3.1      Policies, Procedures, and Resources Available to Investigators and Research Staff 

Section revised: 3/13/13  

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 Research Compliance Office (RCO) has primary responsibility for ensuring the HRPP Policy Manual and related materials are available to the entire STANFORD research community, including:

Š      Investigators

Š      Research staff

Š      IRB staff

Š      IRB members

Š      Employees

Š      Students

The RCO maintains the Human Subjects Research website which provides access to:

Š      The HRPP Policy Manual

Š      Links to pertinent governmental regulations and guidelines

Š      Links to STANFORD policies (Research Policy Handbook, Hospital and Clinic Policies, Lucile Packard Children’s Hospital Policies and the VHA Handbook)

Š      Guidance on various topics, such as sponsor-investigator research, children in research, use of test articles and reportable events

Š      Guidance on additional requirements when research is supported by, or under the purview of, agencies such as Departments of Defense, Education, Energy, and Justice; EPA; ICH-GCP; National Science Foundation; PHS

Š      IRB forms, including checklists, consent form and HIPAA authorization templates

Š      Protocol Application instructions and information

Š      Frequently Asked Questions and Practice Tips for investigators regarding human subject research protections and the IRB review process

Š      Human subject determination information and forms to assist investigators in identifying which protocols involve human subject research requiring IRB review.  For example, the following might not be research under 45 CFR 46, or 21 CFR 50, 56: QA/QI, pilot projects, research practicum, case studies (approximately 3 to 5), and oral histories.  See Is My Project “Research”?

Š      New alerts highlighting the posting of new information or changes in existing policies and procedures

Š      IRB education presentations

The IRB staff is readily available by telephone and in-person meetings to assist investigators and research staff on human subject research matters, particularly IRB applications and review questions.

IRB member and staff education is provided at each convened IRB meeting.  At the beginning of each meeting the IRB Education staff provides an educational presentation on a specific policy or procedures governing human subject research.  Each monthly education presentation is also available to all IRB members on the Human Subjects Research website.

The IRB Education staff and other IRB staff regularly give presentations, often to large research groups, and accept invitations to attend classes and departmental meetings to provide information and guidance to the STANFORD research community on IRB policies and procedures governing human subject research.

Within the RCO, the IRB Education staff is responsible for identifying new information involving human research participant protection such as new organizational policies, or emerging ethical and scientific issues.  Information about new or modified laws might also be identified by legal counsel.  New information is posted on the Human Subjects Research website and is disseminated to the IRB staff, IRB members and the STANFORD research community via other distribution sources as noted above.

3.2      Independence of IRBs

Section revised: 3/13/13

STANFORD has and follows written policies and procedures that allow the Institutional Review Board to function independently of other organizational entities in protecting research participants.  (AAHRPP Element I.1.C)

Organizational Structure that Provides Independence

The President of Stanford University has delegated the authority and responsibility to establish, maintain and oversee the HRPP to the Vice Provost and Dean of Research as specified in the President’s Delegation of Authority letter. 

The Vice Provost and Dean of Research, the Office of the Vice Provost and Dean of Research, and the RCO, which includes the IRBs and reports to the Vice Provost and Dean of Research, are separate from, independent of, and have no direct reporting relationship to any part of STANFORD that carries out research or to any of the other organizations covered by the HRPP.  The duties of the Vice Provost and Dean of Research and the Office of the Vice Provost and Dean of Research relate to establishing policy for research and oversight of research compliance, particularly as it relates to human participant research.

Delegation to the IRB

The Vice Provost and Dean of Research delegates independence and authority to the IRBs through this Chapter 3.2 and the Charge to each IRB Chair (medical and nonmedical) and member at the time of their appointment.  The IRBs have authority to:

Š      Review, approve, disapprove, or require changes in research involving human participants

Š      Suspend or terminate research involving human participants or an investigator’s privilege to conduct such research (e.g., in situations where research is not being conducted in accordance with IRB requirements, or

Š      where the research has been associated with unexpected serious harm to participants)

Š      Observe, or have a third party observe the consent process

Š      Observe, or have a third party observe the conduct of research.

Prohibition against Others Usurping IRB Approval Authority or Using Undue Influence

The Vice Provost and Dean of Research prohibits STANFORD officials, investigators, and employees, and sponsors contracting with STANFORD for research from:

Š      Maintaining or claiming IRB approval of research that has been disapproved or not yet been reviewed by the IRB

Š      Attempting to use or using undue influence with the IRB, any of its members or staff, a PD or any other member of the research team to obtain a particular result, decision or action.

“Undue influence” means attempting to interfere with the normal functioning and decision-making of the IRB or to influence an IRB member or staff, a PD or any other member of the research team outside of established processes or normal and accepted methods, in order to obtain a particular result, decision or action by the IRB or one of its members or staff. 

To help forestall undue influence of IRB members, the IRB preserves the anonymity of members assigned as reviewers to specific protocols or protocol events.

An individual who believes he or she has been subjected to such undue influence should make a report of non-compliance under Chapter 3.9 (e.g., to the Research Compliance Director or Vice Provost and Dean of Research).  Such reports will be reviewed in the same manner as possible non-compliance by an IRB Chair or member by the Vice Provost and Dean of Research as described in Chapter 3.9.  The types of response to attempts to unduly influence the IRB are determined as appropriate to the situation, by either the Research Compliance Director or Vice Provost and Dean of Research.

3.3      Regulatory Definition of Human Subject Research

Section revised: 3/13/13

Human subject research is defined under 45 CFR 46.102(d) and (f), 21 CFR 50.3 (c) and (j), 45 CFR 46.102(f), 21 CFR 50.3(e). See also VHA Handbook 1200.05.

The IRB retains ultimate authority to determine whether an activity meets the definition of human subject research.  Upon receipt of a Determination of Human Subject Research Application, IRB staff make this determination in a timely manner, and communicate to the PD via a Notice of Determination of Human Subject Research their decision on whether the activity meets the definitions as defined in the HRPP Policy Manual.

Chapter 1.4 describes the types of human subject research conducted at STANFORD.

All protocols involving both "research" and "human subjects" (other than those determined to be exempt) must be reviewed and approved by the IRB before recruitment and data collection may start.   See:

Š      Human Subjects Research website topic Human Subject Research

Š      Is My Project “Research”?

Š      Does My Research involve Human Subjects? 

Š      Determination of Human Subject Research Application

Pilot Studies

Stanford University and the VA have different definitions for pilot studies. 

The Stanford Research Policy Handbook defines a pilot study as a preliminary investigation of the feasibility of a study, usually done on a small scale (usually fewer than 10 subjects) and exploratory in nature.  It is designed to help the investigator refine data collection procedures and instruments or prepare a better, more precise research design. At the point of academic discussions, e.g., "how could this survey question be misunderstood?" such a pilot would not contribute to generalizable knowledge and therefore is not considered research and does not require IRB review.  See RPH 5.4 Use of Human Subjects in Student Projects, Pilot Studies and Oral Histories (Non-Medical).

VA Research: Pilot studies are full-fledged research studies that must be approved by the IRB(s), when human subjects are involved.  They are not considered to be activities preparatory to research. (See VHA Handbook 1200.05)

 

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)

Additional Requirements

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

3.4      Exempt Research Determinations

Section revised: 3/13/13

The IRB has and follows written policies and procedures for determining when activities are exempt from applicable laws and regulations, when permitted by law or regulation and exercised by the IRB. Such policies and procedures indicate that exemption determinations are not to be made by Researchers or others who might have a conflict of interest regarding the studies. (AAHRPP Element II.2.A)

Categories of exempt research are stipulated in the Common Rule, Subpart A of 45 CFR 46.  See 45 CFR 46.101(b), and 21 CFR 56.104 (FDA), 38 CFR 16.101(b) (VA), and guidance Exempt Review Categories [GUI-4].

Exempt status shall not be granted when:

Š      Research involves prisoners as participants, pursuant to subpart C (45 CFR 46.305 (a))

Š      Categories (1) through (5) apply and research is subject to FDA regulations

Š      Category (b)(2) applies and research involves children as participants, except for research involving observations of public behavior when the investigator(s) do not participate in the activities being observed, pursuant to subpart D (45 CFR 46.401 (b).

Š      The project involves significant physical invasions or intrusions upon the privacy of participants.

IRB Managers refer to guidance GUI-4 Exempt Review Categories and use the Exemption Eligibility Checklist to verify that the PD has requested an appropriate exemption under the appropriate category.

Confirmation of exempt status is made by IRB members or designated IRB staff who have the knowledge and authority to confirm exemption.  If a protocol meets the criteria for exemption, a Notice of Exempt Review is generated and is available for the PD.  This notice indicates category(ies) under which the exemption is granted.

Emergency use of a test article is exempt from prospective IRB review under 21 CFR56.104. See Chapter 5.8 for more information on this topic.

Making Exemption Determinations without Conflict of Interest

Those IRB members, staff, and consultants involved in reviewing and approving the exempt determination of protocol applications must not participate in the review of protocols in which they have a conflicting interest – see Chapter 6.6 for policies prohibiting such situations.

 

Emergency use of a test article is exempt from prospective IRB review under 21 CFR56.104. See Chapter 5.9 for more information on this topic.

 

3.5      Policies and Procedures for Exempt Research

Section revised: 3/13/13

The IRB has and follows written policies and procedures for addressing protection of participants in research that is exempt from applicable laws and regulations. These functions may be delegated to an entity other than the IRB. (AAHRPP Element II.2.B)

 

STANFORD requires protocols qualifying for exempt review to be submitted for IRB review and confirmation of exempt status.  While such research is exempt from the regulations set forth in 45 CFR 46.101(b), and 21 CFR 56.104 (FDA), and 38 CFR 16.101(b) (VA), the research must meet STANFORD HRPP ethical standards governing the conduct of research.  See Chapter 1.6.

The IRB ascertains that exempt protocols provide appropriate protection of privacy and confidentiality interests (see Chapter 11).

If there are interactions with participants, requirements for the consent process apply to exempt research, such as providing the following information:

Š      The activity involves research

Š      A description of the procedures

Š      Participation is voluntary

Š      Name and contact information for the investigator.

Exempt Review Process

PDs are required to submit the Exempt Application Form.  In reviewing the application, IRB staff refer to guidance Exempt Review Categories and use the Exemption Eligibility Checklist to verify:

Š      Whether the PD has requested an appropriate exemption, and

Š      That exemption, if granted, is assigned under the appropriate category.

The review is performed by IRB staff or IRB members who have the knowledge and authority to confirm exemption, or refer the protocol for expedited or regular review.

If a protocol meets the criteria for exemption, a Notice of Exempt Review is generated and is available for the PD. 

If a protocol does not meet criteria for exemption, it is returned to the PD with notification of failure to meet the criteria.  As appropriate, the application is converted to a Protocol Application for expedited or regular review.

Once a protocol is determined to be exempt, it is not reviewed again unless a modification application is submitted. There is no continuing review process for exempt research, as long as the criteria for exemption remain satisfied.

3.6      Federal versus State Requirements

Section revised: 3/13/13

STANFORD has and follows written policies and procedures that identify applicable laws in the localities where it conducts human research, takes them into account in the review and conduct of research, and resolves differences between federal or national law and local laws.  (AAHRPP Element I.1.G)

The IRB requires that PDs comply with the local, federal and state laws that are applicable to their research. 

A primary responsibility of the legal counsel to the IRB, who is a non-voting member of the IRB, is to provide advice to investigators and the IRB about such laws, particularly compliance with state laws while acting in accordance with the Common Rule and FDA regulations, and to assist in resolving any conflicts among applicable laws.

As needed, and in consultation with legal counsel if necessary, IRB staff develop educational materials for investigators and IRB members and staff relating to new state laws.  Examples of such materials are guidances Research Surrogate Decision Makers  which explains California law, and Consent for Protocols Involving Children and Consenting Minors which includes the definitions for “guardian” under California law.

California Health and Safety Code

See Chapter 12 for situations under California Law which have additional requirements regarding the informed consent process when certain procedures and uses are involved, and for disclosure requirements for HIV testing under CA Health & Safety Code Section 121080.

California Law Exception

Health & Safety Code section 24178(a):

“Except for this section and the requirements set forth in Sections 24172  and 24176, this chapter shall not apply to any person who is conducting a medical experiment as an investigator within an institution that holds an assurance with the United States Department of Health and Human Services pursuant to Part 46 of Title 45 of the Code of Federal Regulations and who obtains informed consent in the method and manner required by those regulations.”

 Laws of Other States (Research Outside of California)

STANFORD investigators conduct research in states other than California.  As each state has different laws, STANFORD investigators are expected to adhere to the laws of the state in which research is being conducted as well as those of California.

When necessary other attorneys in the Office of the General Counsel or outside attorneys retained by it can provide direction and interpretation of California and other state’s laws.

 

3.7      Investigators’ Conflicts of Interest (CoI)

Section revised: 12/07/2015

STANFORD has and follows written policies and procedures to identify, manage, and minimize or eliminate individual financial conflicts of interest of Researchers and Research Staff that could influence the conduct of the research or the integrity of the Human Research Protection Program. The Organization works with the Institutional Review Board in ensuring that financial conflicts of interest are managed and minimized or eliminated, when appropriate. (AAHRPP Element I.6.B.)

Policies for Faculty

Stanford University has the following policies regarding conflict of interest (COI) for research carried out at Stanford University, Stanford Hospital and Clinics (SHC), Lucile Packard Children’s Hospital (LPCH), the VAPAHCS, or elsewhere:

Š      Stanford University Research Policy Handbook (RPH):

-       RPH 4.1 Faculty Policy on Conflict of Commitment and Interest, and

-       RPH 4.2 PHS and NSF Requirements Regarding Financial Disclosures and Agency Notifications.

School Deans are responsible for ensuring implementation of the Faculty Policy on Conflict of Commitment and Interest; the Vice Provost and Dean of Research is responsible for interpretation and overall coordination of the policy.

Policies for Staff and Students

Policies for staff and students are found at:

Š      RPH 4.4 Conflict of Interest and Commitment For Academic Staff  and Other Teaching  Staff

Š      Administrative Guide Memo 1.5.2  Staff Policy on Conflict of Commitment and Interest  for staff members

Š      RPH 10.6 Relationships Between Students (including Postdoctoral Scholars) and Outside Entities     

Disclosure of Financial Interests

Faculty must disclose on an annual basis all financial relationships that reasonably appear to be related to their institutional responsibilities. This is done through Stanford’s Outside Professional Activities Certification System (OPACS).  In addition, as faculty enter into changed or new financial relationships related to their institutional responsibilities, they can access their OPACS disclosures to update previously reported activities or financial relationships, or to enter new activities.

When potential conflicts of interest relate to human subject research protocols, they require a transactional (ad hoc) disclosure in OPACS.  Disclosure must be made by each investigator for him or herself and his or her immediate family.  Immediate family” means the investigator’s spouse or domestic partner and dependent children (as defined by the IRS). 

 

Management of conflicts of interest is vested in the offices of the School Deans at Stanford University. The Vice Provost and Dean of Research is the University officer responsible for interpreting and overseeing implementation of and compliance with this policy.

Before a protocol application can be submitted to the IRB, the Protocol Director, faculty listed on the protocol, and any others identified as presenting a potential conflict of interest must answer the screening questions in OPACS.

Management of Investigator Conflict of Interest Disclosures

If one of the investigators on a protocol has answered “yes” to one of the screening questions, the case is managed in accordance with University policies.  The Managing Conflicts of Interests website discusses questions for the investigator and the institution to consider when assessing COI.

All investigators’ conflicts of interest (for all schools, including SOM) are managed via the Conflict of Interest Review Program (COIRP) and its associated Conflict of Interest Committee (COIC).  Points of contact for each school are listed on the COI website.  

Conflict disclosure in the informed consent process may be an important part of the management strategy, but will not necessarily be the only strategy used. It is the responsibility of the COIC to determine what strategy or strategies are appropriate to eliminate, mitigate, or manage conflict that has the potential to harm subjects or compromise the objectivity of the research, or are likely to be perceived as having that potential. 

Role of the IRB

Review of potential conflicts of interest with initial approval

When a potential conflict of interest has been identified, the IRB communicates closely with the appropriate COI point of contact and the investigator throughout the protocol review process. When appropriate, a plan or strategy to adequately eliminate, mitigate, or manage the conflict must be determined by the COIC and accepted by the IRB.  See Chapter 14.1.  The COI Manager fills out an Action Report Form that informs the IRB of the COIC evaluation including any management plan. The IRB has the final authority to decide whether the potential conflict of interest and its management, if any, allows the research to be approved.

Š      When there are non-substantive outstanding COI matters, a protocol may be approved contingent upon the matters being resolved (e.g., requiring that the investigator modify the informed consent document to include verbatim language).

Š      When there are substantive outstanding COI matters, a protocol will either be tabled or precluded from possible approval until matters are resolved. 

Only when COI matters are completely resolved is the protocol Approval Letter generated.

Review of conflicts of interest disclosed after IRB approval of research

When a potential conflict of interest arises and the investigator discloses it after the IRB has reviewed and approved a protocol, the investigator should immediately notify the IRB of the potential conflict and notify the IRB that enrollment and protocol procedures will stop until the conflict of interest has been reviewed and resolved by the COIC as described above. The determination by the COIC is forwarded to the IRB.

When a known potential conflict of interest is discovered after the IRB review and approval, the IRB will ask the PD to file a conflict of interest disclosure in OPACS as described above, and may, among other possible actions, ask the investigator to disclose the relationship to research participants.  The IRB will assess whether any action should be taken in accordance with Non-Compliance with HRPP Requirements in Chapter 3.9.

Recordkeeping

Records on all disclosures of financial interests and all decisions to manage, reduce, or eliminate conflicts of interest are maintained for three years from the date of final disclosure.  This information will be made available to DHHS upon request, while maintaining the confidentiality of all records of financial interest.

Other agency requirements

VA research: Veterans Affairs Palo Alto Health Care System (VAPAHCS) Memorandum No. 151-14-14 Research Financial Conflict of Interest Disclosures defines policies and procedures regarding conflict of interest as defined in this memorandum.

Additional requirements

Additional requirements might apply, depending on the source of support/funding (e.g., Department of Defense, Department of the Navy), or particular requirements regarding financial disclosures and agency notifications (e.g., if the research must follow Public Health Service (PHS) or National Science Foundation (NSF) regulations):  see Other Federal Agencies - Additional Requirements [GUI-42].

3.8      Institutional Conflict of Interest

Section revised: 3/13/13

STANFORD has and follows written policies and procedures to identify, manage, and minimize or eliminate financial conflicts of interest of the Organization that could influence the conduct of the research or the integrity of the Human Research Protection Program. (AAHRPP Element I.6.A)

The policy is found in the Research Policy Handbook, RPH 4.7 Institutional Conflict of Interest in Research Involving Human Subjects.  An institutional conflict of interest (ICOI) is created if an investigator at Stanford undertakes to do human subjects research on a drug, device, biologic or other item on which Stanford has a patent, has licensed the intellectual property, or receives royalties or other fees.  All new human subjects research protocols submitted for IRB review must indicate the source(s) of all funding to be used in supporting the research, including unrestricted school, department or individual accounts, as well as the name of the manufacturer when applicable.  In addition, the investigators are required to answer questions about the relationship of their research to their administrative duties. When a protocol lists a manufacturer, or when other information indicates a potential conflict, the issues are handled as outlined in RPH 4.7 Institutional Conflict of Interest in Research Involving Human Subjects.  Decisions are communicated to the IRB, to the relevant offices within the University, and to the relevant dean or associate dean so that the recommendations can be implemented at the level of the individual schools as appropriate.

3.9      Non-Compliance with HRPP Requirements  

Section revised: 06/03/2016

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)

STANFORD has and follows written policies and procedures for addressing allegations and findings of non-compliance with Human Research Protection Program requirements, and works with the Institutional Review Board, when appropriate, to ensure that participants are protected when non-compliance occurs. Such policies and procedures include reporting these actions, when appropriate. (AAHRPP Element I.5.D)

Any situation of perceived or actual serious or continuing non-compliance jeopardizes the STANFORD commitment to human subject research protection.  Receiving information about possible non-compliance is essential for accountability and education purposes, correcting non-compliance, deterring it from occurring again, and attempting to mitigate any adverse effects on research participants. 

The Office of the Vice Provost and Dean of Research has expressed the importance of reporting possible non-compliance as follows:  “Integrity and conscience demand not only personal adherence to ethical standards, but reporting of suspected violations of those standards. Reports may be made confidentially, or even anonymously.  Reporting such concern in good faith is a service to the University and to the larger academic community, and will not jeopardize anyone’s employment.”  See Principal Investigator Responsibilities and misconduct and reporting at Stanford University.

Definitions

Non-compliance:  An action or activity in human subject research at variance with the approved IRB protocol, other requirements and determinations of the IRB, the HRPP Policy Manual and other applicable policies of Stanford University, SHC, LPCH, VAPAHCS (e.g., VHA Handbook 1200.5), Palo Alto Veterans Institute for Research (PAVIR) or relevant state or federal laws. 

Serious non-compliance:  Non-compliance that affects the rights or welfare of human subject research participants.

Continuing non-compliance:  A pattern of non-compliance that indicates a deficiency likely to result in further non-compliance (e.g., a pattern that indicates lack of attention to or knowledge or understanding about regulations or ethics) or a circumstance in which an investigator fails to cooperate with investigating or correcting non-compliance.

VA research: The definitions of serious and continuing non-compliance are defined in VHA Handbook 1200.05 - Research Compliance Reporting Requirements.

Allegation of non-compliance:  A report of non-compliance that represents an unproven assertion.

Finding of non-compliance:  Non-compliance that is true, or an allegation of non-compliance that is determined to be true based on a preponderance of the evidence.

Obligation to Report Non-Compliance

Allegations, observations or evidence of non-compliance in human subject research must be reported to the Research Compliance Office by:

Š      Protocol Director (PD) or any research team member

Š      Employee of STANFORD

Š      IRB member or RCO staff

Š      Study monitor, auditor or sponsor either directly or through the PD.

Non-compliance can be reported to the RCO by the PD on the Report Form (self-reported) or by other individuals (may be done anonymously) via telephone, email or letter.  Reports of non-compliance, not self-reported on the Report Form, are recorded by the RCO staff. 

Research participants and individuals not directly involved with conducting or overseeing the research are also encouraged to report suspected non-compliance.  

Reports of possible non-compliance may also be directed to the following individuals, who in turn forward them to the RCO staff:

Š      The PD

Š      The Vice Provost and Dean of Research

Š      Internal Audit: oversight of Institutional Compliance at Stanford resides under the Associate Vie President for Audit, Compliance and Privacy.  Reports can be submitted anonymously through the Helpline Request, or emailed.

Š      For research in the VAPAHCS system: Members of the VA research community must report possible non-compliance in writing to the IRB within five business days after becoming aware of it, and must also report in the same time frame directly to the Medical Center Director, VAPAHCS Associate Chief of Staff for Research and Development, and other relevant research review committees as appropriate.

Possible non-compliance or evidence of non-compliance might also be discovered by RCO staff during the course of their normal duties. 

Non-Compliance – Allegations or Findings

Reports can be either allegations or findings of non-compliance.   Allegations of non-compliance that have yet to be proven are reviewed and investigated.  An allegation determined to be true based on a preponderance of the evidence becomes a finding. Generally, self-reported instances by investigators on the Report Form will be accepted as a finding of non-compliance.

Review of Allegations or Findings of Non-Compliance

All reports of non-compliance are initially evaluated by the IRB staff.  A report will either be designated as not requiring further action, or will be escalated for review by the RCO Director or their delegate.  

The RCO Director or their delegate ensures that immediate action is taken as necessary to prevent unacceptable risk to research participants. For non-compliance that is potentially serious or continuing (in the opinion of the RCO Director), the RCO Director reports orally within five business days to the Vice Provost and Dean of Research and subsequently provides updates on any fact-finding and IRB review process. 

A report requires no further action if the non-compliance is:

Š      A factual assertion of non-compliance (generally self-reported by the investigators);

Š      Neither serious nor continuing; and

Š      Addressed by the investigator through a corrective action plan to remedy the problem.

If a report of non-compliance does not require further action, the incident and corrective action plan will be documented in writing and stored in appropriate files. Findings of possible serious or continuing non-compliance are referred to the IRB for review.  (See below.)    

If a report is an allegation, the RCO Director or delegate will review the report. See Process for Addressing Allegations and Findings of Non-Compliance.

Investigation

The RCO Director or delegate reviews the report and chooses one of the following courses of action in investigating the allegation:

Š      Conducts the review alone

Š      Conducts the initial review in co-ordination with the IRB Chair

Š      Delegates some of the review to IRB staff

Š      Delegates all of the review to IRB staff

Š      Empanels a reviewing subcommittee of the IRB

Š      Requests that legal counsel provide advice and conduct the review,

Š      Requests assistance from others at STANFORD (e.g., Office of Internal Audit, Office of General Counsel, a non-involved Stanford University or VA physician as an expert), SHC, LPCH, VAPAHCS, PAVIR or outside consultants.  

The individual(s) or subcommittee conducting the investigation may take any of the following actions necessary to determine whether allegations are true, and to determine the seriousness or number of occurrences of the actions:

Š      Reviewing written materials

Š      Interviewing knowledgeable sources

Š      Collecting relevant documentation.

During the fact-finding process, the RCO Director or delegate communicates as appropriate with the PD or representative about the progress of the review and investigation.  A factual and objective written record of findings and evidence is made by the RCO and stored in the appropriate files. 

Allegations which, in the opinion of the RCO Director or delegate and the IRB Chair, are supported by the preponderance of evidence are determined to be findings of non-compliance.

Findings of non-compliance are assessed by the RCO Director or delegate and the IRB Chair as to whether they are either serious or continuing.

If the non-compliance is neither serious nor continuing, the RCO Director or delegate, alone or with the IRB Chair, examines whether the PD understands the non-compliance and has an adequate corrective action plan. If so, the decision and corrective action plan are documented and filed, otherwise the report is referred to the IRB (the convened IRB, the IRB Chair, or their delegate) for review (see Internal and External Reporting).

Serious or Continuing Non-Compliance Referred to the IRB

Non-compliance that is believed to be serious or continuing is referred for review by the convened IRB. The report with other relevant portions of the protocol is available to the reviewer(s).  As a result of this review, the following actions may be taken:

Š      The IRB determines that additional information is needed and requests that such information be obtained before further action is taken.

Š      The IRB determines that non-compliance did not occur or that non-compliance occurred but was neither serious nor continuing, and either takes no action or requires or recommends an appropriate corrective action plan.

Š      The IRB determines that non-compliance occurred and that it was serious or continuing. This is referred to as a “Reportable Decision” (see Chapter 3.11), and the IRB:

-       Takes action appropriate to the situation (see possible actions below)

-       Follows the internal reporting procedure required in Chapter 3.11 concerning determinations of serious or continuing non-compliance.

Š      For concerns not within the IRB’s purview, the IRB refers the matter to the appropriate official at Stanford University, SHC, LPCH, or VAPAHCS.

IRB determinations and actions are recorded, and communicated as appropriate to the relevant, involved individual(s), normally including the PD. IRB determinations of serious or continuing non-compliance are reported internally and externally as described in Chapter 3.11.

Possible IRB Actions for Serious or Continuing Non-Compliance

In considering actions for serious or continuing non-compliance, the IRB seeks to:

Š      Correct the non-compliance

Š      Deter it from occurring again (e.g., hold the relevant individuals

Š      accountable for their actions and provide education on how to comply), and

Š      Attempt to mitigate any adverse effects on participants. 

The IRB must consider:

Š      Suspension or termination of the protocol pursuant to Chapter 9.4

Š      Notification of current participants (required when such information may relate to participants’ willingness to continue to take part in the research)

Š      Other possible IRB actions include but are not limited to the following:

Š      Monitoring of the research

Š      Monitoring of the consent process

Š      Referral to other organizational entities (e.g., legal counsel, risk management, institutional official)

Š      Modification of the research protocol

Š      Modification of the information disclosed during the consent process

Š      Provision of additional information to past participants

Š      Requiring re-consent of current participants to continued participation 

Š      Modification of the continuing review schedule 

Š      Participation by research team members in additional training or education

Š      When appropriate, applying any corrective action to all similar protocols.

If the IRB action will affect participants in the protocol (e.g., requires withdrawal of participants), the IRB utilizes a process that takes into account the impact on their health and safety as described in Chapter 9.4.

Additional Requirements

Other Federal Agencies

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

VA research

Refer to VHA Handbook 1200.05 for VA definitions, and timelines for IRB determinations and remedial actions.

 

IRB-related Non-Compliance Involving an IRB Chair, IRB Member or RCO Staff

 

IRB Chairs, IRB Members or RCO Director

The Vice Provost and Dean of Research is primarily responsible for investigating and reviewing IRB-related non-compliance involving an IRB Chair, IRB member or the RCO Director.  If a fact-finding review of an allegation is necessary to assess the evidence, it could include the Vice Provost and Dean of Research acting alone, delegating some or all of the review to IRB staff, empanelling a review committee, requesting that legal counsel provide advice and conduct the review, or requesting assistance from others.  The Vice Provost and Dean of Research finds whether the allegation is true.  If the Vice Provost and Dean of Research makes a finding of serious or continuing non-compliance, the report is referred to the IRB for review.

Any disciplinary action must be taken in accordance with the Statement on Faculty Discipline approved by the Senate of the Academic Council on December 2, 1999 and by the Board of Trustees on December 14, 1999, and any other applicable provision of the Faculty Handbook and the Research Policy Handbook. 

 

RCO Staff

The RCO Director is primarily responsible for reviewing non-compliance involving RCO staff, and determining if allegations are supported by a preponderance of evidence.  The RCO Director may delegate the initial review or fact-finding to others, such as the supervisor of the staff member.  If the non-compliance is deemed to have merit the RCO Director is ultimately responsible for determining the action via Stanford policies and procedures:  Administrative Guide Memo 22.14, Trial Period, and 22.15, Corrective Action and Discipline.

 

Possible IRB Actions for Non-Compliance Involving an IRB Chair, IRB Member or Staff

Possible actions include but are not limited to the following:

Š      As appropriate: Evaluation of the IRB Chair’s or member’s ability to serve on the IRB, or evaluation of the staff member’s ability to support the IRB

Š      Modification of the information disclosed during the consent process

Š      Provision of additional information to past participants

Š      Notification to current participants (required when such information may relate to participants’ willingness to continue to take part in the research )

Š      Requirement to re-consent current participants to continued participation. Modification of the continuing review schedule 

Š      When appropriate, applying any corrective action to all similar protocols.

3.10    Unanticipated Problems Involving Risks to Participants or Others (UPs), and Other Reportable Information

Section revised: 3/13/13

STANFORD has and follows written policies and procedures for addressing allegations and findings of non-compliance with Human Research Protection Program requirements, and works with the Institutional Review Board, when appropriate, to ensure that participants are protected when non-compliance occurs. Such policies and procedures include reporting these actions, when appropriate. (AAHRPP Element I.5.D)

The IRB has and follows written policies and procedures for addressing unanticipated problems involving risks to participants or others, and for reporting these actions, when appropriate. (AAHRPP Element II.2.F)

Protocol Director responsibilities for reporting unanticipated problems involving risks to research participants or others, and other reportable information, are outlined in Chapter 15.2.

Events and Information – Required Reporting to the IRB

Events and information that must be reported to the IRB, along with the timelines for reporting, are listed in the guidance Events and Information that Require Prompt Reporting to the IRB. They should be reported to the IRB using the online IRB Report Form in the eProtocol system.

VA Research – timeframe for reporting

Refer to VHA Handbook 1200.05 for requirements about report timelines and distribution for UPs, and termination or suspension of research.

Additional reporting requirements

Additional requirements might apply, depending on the source of support/funding (e.g., Department of Energy, Department of Justice: National Institute of Justice (NIJ) and research conducted with the Bureau of Prisons): see Other Federal Agencies - Additional Requirements [GUI-42].

Optional reporting

The IRB Report Form may also be used to report other items (category 7 in guidance Events and Information that Require Prompt Reporting to the IRB) – however, PDs should consult with IRB Education before reporting such items.

Review of Reports

See flowchart Process for Handling Reports.  At any point during the review process, the IRB staff, the IRB member, or the convened IRB may seek additional expertise if needed.

IRB Staff evaluation

The IRB staff evaluates reports, checking whether reports have been appropriately completed (e.g., correct report category has been indicated; for events reported as UPs it is indicated that the event was unexpected, related and harmful; supporting documents have been submitted with the report). A report that does not satisfy initial IRB staff evaluation will be returned to the PD with an explanation. 

IRB member review

Reports which appear to be UPs, and reports of other reportable events and information will be assigned to an IRB member with adequate expertise for review.

The IRB member reviews the report and materials from the protocol file, (e.g., protocol, investigator’s brochure, continuing reviews, modifications, and other reports) and assesses whether the report constitutes a UP or other information that should be presented at an IRB convened meeting.

IRB convened meeting review

Prior to the meeting, the IRB staff provides all voting members with a copy of the report and supporting documents. 

At the convened meeting, the IRB discusses and votes on whether the report qualifies as a UP or other reportable information. The vote is recorded in the minutes for the meeting.  The IRB considers whether any action is necessary, and the decision is documented in the minutes and in the protocol file. 

Possible Actions by the IRB

The IRB has a range of available actions it can take if an event is deemed to be a UP or other reportable information.  Depending on the severity of the event and the potential for continuing risk to participants, the IRB determines what further action will be required, including: 

Š      Suspending the research

Š      Terminating the research

Š      Requiring participants to be notified of the event, especially if the event may relate to the participant’s willingness to continue in the study

Š      Requiring a modification to the research (either as soon as possible or at continuing review).  The modification can include a change to the study procedures, informed consent process or written informed consent document

Š      Requiring current participants to be re-consented

Š      Providing additional information to past participants

Š      Requiring monitoring of the research or consent process

Š      Modification of the continuing review schedule

Š      Referral to other organizational entities (e.g., legal counsel, risk management, institutional official)

Š      Other actions as deemed appropriate.

If the convened IRB:

Š      Determines that an unanticipated problem involving risks to participants or others (UP) or some other reportable event has occurred, or

Š      Suspends or terminates the approval of a protocol (see Chapter 9.4), or

Š      Determines that serious or continuing non-compliance has occurred (see Chapter 3.9),

this is designated a “Reportable Decision”, and internal and external reporting proceeds as outlined in Chapter 3.11.

Any action taken by the IRB is communicated to the PD, and to the CCTO if a Cancer Center study.  If the IRB action will affect participants in the protocol (e.g., requires withdrawal of participants), the IRB considers the impact on their health and safety. (See Chapter 9.4.)

VA research

The IRB Coordinator at the VA is notified electronically when a Report (possible UP, etc.) is submitted to the IRB for VA research.

Reports of serious unanticipated problems involving risks to participants or others, or of local unanticipated serious adverse events, will be reviewed and a determination made as specified in VHA Handbook 1200.05.

The IRB Coordinator at the VA is notified of any IRB action, and is responsible for further reporting to the VA Director, and the Office of Research Oversight (ORO) as required. See VHA Handbook 1200.05.

Review of Gene Transfer SAEs

Gene Transfer Serious Adverse Event (SAE): A serious adverse event arising out of a gene transfer protocol as defined in NIH Guidelines I-E-8, I-E-9 and I-E-10.

See NIH Guidelines for Research Involving Recombinant DNA Molecules.


For gene transfer protocols, PDs are instructed that all gene transfer SAEs occurring at STANFORD and at other institutions must be reported to the Biosafety Panel.  This is accomplished by completing the Gene Transfer Adverse Event Report, (which also contains a template for reporting to the NIH Office of Biotechnology Activities), and attaching it to online IRB Report Form in the eProtocol system. The IRB staff:

Routes all gene transfer SAE reports to the Biosafety Panel, then

Assesses each report as described in this section and returns to the PD those that do not meet the IRB reporting requirements as described in the guidance Events and Information that Require Prompt Reporting to the IRB.

See Process for Handling Reports.

3.11    Internal and External Reporting

Section revised: 12/07/2015

STANFORD has and follows written policies and procedures for addressing allegations and findings of non-compliance with Human Research Protection Program requirements, and works with the Institutional Review Board, when appropriate, to ensure that participants are protected when non-compliance occurs. Such policies and procedures include reporting these actions, when appropriate. (AAHRPP Element I.5.D)

The IRB has and follows written policies and procedures for addressing unanticipated problems involving risks to participants or others, and for reporting these actions, when appropriate. (AAHRPP Element II.2.F)

The IRB has and follows written policies and procedures for suspending or terminating IRB approval of research, if warranted, and for reporting these actions, when appropriate. (AAHRPP Element II.2.G)

Reportable Decisions

If the convened IRB:

Š      determines that serious or continuing noncompliance has occurred as specified above under Chapter 3.9, or

Š      determines that an unanticipated problem involving risks to participants or others (UP) or some other reportable event has occurred as specified in Chapter 3.10, or

Š      suspends or terminates the approval of a protocol pursuant to Chapter 9.4

the IRB Chair and the RCO Director send the Reportable Decision to the Vice Provost and Dean of Research.  See Internal and External Reporting flow chart. Written procedures for reporting unanticipated problems, noncompliance, suspension and termination follow the OHRP and FDA regulations (45 CFR 46.103(5); 21 CFR 56.108(b)). 

Additional reporting requirements

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

 

Time-Line For and Content of Report

An oral report by the RCO Director about the Reportable Decision will be made to the Vice Provost and Dean of Research within five business days.  The IRB Chair will provide a written report to the Vice Provost and Dean of Research generally within 30 days of the IRB’s determination.

The report will cover the IRB findings and any applicable actions. The relevant supporting documents will be transmitted with this report. (For VA reportable decisions, notification and reporting timeframes are as described in VHA Handbook 1200.05.)

Distribution

The report is sent to:

Š      For federally-sponsored research, the relevant Department or Agency head, any applicable regulatory body, and OHRP;

Š      For research that is subject to the Food and Drug Administration regulations regarding human subjects (any activity that involves an approved or unapproved drug or medical device except for activities that involve the use of an approved drug or medical device in the course of medical practices, and any activity in which data is reported to or held for inspection by FDA), the sponsor and the FDA;

Š      For non-federally-sponsored research not subject to FDA regulations regarding human subjects, the sponsor only;

Š      Relevant officials of SHC, LPCH and VAPAHCS including

-       The relevant privacy officer, if the report involves any unauthorized use, loss or disclosure of HIPAA protected health information as described in Chapter 11

-       The relevant security officer, if the report involves a violation of the HIPAA electronic security requirements for protected health information as described in Chapter 11

-       Any other individuals who the Vice Provost and Dean of Research, the IRB Chair or RCO Director choose to notify (e.g., School Deans, Department Chairs, Division Chiefs, VA administrators, the Office of the General Counsel).  

This external written report will be sent as soon as possible, but generally not longer than 30 days after the IRB determination.  For more serious incidents, the RCO Director will make an oral or preliminary written report within five business days with an estimated time for the final report. 

For any federally sponsored research, the report will include:

Š      The name(s) of the relevant STANFORD organization(s) conducting the research

Š      The title and number of the IRB protocol and of any federal proposal or award in which the Reportable Decision occurred

Š      The name of the Protocol Director (PD) and the Principal Investigator (PI) on any applicable federal award if different from the PD

Š      A detailed description of the Reportable Decision

Š      The actions taken or planned to be taken to address the circumstance(s) leading to the Reportable Decision.

A report need not be made to federal agencies that have already been made aware of the event through other mechanisms such as the investigator or sponsor.

For multicenter research projects, only the institution at which the participant(s) experienced an adverse event determined to be an unanticipated problem (or the institution at which any other type of unanticipated problem occurred) must report the event to the supporting agency head (or designee) and OHRP (45 CFR 46.103(b)(5)).

Action by the VA Facility Director/Associate Chief of Staff for Research and Development and External Reporting

The VA Facility Director or Associate Chief of Staff for Research and Development either accepts the report or refers it back to the IRB for further information or consideration of other action. 

Once the VA Facility Director and/or the Associate Chief of Staff for Research and Development are notified of any IRB determinations and action, they in turn report to the Office of Research Oversight (ORO), and to the appropriate Federal agency (e.g., OHRP, FDA, NIH, etc.) as stated in the Memorandum of Understanding between Stanford University and the VAPAHCS.  

Notification and reporting timeframes are described in VHA Handbook 1058.01 and Local HCSM 00-15-32.

3.12    Assurance of Compliance

Section revised: 3/13/13                                 

Stanford University and its affiliates covered by the HRPP maintain five Federalwide Assurances under OHRP (45 CFR 46.103), available to investigators and others involved in human subject research. See the Research Policy Handbook, RPH 5.2 Federal-wide Assurance for Protection of Human Subjects.

3.13    HRPP Quality Improvement Activities

Section revised: 3/13/13

The Organization conducts audits or surveys or uses other methods to assess compliance with organizational policies and procedures and applicable laws, regulations, codes, and guidance. The Organization makes improvements to increase compliance, when necessary. (AAHRPP Element I.5.A)

The Organization conducts audits or surveys or uses other methods to assess the quality, efficiency, and effectiveness of the Human Research Protection Program. The Organization identifies strengths and weaknesses of the Human Research Protection Program and makes improvements, when necessary, to increase the quality, efficiency, and effectiveness of the program. (AAHRPP Element I.5.B)

The Continuous Quality Improvement (CQI) Program of the Research Compliance Office (RCO) is designed to:

Š      Evaluate and monitor the effectiveness of the HRPP,

Š      Assess compliance with HRPP policies and procedures, 

Š      Identify areas and implement measures for improvement.

This is accomplished by working with the various components of the HRPP to design, recommend and implement improvements to promote the protection of human subject research participants.

Compliance Monitoring

HRPP staff conduct periodic compliance reviews and for-cause assessments to evaluate adherence to applicable federal regulations, state and local laws and STANFORD policies and procedures, and to verify that research is conducted in accordance with the IRB approved protocols.

Š      Periodic Compliance Reviews: Periodic compliance reviews are conducted using systematic methods to assess investigator and IRB compliance with federal regulations, state and local laws, and STANFORD policies and procedures.  Periodic compliance reviews include but are not limited to:

-       Examinations of executed informed consent forms

-       Reviews of IRB meeting minutes;

-       Detailed examinations of protocol files;

-       Observations of the informed consent process.

Š      For-cause assessments: The HRPP Associate Director or the RCO Director may direct HRPP staff to conduct an assessment in response to a particular concern.  Concerns that may prompt a for-cause assessment include but are not limited to:

-       Failure of routine reviews;

-       Complaints or concerns initiated by a research participant, family member, or research team/workforce member; 

-       Reports of serious or repeated non-compliance;

-       Results of reviews or monitoring conducted by other STANFORD components (e.g., VA, Cancer Center DSMC, Internal Audit) are reported to designated HRPP staff.

Additional Requirements

See Other Federal Agencies - Additional Requirements [GUI-42] for other requirements depending on the source of support/funding.

Reporting of Compliance Monitoring Results

Results of compliance monitoring activities are documented and reported to the HRPP Associate Director, the RCO Director, the IRB, Institutional Officials and other units within STANFORD as appropriate.  These results, supplemented by other review results when available, provide a quantitative and qualitative measurement of compliance with the HRPP.

Other Review Activities

Depending on the results of annual risk assessments, Stanford University’s Internal Audit Department may conduct additional reviews of the IRBs and the various schools and departments within STANFORD that conduct or review human subject research activities. 

Research Community Feedback

HRPP staff track comments, questions and issues received from the STANFORD investigators and participants to identify areas for potential improvement in the effectiveness of HRPP policies and procedures and for ensuring the protection of human subject research participants.  The Protocol Director and key study personnel receive a request to respond to a survey after approval of each event by the IRB.

IRB Performance Metrics

HRPP staff produce periodic metrics and analysis of the IRB operations and functions, including detailed measurements of activity volume and processing times.

Continuous Quality Improvement (CQI)

Based on the results of the aforementioned assessments and feedback received from the communities served by the HRPP, the HRPP staff of the Research Compliance Office partner with other components of the STANFORD HRPP to identify root causes of problems, recommend action plans to correct issues, and provide education, tools and outreach to promote effectiveness of improvements.

Significant changes to the Human Research Protection Program (HRPP) that are implemented as a result of quality assessment and quality improvement activities are monitored to ensure effectiveness and consistency. 

This leads to the continuous improvement of the HRPP and the protection of human subject research participants.

See Continuous Quality Improvement (CQI) [CQI-01] for more information on the goals of the CQI Program.

 

 

3.14    Investigators’ Input to the HRPP

Section revised: 06/03/2016

STANFORD has and follows written policies and procedures so that Researchers and Research Staff may bring forward concerns or suggestions regarding the Human Research Protection Program, including the ethics review process. (AAHRPP Element I.5.C.)

There are a variety of mechanisms available for contacting relevant individuals to bring concerns and suggestions, including:

Š      Reporting possible non-compliance as described in HRPP Chapter 3.9

Š      Reporting possible unanticipated problems as described in HRPP Chapter 3.10

Š      Making general comments and suggestions and expressing concerns about other matters, issues or processes involving the HRPP, including IRB review and operations to any person in the Research Compliance Office or in the Office of the Vice Provost and Dean of Research.

Š      Internal Audit: Institutional Compliance oversight resides under the Associate Vice President for Audit, Compliance and Privacy.  As an additional safeguard to reporter privacy, such information can be submitted anonymously, if desired, through the Helpline Request found on the Internal Audit and Institutional Compliance website, or emailed to compliance@stanford.edu)

Š      For research at the VAPAHCS: Members of the Chief of Staff’s office or the Research and Development Committee.

In addition, input from researchers is actively sought for each protocol review on a continuing basis, via an ongoing survey about the service provided by the IRBs; researchers may comment or provide suggestions on any aspect of the IRB or HRPP, either anonymously or by requesting discussion with the Research Compliance Office.  Aggregate survey results are published periodically on the Humans Subjects Research website.

The RCO Director receives and evaluates the input from any of these sources, with review by other individuals, as needed, (e.g., legal counsel).  If the input is submitted non-anonymously, the researcher receives a direct response.  If the outcome of the review shows a need for ongoing monitoring or education, then the appropriate individuals (e.g., HRPP staff) are asked to contribute their expertise.

The Vice Provost and Dean of Research handles any concerns or complaints related to the Director of Research Compliance.