Stanford University Office of the Dean of Research

Human Research Protection Program (HRPP)

DOMAIN III: INVESTIGATOR

Chapter 15: Investigator Compliance

Protocol Directors (PDs) and research staff must follow requirements for conducting research with participants and comply with all applicable federal, state, and local regulations and STANFORD policies and procedures for protecting research participants. (AAHRPP Standard III-2) These requirements and policies are contained or referenced in this Chapter 15.

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

STANFORD* ensures that PDs and research staff are qualified by training and experience for their research roles, including knowledge of applicable federal, state, and local regulations; relevant professional standards; and STANFORD policies and procedures regarding the protection of research participants. PDs are expected to understand the definition of human research and seek guidance when appropriate. (AAHRPP 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 University’s 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 project’s source of funding. The IRB evaluates during the review whether these requirements are met for each protocol event (new protocol, modification and continuing review).

See Chapter 4 for an outline of education provided for individuals responsible for human research, and description of the required training.

VA Requirements for Protocol Director Eligibility, Education and Training

Investigators associated with the Veterans Affairs Palo Alto Health Care System (VAPAHCS) must meet additional requirements as detailed in VAPAHCS Memoranda 151-03-02 - Research Related Employee, and 151-04-01: Principal Investigator Eligibility.

Knowledge of Applicable Federal, State and Local Laws

The RCO disseminates and makes available via the Human Subjects Website and education programs the following resources in promoting knowledge about applicable Federal, State and organization policies for human subjects research to the STANFORD research community:

Human Research Protection Program policies
Guidances on topics affecting the conduct of research, such as informed consent, vulnerable populations, conflict of interest, reporting requirements, etc.
Template consent forms that include federal, state and local requirements
eProtocol System for protocol submission - with application questions intended to address required considerations
Information and instructions on submitting protocols to the IRB
References and links to federal, state and organizational requirements
Contact information for IRB staff for assistance
The Stanford University Research Policy Handbook (RPH) is also available online, addressing topics such as retention of and access to research data, and rights and responsibilities in the conduct of research. RPH Chapter 7 focuses on Human Subjects in Research.

Where applicable, the California State laws have been included in the STANFORD HRPP 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

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 RCO website: Does My Project Require IRB Review? 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 “clinical investigation” 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

Protocol Directors assess and report unanticipated problems occurring during a research study in accordance with applicable federal, state, and local regulations and STANFORD policies and procedures. (AAHRPP Element III.2.B)

PD Responsibilities

PDs are responsible for reporting unanticipated problems involving risks to participants or others (UPs) and other reportable information to the IRB or the Cancer Center Trials Office (CCTO) for cancer studies. 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 or CCTO. For sponsor-investigator projects, the PD is solely responsible for reporting UPs and other reportable information to the IRB or CCTO.

The IRB Report Form may also be used to report items other than those specified in the guidance Events and Information that Require Prompt Reporting to the IRB – however, PDs should consult with the HRPP Education Specialist 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, or to CCTO, 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

Non-cancer studies: For events required to be reported to the IRB that occur on non-cancer protocols, PDs should submit reports using the online (eProtocol) Report Form.

Cancer studies: For events that occur on cancer protocols; PDs should report these events to the CCTO on the Cancer Center Adverse Event Communication Form. The CCTO will identify those reportable events requiring reporting to the IRB and communicate this information to the PD and to the IRB. Adverse events that are deemed not to be UPs or other reportable information should still be reported to the CCTO under the none of the above category on the Adverse Event Communication Form; these events will be included in the CCTO database, and 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 (or CCTO) within 5 working days from when the PD learns of event.

(If a cancer study, CCTO will promptly forward the Adverse Event Communication Form to IRB.)

Other UP

(not death or life-threatening experience)

Report to IRB (or CCTO)

within 10 working days

from when PD receives assessment from monitoring entity

Report to IRB (or CCTO)

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)

The IRB will review and assess the events and information reported, and addresses 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 (http://www4.od.nih.gov/oba/RAC/guidelines_02/APPENDIX_M.htm#_Appendix_M-I-C._Reporting). (See Gene Transfer Adverse Event Report.)

15.3 Research Oversight

PDs maintain appropriate oversight of their research protocols and research staff including during recruitment, selection of study participants, and study conduct, and they appropriately delegate research responsibilities. (AAHRPP Element III.2.C)

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:

· Chapter 10.1 (equitable selection)

· Chapter 14.4 ( recruitment)

· Guidance on Recruitment.

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

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:

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

· Adhering to the respective institutional Code of Conduct:

- SHC/LPCH; Stanford University Code of Conduct;

- VA Memo 151-05-01, Section 8.h (Investigator responsibilities)

· Fiscal management of the project

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

· Compliance with the sponsor’s terms and conditions (e.g., non-disclosure of sponsor confidential information)

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

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

· 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 PD’s 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 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.

Additional VA Requirements for Monitoring PD’s Files for Compliance

See VAPAHCS Memorandum 151-05-07.

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. IRB approvals are granted for no more than twelve months, and continuing review applications must be submitted in sufficient time to ensure the non-interruption of studies.

Final Report

At the conclusion of the study, PDs involved in biomedical 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 Dean’s 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:

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

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

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

· 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.

Student Investigators and Faculty Sponsors

Student Investigators may assume PD responsibilities with the supervision and guidance of Faculty Sponsors. In a faculty-sponsored study, the student investigator is the PD and has the following responsibilities:

· Design of the study

· Conduct of the study and all study-related activities

· Conduct of self and collaborators

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

· Proper application and reporting to the IRB

· Compliance with approved protocol

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

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

· Overseeing the design and conduct of the study

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

· Reviewing the protocol application prior to submission to the IRB

· Providing guidance in the protection of research subjects

· Assuring proper application and reporting to the IRB

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

The Faculty 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.

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)

The PD designs and carries out research studies with adequate data and safety monitoring during the research, when appropriate. (AAHRPP Element III.2.D)