The protection of human participants in research is the shared responsibility of PDs, sponsors, and the IRBs; and the PDs are ultimately responsible for the safety and welfare of participants. When conducting research with human participants, the PD agrees to, as part of the Protocol Application (see Obligations section):

1. Design studies that are scientifically sound and that will yield valid results and conduct the study according to the protocol approved by the IRB

2. Be appropriately qualified to conduct the research and trained in Human Research Protection ethical principles, regulations and policies and procedures, and ensure all research personnel are adequately trained and supervised

3. Disclose to the appropriate departments any potential conflicts of interest

4. Report promptly any new information, modification, or unanticipated problems

5. Ensure that the rights of participants are protected, including privacy and confidentiality of data

6. Apply relevant professional standards.

15.1 Qualification of Protocol Directors and Research Staff

Section revised: 01/12/2016

Researchers and Research Staff are qualified by training and experience for their research roles, including knowledge of applicable laws, regulations, codes, and guidance; relevant professional standards; and the OrganizationÕs policies and procedures regarding the protection of research participants. (AAAHRPP Element III.2.A)

Training in the Protection of Human Subjects

STANFORD requires that PDs and other personnel involved in the design or conduct of a project, including projects deemed to be exempt research under 45 CFR 46.101, confirm completion of training in the protection of human research participants. Individuals involved in the design or conduct of a project include co-PDs, nurse coordinators, senior professional staff, persons administering informed consent or surveys, post-docs, and students. Collaborating individuals operating under Stanford UniversityÕs FWA and third party (subcontract) research personnel or consultants must also comply with this education requirement.

STANFORD employs the Collaborative Institutional Training Initiative (CITI) course as its training program. Required CITI training for investigations includes, but is not limited to, modules on the history and ethical principles of human subject research, basic IRB regulations and review process, informed consent, and research with vulnerable participants. STANFORD requires a refresher training course to be completed every two years.

Completion of the required training is a condition for IRB approval of protocols and release of funds, regardless of the projectÕs source of funding. During the review the IRB evaluates whether these requirements are met for each protocol event (new protocol, modification and continuing review).

See also:

á Chapter 1.6 Ethical and Legal Principles Governing Human Subject Research

á Chapter 3.1 Policies and Procedures Available to Protocol Directors (PDs) and Research Staff

á Chapter 4 Knowledge of Human Research Protection Requirements, for an outline of education provided for individuals responsible for human research, and description of the required training

á Chapter 5.6 Sponsor-Investigator Research: Additional training is provided for investigators who have additional responsibilities as the research sponsor

á Chapter 16.1 Agreement Includes Protection for Research Participants

Knowledge of Applicable Federal, State and Local Laws

The RCO disseminates and makes available to the STANFORD research community,

á Via the Human Subjects Website and education programs, the following resources to promote knowledge about applicable Federal, State and organization policies for human subjects research: Human Research Protection Program policies

á Guidances on topics affecting the conduct of research, such as informed consent, vulnerable populations, conflict of interest, reporting requirements, etc.

á Template consent forms that include federal, state and local requirements

á eProtocol System for protocol submission - with application questions intended to address required considerations

á Information and instructions on submitting protocols to the IRB

á References and links to federal, state and organizational requirements

á Contact information for IRB staff for assistance

á The Stanford University Research Policy Handbook (RPH) is also available online, addressing topics such as RPH 1.9 Retention of and Access to Research Data, and RPH 1.2 Rights and Responsibilities in the Conduct of Research. RPH Chapter 5 focuses on Human Subjects and Stem Cells in Research.

Where applicable, the California State laws have been included in the STANFORD HRPP Policy Manual, for example, Chapter 12.1 addresses informed consent requirements under the California Health & Safety Code. When STANFORD investigators conduct research in states other than California, they are expected to be knowledgeable of and adhere to the laws of the state in which research is being conducted, as well as those of California. Investigators are advised to seek guidance from the IRB staff or Legal Counsel if they have questions as to the applicable laws.

Knowledge of the Definition of Human Subject Research

Researchers and Research Staff know which of the activities they conduct are overseen by the Human Research Protection Program, and they seek guidance when appropriate. (AAHRPP Element III.1.A)

Prior to submitting a protocol for IRB review investigators are instructed to consider whether their project meets the statutory definition of human subject research or clinical investigation. Step-by-step guidance is available to the investigators on the Human Subjects Research website: Does My Project Require IRB Review? This provides guidance based on DHHS- (OHRP), FDA‑, and VA-specific requirements.

IRB staff is also available to assist investigators in determining if a project needs to be submitted for IRB review. If the proposed activity clearly does not involve "research" or Òclinical investigationÓ and "human subjects", it does not require submission to the IRB. If there is any doubt as to whether an activity is human subject research, the investigator should contact the Research Compliance Office, or submit a Determination of Human Subject Research – Application to the IRB. See Chapter 3.3 for additional information on the definition of human subject research.

15.2 Reporting to the IRB - Unanticipated Problems Involving Risks to Participants or Others (UPs), and Other Reportable Information

Section revised: 01/12/2016

Researchers and Research Staff follow reporting requirements during a research study in accordance with applicable laws, regulations, codes, and guidance; STANFORD policies and procedures; and the IRBÕs requirements. (AAHRPP Element III.2.D)

See also:

á Chapter 3.10

á Events and Information that Require Prompt Reporting to the IRB [GUI-P13].

PD Responsibilities

PDs are responsible for reporting unanticipated problems involving risks to participants or others (UPs) and other reportable information to the IRB.. For industry sponsored projects, PDs are responsible for maintaining contact with the sponsor, and receiving reports from the sponsor, and if applicable, the monitoring entity (e.g., DSMB, DMC) and reporting suspected UPs and other reportable information to the IRB. For sponsor-investigator projects, the PD is solely responsible for reporting UPs and other reportable information to the IRB.

The IRB Report Form may also be used to report to the IRB events or information other than those required by regulation; these may be reported under item (7) in the Report Form, but PDs should consult with IRB Education before reporting such items.

Routine, periodic reports (e.g., Data Monitoring Committee reports, annual progress reports) should be submitted to the IRB at Continuing Review. The IRB Report Form should not be used to submit these reports to the IRB.

Assessment by Protocol Director

The PD is responsible for the initial assessment of whether an event is a UP or other reportable information.

PDs must assess each adverse event, whether received from a sponsor, monitoring entity or occurring on a sponsor-investigator project, and promptly report to the IRB, UPs and other reportable information according to the guidance Events and Information that Require Prompt Reporting to the IRB. (See flowchart Process for Handling Reports.)

In all cases, UPs that are deaths or life-threatening experiences (at STANFORD or when STANFORD is the coordinating institution in a multi-site study), must be reported within 5 working days from when the PD learns of the event.

Reporting Assessed Events and Information

For events required to be reported to the IRB, PDs should submit reports using the online (eProtocol) Report Form. Adverse events that are deemed not to be UPs or other reportable information should be included in the narrative summary for the IRB at Continuing Review.

Reporting Timeframes

Type of event or information	Protocol has a monitoring entity in addition to, or other than, the PD	PD is the only monitoring entity for the protocol
UP that is a death or life-threatening experience, (at STANFORD or when STANFORD is the coordinating institution in a multi-site study)	Report to IRB within 5 working days from when the PD learns of event.
Other UP * (not death or life-threatening experience)	Report to IRB within 10 working days from when PD receives assessment from monitoring entity	Report to IRB within 10 working days from when PD learns of event or new information
Reportable information (items 2-6 in guidance Events and Information that Require Prompt Reporting to the IRB)

* VA research: Local adverse events that are serious and unanticipated must be reported to the IRB within 5 business days. VHA Handbook 1200.05 and VHA Handbook 1058.01 detail research compliance reporting requirements.

The IRB will review and assess the events and information reported, and address them as described in Chapter 3.10.

When Modifying the Protocol is Indicated

An event or new information might prompt a protocol modification – either initiated by the PD, or specified by the IRB after reviewing a report. When an event or new information requires a modification to a previously approved protocol (e.g., new side-effect in the consent form or suspension of enrollment) a modification must be submitted for IRB review, and must be approved by the IRB prior to implementation of the proposed changes. The only exception to pre-approval is for modifications necessary to eliminate apparent immediate hazard to the research participants; in this case, the PD must submit the modification to the IRB within 5 days following its implementation.

Gene Transfer Protocols

The above information on reporting UPs and other reportable information does not apply to gene transfer protocols. For these protocols, all injuries and serious adverse events occurring at STANFORD or at other participating institutions must be reported to both the IRB and the Biosafety Panel as outlined in the NIH Guidelines; Safety Reporting: Content and Format. (See Gene Transfer Adverse Event Report.)

15.3 Research Oversight

Section revised: 01/12/2016

Researchers maintain appropriate oversight of each research study, as well as Research Staff and trainees, and appropriately delegate research responsibilities and functions. (AAHRPP Element III.2.B)

The general principles stated here apply to all research, including behavioral/social science research.

Oversight of Research Staff during Recruitment

The PD is responsible for ensuring recruitment activities, whether undertaken by research staff or the PD, are via methods set forth in the protocol application and approved by the IRB. The PD must ensure that informed consent is obtained from each research participant before that individual participates in the research study. The PD may delegate the task of obtaining informed consent to another individual knowledgeable about the research, while retaining ultimate responsibility over the conduct of the study.

Selection of Study Participants

The PD must ensure selection of study participants is equitable and appropriate to the goals of the study. Adequate safeguards for the protection of participants during the recruitment and conduct of research must be set forth in the protocol application. See:

á Chapter 10.1 (equitable selection)

á Chapter 14.4 ( recruitment)

á Recruitment [GUI-33].

Informed Consent

PDs are responsible for assuring the quality of the informed consent process and for making sure that consent is obtained and documented before subject participation, unless waivers are granted by the IRB. For a detailed discussion of the informed consent process requirements and description of available templates and guidance, see Chapter 12.

Study Conduct

Researchers and Research Staff follow the requirements of the research protocol or plan and adhere to STANFORD policies and procedures and to the requirements or determinations of the IRB. (AAHRPP Element III.2.C)

The PD is responsible for conducting the study in a manner that is scientifically and ethically sound and for ensuring the use of appropriate methods and correct procedures, according to the approved protocol. Any new information, modification, or unanticipated problem involving risks to participants or others must be promptly reported to the IRB (Chapter 15.2), and research participants must be informed of any change that may affect their willingness to participate.

The PD must assure that all personnel under his or her supervision are adequately trained and supervised and that research duties are delegated to individuals qualified to perform the assigned tasks. Any non-compliance must be reported promptly to the IRB as required in Chapter 3.9.

The PD is also responsible for the timely and proper administration of the research project. Beyond the scientific and clinical conduct of the study, responsibilities include:

á Compliance with federal, state, and local laws and STANFORD policies, including disclosure of any potential conflict of interest

á Adhering to the respective institutional Code of Conduct:

- SHC/LPCH; Stanford University Code of Conduct;

- VAPAHCS Memo 151-15.01; Section 6.j (Responsibilities - Principal Investigator); VHA Handbook 1200.05.

á Fiscal management of the project

á Training and supervision of postdoctoral candidates, students, and residents

á Compliance with the sponsorÕs terms and conditions (e.g., non-disclosure of sponsor confidential information)

á Submission of all technical, progress, financial, and invention reports on a timely basis

á Submission of modification and continuing review applications in a timely manner

á Obtaining approval for changes prior to implementation.

Compliance with the IRB

Federal regulations require that any research study involving human subjects be reviewed and approved by an IRB. IRB approval must be obtained before any recruitment or screening can take place.

It is the PDÕs responsibility to submit a written protocol to the IRB for review. At submission, the obligations of the PD with respect to oversight of their research protocols and research staff during recruitment, selection of study participants, and conduct of the study according to the protocol as approved by the IRB are stated in the Protocol Application, and must be agreed to by the PD for the submission to be accepted. The PD is responsible for ongoing adherence to the determinations and requirements of the IRB for the duration of the research.

The documents required for protocol submission are listed in Chapter 8.1.

A detailed discussion of the roles and responsibilities of IRBs is presented in Chapter 6.

Progress Report and Continuing Review Application

PDs must submit protocols (other than those subject to 45 CFR 46.101(b) - Exempt research) for continuing review by the IRB before the expiration date of the protocols, and in sufficient time to ensure the non-interruption of studies.

Final Report

At the conclusion of the study, PDs involved in research approved under regular review must submit a final report to the IRB within 30 days – if this is not done, a memorandum is sent to the appropriate Department Chair, or to the DeanÕs Office of the School of Medicine.

Confidentiality of Records and Personal Data

PDs working with human subjects must safeguard the privacy of participants and protect the confidentiality of personal information:

á Safeguard mechanisms must be established, maintained, and documented throughout the research process.

á Sustained attention must be paid to maintaining confidentiality of research data in the design, implementation, conduct, and reporting of research.

á Full information about the privacy and confidentiality of data must be provided to prospective participants through the informed consent process.

á Unintentional breaches must be avoided by taking additional precautions in communication, administration and storage of information.

Privacy and confidentiality are addressed in Chapter 11.

Privacy Rule (HIPAA)

When conducting research that involves the use and disclosure of protected health information (PHI), the PD must abide by the applicable HIPAA policy of the STANFORD organization, and must be able to account for disclosures of PHI when an individual requests such accounting. See Chapter 11.3, and Stanford University HIPAA Policy Research and Patient Privacy.

Delegation of Research Responsibilities

PDs may delegate research responsibility. However, PDs maintain oversight and retain ultimate responsibility for the conduct of those to whom they delegate responsibility. The conduct of a study usually requires the involvement and contribution of other individuals under the direction of the PD, based on their qualifications and capabilities. In delegating study-specific tasks and responsibilities to other members of the research team, the PD must ensure that those assuming a duty are well trained and competent.

Additional Requirements

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

Student Investigators and Academic Sponsors

Student Investigators may assume PD responsibilities with the supervision and guidance of Academic Sponsors. In a study with an Academic Sponsor, the student investigator is the PD and has the following responsibilities:

á Design of the study

á Conduct of the study and all study-related activities

á Conduct of self and collaborators

á Protection of the rights and welfare of participants, including obtaining informed consent and maintaining privacy and confidentiality of data

á Proper application and reporting to the IRB

á Compliance with approved protocol

á Consultation with the Academic Sponsor and identification of protocol modifications warranted by unexpected events/circumstances.

Academic Sponsors are responsible for providing supervision and guidance to Student Investigators by:

á Overseeing the design and conduct of the study

á Ensuring that the student/staff investigator assuming duties are well-trained and competent

á Reviewing the protocol application prior to submission to the IRB

á Providing guidance in the protection of research subjects

á Assuring proper application and reporting to the IRB

á Working with student/staff investigator to identify modifications warranted by unanticipated problems or circumstances involving risks to participants or others.

The Academic Sponsor must confirm the scientific validity of the study and to his/her agreement to fulfill the above responsibilities. This Review of Scientific and Scholarly Validity and Oversight must be forwarded to the IRB before the protocol can be approved. See Chapter 1.7.

VA Research: Requirements for Research Conducted by Students at VA are specified in VHA Handbook 1200.05 (Paragraph 28)

Special Considerations for the Oversight of Research Protocols in FDA-Regulated Drug or Device Studies

FDA regulations and guidance specify the responsibilities of sponsors (and their investigators) using FDA test articles. [21 CFR 31 Subpart D; 21 CFR 812 Subparts C,E]. The FDA requirements are summarized in guidance Special Considerations for the Oversight of Research Protocols in FDA-regulated Drug or Device Studies.

In sponsor-investigator research, the PD assumes all of the responsibilities in overseeing the research normally assumed by sponsors in industry-sponsored projects.

15.4 Data Monitoring Plan (DMP)

Section revised: 3/13/13

Researchers and Research Staff follow reporting requirements during a research study in accordance with applicable laws, regulations, codes, and guidance; STANFORD policies and procedures; and the IRBÕs requirements. (AAHRPP Element III.2.D)

When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects. (45 CFR 46.111(a)(6); 21 CFR 56.111(a)(6))

See also Chapter 9.2.

The responsibility for human participant protection in human subject research is shared among the IRB, PD, trial sponsors and oversight boards or committees. The safety of participants must be considered in study design.

Studies that are more than low risk to participants must include a data monitoring plan (DMP) to evaluate whether the character, incidence, and severity of expected harms match those expected, and to evaluate the causality of unexpected harms. Requirements for a DMP are discussed in Data Monitoring Plans [GUI-P20]. Additionally, a description of the DMP is required in the Protocol Application submitted to the IRB. In order to approve research, the IRB determines that when appropriate, there will be adequate monitoring of data to protect the safety and well-being of participants.

Monitoring may be conducted by the PD, or a Monitoring Entity (ME). (See Data Monitoring Plans [GUI-P20] for examples of MEs.) In all studies, the PD has ultimate responsibility for identifying potential risks and identifying adverse events occurring in the study population and reporting the events to the sponsor and to the IRB as required in Chapter 3.10.

Sponsor Responsibilities

Sponsor responsibilities may include (but are not limited to), as appropriate to the scope and complexity of the research:

á Establishing procedures to assure that interim data remains confidential

á Notifying all participating IRBs of unanticipated problems involving risks to participants or others

á Notifying FDA and the responsible IRBs of any recommendations or requests made by a Monitoring Entity to the sponsor that address safety of participants.

If there is a Data Safety Monitoring Committee, sponsor responsibilities may include:

á Appointing a Chair

á Establishing procedures to assess potential conflicts of interest of proposed members

á Establishing Standard Operating Procedures (SOPs) for statistical analyses, report format, and meeting schedules

á Submitting SOPs to the FDA prior to interim data analyses, optimally before the initiation of the trial.

In sponsor-investigator research, the PD assumes all of the responsibilities in overseeing the research normally assumed by sponsors in industry-sponsored projects.