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
and Procedures Available to Protocol Directors (PDs) 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)
STANFORD makes available its HRPP as the most
comprehensive set of policies and procedures relating to human research at
STANFORD. The Research Compliance Office
(RCO) has the primary responsibility for ensuring that the HRPP or portions of
it and related materials are available to the entire STANFORD research
community, including:
·
Investigators
·
Research
staff
·
IRB
staff
·
IRB
members
·
Employees
·
Students.
The RCO maintains a website (http://humansubjects.stanford.edu)
which:
·
Contains
the HRPP
·
Provides
links to pertinent governmental regulations and guidelines
·
Through
its educational resources section provides specific information for
investigators regarding human research protections, preparation of IRB
application materials and the IRB review process
·
Through
its protocol submission section assists Protocol Directors (PDs) with identifying
which protocols are human subject research (see guidance Determining
if Activities Meet Organizational Definition of Human Subject Research),
and which protocols are exempt from research review
·
Contains
postings of the IRB newsletters that describe new developments, policies and
procedural changes.
The RCO makes
its IRB staff readily available to assist and answer questions of investigators
and research staff on human research matters, particularly IRB applications and
review questions.
The RCO is
responsible for identifying new information such as new or modified laws, new
organizational policies, or emerging ethical and scientific issues. In particular, its Education and Training Specialists
and legal counsel identify new information and draft announcements and
explanations for its newsletters and other distribution sources.
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
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 (Dean of Research) as specified in the President’s Delegation of Authority letter. This delegation includes but is not limited to:
· Direct oversight of the RCO, the Administrative Panels on Human Subjects in Medical Research, and the Administrative Panel on Human Subjects in Non-medical Research; including the appointment of the Chairs and members of these panels
·
Creating, establishing and maintaining the
policies and procedures for the HRPP and related research policies and
procedures on behalf of
· Overseeing the protection of human research participants, regulatory compliance, and the implementation of the HRPP
· Overseeing research investigators and staff, and research management
· Ensuring the independence of the IRB, including the authority to act without undue influence.
The Dean of Research, his Office, and the RCO, which includes the IRBs and reports to him, 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 Dean of Research and his Office relate to establishing policy for research and oversight of research compliance, particularly as it relates to human participant research.
Delegation to the IRB
The Dean of Research delegates independence and authority to the IRBs through this Chapter 3.2 and his 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
· Observe, or have a third party observe the consent process, or the conduct of research, or both.
Prohibition against Others Usurping IRB Approval Authority or Using
Undue Influence
The 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.
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 Associate Dean of Research). Such
reports will be reviewed in the same manner as possible non-compliance by an
IRB Chair or member by the Associate Dean of Research as described in Chapter 3.9.
3.3 Regulatory Definition of
Human Research rev 10/11/07
STANFORD has written policies and procedures in the
HRPP for determining when studies meet the regulatory definitions of human
research. (AAHRPP Element I.3.C)
See: Chapter 1.3;
Does
My Project Need IRB Review?;
Does
My Project Involve “Human Subjects”?;
Determination
of Human Subject Research – Application to the IRB;
Determination
of Human Subject Research – Definitions and Regulations;
Engagement of Institutions in Research (OHRP
January 26, 1999 guidance).
All protocols involving
"research" and "human subjects", and in which STANFORD (or
its employees or agents) is “engaged” in research, must be reviewed and
approved by the IRB before recruitment and data collection may start.
If the project will involve
a drug or device, and a human participant – either as a recipient of the test
article or as a control – it should be assumed that the activity constitutes
human subject research, and a New Protocol Application must be submitted for
IRB review.
If the proposed activity clearly does not involve
"research" and "human subjects", it does not require
submission to the IRB. See Does My Project Need IRB Review? If there is any doubt as to whether an activity is human subject research, the
investigator should contact
the Research Compliance Office, or submit a Determination
of Human Subject Research – Application to the IRB.
In some circumstances, an
investigator might have need for a written determination from the IRB as to
whether an activity constitutes "human subject research". In such
cases, a Determination
of Human Subject Research – Application to the IRB must be
submitted.
Determination by the IRB of
Human Subject Research is made by considering whether:
To assist the IRB in making
this determination, a checklist
is available to staff.
The IRB notifies investigators
about whether the proposed activity does,
or does
not meet the definitions of Human Subject Research.
Activities Not Considered to be Human Subject
Research
The Research Policy
Handbook, RPH 7.3,
discusses which activities are generally not considered to constitute research;
additional information is given in Is
My Project “Research”? and Examples
of “Not Research”.
Similarly, Does
My Project Involve “Human Subjects”? and Examples
of “Not Human Subjects” provide information about whether activities
involve a living individual, and which activities - including cadaveric
studies, and specific situations
concerning data and specimens - are generally not considered to be human
subject research.
VA research
If the project is being conducted – all, or in part – at the VA, or if it involves VA resources or personnel, the definitions of “research” and “human subject” as defined in the VHA Handbook 1200.5 (based on 38 CFR 16) are considered.
3.4 Exempt
Research Determinations
STANFORD has
written policies and procedures in Chapter 7.6-8
of the HRPP 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) Guidance is provided by the yellow laminated sheet Exempt/Expedited
Review Categories and the Exemption
Eligibility Checklist.
3.5 Policies and Procedures for Exempt Research
STANFORD has
written policies and procedures in Chapter 1.4
and Chapter
7.6-8 of the HRPP for addressing protection of participants in research
exempt from applicable federal regulations. (AAHRPP Element I.3.E) The ethical principles listed in Chapter 1.4 apply to all
research covered by the HRPP, including protocols “exempt” under federal
regulations pertaining to human subject research. The IRB will ascertain that exempt protocols
provide adequate opportunity to consent and appropriate protection of privacy
and confidentiality interests.
3.6 Federal
versus State Requirements
Where applicable in each chapter of the HRPP, 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) Additionally, the IRB requires that the PD comply with the local, federal and state laws that are applicable to his or her protocol.
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. From time-to-time the IRB in consultation with its legal counsel develops handouts and educational materials for investigators and IRB members and staff relating to new state laws (e.g., see explanation on California law relating to surrogate decision-makers in the research setting and Q&A’s on California requirement that all stem cell research be reviewed by an IRB).
Other State Laws
STANFORD researchers
conduct research in states other than
When necessary other attorneys in the Office of the General
Counsel or outside attorneys retained by it can provide direction and
interpretation of
3.7
Investigators’ Conflicts of Interest
Because
of the possibility that financial and other personal considerations might
affect research objectivity and harm human 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)
·
academic
staff member: Stanford University Research Policy Handbook,
RPH 4.4 “Policy on
Conflict of Interest and Commitment For Academic Staff” (See also Chapter 9.1).
·
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 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.
In addition, when applying
to the IRBs for review of a new protocol, the PD must answer questions designed
to determine whether or not the PD or the PD’s immediate family has a financial
interest or relationship. If the PD
answers “yes” to any of the questions in the “Potential Conflict of Interest”
section of the New Protocol Application, the PD is instructed to draft a statement in the
consent form to disclose the relationship to research participants, and to file
a conflict of interest disclosure.
Similar questions are found on the applications for Continuing
Review and Modification
of protocols.
Financial Interest Thresholds
STANFORD regards financial
interests that are above certain thresholds as automatically constituting
significant conflicts of interest, thereby requiring closer scrutiny. The thresholds are as follows:
When these thresholds are
reached, STANFORD requires investigators to provide compelling reasons to justify
their involvement in the research despite the conflict. A simple statement of an investigator’s
importance or expertise will not suffice.
The investigator must provide a sufficient reason detailing his/her
unique contribution to the study and a reasonable plan that will protect the
human subjects, the data, and the University.
See “How and When Disclosures Are Made” above for information on ad hoc disclosure.
Review of Financial Interests Exceeding Thresholds
Disclosures of financial interests
and relationships exceeding the thresholds are reviewed by the Conflict of
Interest Review Program (COIRP). The COIRP
reviews each financial interest above the threshold to determine if it is
significant enough to:
In assessing whether or not
the 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 appropriate School Dean’s office considers the following
questions:
For SOM research, the COIRP
refers all financial interests that have the potential to harm subjects or
compromise the objectivity of the research, or are likely to be perceived as
having that potential, to the Conflict of Interest Committee (COIC). The COIC is composed of senior faculty and
management.
Management of Conflicts of Interest
STANFORD requires that all
financial interests or relationships that have the potential to harm subjects
or compromise the objectivity of the research, or are likely to be perceived as
having that potential, be eliminated, mitigated, or managed. It is the responsibility of the appropriate
School Dean’s office to determine what strategy or strategies are appropriate
to eliminate, mitigate, or manage the conflict.
Possible strategies include the following:
While conflict disclosure in
the informed consent process may be an important part of the management
strategy, disclosure will not necessarily be the only strategy used.
Role of the IRB
When a financial interest or
relationship relevant to the research has been identified, the IRB and the appropriate
School Dean’s office will conduct their relevant reviews in parallel, but the
IRB will not issue an approval until conflict of interest resolution is
reached. The School Dean’s office is
responsible for communicating the outcome of the conflict of interest
resolution process to the IRB.
The convened IRB will review
the final management plan for any financial interest or relationship that has
been determined to have the potential to harm subjects or compromise the
objectivity of the research, or is likely to be perceived as having that
potential. The convened IRB must review
the final management plan, and may either accept the plan, reject the plan, or
require additional protections. The IRB
shall be provided with sufficient information to determine whether any proposed
plan sufficiently manages any financial interest so as to safeguard
satisfactorily the rights, welfare, and safety of the research participants.
When a potential conflict of
interest arises and is immediately 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 resolution is
reached and communicated by the appropriate School Dean’s office and reviewed
and deemed acceptable by the IRB. The
IRB will ask the researcher to contact his or her School Dean’s office for
review and management of the conflict.
However,
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 researcher to contact his or her
School Dean’s office for review and management of the conflict. The PD must stop any enrollment into the
study, until conflict of interest resolution is reached and communicated by the
School Dean’s office and reviewed and deemed acceptable by the IRB. Such action will be considered a suspension
of IRB approval, will be handled according to the organization’s 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
In conjunction with the
IRBs, each School maintains records on all disclosures of financial interests
and all decisions to manage, reduce, or eliminate conflicts of interest 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”.
Currently, some possible institutional conflicts of
interest of STANFORD are identified through a Conflict of Interest Section
on the New
Protocol Application. It asks if the
investigator has knowledge that
rev 05/14/07
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)
Definitions
Non-compliance: An action or activity in human research at variation with the approved IRB protocol, other requirements and determinations of the IRB, the HRPP 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 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 entered onto an experimental protocol anyway, 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 (e.g., a pattern that indicates lack of attention to or knowledge or understanding about regulations or ethics) that might jeopardize the rights and welfare of participants or the integrity of the study data.
Allegation of non-compliance: A report of non-compliance that represents an unproven assertion.
Finding of non-compliance: A report of non-compliance that is true, or an allegation of non-compliance that is determined to be true based on a preponderance of the evidence.
Any situation of perceived or actual serious or continuing non-compliance jeopardizes the STANFORD commitment to human 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…Violations should be reported in confidence through normal organizational channels. 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.
Obligation to Report
Allegations, observations or evidence of possible non-compliance in human research must be reported to the Research Compliance Office by:
· Protocol Director (PD) or any research team member
· Employee of STANFORD
· IRB member
· Study monitor, auditor or sponsor either directly or through the PD.
Research participants and individuals not directly involved with conducting or overseeing the research are also encouraged to report.
Receipt of Reports of Non-Compliance
The RCO staff has primary responsibility for receiving reports of non-compliance, e.g., allegations (anonymous or otherwise) or evidence, particularly of possible serious or continuing non-compliance.
Reports of non-compliance may also be directed to the following individuals, who in turn forward them to the RCO staff:
· The PD
· The 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.
Reports of Non-Compliance – Allegations or Findings
Reports will be either allegations, or