chair who will preside over the meeting is a listed investigator on the submission or holds a significant financial interest in the sponsor of the research or the technology being evaluated. Under extenuating circumstances, exceptions to this policy can be made by the IRB Chair or his designee. In the event an exception is deemed necessary, the conflicted IRB Vice Chair will be asked to step out of the room during the review, discussion and vote of the research submission. Another IRB Committee member will act as vice chair during the meeting and will review and approve that portion of the minutes.

Evaluations of Potential Conflicts at Meetings

IRB members and consultants are polled upon initiation of each IRB meeting to determine if they (or a member of their immediate family) are a listed investigator on any research study being reviewed at the meeting, or if they (or a member of their immediate family) hold a significant financial interest in the sponsor of any research study or any technology being evaluated in a research study being reviewed at the meeting or if any other potential conflicts exists.

Abstentions from Deliberations

IRB members and consultants will abstain from participation in any IRB deliberations or approval decisions relating to a research study in which they (or a member of their immediate family) have a potential financial conflict-of-interest.

IRB members and consultants will absent themselves from the IRB meeting room during IRB deliberations and decisions relating to a research study in which the individual (or a member of his/her immediate family) is listed as an investigator or has a potential non-financial conflict (e.g., consultant on the project). An exception is to provide information specifically requested by the committee.

Documentation in Minutes

The absence of members or consultants due to a conflict (i.e., a listed investigator, financial or other conflict) during the discussion of the research protocol and the vote will be documented in the minutes of the full board IRB meeting to include the reason for their absence.

The IRB Office is responsible for maintaining records related to the functions and activities of the IRB.

IRB Membership Records

The IRB Office maintains a database of IRB committee members identified by name; earned degree(s); indications of experience such as board certifications, licenses, etc., sufficient to describe each member’s primary anticipated contributions to IRB deliberations; representative capacity (e.g., scientific or non-scientific reviewer); and any employment or other relationship between the member and the University of Pittsburgh, UPMC, UPMC Cancer Centers, Children’s Hospital of Pittsburgh, Magee Women’s Research Institute or the VA Pittsburgh Healthcare System. This information will be utilized by the IRB Membership Coordinator in formulating the roster for OHRP.

Changes in IRB committee membership will be reported to OHRP in a timely manner by the IRB Board Member Coordinator.

Research Submissions

The IRB Office will maintain records (paper or electronic) of all research submitted for IRB review and approval.

• Paper files will be maintained within the IRB Office by principal investigator name and IRB number.
• Electronic records will be maintained within the OSIRIS system and can be accessed through a variety of search mechanisms.

Submissions will be retained regardless of whether subjects were enrolled.

No Human Subjects Research Designation/Exempt Submissions

For projects determined by the IRB to qualify for a no human subject research designation or exempt status the IRB record will contain the applicable application form, all investigator-IRB correspondence related to the submission and the letter of exempt concurrence.

Expedited or Full Board Submissions

For research submitted for expedited or full board review, the IRB record contains:

• the initial research application;
• the approved informed consent document (if applicable)the initial IRB approval letter;
• modification requests and the applicable IRB approval letter;
• continuing review requests and the applicable IRB approval letter;
• for multicenter studies, the sponsor’s protocol;
• for studies involving an investigational drug or device, the investigational drug brochure
• for federally funded studies, the federal grant application;
• for investigator-initiated studies involving a drug or device, all correspondence with the FDA including the IND or IDE application and any other pertinent documentation;
• any reports of unanticipated problems involving risks to human subjects or others (including adverse events) encountered in the conduct of the research;
• advertisement used to recruit potential subjects as well as screening scripts;
• non-standard measures;
• all correspondence between the investigator/research team and the IRB;
• a summary of audits conducted by the Education and Compliance Office. Full audit reports, responses from investigators, as well as actions taken by the IRB Executive Committee (Committee F) will be available for review upon request in the Education and Compliance Office;
• documentation of actions taken by the IRB Executive Committee (Committee F) in response to unanticipated problems involving risks to human subjects or others and/or identified non-compliance and the corresponding responses of investigators.

Research files are maintained by the IRB Office at a secure storage facility until 3 years following termination of IRB approval of the research (21 years for research involving children). Following the required maintenance interval, research files will be shredded.

IRB Minutes

The agendas and minutes of full-board IRB as well as Executive Committee (Committee F) meetings will be maintained indefinitely by the IRB Office.

Research Subject Complaints

The IRB Office maintains files of research subject complaints and the actions taken by the IRB Office staff, IRB Committees, or investigators to resolve such complaints. Such files are maintained until 3 years following termination of IRB approval of the research study.

Adverse Events Reports

The IRB Office maintains a database of adverse events reported in compliance with the IRB’s policies for the reporting of serious or unexpected adverse events.

• The written copies of such reports will be maintained on file, by principal investigator name, within the IRB Office.
• Adverse event reports will be maintained within the database and on file until 3 years following termination of IRB approval of the respective research study.

Emergency Use Reports

The IRB Office maintains files of emergency use requests and reports at a secure storage facility for an indefinite period of time. Files are be maintained by physician name and the “EU” number.

Inspections by Authorized Representatives

IRB records are accessible for inspection and copying by authorized representatives.

It is policy of the University of Pittsburgh IRB that all involved in the review, conduct and oversight of human subject research (investigators, key personnel, mentors, IRB members, IRB chairs and IRB staff) must complete initial and continuing education in human research protections.

IRB Committee Members

Initial Training and Education

In-House Orientation

All prospective IRB Committee members are required to complete an initial two hour orientation session prior to serving on the IRB. The orientation session is conducted by the IRB Medical Director or IRB Chair and the IRB Membership Coordinator. All new members are provided with electronic versions of the following information:

• IRB Policy and Procedure Manual;
• DHHS regulations (45 CFR 46)FDA regulations (21 CFR 50 and 56);
• Belmont Report;
• Declaration of Helsinki;
• Nuremberg Code;
• University of Pittsburgh Conflict of Interest Policy;
• HIPAA Q&A;
• Institutional Review Board, Member Handbook;
• Relevant IRB Forms.

Observation of IRB Meeting

All new IRB Committee members are required to observe at least one IRB committee meeting prior to functioning as a voting member.

OSIRIS Training

All new IRB Committee members will be trained by the IRB Membership Coordinator in the use of the electronic submission system (OSIRIS). This training will include how to review electronic applications, post reviewer notes, and access checklists and other supporting documentation. OSIRIS tips specific to IRB Committee members are sent via e-mail to enhance the members’ understanding and knowledge of OSIRIS.

Required Educational Modules

New IRB Committee members are required to complete specific research ethic courses using the CITI training program. The courses are designed for three user groups: biomedical researcher (includes all health science students), social and behavioral researcher, and undergraduate student researcher. At a minimum, all users must completed courses in Human Subjects Protections and Responsible Conduct of Research. Go to www.citi.pitt.edu for more information and to access the courses. If you have any questions, email us at irb@pitt.edu.

All IRB Committee members may elect to take the IRB Member Education module.

Continuing Education

IRB members will receive, on an ongoing basis, continuing education related to human subject protection issues and requirements.

• Every month, the IRB Chair and Program Manager will identify a topic to be reviewed at each scheduled committee meeting. In order to ensure consistency with the information provided to the Committee members, the Program Manager (or his/her designee) will make a presentation at the beginning of each meeting. The content will be recorded in the minutes for the meeting as well as the members present at the meeting

• In addition, an educational presentation for IRB board members will be held throughout the year on topics related to the protection of human subjects. The IRB Office will maintain documentation of the attendance of IRB board members at the sessions.
• The IRB Chair, IRB Vice Chairs, Director of the IRB Office/IRB Vice Chair, and IRB Office staff are be routinely available to address any questions or concerns of the IRB members.

• IRB members are provided access to reference materials and research protocol files maintained within the IRB Office as such access may relate to their functions as an IRB member.

Re-Appointed IRB Committee Member

IRB Committee members are appointed for a three year period. This includes those individuals serving as alternate IRB members. If members are reappointed another three year term, the member must complete the CITI IRB Member module.

IRB Staff Training

Initial Education and Orientation

New hires to the University of Pittsburgh must complete a general orientation conducted by the University of Pittsburgh, Office of Human Resources. The university orientation is an introduction to the university working environment and includes an overview of university policies and procedures, employment expectations, performance and relationships, and mandatory training requirements set forth by the university.

New IRB staff members are required to complete the following training modules found on the University of Pittsburgh Internet-Based Studies in Education and Research:

• IRB Member Education;
• Research Integrity; and either
• Human Subject Research in Biomedical Science; or
• Human Subject Research in Social and Behavior Sciences
• Good Clinical Practice;
• Conflict of Interest.

These internet-based educational courses are specifically designed for all personnel that have a significant involvement in the planning, conduct, and analysis of any scientific activity that employs human research participants. A minimum score of 80% must be obtained. IRB staff members who do not achieve a passing score will need to re-take the exam until a score of 80% or greater is obtained.

New staff designated as Research Review Coordinators will attend and observe at least 3 IRB Committee meetings during the first 3 months of employment. The new staff member will then review the minutes from the committee meeting with the assigned Research Review Coordinator.

New IRB staff members will attend the Research Coordinators’ Orientation Program. This course consists of an overview of human subject research, a description of the ethical principles underlying the concept of human subject research, and an overview of the federal regulations governing IRB operations and human subject research.

New IRB staff members will spend their provisional period of employment (six months) under the direct supervision of the Assistant IRB Director, Program Manager, and IRB Office Manager and will be oriented to the following:

• The Belmont Report;
• Federal Regulations (DHHS 45 CFR 46 and FDA 21 CFR 50 and 56);
• Full Board Committee Review Process;
• Expedited Review Process;
• Exempt Review Process;
• University of Pittsburgh IRB Policies and Procedures;
• Job Description and Core Duties;
• Performance Evaluation Process.

Overview of reference websites which include the following:

• University of Pittsburgh Institutional Review Board;
• University of Pittsburgh Research Conduct and Compliance Office;
• Office for Human Research Protections;
• Food and Drug Administration;
• Health Insurance Portability and Accountability Act (HIPAA);
• Public Responsibility in Medicine and Research (PRIM&R).

After completion of the outlined training procedures, the IRB Director or his/her designee makes the determination if the research review coordinator has obtained sufficient experience to work independently. This will be documented in the employee record. All research review coordinators (full board and exempt and expedited) are members of the IRB.

The IRB houses a reference library containing information on several topics related to issues and regulations pertaining to human subject research. Materials are available for IRB staff members to review.

Continuing Education

IRB Staff members are expected to take part in continuing education activities as follows:

1. Completion of the CITI Basic Course every three years;
2. It is recommended that staff obtain the Certified IRB Professional (CIP) certificate after two years of employment;

As part of their professional development, IRB staff members are offered the opportunity to attend (at a minimum) one local, regional, or national conference in human subject protection during each year of employment.

Vice Chair Training

Initial Education and Orientation

All newly appointed IRB Vice Chairs, who were not currently members of the IRB, are required to undergo the initial orientation as outlined in the section entitled Education and Training –IRB Board Members.

Newly appointed IRB Vice Chairs receive training and support respective to the duties and functions of the position. This training and support will be provided by the IRB Chair, the other current IRB Vice Chairs, the Director of the IRB Office, the IRB Office staff.

The IRB Chair or IRB Assistant Director are required to attend all IRB meetings overseen by the newly appointed IRB Vice Chair until such time that the latter individual has achieved an appropriate level of experience and comfort with this position.

IRB Vice Chairs are required to complete the following training modules found on the University of Pittsburgh Internet-Based Studies in Education and Research:

• Research Integrity; and either
• Human Subject Research in Biomedical Science; or
• Human Subject Research in Social and Behavior Sciences
• Good Clinical Practice;
• Conflict of Interest.

For DoD funded projects, training requirements for IRB leadership will be reviewed each time a DoD addendum/agreement is executed to ensure adherence to the specific requirements within the respective DoD component.

Continuing Education

The IRB Vice Chairs meet on a monthly basis to discuss issues relevant to human subject protections.

IRB Vice Chairs will receive, on an ongoing basis, continuing education related to human subject protection issues and requirements.

• Every month, the IRB Chair and Program Manager will identify a topic to be reviewed at each scheduled committee meeting. In order to ensure consistency with the information provided to the IRB Vice Chairs and Committee members, the Program Manager (or his/her designee) will make a presentation at the beginning of each meeting. The content will be recorded in the minutes for the meeting as well as the members present at the meeting.
• The IRB Chair, Director of the IRB Office/IRB Vice Chair, and IRB Office staff are be routinely available to address any questions or concerns of the IRB Vice Chairs.IRB Vice Chairs are provided access to reference materials and research protocol files maintained within the IRB Office as such access may relate to their functions as an IRB member.
• IRB Vice Chairs will complete the CITI IRB Member module every three years.

For DoD funded projects, training requirements for IRB leadership will be reviewed each time a DoD addendum/agreement is executed to ensure adherence to the specific requirements within the respective DoD component.

Investigator and Research Personnel

Initial Education and Training

All investigators and key personnel involved in Human Subject Research (including Faculty Mentors) are required to complete specific research ethic courses using the CITI training program. Only those individuals who have completed the required training are permitted to conduct human subject research or to access OSIRIS (IRB on-line application). The courses are designed for three user groups: biomedical researcher (includes all health science students), social and behavioral researcher, and undergraduate student researcher. At a minimum, all users must completed courses in Human Subjects Protections and Responsible Conduct of Research. Go to www.citi.pitt.edu for more information and to access the courses. If you have any questions, email us at irb@pitt.edu.

Investigators and research staff are expected to adhere to the ethical and regulatory requirements outlined in the training modules. In addition, all principal investigators, listed co-investigators and study coordinators will be required to complete the Good Clinical Practice module if the study that is being conducted involves an IND or IDE.

Investigators conducting research funded by the Department of Defense (DOD) are subject to additional DOD educational requirements. Details related to the specific educational requirements are available through Program Officials.

There are also several other modules that can be used as resources for the research community. The modules can be accessed from the IRB web site or at http://cme.hs.pitt.edu.

Additional Resources

The IRB website at www.irb.pitt.edu provides guidance documents to assist in navigating the IRB process and adhering to federal regulations as well as IRB policies and procedures related to human research protections. In additional links are provided for local, state, and federal entities.

Electronic Communication

Each member of the research community has the opportunity to become a member of the IRB’s distribution e-mail list. All announcements related to updates in federal regulations as well as revisions to the IRB Reference Manual are communicated to the research community through this medium.

The IRB has a designated email address, ASKIRB@pitt.edu, to be used to answer general questions in a timely fashion.

Outreach Programs

The IRB engages in outreach programs that include, but are not limited to:

• "Ask the IRB" Sessions
• IRB Workshops
• IRB 101
• OSIRIS Training
• Open Office Hours

Continuing Education

All investigators and study team members are required to complete additional human subjects protection training every three years. Investigators conducting research funded by the Department of Defense (DOD) may be subject to additional DOD continuing education requirements. Please contact your Program Official to determine these requirements.

The Principal Investigator is responsible for maintaining the records of completion for all members of the research team. These documents must be available for audit by the Education and Compliance Office for Human Subject Research (ECO-HSR). Failure to complete the requirements will result in the inability to access the online submission application (OSIRIS). At the discretion of the IRB Chair or IRB Director, exceptions to this rule will be made permitting access to OSIRIS for the submission of adverse events, other unanticipated problems, or protocol modifications to ensure the safety and well being of the research subjects.

1. Starting January 2012, all study team members must complete the CITI Refresher Course at least every three years
2. Members of the research community are encouraged to complete continuing education credits related to human subjects protection or ethical considerations in the conduct of human subject research. Examples of available programs include:
   • Designated IRB -sponsored programs;
   • Other Modules by CITI;
   • Research Coordinator Orientation program;
   • Participation in a Research Investigator Start-up Education (RISE) Interview;
   • FDA Training Continuing Education Courses http://www.fda.gov/Training/CDRHLearn/ucm162015.htm;
   • Attendance at IRB-approved bioethics programs;
   • Attendance at programs sponsored by PRIM&R or its affiliates on human subjects protections.
3. Faculty members who are listed as the designated faculty mentor to undergraduate and graduate students conducting human subject research must complete the CITI Refresher Course at least every 3 years. Mentors should maintain records of completion for this training. These documents must be available for audit by the Education and Compliance Office for Human Subject Research (ECO-HSR).

Contact the IRB Director if you have questions related to meeting the education requirements.

If any IRB Office staff member, IRB member, Vice Chair or member of the research community believes s/he has been subjected to undue influence, they should report this matter to the IRB Chair, who will investigate the matter and, in collaboration with the Vice Chancellor for Research Conduct and Compliance (the Institutional Official), will take appropriate action. If the IRB Office staff member or Vice Chair feels that the IRB Chair is responsible for the undue influence, this matter will be brought directly to the attention of the Vice Chancellor for Research Conduct and Compliance, who will investigate the matter and take appropriate action. If the Vice Chancellor for Research Conduct and Compliance is responsible for the undue influence, the IRB Chair will bring this matter to the attention of the Chancellor, who will investigate the matter and take appropriate action.

• At any time an individual may report undue influence to the University of Pittsburgh AlertLine (http://www.hr.pitt.edu/empreledu/staffhb/GeneralPolicies.htm#AlertLine ).

Alertline

AlertLine is a toll-free telephone line, 1-866-858-4456, that University of Pittsburgh employees can use to report certain irregular or troublesome workplace issues so that these issues can be investigated and resolved.
AlertLine is available to all full-time and part-time faculty, staff, and research associates at the Pittsburgh and regional campuses and other off-campus work locations. Callers can remain anonymous. The line answers 24 hours a day, seven days a week, and can be accessed from any telephone in North America, including pay telephones.
Issues that can be reported on the AlertLine include:

• Financial improprieties, including fraud, theft, falsification of records, and improper use of University assets.
• Human resource matters, including perceived harassment, discrimination, misconduct, and other workplace issues.
• Research compliance concerns, including conflict of interest, improper charging of grants, violation of human subject research regulations, and violation of other research compliance rules.
• Other legal/regulatory matters, such as those pertaining to environmental health and safety.

Trials Eligible for Facilitated Review by the University of Pittsburgh IRB

The University of Pittsburgh Institutional Review Board (UP IRB) (FWA00006790) has designated the National Cancer Institute (NCI) Central Institutional Review Board (CIRB) (FWA00002195) as the IRB of Record for:

1. Phase III Adult Cancer Cooperative Group Trials and
2. Phase II and III Pediatric Cancer Cooperative Group Trials

This policy sets forth the scope of the UP IRB local oversight and review of CIRB protocols carried out at all sites under the University of Pittsburgh’s jurisdiction.

Responsibilities of the University of Pittsburgh IRB

For both initial and continuing review of Pediatric Phase II and III cancer cooperative group trials and Adult Phase III cancer cooperative group trials, the UP IRB will be responsible for the following:

1. Ensuring the safe and appropriate performance of the research at this site. This includes, but is not limited to, monitoring protocol compliance, reviewing any serious unanticipated problems, and/or any serious adverse events occurring at the site that meet University of Pittsburgh reporting requirements, reviewing all progress reports and modifications and providing a mechanism by which complaints about the research can be made by local study participants or others. Any actions taken as a result of problems that are identified in these areas should be shared with the CIRB and reported as required by the procedures established by the UOP IRB;
2. Ensuring that the investigators and other staff at this site who are conducting the research are appropriately qualified and meet the institution’s standards for eligibility to conduct research;
3. Notifying the CIRB immediately if there is a suspension or restriction of a local investigator;
4. Reviewing the CIRB protocol and related materials that is submitted to the UP IRB by a local investigator and determining if:
   1. there are any local research context issues or state or local laws that must be addressed by the UP IRB;
   2. the CIRB review is acceptable to the UP IRB; and, if it is not acceptable, the PI will submit the protocol for local full board IRB review.
5. Requiring as appropriate, that the investigator/research staff add local restrictions, stipulations or substitutions to CIRB approved informed consent document;
6. Maintaining in the local IRB records documentation of the decision to accept or reject the CIRB decision and evidence that it has received and considered all CIRB material relevant to the protocol;
7. Communicating with the CIRB regarding the acceptance or rejection of CIRB review. This is performed via the NCI – CIRB website and is applicable only to new submissions.

Responsibilities of the NCI Central IRB

The UP IRB will rely on the NCI CIRB to fulfill stated responsibilities as set forth in its policies, which are available for review at http://www.ncicirb.org/Div_Responsibilities1.pdf.

PI Responsibilities

Initial Review

After determining if he/she wants to participate in a facilitated review of an eligible CIRB reviewed cancer cooperative group trial, the PI or his or her designee will:

1. Download the following documents from the Participant’s Area of the CIRB website (http://www.ncicirb.org): the CIRB protocol, CIRB informed consent document(s) and approval letter;
2. Complete the appropriate UP IRB’s Facilitated Review Application Form, insert local IRB approved elements into the consent form to comply with local requirements;
3. Submit all documents to the UP IRB by email (UP-CIRB@upmc.edu).

Continuing Review

At the time of continuing review, the PI or his or her designee will:

1. Ensure that CIRB recertification is submitted and receives approval in a timely manner
2. Download all the documents from the Participant’s Area of the CIRB website (http://www.ncicirb.org), including informed consent and recertification letter
3. Complete the appropriate UP IRB’s Renewal Report Form, an IRB coversheet including CIRB related documents (data and safety monitoring report) and email to the UP IRB for facilitated review

Modifications

For protocol modifications, the PI is responsible for confirming that an amendment posted on the Group website has been CIRB approved before emailing to the amendment to the UP IRB. The PI is also responsible for completing an IRB coversheet, a UP IRB Modification Request Form, including copies of any modifications made to local documents and emailing this material to the UP IRB.

Responsibilities of the Designated UOP IRB Staff Members

The Staff member designated to review NCI Central IRB Submissions will:

1. Print the CIRB minutes, scientific and non-scientific review materials from the CIRB website. Conduct an administrative review to ensure all appropriate materials are available. Follow up on local administrative requirements.
2. Forward the materials to the appointed voting member of the UP IRB as defined above. If a minor modification is submitted, the AERRC may review and approve the modification with review by the IRB Chair.
3. Review the protocol and consent document for local IRB requirements as well as applicable federal, state and local laws.
4. Ensure that all administrative/facilitated review requirements are met, and accept CIRB approval on the CIRB website.
5. Update the UP IRB database so a report can be generated for inclusion on the next UP IRB full board agenda for information purposes.

Reviewer Designation

The UP IRB review will be known as “facilitated review” and will be conducted by two voting members of the UP IRB who are appointed by the Chair. The first reviewer will be an IRB member with expertise sufficient for the research being conducted. The second reviewer will be an IRB staff member with expertise in regulatory issues as well as local policy.

• Either reviewer may request consultation with other members of the IRB, as necessary, to conduct a review of the research study.
• In the absence of the appointed reviewer, the IRB Chair may identify an alternate member with appropriate expertise to conduct reviews.
• The UP IRB’s existing conflict of interest policy remains in effect. (See Section XVIII) In addition, to avoid potential conflicts of interest, no IRB member who is currently a member of the CIRB will be assigned as a reviewer for a facilitated review.
• All members serving in this capacity will have completed training in human subject protection and local research requirements. (See Section XX)

Standard Administrative Requirements

The UP IRB will ensure compliance with standard administrative requirements and the appropriateness of the protocol and informed consent document (ICD), in accordance with the following guidelines:

All UP IRB pre-submission requirements must be fulfilled including, but not limited to the following:

• Prior scientific review (PCI protocols only);
• fiscal review;
• RDRC/HUSC approval (if protocol involves ionizing radiation);
• IBC-rDNA approval (if protocol involves gene transfer);
• Investigational Drug Service notification;
• Conflict of interest review.

During review of the protocol, consideration will be given to requirements of state and local law, institutional requirements and/or UP IRB policies. This includes, but may not be limited to:

• issues related to the inclusion of children in research;
• issues related to proxy consent in research involving decisionally-impaired adults;
• issues related to the enrollment of pregnant women;
• any other local or state requirements applicable to the protocol;

Local additions to the informed consent dealing with state and local law, institutional requirements or UP IRB policies will be added to the local consent document. The following sections of the informed consent document must rely on the language requirements of the UP IRB:

• child abuse statement which is required by PA law;
• HIPAA/confidentiality language which should indicate that the CIRB will have access to subject information;
• compensation for subject injury;
• costs to the subjects (based on local fiscal review)radiation risk language (if the protocol involves ionizing radiation)contact information for the Human Subject Protection Advocate at the UP IRB;
• investigator certification, verification of explanation and appropriate signature spaces;
• New information section;
• Standard risk statement.

UP IRB may make minor word substitutions or additions in the ICD particularly to facilitate better comprehension by the local population, as long as the proposed changes do not alter the meaning of the CIRB approved consents.

Revisions/changes to the local consent form other than those described above require full board review at the local level, and facilitated review may not be used.

Possible Review Determinations

The UP IRB retains the authority to accept or reject a "facilitated review" on a study-by-study basis and may require full board review.

• The UP IRB retains the authority to request an audit of any aspect of the research study, including CIRB studies, (including the informed consent process).
• Possible decisions of the reviewers include:
• accept the CIRB review;
• accept with minor modifications;

not accept the CIRB review in which case the study will be removed from CIRB consideration and returned to the PI for submission to the full board of the UP IRB. (If uncertain whether minor modifications requested by the UP IRB meet CIRB requirements, staff will confirm with CIRB).

Post Review Correspondence

If the CIRB review is accepted, the PI will be sent written notification that the CIRB approval is affirmed, providing the approval date and expiration date to be affixed to the consent document(s).

Approval Periods

Since the initial approval period will be assigned by the CIRB, the approval period provided to the local PI may be less than 365 days. Thereafter, the UP IRB approval/expiration dates will reflect the CIRB full recertification period.

Unanticipated Problems

All procedures outlined in the IRB Policy and Procedure Manual remain in effect with the exception of external adverse events, which are not required to be reported to the UP IRB.

Special policies and procedures cover research activities conducted at performance settings that are considered to be "off-site" or "non-local."  These are activities that are conducted at sites that do not fall under the authority of the University of Pittsburgh IRB, and (a) are not owned or operated by the University of Pittsburgh, UPMC, or affiliated institutions and (b) are geographically outside of the greater Pittsburgh area.  More than one IRB may be responsible for these off-site research activities.  Note that the Pittsburgh VA Medical Center and the CMU Brain Imaging Research Center are not considered to be off-site, and are not covered by these policies. 

Special provisions for off-site research reflect the regulatory mandate that IRBs must have sufficient knowledge of the local research context to ensure that (a) selection of subjects is equitable, (b) subject privacy is protected and confidentiality of data is maintained, (c) informed consent is sought in a language that is understandable to the subject and under conditions that minimize the possibility of undue influence, and (d) appropriate safeguards exist to protect the rights and welfare of vulnerable subjects [45 CFR 46.111(a)(3), (a)(4), (a)(7), (b), and 46.116].  The following policies pertain not only to non-exempt research conducted at sites outside of the U.S., but also to off-site research conducted within the U.S. This is particularly important when the domestic research is being conducted in an environment comprised largely of subjects who differ markedly from those in the greater Pittsburgh area because of differences in ethnicity or national origin (e.g., Hispanics; Russian immigrants), religion (e.g., Old Order Mennonites or Amish), and/or customs and values (e.g., Native Americans).

For any non-exempt research activity conducted at a non-local domestic or international institution or site, the following must be addressed in the IRB protocol by the Pitt/UPMC investigator:

• the anticipated scope of the research activities to be conducted at the non-local institution or site;
• the types of subject populations likely to be involved and the languages spoken by them;
• the size and complexity of the institution or site where the research is being conducted;
• applicable law at that site;
• standards of professional conduct and practice;
• the methods for ensuring equitable selection of subjects;
• the methods for protecting subjects’ privacy;
• the methods for maintaining the confidentiality of the research data;
• the methods for minimizing the possibility of coercion or undue influence in seeking consent;
• the safeguards to protect the rights and welfare of vulnerable subjects;
• whether the off-site institution is, or is not, engaged in research, as defined by the OHRP guidance document titled "Engagement of Institutions in Research" if the site is engaged in research, written confirmation is needed that facility personnel have appropriate expertise (including the name and qualifications of the individual designated as being responsible for the conduct of this research study for each foreign/non-local site is specified.) to carry out the research procedures as reviewed and approved by the IRB if the research is supported by a division of DHHS, an FWA must be submitted.

For off-site research activities that involve either (a) minimal risk to subjects OR (b) more than minimal risk but at that non-local site the research involves no intervention or interaction with subjects and breach of confidentiality is the principal risk:

• The research protocol must be accompanied by a letter that allows the investigator to conduct the study at the non-local site, signed by the individual authorized to commit the site to study participation.  In addition to specifying such agreement, the letter must indicate that institutional commitments and regulations, applicable laws, and standards for professional conduct and practice have been appropriately addressed by the investigator.
• In granting approval for the conduct of such a study at the non-local site, the IRB must determine and specifically document that provisions to protect the privacy of subjects and maintain the confidentiality of data are adequate.

When the research activities involve greater than minimal risk to subjects and the investigators are interacting or intervening with subjects at the non-local site, the IRB has the following responsibilities:

Meeting minutes must document that the IRB has obtained appropriate information about the local research context through one or more of the following means:

• Personal knowledge of the local research context on the part of one or more IRB members, such knowledge having been obtained through extended, direct experience with the non-local research site, its subject populations, and its surrounding community;
• Participation by one or more appropriate consultants in the IRB Committee discussion of the research study, either physically or via teleconferencing;
• Prior written review of the proposed research by one or more appropriate consultants, with consultants available either in person or via teleconference to address questions, when needed, raised during the Committee meeting.

To ensure that these elements are included in the minutes, the research review coordinator will utilize the non-local research form.

The IRB must also include all of the following in the IRB records for this project:

1. Written notification that the research study has been approved by an IRB or other human subject protections entity located at the site where the research is to be conducted;
2. A copy of the written review (e.g., meeting minutes) of the research study performed by the non-local IRB entity;
3. A letter from the chair of the non-local IRB/entity indicating that they will not require that a representative of their IRB/entity participate in the University of Pittsburgh IRB review of the research study.

Additional Requirements When Research is Conducted Outside of the United States

When human subject research is conducted outside of the United States, additional matters must be addressed.  If the foreign site will be engaged in human subject research and if the research is federally funded in whole or in part, the foreign site must file an International FWA.  The International FWA number should be provided in the protocol.  Investigators may direct the foreign site to this OHRP site to obtain the necessary paperwork: http://www.hhs.gov/ohrp/humansubjects/assurance/ifilasuri.htm

If investigational drugs or devices will be used at the foreign site, the foreign site must agree to abide by the FDA Guidance on Good Clinical Practice (“GCP Guidance”), which was developed as part of the work of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).   The Guidance is available at:  http://www.fda.gov/cder/guidance/index.htm#clinical%20medicine

1.  GCP Guidance provides a consistent set of definitions and requirements for record-keeping, adverse event reporting and all other aspects of clinical trial conduct.
2. Any agreement with the foreign site should expressly reference the GCP Guidance, and the University investigator must be comfortable that the foreign site is equipped to meet GCP Guidance standards.

If the investigational drugs or devices will be shipped from the University to the foreign site, the investigators must obtain written permission from the manufacturer and meet any necessary import requirements from the receiving country.   Investigators should obtain written documentation from the foreign site stipulating that all necessary approvals for use of an investigational drug or device under the local laws have been obtained.

Department of Defense

Overview

Research supported by the Department of Defense (DoD), including the separate components, the Army, Navy, Air Force and Marine Corps, or recruitment of DoD personnel requires compliance with additional federal regulations, Directives and Instructions. This procedure applies to human subject research that is funded by any DOD component or that recruits participants from the DoD.

Definitions

DoD Addendum: An application to the Department of Defense attesting that the University of Pittsburgh will comply with all relevant federal regulations, DoD Instructions and Directives and other relevant documents regarding the protection of human subjects in research. The Addendum applies to research supported by the DoD, Air Force, Navy, and Marine Corps. The Army does not use the mechanism of an Addendum. Additional Army requirements are managed through the contracting process.

The University of Pittsburgh has a DoD Addendum in place for the Air Force and Navy. Copies of these documents are available on the IRB web site (http://www.irb.pitt.edu/FWA/).

Research Involving a Human Being as an Experimental Subject: An activity, for research purposes, where there is an intervention or interaction with a human being for the primary purpose of obtaining data regarding the effect of the intervention or interaction (32 CFR 219.103(f) reference (c)). Examples of interventions or interactions include, but are not limited to, a physical procedure, a drug, a manipulation of the subject or subject’s environment, the withholding of an intervention that would have been undertaken if not for the research purpose. Further information surrounding this definition may be found at: http://www.dtic.mil/whs/directives/corres/pdf/321602p.pdf.

Educational Requirements

Initial and continuing research ethics education is required for all personnel who conduct, review, approve, oversee, support or manage human research supported by the DoD or its components. At the present time, the University of Pittsburgh IRB requires that individuals conducting human subjects research complete modules on Research Integrity and Human Subjects Protection as described on the IRB website. Individual DoD components may have stricter or specific educational requirements, and may require re-certifications more frequently than currently mandated by the University of Pittsburgh IRB. Researchers should contact their Program Officer at the DoD, or DoD component, to ensure adherence to any unique requirements. It is the Principal Investigator’s responsibility to ensure that research staff has completed all appropriate educational requirements as mandated by DoD policy.

Scientific Review

New research and substantive modifications to approved research must undergo scientific review prior to or at the time of IRB review. This requirement can be met by University departmental scientific review process. Evidence of scientific review for DoD funded studies should be uploaded into the OSIRIS application under the "Other Attachments" section.

Medical Monitor

For studies involving greater than minimal risk, appointment of an independent medical monitor is required.

• The medical monitor must be a physician, dentist, psychologist, nurse, or other healthcare provider capable of overseeing the progress of the research protocol, especially issues of individual subject/patient management and safety.
• The medical monitor must be independent of the investigative team and possess sufficient educational and professional experience to serve as the subject/patient advocate. Depending on the nature of the study, the medical monitor may be assigned to assess one or more of the following phases of a research project: subject recruitment, subject enrollment, data collection, or data storage and analysis.
• At the discretion of the IRB, the medical monitor may be assigned to discuss research progress with the Principal Investigator, interview subjects, consult on individual cases, or evaluate adverse event reports.
• The medical monitor must promptly report any discrepancies or problems to the IRB
• The medical monitor has the authority to stop a research study in progress, remove individuals from a study, and/or take any steps to protect the safety and well being of subjects until the IRB can make an assessment.

The Principal Investigator is responsible for providing the name, contact information and responsibilities of the monitor to the IRB in Section 5.13 of the OSIRIS application.

Research Related Injury

The Department of Defense components may have stricter requirements regarding research-related injury than those outlined in the policies of the University of Pittsburgh and federal regulations. Investigators should work with their Program Officer within the DoD component to identify such requirements. Additional language regarding specific requirements by the DoD should be incorporated into the informed consent document as appropriate.

International Research

When DoD-sponsored research involves human subjects who are not U.S. citizens or DoD personnel and the research is conducted outside the United States, and its territories, the Principal Investigator must obtain permission from the host country. The laws, customs, regulations and practices of the host country and those required by the University of Pittsburgh IRB will be followed. An ethics review by the host country, or local DoD IRB with host country representation is required. Evidence of permission to conduct the research in the host country by certification or local ethics review must be submitted to the University of Pittsburgh IRB prior to initiation of the project.

Studies Involving Department of Defense Personnel

Undue Influence

For research involving more than minimal risk and also involving military personnel, the following additional protections must be in place and articulated in the OSIRIS application to minimize undue influence:

• Officers cannot influence the decision of their subordinates to participate in the research.
• Officers and senior non-commissioned officers cannot be present at the time of recruitment into the research.
• Officers and senior non-commissioned officers must have a separate opportunity to participate in the research.
• When recruitment involves a percentage of a unit, an ombudsman, who is independent of both the proposed research as well as the unit must be present to monitor that the voluntary nature of the individual participants is adequately stressed and that the information provided about the research is adequate and correct.

Compensation

The following limitations on dual compensation for U.S. military personnel apply:

• An individual may not receive pay from more than one position for more than 40 hours of work in one calendar week. This limitation on dual compensation includes temporary, part-time and intermittent appointments.
• Individuals may receive compensation for research activities if the research activities take place outside of scheduled work hours.

Vulnerable Populations

Research supported or conducted by the Department of Defense that affects vulnerable classes of subjects must meet the additional protections of 45 CFR Part 46, Subparts B, C, and D. Determinations authorizing or requiring any action by an official of DHHS is under the authority of the Director, Defense Research and Engineering.

Prisoners of War

Research involving persons considered prisoners of war (POW) is prohibited. Refer to the definition of "prisoner of war" for the Department of Defense component funding the project.

Waiver of Consent

If the research subject of a study funded by the DoD or its components meets the definition of "experimental subject" then a waiver of consent (including an exception from consent in emergency medicine research) by the IRB is prohibited unless a waiver is obtained from the Secretary of Defense. However, if the research subject does not meet the definition of "experimental subject," then the IRB may waive the consent process.

Additional DoD Review Requirements

Surveys

Surveys involving Department of Defense personnel must be submitted, reviewed, and approved by the Department of Defense after the research protocol is reviewed and approved by the IRB. Any requested DOD changes must subsequently be submitted to the IRB for review.

Continuing Review Reports

As specified in the DoD Addendum, a copy of all continuing review reports submitted to the IRB must be submitted to the DoD.

References

32 CFR 219
10 USC 980
DoD Directive 3216.2
SECNAVINST 3900.39D
OPNAVINST 5300.8B
DoD Dual Compensation Act, 24 U.S.C 301

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Department of Justice

The University of Pittsburgh IRB will review submissions supported by the Department of Justice (DOJ) or conducted within the federal Bureau of Prisons with respect to the following additional requirements.

Research funded through the National Institute of Justice (NIJ) must comply with the provisions of 28 CFR Part 46, related to human subject protections, and also 28 CFR Part 22, related to privacy and confidentiality of research data. Specific requirements for such research are outlined below.
The research must have a privacy certificate approved by the NIJ Human Subjects Protection Officer. The NIJ requirements for privacy certificates are very specific and are available at: http://www.nij.gov/nij/funding/humansubjects/privacy-certificate-guidance.htm. A model form for a privacy certificate can be found at: http://www.nij.gov/nij/funding/humansubjects/model-privacy-certificate.htm

1. A statement must be included in the consent document that confidentiality may only be broken if the participant reports immediate harm to participants or others.
2. All Researchers and Research Staff are required to acknowledge in writing the confidentiality protections of the study, and copies of that acknowledgement must be maintained by the responsible Researcher.
3. Identifiable portions of the data must be destroyed after the three year data retention period has expired and a copy of all de-identified data must be sent to the National Archive of Criminal Justice Data including de-identified informed consent documents, data collection instruments, surveys or other relevant research materials.

Research Involving the Bureau of Prisons

Research within the federal Bureau of Prisons is subject to the additional requirements of 28 CFR 512. The regulations apply to any research involving inmates in the custody of the Attorney General, and assigned to the Bureau of Prisons, regardless of the institution in which the inmate is incarcerated (e.g., even if the inmate is resident in a state institution).

Approval Process

1. Research protocols within the Bureau of Prisons must be approved in advance by the federal Bureau Research Review Board (“BRRB”), and by the warden of the individual facility in which the research is to be conducted.
2. No medical experimentation, cosmetic research or pharmaceutical testing is permitted. Only research studies that advance knowledge about corrections will be considered.
3. Research protocols may not offer incentives to inmate subjects, except for soft drinks and snacks to be consumed at the test site. Non-confined research subjects may be offered nominal monetary recompense for time and effort provided that such subjects are 1) no longer in Bureau of Prisons custody, and 2) participating in approved research being conducted by Bureau of Prisons employees or contractors.
4. The investigator must assume responsibility for actions of any research staff engaged to participate in the project, and all researchers must agree to abide by the rules of the institution where the research will be conducted. Researchers must sign an acknowledgement to adhere to the regulations of the Bureau of Prisons at 28 CFR Part 512.
5. The investigator must agree not to provide research information that identifies a subject to any person without the subject’s prior written consent to release the information.

Informed Consent

The informed consent document for a study to be conducted in the Bureau of Prisons must include the following elements, in addition to the elements required under the Common Rule:

• Identification of the investigators;
• Anticipated uses of the results of the research;
• A statement that participation is completely voluntary and that the subject may withdraw consent and end participation in the project at any time without penalty or prejudice (e.g. the inmate will be returned to regular assignment or activity by staff as soon as possible);
• A statement regarding the confidentiality of the research information and exceptions to any guarantees of confidentiality required by federal or state law (i.e. an investigator may not guarantee confidentiality when the subject indicates intent to commit future criminal conduct or harm himself/herself or someone else, or if the subject is an inmate, indicates intent to leave the facility without authorization);
• A statement that participation in the research project will have no effect on the inmate subject’s release date or parole eligibility.

Storage of Data and Confidentiality

Research protocols must include documentation for maintaining confidentiality of data preliminary to the research, during and after the conclusion of the research by assuring:

• Records are not in an individually identifiable form; and,
• Advance written assurance has been provided to the Bureau of Prisons that the records will be used solely for statistical research or reporting
• Research data may not be maintained electronically at the University that contain non-disclosable information directly traceable to a specific person (NOTE: Computerized data records may only be maintained at an official DOJ site)
• The principal investigator must negotiate arrangements, prior to the beginning of the data collection of the project, to provide non-identifiable computerized data on individual subjects along with documentation to the Office of Research and Evaluation (ORE) if requested
• At the conclusion of the research, the investigator must document that research records will be destroyed or individual identifiers will be removed from the records.

Post Study Obligations

Research conducted in the Bureau of Prisons must acknowledge the Bureau of Prisons participation in any publication of the results and include a disclaimer in the results for publication that the approval or endorsement of the published material is an expression of the policies or view of the Bureau of Prisons;

Researchers must provide, at least 12 working days before any report of findings to be released, one (1) copy of the report, which includes an abstract of the findings, to each of the following:

• The Chairperson of the BRRB;
• The Regional Bureau of Prisons Director; and
• The Warden of each institution which provided data or assistance.

Researchers must submit two (2) copies of the results of the research project for informational purposes only to the Chief, Office of Research and Evaluation, Central Office, Bureau of Prisons prior to submission for publication.

References

28 CFR 22
28 CFR 512

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Environmental Protection Agency

Overview

Research that is either: 1) conducted by the EPA, 2) supported by the EPA or 3) conducted by any party with the intent that the results will be submitted to the EPA for consideration under the Federal Insecticide, Fungicide, and Rodenticide Act, or under Section 408 of the Food, Drug and Cosmetic Act. 40 C.F.R. § 26.1203, is subject to additional regulations specific to the Environmental Protection Agency (EPA)found at 40 CFR 26. These regulations outline additional protections and prohibitions for children, pregnant women and fetuses, and nursing women.

Definitions

Research involving intentional exposure of a human subject: a study of a substance in which the exposure to the substance experienced by a human subject participating in the study would not have occurred but for the human subject’s participation in the study.

Observational Research: any human research that does not meet the definition of research involving intentional exposure of a human subject.

Specific EPA Requirements and Restrictions

The EPA prohibits research involving the intentional exposure of pregnant women, nursing women, or children.

While intentional exposure is prohibited in pregnant women and fetuses, in EPA sponsored studies, observational research is permitted provided all of the conditions outlined in 45 CFR § 46.204 and 45 CFR § 46.206 are met.

Children may also be enrolled in observational studies provided that the study either presents minimal risk, or the study presents greater than minimal risk, but holds out the prospect of direct benefit to the child or "is likely to contribute to the subject's well being." 40 C.F.R. § 26.405(a). In reviewing studies of this nature, the IRB must determine that the risk is justified by the anticipated benefit, and that the relation of the anticipated benefit to the risk is at least as favorable as the available alternative approaches. 40 CFR § 26.405. Appropriate mechanisms must be employed for soliciting the permission of the parents and the assent of the children in such observational studies. 40 CFR § 26.406.

Prior Submission of Proposed Human Subject Research for EPA

All human subject research studies supported by the EPA must either be approved or be determined to be exempt research by the EPA Human Subjects Research Review Official before any contract, grant, or formal agreement involving EPA support is awarded or entered into.

To obtain approval by the EPA Human Subjects Research Review Official (Review Official), the following documents must be submitted by the investigator to the EPA:

• The Primary Awardees Federalwide Assurance (FWA) number
• Copies of:
• the IRB approval (or exemption) letter
• the study protocol(s) as submitted to the IRB (the pre-award document is not sufficient)
• the IRB approved consent forms and subject recruitment materials if applicable
• all supplementary IRB correspondence

The materials should be submitted to :

By E-mail Attachment:
lux.warren@epa.gov

By Regular Mail or EPA Pouch Mail:
Warren Lux, M.D.
U.S. Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Mail Code 8105R
Washington, DC 20460

By Private Carrier (FedEx, UPS, etc.):
Warren Lux, M.D.
U.S. Environmental Protection Agency
1300 Pennsylvania Avenue

References

CFR 40 Part 26
Project Review by the Hrman Subjects Research Review Official (www.epa.gov/phre/project.htm )