Human Research Protection Program (HRPP)
DOMAIN II:
RESEARCH COMPLIANCE OFFICE, INCLUDING IRBs
Chapter 7: Systematic Review
The IRBs have the following written policies and procedures
for conducting initial and continuing review and procedures for handling
modifications to research studies.
(AAHRPP Element II.2.A)
All STANFORD* new human
research (as defined in Chapter 1.3) and modifications to approved
research (except
when the modification is necessary to eliminate apparent immediate hazards to
participants) must be prospectively reviewed by
the IRB. In addition, no previously
approved human subject research may be continued beyond the expiration date without
prospective approval (continuing review).
7.2 IRB Protocol Applications (eProtocol System)
Most
submissions to the IRB are via an online web-based system called “eProtocol". Forms available for online submission include:
·
Protocol applications for:
– New
protocols
– Modifications
– Continuing
Review
·
Reports (of unanticipated problems
and events and information requiring prompt
reporting)
·
Final Reports
Protocol applications include the following sections
that must be completed by the investigators, as applicable: personnel, study location, funding,
resources, collaboration/multi-site, participant population, purpose, procedures,
background, use of radiation producing machines, use of drugs (investigational
and commercial) and devices (non-significant risk and significant risk), recruitment
methods and screening procedures, inclusion and exclusion criteria, inclusion
of vulnerable populations, potential risks and benefits, procedures to protect
privacy and maintain confidentiality of data, conflict of interest, consent and
assent and HIPAA. A “check for
completeness” feature requires that each question applicable to the study is
answered before submission to the IRB is permitted.
Investigators
must select a protocol review type (exempt, expedited or regular) and protocol form
(medical or nonmedical). Application
form questions vary depending on the review type and protocol form
selected.
Protocol Application Form
Medical Protocols: Protocols conducted by personnel within, or
conducted through, the School of Medicine (SOM), the Veterans Affairs Palo Alto
Health Care System (VAPAHCS), the Palo Alto Institute for Research and
Education (PAIRE), or otherwise involving any medical procedure or use of
personally identifiable health information are submitted on the medical Protocol
Application.
Nonmedical
Protocols: Protocols for research not being
conducted by personnel within, or conducted through, the
Protocol Review Types (Exempt, Expedited or Regular)
Exempt: STANFORD requires protocols qualifying for exemption from
applicable federal, state and local regulations to be submitted for IRB review
and confirmation. See Chapter 3.4 for determining if such
exemption can be granted.
Expedited Review: Protocols submitted for
expedited review must meet the requirements set forth in 45 CFR 46.110 at http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.110,
i.e., the research involves no more than minimal risk and falls within the
categories published in the November 9, 1998, Federal Register 63 FR
60364-60367; 63 FR 60353-60356 DHHS-FDA list of research eligible for expedited
IRB review.
Regular Review: All protocols that do not qualify for exempt or
expedited review are subject to regular review at a convened IRB meeting.
Other Research or Special Situations
Protocols Using Biological Agents or Recombinant DNA
Vectors: Investigators are required to submit a Protocol
Application with a copy of the Gene transfer Application Supplemental Questions.
This is a combined application for studies which include human participants and
the use of biological agents or recombinant DNA vectors. It is reviewed by both
the IRB and the Biosafety Panel.
Emergency Use of a Test Article: Chapter 5.8 describes the
requirements for the emergency use of an investigational drug, device, or
biologic under FDA regulations at 21 CFR 56.104(c), and materials which must be
submitted to the IRB.
The submitted material is
assigned to a medical IRB. If the IRB
manager or the assigned reviewer has comments they are sent to the investigator
for response. Responses are reviewed and
additional comments sent if needed. The
reviewer documents his/her findings on the Exemption from IRB
Review: Emergency Use of a Test
Article. At the convened meeting the IRB notes the
emergency use of the test article, which is reflected in the minutes.
7.3
Submission, Preliminary Review and
Assignment to IRBs –
New Protocols, Modifications, Continuing Review,
Reports, Final
Reports
Submission and Preliminary Review -
New Protocols
Nonmedical Protocols: New nonmedical protocols are received directly by the IRB manager for the
Nonmedical IRB. Nonmedical protocols
subject to regular review are assigned to IRB 2 and nonmedical protocols
subject to exempt and expedited review are assigned to IRB 2 and IRB 8. The IRB manager performs the preliminary review for protocol
completeness and confirms the review and protocol type selected by the PD as
appropriate for the study.
Medical Protocols: Upon receipt of a new medical Protocol Application, the IRB intake staff reviews the application for
completeness, including ensuring all required supplemental documents and
information are provided. The IRB
intake staff also performs a preliminary review to confirm the PD’s selection
of the protocol review type (Exempt, Expedited, or Regular) and protocol form type
(medical or nonmedical).
For both medical and nonmedical, protocols submitted for a review type
determined not appropriate are converted to the appropriate review type by RCO
staff. If the change in review type
requires additional information from the PD, the protocol is returned to the
PD. If the conversion does not require
additional information, the protocol is assigned to an IRB. If the nonmedical IRB manager receives a
protocol that should be reviewed by a medical IRB the protocol is assigned to a
medical IRB.
Assignment to IRBs - New Protocols
Once a new medical Protocol
Application is deemed complete, the protocol is assigned to a medical IRB for
review. To avoid any potential
conflicting interest, new medical protocols are not assigned to an IRB where a
member of that IRB is also an investigator on the research project. After taking into consideration any
conflicting interest issues, assignment of protocols to IRBs is based on the
protocol review type, the order (by date) the protocol was submitted to the
IRB, and for protocols subject to regular review the order of the monthly IRB
meetings:
·
Medical protocols subject to expedited and exempt review are
generally assigned to IRBs 6 and 8.
These IRBs do not generally have convened meetings. IRB 6 reviews only medical protocols; IRB 8
reviews both medical and nonmedical protocols.
·
Medical protocols subject to regular review are assigned to
IRBs 1, 3, 4, 5 and 7 with assignment to the next IRB starting after the
preceding IRB has reached its protocol load for that meeting.
·
Nonmedical protocols subject to regular, expedited or exempt
review are assigned to IRB 2.
Special Assignment
Considerations:
·
Protocols involving biological agents or recombinant DNA
vectors (gene transfer) or prisoners are assigned to IRB 1.
·
Protocols reviewed by the Central IRB (CIRB) are assigned to IRB 6 for facilitated review.
·
Generally, protocols that involve both human subject and
stem cell research are assigned to IRB 3.
Assignment to IRBs – Modifications, Continuing Review
(except for exempt research), Reports (of unanticipated problems and events and
information requiring prompt reporting) and Final Reports
All subsequent events
submitted on approved protocols are received directly by the IRB that initially
reviewed and approved the protocol.
7.4 Assignment of protocols to IRB members
Reviewer assignments are made with the objective of
matching reviewer expertise and experience with protocol subject matter. See Chapter 6. “Nonscientific” members assigned to review
protocols are valued for the community perspective they bring to the process of
ensuring the protection of research participants. For approved protocols an attempt is made to
assign any subsequent protocol events to a member who was a primary reviewer
when the study was first approved.
Protocols Subject to
Regular Review – New, Modifications, Continuing
Review and Reports
New Protocols: The medical and nonmedical
IRBs utilize a primary reviewer system for protocols subject to regular
review. New protocols are assigned by
the IRB manager to a minimum of two primary reviewers, with one of the primary
reviewers assigned to present the protocol at the convened meeting. The IRB manager assigns other expert reviewers
to protocols when applicable; Radiation Safety when a project involves
radiation producing machines, Biosafety when a project involves a biological
agent or recombinant DNA vectors and Conflict of Interest Committee or
Institutional Conflict of Interest Reviewer when a potential conflict of
interest has been disclosed in the Protocol Application.
Modifications (Major): A
major modification is one in which there is an increase in the level of risks
to participants or a greater than minor modification in any of the following:
1.
The consent form
2.
Research design or methodology
3.
The subject population enrolled in the research
4.
The qualifications of the research team
5.
The facilities available to support safe conduct
of the research
6.
Any other factor which would warrant review of
the proposed changes by the convened IRB.
Major modifications are subject to regular review and are assigned by the IRB
manager to one reviewer who reviews and
presents the protocol at the convened meeting.
Continuing Review: For all protocols initially subject to regular review, the continuing
review application undergoes regular review, unless it meets the criteria for
expedited review (see below). Those
which will undergo regular review are assigned to one reviewer who reviews and presents the protocol at
the convened meeting.
Reports (of
unanticipated problems and events and information requiring prompt reporting): See
Chapter 3.10.
Protocols Subject to
Expedited and Exempt Review - New,
Modifications, Continuing Review and Final Reports
The IRB has and follows written policies and
procedures to conduct reviews by the expedited procedure. (AAHRPP Element
II.2.B)
New
Protocols: Protocols
subject to expedited and exempt review follow a single reviewer process and are
assigned by the IRB manager to either the Chair of the IRB or to a single
reviewer designated by the Chair as qualified to conduct expedited review. See Chapter 6 for reviewer
qualifications.
Modifications (Minor): A
minor modification eligible for expedited review is one in which all of the
following are true in the judgment of the IRB reviewer:
1.
Any increment in risk is less than minimal risk.
2.
All additional activities or procedures would have been eligible
for expedited review had they been part of the initial protocol review.
3.
Either the research is minimal risk or the
proposed changes do not alter the study design.
If the modification changes
the review type appropriate for the study, the IRB staff will convert the
protocol to the appropriate review type.
The IRB reviewer makes the final
determination of whether changes to the protocol are “major” or “minor.”
Continuing
Review (Protocols subject to regular review initially): For a protocol initially subject to regular
review, the continuing review application undergoes expedited review if:
Protocols
subject to expedited continuing review are assigned to one reviewer and are not presented at a convened
meeting.
Continuing
Review (Protocols subject to expedited review initially): For a protocol initially subject to expedited
review, the continuing review application undergoes expedited review if:
·
It does not include any modifications, or
·
If
modifications are included, the proposed modifications would have been eligible
for expedited review had they been part of the initial protocol.
Protocols
subject to expedited continuing review are assigned to one reviewer and are not presented at a convened
meeting.
Protocols Qualifying for CIRB Review: The CIRB (
STANFORD investigators who wish to enroll subjects in
a CIRB-approved protocol submit the Cooperative Oncology Group application
packet for facilitated review to the Stanford University IRB. CIRB
protocols are assigned to a single designated CIRB reviewer who reviews the
protocol with an emphasis on the local context issues and determination of
adequacy of CIRB review. CIRB protocols are not presented at the convened
meeting.
The Stanford University IRB notifies the CIRB
Administrative Office of its “acceptance” of CIRB as the IRB of Record (if
appropriate). The CIRB is responsible
for continuing review, as well as review of subsequent modifications and
serious adverse events (SAEs) as notified by the Cooperative Oncology Group. The
Stanford University IRB is responsible for review of local UPs and oversight of
the local conduct of the study.
Final
Reports: Final Reports are subject
to expedited review and are assigned by the IRB Associate to one reviewer and
are not presented at a convened meeting.
7.5
Protocol Review Material and Information
The IRB receives and reviews the relevant information
to evaluate research studies during initial review for Regular and Expedited
Review protocols. (AAHRPP Element
II.2.C)
Upon protocol assignment, the reviewers and IRB staff have full access
to all protocol information and materials submitted. Review materials always
include the Protocol Application.
Depending on the protocol event under review, the Protocol Application
will be supplemented with a Modification, Continuing Review, Report or Final
Report setting forth the dispositive information supporting the event.
In addition, reviewers have access to all documents
submitted in support of the Protocol Application and may include as applicable:
If additional information is needed to complete the
review of a protocol, it will be requested during the pre-review process.
7.6 Protocol Review - Pre-Review Parallel Process
General Process for
All Protocol Events
The medical and nonmedical IRBs utilize a parallel process of pre-review,
which involves an interactive review process between reviewer(s), IRB staff and
investigators. For protocols assigned to
a convened meeting, this system allows all presented protocols to be fully
reviewed by the reviewer(s), so that recommended changes to the protocols have
been made and questions answered when the protocol is presented and considered
by the convened members for approval.
Comment and
Response Cycle(s)
During the parallel review of a protocol, the IRB staff
and reviewer(s) enter any comments or questions or recommended changes to the
protocol or associated documents (e.g. consent forms, advertisements) stemming
from their review into the eProtocol Comments/Responses page. After reviewing and editing all comments
received for consistency and duplication, the IRB staff sends the comments to
the investigators. Investigators are
notified via an auto-generated email that comments have been sent on the
protocol. All comments are sent without
referencing the author of the comment, thus preserving their anonymity. Comments
are sent out with a request for response within three business days.
Upon return receipt of the
investigators’ responses to the comments and recommended changes to the
protocol and associate documents, the IRB staff review the responses and
changes for completion then forward responses to the reviewers. Comments and changes are reviewed by the
reviewer. If additional questions remain
or changes need to be made, another round of comments is generated and sent to
the investigators for responses. This process is repeated as often as necessary, until all reviewer
questions have been answered and requested changes to the protocol and
documents have been made.
Protocols may be moved for review to a subsequent meeting
pending receipt of additional substantive information or if the comments and
response cycles are not completed prior to the convened meeting. The IRB manager notifies the PD that the
protocol was moved and why it was moved.
Approval Criteria
All
proposed research must meet STANFORD HRPP ethical standards governing the
conduct of research (e.g., acceptable risk-benefit relationship, equitable
selection, informed consent, protections of privacy, maintenance of
confidentiality, and protections for vulnerable populations). The reviewers consider the approval criteria
set forth in 45 CFR 46 and 21 CFR 50 in reviewing and approving a
protocol. The IRB confirms that proposed
Protocol Application, informed consent documents and recruitment documents are
accurate and complete.
The reviewers consider the
regulations in reviewing and approving a protocol. They are aided in their consideration by
regulatory guidance provided in the form of:
-
Criteria for IRB Approval of Research
-
General Requirements for Informed Consent
Special Considerations
Protocol
Subject to Exempt Review
See Chapter 3.5.
Continuing Review
The IRB receives and considers relevant information to conduct
continuing reviews of research studies and, when appropriate, requests changes
for Regular and Expedited Review protocols.
(AAHRPP Element II.2.D)
Submission of a protocol for continuing review is required on all
non-exempt approved protocols where research activities are ongoing, including
but not limited to continuing recruitment and enrollment of participants;
research tests, procedures, and other interactions and interventions; review of
identifiable information; data analysis; and follow-up of previously enrolled
participants.
The continuing review of
protocols that also include proposed modifications to a previously approved
project, including supporting documents (e.g. consent forms, advertisements,
sponsor protocol) or the addition of new documents must be accompanied by the
new documents or the proposed revised versions of the previously approved or
submitted documents.
Modifications
The
IRB receives and considers relevant information to evaluate proposed
modifications (amendments) to research
studies. (AAHRPP Element II.2.E)
No modifications may be initiated without prior
approval of the IRB, except where necessary to eliminate apparent immediate
hazards to participants. Investigators are required
to complete a Modification application setting forth a summary of the proposed
modification and indicate the change in the risks to participants associated
with the modification (e.g. increase, decrease, no change). Modifications involving changes to previously
approved or submitted documents (e.g. consent forms, advertisements, sponsor
protocol) or the addition of new documents must be accompanied by the new
documents and/or the proposed revised versions of the previously approved or
submitted documents.
In the rare situation where a modification is made
without prior IRB approval because it is necessary to eliminate apparent
immediate hazards to subjects, the investigator must report this change to the
IRB, (see guidance Events and
Information that Require Prompt Reporting to the IRB). The IRB will determine whether the change was
consistent with ensuring the participants’ continued welfare. See Chapter 3.10.
If significant new findings or information are
submitted as part of a modification or continuing review, the IRB may require
the reporting of this information to participants if the information could
reasonably affect participants’ willingness to continue participation.
Final Reports
Upon completion of a research project investigators
may be required to submit a Final Report notifying the IRB of the completion of
the project. Final Reports are required
on all projects that were subjected to regular review and that enrolled
participants. Final Reports are not
required for research subject to expedited or exempt review and research
projects subject to regular review that never started or enrolled participants
at STANFORD.
Protocols Using Biological Agents or Recombinant DNA Vectors
The review processes described above for protocols
subject to regular review are used for protocols using biological agents or
recombinant DNA vectors, except for the following:
1. Protocols using recombinant
DNA vectors must first be submitted to the DHHS National Institutes of Health
(NIH) Recombinant DNA Advisory Committee (RAC).
The RAC determines whether the protocol requires an in-depth review and
public RAC discussion prior to submission to the Institutional Biosafety
Committee (IBC) and Institutional Review Board (IRB).