Stanford University Office of the Dean of Research

Human Research Protection Program (HRPP)

DOMAIN I:  ORGANIZATION

Chapter 3:  Compliance Monitoring

STANFORD* monitors compliance of all those involved in the research process.  (AAHRPP Standard I-3)

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

STANFORD has the following written policies and procedures governing research with research participants that are available to investigators and research staff affiliated with STANFORD.  (AAHRPP Element I.3.A)

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

·         Investigators

·         Research staff

·         IRB staff

·         IRB members

·         Employees

·         Students

 

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

·         The HRPP Manual

·         Links to pertinent governmental regulations and guidelines

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

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

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

·         Protocol Application instructions and information

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

·         Human subject determination information and forms to assist investigators in identifying which protocols involve human subject research requiring IRB review. (See Does My Project Need IRB Review?)

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

·         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 Training Specialist provides an educational presentation on a specific policy or procedures governing human subject research. Each monthly education presentation is also emailed to all IRB members, whether or not they attended the meeting.

The HRPP Education Specialist 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 HRPP Education Specialist and the IRB Training Specialist are 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

STANFORD has the following written organizational structure, policies and procedures that allow the STANFORD HRPP to function independently of other organizational entities in its role in protecting research participants.  (AAHRPP Element I.3.B) 

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 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 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:

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

·         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

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

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

·         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:

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

·         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

STANFORD has written policies and procedures in the HRPP Manual for determining when studies meet the regulatory definitions of human subject research.  (AAHRPP Element I.3.C) 

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 1200.5 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=418.

See Chapter 1.4 for a description of 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:

·         Human Subjects Research website topic Human Subject Research

·         Does My Project need IRB Review?

·         Determination of Human Subject Research Application

·         Is My Project “Research”?

·         Does My Project involve “Human Subjects”?

·         Definitions

·         Regulations

 

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 does or does not meet the definitions as defined in the HRPP Manual.

 

3.4 Exempt Research Determinations

STANFORD has written policies and procedures for determining when studies are exempt under applicable federal, state, and local regulations.  Such policies and procedures indicate that exemption determinations are not to be made by investigators or others who might have a conflicting interest regarding the studies.  (AAHRPP Element I.3.D)  

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), and for VA research

38 CFR 16.101(b)).

 

IRB staff refer to guidance 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 staff or IRB members who have the knowledge and authority to confirm exemption.

 

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.

 

Conditions under which Exemption cannot be granted

Exempt status shall not be granted when:

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

·         Category (2)(b) 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)).

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

·         Research involves Human Embryonic Stem Cells, pursuant to California Health and Safety Code Section 125119

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

 

Making Exemption Determinations without Conflict of Interest

Exempt research determinations must not be made by those who might have a conflicting interest regarding the research. 

Those IRB members 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 6.3 for policies prohibiting such situations.

 

3.5  Policies and Procedures for Exempt Research

STANFORD has written policies and procedures for addressing protection of participants in research exempt from applicable federal regulations.  (AAHRPP Element I.3.E)  

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.

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:

·         The activity involves research

·         A description of the procedures

·         Participation is voluntary

·         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:

·         Whether the PD has requested an appropriate exemption, and

·         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

Where applicable in each chapter of the HRPP Manual, STANFORD includes policies, procedures and a description or reference regarding the relevant areas in which federal and state law might apply and how they are different, and provides guidance about regulatory compliance.  (AAHRPP Element I.3.F) 

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. 

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.

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

Because of the possibility that financial and other personal considerations might affect research objectivity and harm human subject research participants, STANFORD has written policies and procedures to identify, review, and manage, minimize or eliminate conflicts of interest or apparent conflicts of interest of investigators.  (AAHRPP Element I.3.G) 

 

Stanford University has the following policies and procedures regarding conflict of interest for research carried out at Stanford University, Stanford Hospital and Clinics (SHC), Lucile Packard Children’s Hospital (LPCH), or the Veterans Affairs Palo Alto Health Care System (VAPAHCS) or elsewhere and involving:

·         faculty members (all – including School of Medicine):  Stanford University Research Policy Handbook –

-    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.”

 

Stanford University has a process for annual reporting and certification of compliance with the Faculty Policy on Conflict of Commitment and Interest.

·         Additionally for faculty members (non School of Medicine only)

“Annual Certification of Compliance with Faculty Policy on Conflict of Interest and Commitment” 

·         additionally for faculty members (School of Medicine only)

-       School of Medicine Policy Annual Certification of Compliance” with Faculty Policy on Conflict of Interest and Commitment” 

-       School of Medicine Procedures

 

Policies for staff and students are found at:

·         academic staff member:  Stanford University Research Policy Handbook, RPH 4.4 “Policy on Conflict of Interest and Commitment For Academic Staff” (See also Chapter 9).

·         regular staff member:  Administrative Guide Memo 15.2  “Staff Policy on Conflict of Commitment and Interest” 

·         student:  Stanford University Research Policy Handbook, RPH 2.11 “Relationships Between Students (including Postdoctoral Scholars) and Outside Entities” 

     

VAPAHCS Memorandum No. 151-05-03 Conflict of Interest in the Conduct of Research defines policies and procedures regarding conflict of interest for VA research, as defined in this memorandum.

 

STANFORD does not consider such conflicts of interest, in and of themselves, as unethical or constituting or implying any wrongdoing, but they can lead to either an appearance of divided interest, or actual misconduct when considerations of personal gain, financial or otherwise, influence or compromise an investigator’s judgment and actions.

 

Disclosure of Financial Interests

STANFORD requires that investigators disclose any financial interest or relationship that is related to their research with human participants, regardless of the dollar amount.  For purposes of disclosure, an investigator includes any research personnel responsible for the design, conduct, data analysis, or reporting of human subject research.

The disclosure requirement applies to the following:

 

Disclosure must be made with respect to the investigator and his or her immediate family.  “Immediate family” means the investigator’s spouse or domestic partner and dependent children (as defined by the IRS).  

 

How and When Disclosures Are Made

Non-SOM Faculty: Disclosures are made annually in the form of an Annual Certification of Compliance with the Faculty Policy on Conflict of Commitment and Interest.  Disclosures are also made on an ad hoc basis, as new financial interests or relationships are acquired.  Ad hoc disclosure must be made as soon as such situations become known to the individual.  See form Ad Hoc Disclosure of Financial Interests. 

SOM Faculty: The Annual Disclosure process is completed online at: http://med.stanford.edu/conflict/.  Ad hoc disclosures must be made as soon as such situations become known to the individual, and are made using the Ad Hoc Faculty Disclosure Form.  For each proposed protocol, a Sponsored Projects Routing Sheet, the “SU-42” form with attached supplement Disclosure of Financial Interests Related to Research must be submitted. For additional information, see http://med.stanford.edu/coi/som_proceedures.html.

Disclosure forms are filed with the appropriate School Dean.

When submitting a Protocol Application to the IRB, the PD must complete the “Potential Conflict of Interest” section, which addresses whether any person who:

·         recruits, selects, consents, or treats participants,

·         plans to analyze data, or

·         plans to serve as an author on any papers originating from this research, has a conflicting interest or, whether any person who:

·         is an immediate family member (spouse, dependent child as defined by IRS, domestic partner of any of the above), or

·         is in a supervisory role to the PD

has a conflicting interest.  Similar questions are posed on the applications for continuing review and modification of protocols.  If any conflicting interest is indicated, the PD is instructed to contact the Conflict of Interest Committee (COIC).  The COIC Manager is provided a copy of the PD’s disclosure, including the protocol application and consent form(s), if applicable. 

 

 

Management of Investigator Conflict of Interest Disclosures

All investigator conflicting interest (for all schools, including SOM) is managed via the Conflict of Interest Review Program (COIRP) and its associated Conflict of Interest Committee (COIC).  The COIRP/COIC follow the policy “Faculty Disclosure of Conflicts of Interest” which addresses:

·         Disclosure of financial interests

·         Financial interest or relationships that pose conflicts of interest

·         Assessing conflicts of interest

·         Eliminating, mitigating or managing conflicts of interest

·         Stanford University policies on conflict of interest for faculty, academic staff, and non-academic staff

·         Thresholds above which interests are automatically deemed significant conflicts of interest requiring closer scrutiny and possible elimination, mitigation, or management

·         Review of financial interest exceeding thresholds

·         Management of conflicts of interest, including possible strategies

 

Assessing conflict of interest

In assessing whether a financial interest has the potential to harm subjects or compromise the objectivity of the research, or is likely to be perceived as having that potential, the COIRP considers the following:

 

Strategies to address conflict of interest

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.  See policy “Faculty Disclosure of Conflicts of Interest”.

 

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, and may not alone be used to manage a financial interest that may affect participant protections.

 

Role of the IRB

The IRB communicates closely with the COI Manager and the investigator throughout the protocol review process. An individualized form detailing any COI matters is sent from the IRB to both the PD and the COI Manager. Only when COI matters are completely resolved can a protocol be approved. When there are non-substantive outstanding COI matters, a protocol can be approved contingent upon the matters being resolved. When there are substantive outstanding COI matters, a protocol will either be tabled or not assigned to a meeting for possible approval until matters are resolved.  As appropriate, a plan or strategy to adequately eliminate, mitigate, or manage the conflict must be determined by the COIRP/COIC and accepted by the IRB.  See Chapters 6.3 and 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.

 

Conflicts of Interest Disclosed After IRB Approval of Research

When a potential conflict of interest arises and is disclosed 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 COIRP/COIC as described above.

 

If a known potential conflict of interest is not reported during the protocol review cycle and is disclosed after the IRB has reviewed and approved a protocol, the IRB will ask the PD to file a conflict of interest disclosure as described above, and may, among other possible actions, ask the investigator to disclose the relationship to research participants.  Generally, the PD will voluntarily stop any enrollment into the study, until any disclosed COI has been reviewed and resolved by the COIRP/COIC, and as appropriate, a plan or strategy to adequately eliminate, mitigate, or manage the conflict has been determined by the COIRP/COIC.  Any suspension of the study by the IRB will be handled according to the policies and procedures on Suspension and Termination of IRB Approval in Chapter 9.3, and will be reported to the IRB, regulatory agencies, and institutional officials in accordance with Chapter 3.11.

 

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.

 

 

3.8  Institutional Conflict of Interest

STANFORD has a written policy and procedure for recognizing and managing institutional conflicts of interest.  (AAHRPP Element I.3.H) 

The policy is found in the Research Policy Handbook, RPH 4.7  “Institutional Conflict of Interest”.

Possible institutional conflicts of interest of STANFORD are identified through the Conflict of Interest Section on the Protocol Application for initial review, continuing review, and modification.  If the investigator indicates they have knowledge that Stanford University has any ownership or royalty interest in any intellectual property utilized in the research, the matter is handled as outlined in RPH 4.7.  The Office of Technology and Licensing (OTL) completes the Institutional Conflict of Interest Action Report Form to the IRB, and forwards it to the IRB to be filed with the Protocol Application. Additionally, as described in the institutional policy, the OTL and the Vice Provost and Dean of Research receive information from the RCO pertaining to protocols that include drugs, devices, and biologics along with the manufacturer name and funding source.

 

3.9 Non-Compliance with HRPP Requirements                                   

STANFORD has the following written policies and procedures for addressing allegations and findings of non-compliance with Human Research Protection Program requirements.  (AAHRPP Element I.3.I) 

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 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 at Stanford University.

 

Definitions

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

Serious non-compliance:  Non-compliance that jeopardizes the rights and welfare of the human subject research participants or the integrity of the study data.  Examples of serious non-compliance may include: research participants do not meet inclusion and exclusion criteria but are enrolled in an experimental protocol, with possible serious health-related consequences for participants; the current IRB-approved consent form, with all potential risks and alternatives to participation listed, is not used.

Continuing non-compliance:  Non-compliance that evidences a pattern of behavior  that might jeopardize the rights and welfare of participants or the integrity of the study data (e.g., a pattern that indicates lack of attention to or knowledge or understanding about regulations or ethics).

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:

·         Protocol Director (PD) or any research team member

·         Employee of STANFORD

·         IRB member or RCO staff

·         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 on a Communications Notes form.  The RCO staff has primary responsibility for receiving all reports of non-compliance.

 

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:

·         The PD

·         The Vice Provost and Dean of Research

·         Internal Audit: oversight of Institutional Compliance at Stanford resides under the Director of Internal Audit and Institutional Compliance.  Reports can be submitted anonymously through the Helpline Request found at  http://www.stanford.edu/dept/Internal-Audit/compliance/index.html, or emailed to compliance@stanford.edu)

·         Members of the Chief of Staff’s office or the Research and Development Committee, for research in the VAPAHCS system.

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:

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

·         Neither serious nor continuing;

·         An administrative problem; and

·         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:

·         Conducts the review alone

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

·         Delegates some of the review to IRB staff

·         Delegates all of the review to IRB staff

·         Empanels a reviewing subcommittee of the IRB

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

·         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, PAIRE 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:

·         Reviewing written materials

·         Interviewing knowledgeable sources

·         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 (i.e., either 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 IRB (i.e., either the convened IRB, the IRB Chair, or their delegate).  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:

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

·         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.

·         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.

·         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:

 

·         Correct the non-compliance

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

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

·         Attempt to mitigate any adverse effects on participants. 

Possible IRB actions include but are not limited to the following:

·         Monitoring of the research

·         Monitoring of the consent process

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

·         Modification of the research protocol

·         Modification of the information disclosed during the consent process

·         Additional information provided to past participants

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

·         Current participants to re-consent to participation 

·         Modification of the continuing review schedule 

·         Participation by research team members in additional training or education

·         Suspension or termination of the protocol pursuant to Chapter 9.4

·         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 inChapter 9.4.

 

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:

·         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

·         Modification of the information disclosed during the consent process

·         Additional information provided to past participants

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

·         Current participants to re-consent to participation 

·         Modification of the continuing review schedule 

·         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

 

STANFORD has the following written policies and procedures for addressing unanticipated problems involving risks to research participants or others.  (AAHRPP Element I.3.J) 

 

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 (if the event did not occur on a Cancer Center study), or the Cancer Center Adverse Event Communication Form (if the event occurred on a Cancer Center study.) 

 

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 the HRPP Education Specialist 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 review

The IRB staff performs an initial review of the 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 review will be returned to the PD or the Cancer Center Trials Office (CCTO) 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 for review.  The preferred assignment is to the primary reviewer who reviewed the original protocol or another reviewer of that IRB with adequate expertise. 

 

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: 

·         Suspending the research

·         Terminating the research

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

·         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

·         Requiring current participants to be re-consented

·         Providing additional information to past participants

·         Requiring monitoring of the research or consent process

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

·         Other actions as deemed appropriate.

 

If the convened IRB:

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

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

·         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 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 1058.1 at http://www1.va.gov/vhapublications/ViewPublication.asp?pub_ID=1199).

 

 

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 at http://www4.od.nih.gov/oba/rac/guidelines/guidelines.html.


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:

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

2.    Assesses each report as described in Chapter 3.10 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                                               

If the convened IRB:

·         Determines that serious or continuing non-compliance has occurred as specified above under Chapter 3.9,

·         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

·         Suspends or terminates the approval of a protocol pursuant to Chapter 9.4

 

(each referred to as a “Reportable Decision”) 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)).

 

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 about the Reportable Decision to the Vice Provost and Dean of Research within 30 days.  The report will cover the nature of the event, the findings of the IRB, actions taken by the IRB or others, reasons for the actions, and plans for continuing review or action (if applicable).

 

Action by the Office of the Dean of Research and External Reporting

The Vice Provost and Dean of Research either accepts the report or refers it back to the IRB for further information or to consider other action.  Once the Vice Provost and Dean of Research accepts a report, the Vice Provost and Dean of Research sends it to:

·         The IRB, indicating acceptance of the IRB’s report

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

·         For research that is subject to the FDA 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 by inspection by FDA), the sponsor and the Food and Drug Administration

·         For non-federally-sponsored research that is not subject to the FDA regulations regarding human subjects, the sponsor only (as approved by OHRP under Stanford University’s FWA)  

·         For VA and PAIRE research,

                        a.    The regional VA Office of Research Oversight through the Associate Chief of Staff for Research and Development

                        b.    OHRP

                        c.    The sponsor (for non-federally-sponsored research that is not subject to the FDA regulations regarding human subjects)

·         Relevant officials of SHC, LPCH, and VAPAHCS including

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

                        b.    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 written report will be sent as soon as possible, but 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:

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

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

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

·         A detailed description of the Reportable Decision

·         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.

 

 

3.12  Assurance of Compliance

STANFORD maintains and supports an assurance of compliance that identifies how it protects research participants, when applicable.  (AAHRPP Element I.3.K) 

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 7.1.

 

 

3.13  HRPP Quality Improvement Activities

STANFORD implements a plan to measure and improve Human Research Protection Program effectiveness, quality, and compliance with organizational policies and procedures and applicable federal, state, and local laws.  (AAHRPP Element I.3.L)

The Research Compliance Office established the Continuous Quality Improvement (CQI) unit (“CQI Team”) to design, implement and maintain a program to evaluate and monitor the effectiveness of the STANFORD HRPP.   The CQI Team is responsible for evaluating compliance with and assessing the effectiveness of HRPP policies and procedures.  The CQI Team identifies and works with the various components of STANFORD HRPP to design, recommend and implement improvements to promote the protection of human subject research participants.

 

Compliance Monitoring

The CQI Team and other designated RCO staff conduct periodic compliance audits 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.

·         Periodic Compliance Audits: Periodic compliance audits 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 audits include but are not limited to:

-   Examinations of executed informed consent forms and HIPAA authorizations;

-   Reviews of IRB meeting minutes;

-   Detailed examinations of protocol files;

-   In-person observations of the informed consent process.

·         For-cause assessments:  The IRB or the RCO Director may direct the CQI Team or other designees 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 audits;

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

-       Reports of serious or repeated non-compliance;

-       Results of audits or monitoring conducted by other STANFORD components (e.g., VA, Cancer Center DSMC, Internal Audit) reported to the CQI Team or other RCO staff.

 

Reporting of Compliance Monitoring Results

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

 

Internal Audit Activities

Stanford University’s Internal Audit Department periodically reviews each IRB and the various schools and departments within STANFORD that conduct or review human subject research activities.  A random selection of investigators’ human subject research records and consent forms are reviewed during these audits.

 

 

Research Community Feedback Tracking

The CQI Team tracks 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. 

 

 

 

Continuous Quality Improvement (QI)

Based on the results of the aforementioned assessments and feedback received from the communities served by the IRB, the CQI Team works in partnership with RCO staff and other components of the STANFORD HRPP to identify root causes of problems, and develop and implement or recommend action plans to correct issues and provide education 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.

 

 

3.14  Investigators’ Input to HRPP

STANFORD has the following written policies and procedures so that investigators may bring forward concerns or suggestions regarding the Human Research Protection Program, including the IRB review process.  (AAHRPP Element I.3.M) 

The Research Policy Handbook RPH 7.0 contains a description of procedures for contacting relevant individuals to bring concerns and suggestions.

The mechanisms that are available to them include:

·         reporting possible non-compliance as described in Section 3.9

·         reporting possible unanticipated problems as described in Section 3.10

·         making general comments and suggestions and expressing concerns about other matters, issues or processes involving the HRPP, including IRB review and operations to:

                        a.    The Vice Provost and Dean of Research

                        b.    The Research Compliance Director

                        c.    The IRB Chair

                        d.    The HRPP Associate Director

                        e.    Any person in the Research Compliance Office

                         f.    Internal Audit: Institutional Compliance oversight resides under the Director of Internal Audit and Institutional Compliance.  As an additional safeguard to reporter privacy, such information can be submitted anonymously, if desired, through the Helpline Request found on   http://www.stanford.edu/dept/Internal-Audit/compliance/index.html or

   emailed to compliance@stanford.edu)

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

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 investigator is apprised of the outcome of the review.  If the outcome of the review shows a need for ongoing monitoring or education, then the appropriate individuals (e.g., HRPP Compliance Manager, HRPP Education Specialist) 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.