STANFORD has and follows written policies and procedures setting forth the ethical standards and practices of the Human Research Protection Program. Relevant policies and procedures are made available to Sponsors, Researchers, Research Staff, research participants, and the Institutional Review Board, as appropriate. (AAHRPP Element I.1.D)

The Stanford University Research Policy Handbook Human Research Protection Program provides information about the organization, scope, authority and responsibilities associated with the Stanford University HRPP for the research community at Stanford University and its affiliates, and explains how the HRPP has been incorporated into one core document.

1.1 Organizations Covered by the HRPP

Section revised: 3/13/13

The five STANFORD affiliated organizations are:

· Stanford University

· Stanford Hospital and Clinics (SHC)

· Lucile Packard Children’s Hospital at Stanford (LPCH)

· Veterans Affairs Palo Alto Health Care System (VAPAHCS)

· Palo Alto Institute for Research and Education (PAIRE).

Any components of these organizations as listed in their Federalwide Assurances (FWAs) are considered part of that organization for purposes of the HRPP and are covered by this HRPP Policy Manual.

SHC and LPCH are California non-profit corporations whose sole member is the Board of Trustees of Stanford University. They provide hospital, clinic and physician services in affiliation with the Stanford University School of Medicine. They each maintain a memorandum of understanding with Stanford University that retains and requires Stanford University to carry out the HRPP on their behalf. This document also requires that they agree to cooperate with Stanford University and take all necessary actions to allow Stanford University to carry out the HRPP. Both SHC and LPCH file a FWA appointing the Stanford University IRBs to review their human subject research.

VAPAHCS is operated by the US Department of Veterans Affairs to provide hospital, clinic and physician services in the region of Palo Alto and Stanford, California. It is affiliated with Stanford University and its School of Medicine. Many of its physicians and investigators are also faculty at the School of Medicine who conduct research at VAPAHCS facilities. PAIRE is a non-profit corporation established and controlled by VAPAHCS pursuant to 38 USC 7361 and 7368. Its purpose is to provide a flexible funding mechanism for the conduct of approved research (i.e., externally sponsored research) at VAPAHCS facilities and through VAPAHCS physicians and investigators. Both VAPAHCS and PAIRE file a FWA appointing the Stanford University IRBs to review their human subject research. VAPAHCS and PAIRE also maintain a memorandum of understanding with Stanford University relating to the HRPP. This document is similar to the agreement with SHC and LPCH, but provides that VAPAHCS “remains ultimately responsible for the maintenance of its overall institutional system to protect human subjects.” This occurs through the VAPAHCS Research and Development Committee. Additionally, the memorandum of understanding between VAPAHCS and Stanford University formally establishes the Stanford University IRBs as the Research Privacy Board for VAPAHCS and PAIRE.

1.2 Goal and Objectives of the HRPP

Section revised: 3/13/13

The goal of the HRPP is to protect human research participants by ensuring that in all STANFORD research:

· The rights and welfare of human research participants are adequately protected.

· Such research is guided by the ethical principles of respect for persons, beneficence, and justice as set forth in the Belmont Report, and is conducted with the highest level of expertise and integrity.

· Such research complies with applicable laws.

Objectives of the HRPP

The HRPP includes mechanisms to:

· Establish a formal process to monitor, evaluate, and continually improve the protection of human research participants and dedicate resources sufficient to do so

· Exercise oversight of research protection

· Educate investigators and research staff about their ethical responsibility to protect research participants

· When appropriate, intervene in research and respond directly to concerns of research participants.

Written Plan for the HRPP

The written plan for the HRPP is comprised of policies, guidances, and supporting documents governing human subject research and the protection of participants. The HRPP is approved by the Vice Provost and Dean of Research. All documentation comprising the HRPP is available on the Human Subjects Website.

1.3 Delegation of Responsibility for Stanford University HRPP Implementation

Section revised: 3/13/13

STANFORD delegates responsibility for the Human Research Protection Program to an official with sufficient standing, authority, and independence to ensure implementation and maintenance of the program. (AAHRPP Element I.1.B)

For the organizations covered by the HRPP, the President of Stanford University delegates the primary responsibility to the Vice Provost and Dean of Research to establish, maintain, and oversee the HRPP. (See Delegation of Authority to Institutional Officer and Research Policy Handbook).

STANFORD considers the HRPP Policy Manual to be a dynamic document, because the scientific developments, ethical issues, and regulatory circumstances that shape it are continuously evolving and improving. The Research Compliance Office (RCO) maintains policies and procedures reflecting the current practices of the IRB in conducting reviews and approvals of human research. As part of the RCO Continuous Quality Improvement (CQI) program, the RCO Director, in consultation with senior HRPP staff, regularly reviews (i.e., at least annually) and refines the HRPP Policy Manual and makes recommendations for modifications, or develops new policies and procedures as appropriate. The Vice Provost and Dean of Research may approve a modification of any portion of the HRPP Policy Manual. The RCO Director may approve modifications to the HRPP Policy Manual that relate to the day-to-day review and operational functions of the IRB; other modifications of the HRPP Policy Manual must be approved by the Vice Provost and Dean of Research.

The RCO is responsible for disseminating all modifications to the HRPP Policy Manual and incorporating them into the relevant educational programs (discussed in Chapter 4).

1.4 Research Covered by the HRPP

Section revised: 3/13/13

STANFORD has and follows written policies and procedures for determining when activities are overseen by the Human Research Protection Program. (AAHRPP Element I.1.A)

Types of human subject research at STANFORD

STANFORD conducts or oversees biomedical, social science and behavioral research. Human subject research is covered as stated in the Federalwide Assurance – for each STANFORD affiliated organization. Stanford University has chosen to limit the scope of its Federalwide Assurance (FWA) to federally funded research by “unchecking the box” on its FWA, thus allowing flexibility in the approval period for certain research – see Triennial Review (Chapter 7.8.)

All human subject research in which STANFORD is engaged is covered by the HRPP.

An activity is covered by the HRPP when:

· It is considered “human subject research” - as defined in any one of the following:

- FDA regulations

- DHHS regulations or other Common Rule regulations

- VA regulations (VHA Handbook 1200.5), or

- Any other applicable state or local regulations, e.g. California State regulations

and

· STANFORD (or its employees or agents) is engaged in the research – as defined by being involved in one or more of the following activities (in accordance with the OHRP guidance Engagement of Institutions in Human Subjects Research):

- Receiving an award through a grant, contract, or cooperative agreement directly from HHS or other federal agency for the non-exempt human subjects research;

- Intervening for research purposes with any human subjects of the research by performing invasive or noninvasive procedures;

- Intervening for research purposes with any human subject of the research by manipulating the environment;

- Interacting for research purposes with any human subject of the research;

- Obtaining the informed consent of human subjects for the research.

- Obtaining for research purposes identifiable private information or identifiable biological specimens from any source for the research.

Agents include all individuals performing institutionally designated activities or exercising institutionally delegated authority or responsibility, including students, faculty, staff, employees, visiting scholars.

See Chapter 3.3 for HRPP Policy Manual policies and procedures for determining when studies meet the regulatory definitions of human subject research.

Approvals Required Before Human Subject Research Commences

IRB approval is required before research activities may commence.

In addition to approval from the IRB, depending on the funding source, either contract finalization or departmental approval is required before research involving human participants can commence, as follows:

· Externally funded research (industry-sponsored clinical trials and other clinical research) undergoes a parallel review process by a combination of the following, depending on the funding source:

- For the School of Medicine: Research Management Group (RMG) develops and negotiates budget and payment schedules, routes/ensures approvals, negotiates terms and conditions, signs contracts, issues notices of award (NOA) for industry-sponsored clinical trials

- For other Schools: Office of Sponsored Research (OSR) negotiates terms and conditions, signs contracts, issues notices of award (NOA) for industry-sponsored clinical trials

- For all Schools: Industrial Contracts Office (ICO) handles Industry Research Agreements and Material Transfer Agreements (MTAs)

· Other research (see Chapter 1.7) requires approval by a Division Chief, Department Chair, School Dean or designee, or Academic Sponsor as appropriate, confirming:

- Scientific and scholarly validity

- Adequacy of resources.

Some protocol-specific situations require additional review and approval by other organizational components, or must meet their standards (see Chapter 2.4).

1.4.1 International Research

Section revised: 7/15/2015

STANFORD international (transnational) research activities are consistent with the ethical principles set forth in its Human Research Protection Program and meet equivalent levels of participant protection as research conducted in the STANFORD principal location while complying with local laws and taking into account cultural context. (AAHRPP Standard I-3)

Researchers should ensure that participants outside the US have the equivalent protections that participants would be afforded in the US. OHRP provides a compilation of regulations and guidelines that govern human subjects research in other countries, as well as standards from a number of international and regional organizations.

See:

· OHRP International Compilation of Human Subject Protections

· For VA research: VHA Handbook 1200.05 for definitions and requirements for international research.

The IRB has and follows written policies and procedures for determining the risks to prospective participants who are vulnerable to coercion or undue influence and ensuring that additional protections are provided as required by applicable laws, regulations, codes, and guidance. (AAHRPP Element II.4.A as of 2011)

Permission must be obtained from the local Medical Center Director, prior to initiating any VA-approved international research. The local Medical Center Director will not grant permission for an international research study involving prisoners as research subjects.

Researcher Responsibilities

When studies are conducted in other countries (i.e. outside the US) researchers should be knowledgeable about the local laws and customs which apply to the research, and the cultural context in which they will be working. They should ensure that participants in international research are afforded equivalent protections to those participating in the US, and must describe their qualifications and preparation for the research that enable them to estimate and minimize risks to subjects. Researchers are asked to consider these issues on the International Research form, APP-11.

IRB Responsibilities

Stanford IRB review of international research adheres to the same policies applied to domestic (US) research, when appropriate. Additional legal or cultural expertise may be consulted by the IRB during its review, and the IRB will make those determinations required by the laws of the countries in which the research is conducted. The IRB will also request documentation of local IRB or local research/ethics committee review, when appropriate.

Considerations for Informed Consent

The IRB has and follows written policies and procedures to evaluate the consent process and to require that the Researcher appropriately document the consent process. (AAHRPP Element II.3.F)

In some circumstances it may be inappropriate to document consent by using the standard written and signed consent document, and there might be different rules on determining e.g., who may serve as a legally authorized representative (LAR). Refer to HRPP Chapter 12 for information on waivers and alteration of consent, etc.

Additional Requirements

For federally funded research, the regulations of that sponsoring agency apply and the required federal protections must be provided; it is not sufficient to provide “equivalent” protections.

See Other Federal Agencies - Additional Requirements [GUI-42] for other requirements depending on the source of support/funding (e.g., Department of Defense, Department of the Navy).

1.5 Primary Officials, Administrative Units and Individuals of the HRPP

Section revised: 3/13/13

Officials Responsible for the HRPP
The primary responsibility for the HRPP lies with Stanford University through the Vice Provost and Dean of Research. See RPH Human Research Protection Program. The President of Stanford University delegates this responsibility to the Vice Provost and Dean of Research. The Board of Trustees of Stanford University, the governing body of Stanford University (as established by Jane and Leland Stanford in the 1885 Founding Grant), appoints the President.

Ann Arvin, M.D.: In 2006 President John Hennessy appointed Ann Arvin, Lucile Salter Packard Professor of Pediatrics and Professor of Microbiology/Immunology, to the position of Vice Provost and Dean of Research. In this position she serves on the University's Executive Cabinet. Dr. Arvin’s responsibilities and organization chart are in Administrative Guide Memo 12.12.

As Stanford University’s Institutional Official, the Vice Provost and Dean of Research signs the Federalwide Assurance of Compliance (FWA) on behalf of the institution and is ultimately responsible for:

· Creating, establishing and maintaining the policies and procedures for the HRPP and related research policies and procedures on behalf of Stanford University

· Overseeing the protection of human participants, regulatory compliance, and the implementation of the HRPP for STANFORD

· Ensuring that open channels of communication are maintained between the components of the HRPP

· Overseeing research investigators and staff, and research management

· Ensuring the independence of the IRB, including the authority to act without undue influence

· Requiring periodic reviews of the HRPP

·       Ensuring that the HRPP is functional, adequately staffed and funded, involving:
       i) Annual review of the resources allocated to the HRPP
      ii) Participation in the annual budget preparation for the HRPP and incorporation of the HRPP budget into the budget of Stanford University.

The day-to-day operational and oversight responsibility for the HRPP is delegated to the Research Compliance Office (RCO) Director, a non-faculty, full-time administrator. The RCO Director reports to the Vice Provost and Dean of Research.

Kathy McClelland: The Research Compliance Office (RCO) Director, Kathy McClelland, has day-to-day operational responsibility for the HRPP through the RCO. She has over 30 years’ experience at Stanford dealing with aspects of research integrity and compliance. She has served as Director for the last fifteen years. Before joining the Office of the Vice Provost and Dean of Research, she held positions in the School of Medicine as an IRB manager; in the Office of Sponsored Research (OSR) as nonmedical IRB manager and Institutional Animal Care and Use Committee (IACUC) manager; and as Assistant Director of OSR in charge of compliance, as it pertained to research participants and animal welfare. Among other functions as the RCO Director, she is administratively responsible for the operations of the IRBs, the Institutional Animal Care and Use Committee (IACUC), the IRB/SCRO (IRB and Stem Cell Research Oversight) Panel, and in conjunction with Environmental Health and Safety, assists the Biosafety and Radiological Safety Committees.

VAPAHCS Research and Development Committee: This committee is ultimately responsible for all human subject research which occurs at VAPAHCS. Its membership, functions and responsibilities are described in the VAPAHCS Health Care System Memorandum No. 151-05-08, Research and Development Committee and Associated Subcommittees.

IRBs

The Administrative Panels on Human Subjects in Medical Research and the Administrative Panel on Human Subjects in Non-Medical Research are the Institutional Review Boards (IRBs) and perform many of the core functions of the HRPP. The Vice Provost and Dean of Research appoints the chairs and the members of the IRBs and assigns their authority and responsibility in the “charge” to the Chairs and members. See Charge to the Administrative Panel on Human Subjects in Medical Research - IRB by the Vice Provost and Dean of Research, Charge to the Administrative Panel on Human Subjects in Medical Research – IRB/SCRO by the Vice Provost and Dean of Research, and Charge to the Administrative Panel on Human Subjects in Non-Medical Research by the Vice Provost and Dean of Research. The charge emphasizes that the IRBs are functionally independent (e.g., of the individuals who are conducting the research) and have ready access to the highest officials of the covered organizations, if needed, to ensure protection for human research participants.

There are seven medical IRBs and one nonmedical IRB. Their authority, membership requirements, and responsibilities are described in Chapter 6. IRBs are responsible for the initial and continuing review, review of modifications, approval of all research subject to the HRPP, determining serious or continuing noncompliance, requiring modification (to secure approval), disapproving research, and applying applicable ethical standards.

STANFORD ensures that the Human Research Protection Program has resources sufficient to protect the rights and welfare of research participants for the research activities that Stanford conducts or oversees. (AAHRPP Standard I-2)

Stanford University also participates in the independent (pilot) model of the Adult and Pediatric Central Institutional Review Board (CIRB) Initiative of the National Cancer Institute (NCI). The CIRBs are the IRB of record for certain adult and pediatric national multi-center cooperative oncology group cancer treatment trials.

HRPP Staff in the Research Compliance Office (RCO): The HRPP Associate Director is responsible for supporting the daily operations of the IRBs, and the education program. The IRB staff (Managers and Associates) review protocol applications for accuracy and completeness and act as liaisons between the Protocol Directors (PDs) and the IRB members. The IRB Education staff is responsible for the training of all individuals who are affected by the Human Research Protection Program. The Continuous Quality Improvement (CQI) program is an integrated part of the Research Compliance Office, and ensures periodic evaluation and strengthening of the HRPP.

Upon request, the RCO has responsibility for review and comment on proposed external regulations dealing with human research. When appropriate, the RCO formulates and recommends draft policies and procedures for approval by the appropriate Stanford University bodies and promulgation by the Vice Provost and Dean of Research.

Researchers

Principal Investigator/Protocol Director: The STANFORD individual ultimately responsible for a protocol is the Protocol Director (PD). Most (but not all PDs) have faculty appointments at Stanford University. PD responsibilities are specified in the HRPP Policy Manual and include ensuring that:

· All STANFORD human subject research has received initial prospective review and approval by the IRB.

· Continuing review and approval of the research has been accomplished within the time frame stipulated by the IRB.

· The research is conducted at all times in compliance with all applicable regulatory requirements and the determinations of the IRB.

Other Members of the Research Team: Every member of the research team is responsible for protecting human participants. Co-investigators, study coordinators, nurses, research assistants, Academic Sponsors, student/staff investigators, and all other research staff have the following strict obligations to:

· Comply with all IRB determinations and procedures

· Adhere rigorously to all protocol requirements

· Inform the PD, and thus IRB, of unanticipated problems

· Ensure the adequacy of the informed consent process

· Take necessary measures to ensure adequate protection for study participants.

See Chapter 14 and Chapter 15 for more on responsibilities and duties under the HRPP.

Sponsored Research

Sponsors can be a company, institution, individual donor or organization responsible for the initiation, management, or financing of a research study. Both the sponsor and STANFORD have obligations to protect research participants.

Participant Outreach

Participants in a research project also have responsibilities. These include telling the truth, asking for clarification, following the protocol, notifying study personnel of their non-compliance, and telling investigators if they wish to withdraw from the study.

HRPP Organizational Components

In addition to the Vice Provost and Dean of Research and the RCO, human research protection responsibilities are shared by these Stanford University HRPP components:

The Stanford Cancer Institute (SCI) draws upon the expertise of more than 300 researchers and clinicians from the Schools of Medicine, Engineering and Humanities & Sciences to advance research discoveries and medical innovation and provide comprehensive patient care. Within SCI, the Cancer Clinical Trials Office (CCTO): provides administrative, research, and educational services to Cancer Center investigators conducting clinical trials. Programs serve to increase awareness and accrual to clinical trials as well as to improve the quality and efficiencies of conducting clinical trials in compliance with regulatory, documentation, and oversight requirements. Its goals are to:

· Facilitate clinical trials and translational research by providing administrative support to all Cancer Center investigators

· Enhance and facilitate data collection and reporting of clinical cancer research

· Provide programs to contribute to quality assurance and the ongoing education of Cancer Center Clinical Research Personnel

· Coordinate outreach efforts in the community to increase clinical trials awareness and accrual, and

· Promote interdisciplinary collaborations and translational medical research.

All cancer-related studies are reviewed by the CCTO Scientific Review Committee (SRC), (except observational studies, retrospective chart reviews, compassionate use studies, and multiple program projects (MPPs)). The Data Safety Monitoring Committee of the CCTO reviews adverse event reports and requires them, as appropriate, to be submitted to the IRB. (See Chapter 3.10).

Conflict of Interest Committee (COIC): The COIC of the School of Medicine (SOM) reviews CoI disclosures from all protocols (SOM and non-SOM) submitted to the IRB. The COIC considers the conflicting interests, determines or assesses any mitigation or management plan, and determines whether the conflict can be managed or needs to be eliminated. If further review is appropriate, the case is examined by the Vice Provost and Dean of Research. The decisions and actions of the COIC are reported to the IRB staff, and considered by an experienced IRB member or at an IRB convened meeting. See Chapter 3.7 for more information.

Environmental Health and Safety (EH&S): EH&S provides and coordinates programs and services that minimize risks to safety and health, and environmental and regulatory risks to the Stanford University community in a manner consistent with responsible fiscal and environmental stewardship. EH&S works with investigators to promote safe and healthful laboratory environments that support the University's science and research mission. The Administrative Panel on Biosafety (APB) and Health Physics Radiation Safety are under the auspices of EH&S. As appropriate:

· Human subject research must have APB approval before research activities may commence;

· The Protocol Application contains questions about radioisotopes and radiation machines; the Radiation Safety Committee must certify that it has reviewed a protocol using radioisotopes or radiation machines and recommends it for approval. Without this approval, a study which employs these modalities cannot be approved by the IRB, and must either be approved contingent upon receiving Radiation Safety Committee approval, or tabled to a future convened meeting;

· The Protocol Application instructs that patient related equipment, if used, must meet standards established by the Hospital Instrumentation and Electrical Safety Committee.

Clinical and Translational Research Unit (CTRU): The CTRU was formerly the General Clinical Research Center (GCRC). The CTRU is an NIH-funded core facility for the Stanford University School of Medicine. CTRU facilities and services include:

· Clinical space (in- & outpatient)

· Research nursing support

· Clinical sample laboratory processing and specialized assays

· Bionutrition research support

· Mentorship of junior investigators

It supports studies (including cancer studies) that are conducted in the main hospital, the Veterans Affairs Palo Alto Health Care System, and Lucile Packard Children's Hospital.

Stanford Affiliated Covered Entity [SACE]: SACE includes Stanford Hospital and Clinics, Lucile Packard Children's Hospital, and the Stanford University HIPAA Components.

· HIPAA Council: The HIPAA Council is convened by the Stanford University Privacy Officer to explore issues related to the implementation and enforcement of the Privacy and Security rules under HIPAA for the Stanford Affiliated Covered Entity.

Internal Audit and Institutional Compliance: Audit liaisons work with the various entities to carry out audit activities. In addition, the Institutional Compliance Program is carried out by a number of compliance offices, with oversight residing under the Associate Vice President for Internal Audit and Institutional Compliance.

Office of the General Counsel (OGC): The OGC is responsible for addressing all of the legal issues arising out of the activities of Stanford University, Stanford Hospital and Clinics and Lucile Salter Packard Children's Hospital at Stanford. A representative of the OGC serves as an ex-officio IRB member, and is available for consultation on issues regarding human subject research and participant protection.

Leadership for research administration at Stanford University is jointly shared between the Office of the Vice Provost and Dean of Research and the Office of Business Affairs. The Office of Sponsored Research (OSR) manages pre- and post-award research services for the university, including negotiation of sponsored agreements, award set-up and closeout. OSR works in close collaboration with a number of partner groups in other central and school offices to help ensure the overall effective coordination of research administration services, systems, policies, and processes. OSR prepares, negotiates and oversees federally-funded contracts, sub-awards and subcontracts. Effective October 2011, contract administration for industry-sponsored clinical trials has been consolidated within the School of Medicine Research Management Group (RMG).

The Research Financial Compliance and Services Office (RFCS) oversees Cost & Management Analysis (CMA), Property Management, Accounts Receivable, Service Centers and Space Management.

Office of Technology Licensing (OTL): OTL is responsible for managing the intellectual property assets of Stanford University. The OTL charter is to help turn scientific progress into tangible products, while returning income to the inventor and to the University to support further research. OTL has signature authority on behalf of the University for license agreements, material transfer agreements, industrial contracts and other agreements that pertain to intellectual property*. Of particular relevance to human subject research protections are:

· Clinical Technology Assessment Agreements (CTAA’s) - created when a sponsor provides an investigational drug or device for research; the protocol must have IRB approval, and, as appropriate an IND or IDE.

· Material Transfer Agreements (MTA’s) - these govern the use of tangible research materials distributed to other institutions. The Protocol Application asks whether tissues are to be distributed as part of such an agreement.

* Except for clinical trial agreements, which are handled by the Office of Sponsored Research (OSR), the Industrial Contracts Office (ICO) within OTL is responsible for negotiating and signing sponsored research, material transfers (including Material Transfer Agreements with non-profits and government agencies) and related research agreements with industry.

Risk Assessment Committee (RAC): The Risk Assessment Committee is a high-level, multi-disciplinary group that evaluates human subject research protocols for financial or administrative risks, or when a request is made to waive a policy related to clinical trial operations and administration. The RAC is comprised of representatives from the School of Medicine, Hospital Financial Services, Hospital Compliance, Office of the General Counsel and University Risk Management. RAC provides an additional vehicle for risk analysis but does not evaluate human subject protections, conflict of interest, or scientific validity; RAC may have observations in these three areas, but does not have any formal responsibility for action in such matters. RAC makes recommendations on whether or not to waive School of Medicine policy to the Senior Associate Dean for Research.

Research Management Group (RMG): For School of Medicine research - Provides oversight and management of sponsored projects and ensures compliance with sponsor and University expectations for managing sponsored funds. RMG performs a parallel review to the IRB, and confirms IRB approval before routing sponsored project information to the Office of Sponsored Research (OSR) contracts office. Effective October 2011, it also supports contract administration for industry-sponsored clinical trials (see above).

Stanford Center for Biomedical Ethics (SCBE): The SCBE is dedicated to interdisciplinary research and education in biomedical ethics, and provides clinical and research ethics consultation. SCBE serves as a scholarly resource on emerging ethical issues raised by medicine and biomedical research, and is called upon for consultation by the IRB when needed.

Stanford/Packard Center for Translational Research in Medicine (Spectrum): Spectrum serves STANFORD faculty and clinical research personnel in the School of Medicine (SOM), Stanford University Medical Center, Lucile Packard Children's Hospital (LPCH) and Veterans Affairs Palo Alto Health Care System (VAPAHCS). Its mission is to enhance the quality of clinical and translational research by:

· Aligning organizational “service” based activities

· Providing education, training and mentoring to clinical research coordinators and staff

· Developing an integrated research infrastructure

IRB staff and Spectrum collaborate to provide education to the research community, disseminate information about the HRPP, and to facilitate quality improvement activities such as compliance reviews.

Stanford University Schools: Although human subject research (including undergraduate research programs) takes place within any of the seven Schools, most human subject research is performed by the Schools of Medicine, Education, and Humanities & Sciences, which includes the Department of Psychology. All such research must receive IRB approval before research activities can commence.

1.6 Ethical and Legal Principles Governing Human Subject Research

Section revised: 3/13/13

Ethical Principles

The primary ethical principles applied to research covered by the HRPP, including protocols “exempt” under federal regulations pertaining to human subject research, are those set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (Belmont Report).

The three main principles are:

1. Respect for persons (e.g., applied by obtaining informed consent, giving consideration to privacy and confidentiality, and adding protections for vulnerable populations)

2. Beneficence (e.g., applied by weighing risks and benefits)

3. Justice (e.g., applied by the equitable selection of subjects)

All parties involved in the conduct of research are expected to also adhere to the principles of expertise (“competent to do the work”) and integrity (“faithfully adhere to professional principles”). Ethical principles from other sources (e.g., International Conference on Harmonization) may also be applied to research covered by the HRPP, for example:

· To an individual protocol because its particular circumstances raise a type of ethical issue that most other protocols do not

· When they are recognized by the federal or other funding source or the state or country where the research will occur

· When they have been developed for specific areas or types of subjects (e.g., embryos and fetal tissue, illiterate subjects).

Investigator training on the ethical principles governing human subject research and investigator responsibilities is provided by the tutorial Principal Investigator Responsibilities at Stanford University. These principles are also covered in the CITI tutorial for investigators, IRB Members, and IRB Staff, and in the orientation given to new IRB members.

With respect to sponsored research, Stanford University and PAIRE address the protection of research participants by including in their standard contract templates a provision that the sponsor acknowledges and understands that the STANFORD HRPP is applicable to all human participant research. See Chapter 16.

Legal Principles

The basic legal principles governing human subject research, covered by the HRPP and applicable to individual protocols are:

· Federal Policy for Protection of Human Subjects (Common Rule) in 45 CFR Part 46

· Food and Drug Administration Regulations for the Protection of Human Subjects in 21 CFR Parts 50 and 56

· Standards for Privacy of Individually Identifiable Health Information (HIPAA Privacy Rule) in 45 CFR Parts 160 and 164.

· Department of Veterans Affairs regulations in 38 CFR Part 16 and VHA Handbook 1200.5

· Applicable California law.

These and other legal principles are addressed when applicable in individual HRPP chapters.

Additional Requirements

Depending on the source of support for research, regulations from other agencies such as DoD, DOJ, etc. might apply. See Other Federal Agencies - Additional Requirements [GUI-42].

1.7 Scientific and Scholarly Validity Review and Ethics Review

Section revised: 07/22/2015

STANFORD has and follows written policies and procedures for reviewing the scientific or scholarly validity of a proposed research study. Such procedures are coordinated with the ethics review process. (AAHRPP Element I.1.F)

Scientific and Scholarly Validity Review

When evaluating the scientific and scholarly validity of a protocol, the IRB relies on the review provided by different entities, as follows:

· For federally sponsored research, including VA-funded research, the peer review process by the sponsoring agency (e.g., NIH, NCI, DOD) provides scientific and scholarly review.

· For research subject to FDA review, the FDA conducts a rigorous scientific design review during IND or IDE evaluation. Most industry-sponsored research falls within this category. An important exception is Non-Significant Risk (NSR) device research, where the IRB serves, in a sense, as the FDA’s surrogate with respect to review and approval of NSR studies.

· For research occurring at the VA Palo Alto Health Care System (VAPAHCS), the VA Research and Development Committee (R&D) and subcommittees perform scientific review of all activities prior to initiation and at least annually thereafter, in order to evaluate the quality, design, desirability and feasibility of each new R&D proposal/application for funding, to assure maintenance of high scientific standards, protection of human research participants including privacy and confidentiality, and adequate safety measures. The process is described in VAPAHCS Memorandum No. 151-05-08, Research and Development Committee and Associated Subcommittees.

· The Cancer Center Scientific Review Committee (SRC) provides a peer review of local and national research protocols involving cancer patients treated at Stanford University Clinical Cancer Center and Lucile Packard Children's Hospital. The review primarily focuses on the scientific merit of the study and applies to all phases of clinical therapeutic intervention, behavioral clinical trials, tissue and body fluid research, and diagnostic trials, which impact medical decision making for the treatment of cancer patients. The process is described in the SRC website. All cancer studies are required to undergo SRC review with the exception of prospective biospecimen studies that are not investigating a scientific hypothesis and compassionate use studies for a single patient.

For research that has departmental funding, gift funding or no funding, or that has not otherwise gone through a scientific review as described above, the IRB requires that:

· In the School of Medicine: the Division Chief or Department Chair of the PD’s department, (or the School Dean or his designee when the Division Chief or Department Chair has a conflicting interest), or

· In other schools: the School Dean or designee

submit a Review of Scientific and Scholarly Validity [APP-10]) and confirm to the IRB that scientific review of the protocol has occurred. This submission is not necessary for retrospective charts reviews.

For all research conducted by students, including student research that may undergo scientific review by an awarding entity, this confirmation is provided by the Academic Sponsor who is responsible for the scientific review. The Academic Sponsor must submit a Review of Scientific and Scholarly Validity, and Oversight [APP-9] to the IRB.

The signatures on these documents confirm the soundness of the research design and the ability of the research to achieve its aims.

Submission of APP-10 is not required for minimal risk retrospective chart reviews. However, APP-9 is still required for student chart reviews, since this form also confirms faculty oversight. For regular review protocols, the PD must answer the questions in the Scientific Review Protocol for Human Subjects Research [NOT-13].

For all research, the IRB evaluates, in accordance with federal research regulations [45 CFR 46.111(a) and 21 CFR 56.111(a)] whether the following requirements are satisfied:

a. Risks to participants (physical, psychological, social, legal and economic) are minimized (i) by using procedures which are consistent with sound research design and which do not unnecessarily expose participants to risk; and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

b. Risks to participants are reasonable in relation to anticipated benefits, if any, to participants, and the importance of the knowledge that may be expected to result.

If the requirements noted above are not satisfied, the protocol may not be approved as written. The IRB reviewer(s) may consider other scientific reviews, as noted above, (e.g., NIH peer review, GCRC internal review board, SRC review) in their evaluation. For protocols where the protocol design is unusual or novel, in addition to the protocol being assigned to primary reviewer(s) with relevant expertise, input from ad hoc consultants may also be obtained. For further information, refer to guidance Evaluating Sound Study Design [GUI-17].

Ethics Review

The IRB review of the study procedures, risks and benefits includes the identification, evaluation and resolution of the ethics issues presented in the study in accordance with the ethical principles outlined in Chapter 1.4. If necessary, the IRB may seek ad hoc assistance from ethical consultants, both internal and external (e.g., members of the hospital ethics committees of SHC, LPCH, or VAPAHCS, or members of Stanford University’s Center for Biomedical Ethics).

An ethics review (in addition to the scientific review) is also conducted by the internal review committees for research done in the Clinical and Translational Research Unit (CTRU) at SHC and LPCH, and in the Cancer Center at SHC and LPCH.

An ethics review (in addition to the scientific review) is also conducted by the internal review committees for research done in the Cancer Center at SHC and LPCH.

Ethics consults are also available for researchers, via the Spectrum Biomedical Ethics program, with the Stanford Center for Biomedical Ethics (SCBE). Initial ethics consultations for study design, bedside or benchside consultations, are scheduled through Spectrum Study Navigator.

Additional Requirements

See Other Federal Agencies - Additional Requirements [GUI-42] for other requirements depending on the source of support/funding (e.g., Department of Defense, Department of Justice).