Human Research Protection Program: Policy
Review of Change of Protocols by Full IRB
Adopted
By: All Campus IRB
Adoption Date: November 10, 2005
Revised: April 12, 2007
Revised: January 22, 2009
Purpose: This document describes the
policies and procedures of the UW-Madison IRBs in conducting reviews by the
full IRB of changes in protocols.
Policy
I. Any change in an approved human subjects research protocol must be
reviewed and approved by a UW-Madison IRB before the change can be implemented
by the investigator, except when a change is necessary to eliminate apparent
immediate hazards to a participant. See, Changes to Eliminate Immediate
Hazards Guidance. The investigator is responsible for ensuring that any
changes to the protocol are submitted to the IRB for review before the changes
are incorporated into the research.
II. Changes in approved research initiated without prior IRB review and
approval to eliminate apparent immediate hazards to a participant must be:
A. reported to the IRB within ten (10) days of implementation, at which
time an amendment to the protocol and, if needed, to the informed consent
document must be submitted to the IRB and
B. reviewed by the IRB to determine that:
1. the action taken by the investigator was necessary to eliminate an
apparent immediate hazard to the participant(s), and
2. the change of protocol is consistent with ensuring the participants’
continued welfare.
III. Any change of protocol for studies that enroll Veterans
Administration (VA) patients as subjects requires approval by the William S.
Middleton Memorial Veterans Hospital VA Research and Development Committee in
addition to approval by a UW-Madison IRB.
IV. Applications for change of protocol are reviewed by the full IRB,
except for those changes that qualify for expedited review. See, Expedited
Review Policy.
V. Review Criteria
A. UW-Madison IRBs must review proposed changes to previously approved
research to determine whether the modified research continues to fulfill the
criteria for approval of human subjects research. The criteria for approval of
a change of protocol are the same as for initial review [See, Policy on
Initial Review by Full IRB]:
1. Risks to subjects are minimized.
a. Risks to participants are minimized by using
procedures which are consistent with sound research design and which do not
unnecessarily expose participants to risk, and
b. Whenever appropriate, risks to participants
are minimized by using procedures already being performed on the participants
for diagnostic or treatment purposes.
2. Risks to subjects are reasonable in relation to anticipated benefits,
if any, to subjects, and the importance of the knowledge that may reasonably be
expected to result from the research.
3. Selection of subjects is equitable.
4. Informed consent will be sought from each prospective subject or the
subject's legally authorized representative and appropriately documented as
required by 45 CFR 46.116 and 46.117
5. When appropriate, the research plan makes adequate provision for monitoring
the data collected to ensure the safety of subjects.
6. When appropriate, there are adequate provisions to protect the privacy
of subjects and to maintain the confidentiality of data.
7. When some or all of the subjects are likely to be vulnerable to
coercion or undue influence, such as children, prisoners, pregnant women,
mentally disabled persons, or economically or educationally disadvantaged
persons, additional safeguards have been included in the study to protect the
rights and welfare of these subjects. (45 CFR 46.111)
Procedure
I. Submission Requirements
A. To apply for review of a change in a protocol by the full IRB, the
investigator must submit:
1. For HS IRB and MR IRB protocols: An Application for Change of Protocol
(for full IRB review).
If an Investigational Drug Brochure is being
revised, investigators must use the Revised Investigator Drug Brochure form
instead of or in addition to the Application for Change of Protocol form.
NOTE: For submissions to the HS IRB
and MR IRB, there are separate forms for submitting an Application for Change
of Protocol (for full IRB review) and an Expedited Change of Protocol (minor,
administrative changes). For expedited review of minor changes in protocols,
the investigator should submit an Expedited Change of Protocol form. See, Expedited
Review Policy.
2. For ED IRB and SBS IRB protocols: A Change of Protocol form.
B. Applications for change of protocol are directed to the IRB that
conducted the initial review of the research. See, Review
by Expert Policy.
II. Screening of Applications for Change of Protocol
A. The IRB Office screens each application for change of protocol to
determine whether the materials provided by the investigator are complete and
contacts the investigator to obtain missing information. Incomplete
submissions may be returned to the investigator.
B. Once all requested information is received, the IRB Director determines
whether the application will be reviewed by the full IRB or is eligible for
expedited review. If the application is eligible for expedited review, the IRB
Office will follow UW-Madison procedures applicable to expedited change of
protocol. See, Expedited Review Policy.
III. Review of Applications for Change of Protocol
A. ED IRB and SBS IRB
1. If the IRB Director determines that an application for change of
protocol will be reviewed by the full IRB, the review proceeds as follows:
a. Both the ED IRB and SBS IRB use a primary
reviewer system for all change of protocols by the full IRB. Each IRB assigns
at least two primary reviewers, who are members of the reviewing IRB, to each
application for change of protocol. See, Review by Expert Policy. The
assignments are made by the ED/SBS IRB Office (IRB Office) and reflect the
expertise of the primary reviewers. The IRB Office also checks for conflicts
of interest between primary reviewers and research protocols. See, IRB
Conflict of Interest Policy.
b. The IRB Office forwards all of the materials
submitted by the investigator to the members of the reviewing IRB, including any
alternate substituting for an IRB member, except for the complete protocol
file, which is made available to all IRB members through the electronic
protocol submission system, and any relevant grant application, which is
reviewed by one member of the reviewing IRB. The grant application and any
additional information provided to any primary reviewer is available from the
IRB Office to any IRB member who wishes to review it before or during the
convened meeting.
c. The assigned primary reviewers conduct the
in-depth review of the application for change of protocol and all provided
materials and lead the discussion of the application at the full IRB meeting.
All other members of the reviewing IRB, including any alternate substituting
for an IRB member, are expected to review the provided materials in enough
depth to be familiar with them and be prepared to discuss them at the convened
meeting.
2. After the IRB discusses the change of protocol application, the IRB
makes the determination whether to approve the application, require
modifications in the application, defer the application until additional
information is obtained, or disapprove the application. [See, Section IV,
below.]
3. If, after discussion by the IRB, questions remain unanswered, the IRB
may request additional written information from the investigator and may invite
the investigator to meet with the IRB during the next review to answer
questions.
4. In reviewing an application for change of protocol, the IRB may also
consult with individuals representing areas of expertise not represented on the
IRB.
B. HS IRB and MR IRB.
1. The HS IRB and MR IRB use both a staff reviewer and primary reviewer
system.
a. Change of protocols that need review by the
full IRB are first assigned to staff reviewers by the IRB Director.
b. The IRB Office forwards to the assigned staff
reviewer all of the materials submitted by the investigator and the complete
protocol file, which contains all minutes, correspondence between the IRB and
researcher, consent documents (if applicable), and all prior submissions for
IRB review (e.g., prior changes, progress reports, the Initial Review
Application and supporting materials)
c. Staff reviewers prepare a summary and
detailed analysis of each application for change of protocol. As part of this
review, the staff reviewers evaluate the appropriateness of any consent forms.
The staff reviewer’s report generally contains the following:
•
Version and date of protocol or amendment
•
Brief statement regarding the general reason for the change in protocol
•
Categories of specific proposed revisions and rationale for each
•
Explanation of how changes differ from what was previously approved
•
Comment on how changes affect risk/benefit ratio
•
Recommendations regarding potential ethical, safety or medical issues
the change may raise and whether additional monitoring or expert review may be
required
•
Description of any potential regulatory findings the change would
require
•
Contextualizing the change in light of IRB past decisions, when
appropriate
•
Description of any proposed changes to the consent or HIPAA documents or
recommendations for changes to these documents if appropriate
d. The HS IRB and MR IRB use a preliminary
review system to evaluate applications for change of protocol. See, Review by
Expert Policy. The IRB Director assigns each application for change of
protocol to primary reviewers, who are IRB members and who review the
application in a preliminary review session (PRS) held prior to a scheduled
meeting of the full IRB. The IRB Director screens for conflicts of interest
between primary reviewers and research protocols when making these
assignments. See, IRB Conflict of Interest Policy.
e. The assigned primary reviewers are provided
the following information:
•
The complete protocol file
•
Copy of the change of protocol and any other relevant supporting
materials the investigator has submitted for IRB review
•
A staff reviewer report that provides a detailed summary and expert
analysis of the change of protocol assigned to the primary reviewers
f. In the preliminary review session (PRS), the
primary reviewers evaluate each staff reviewer report in conjunction with the
investigator’s change of protocol application. The primary reviewers prepare
written assessments of each application and make recommendations to the full
IRB regarding whether the application should be (a) approved without
modification/clarification, (b) approved after modifications/clarifications
have been obtained, or (c) deferred due to the inadequacy of the submission.
As part of their assessment, primary reviewers may request additional review by
someone with a specific expertise (e.g., review by an individual with a
different medical expertise).
2. Applications for changes to the protocol and supporting materials,
including consent documents and revised study protocols, as well as a Change of
Protocol - Staff and Primary Reviewer Worksheet (Doc 1059) will be posted on a
secure website for IRB members to access prior to the IRB meeting. The Change of
Protocol - Staff and Primary Reviewer Worksheet (Doc 1059) includes a summary
of the changes as well as the criteria for IRB approval. In addition this
worksheet documents any concerns, questions, and recommendations to the full
committee raised by the primary reviewers and IRB staff. IRB members will be
reminded via email that these materials are posted so that they can review them
in sufficient depth to make an informed decision at the convened IRB meeting
regarding whether the study continues to meet the criteria for IRB approval
pursuant to 45 CFR 46.111 and, if applicable, 21 CFR 56.111, and 38 CFR 16.111
and whether any new information has arisen that should be conveyed to subjects.
3. The assigned primary reviewers conduct the in-depth review of the
application for change of protocol and all provided materials, and lead the
discussion of the application at the full IRB meeting. All other IRB members,
including any alternate substituting for an IRB member, are expected to review
the provided materials in enough depth to be familiar with them and be prepared
to consider them at the convened meeting.
4. The full IRB makes the determination whether to approve the
application, require modifications in the application, defer the application
until additional information is obtained, or disapprove the application. [See,
Section IV, below.]
5. If, after discussion, questions remain unanswered, the IRB may request
additional written information from the investigator and may invite the
investigator to meet with the IRB during the next review to answer questions.
6. In reviewing an application for change of protocol, the IRB may also
consult with individuals representing areas of expertise not represented on the
IRB.
IV. IRB Determinations on Applications for Change of Protocol
A. On application for change of protocol, the full IRB may:
1. approve the application
2. require modifications in the application
3. defer the application until additional information is obtained, or
4. disapprove the application.
In each case, the IRB Office notifies the investigator of the action
taken and the reasons for that action. Where necessary, the IRB Office also
reports the IRB action to appropriate University officials or, where the
protocol is submitted by an investigator from another institution for whom the
IRB acts as the IRB of record (e.g., the Veterans Administration), to
appropriate officials within that institution.
B. To approve a protocol pending resolution of requested modifications:
1. IRB members may agree during an appropriately convened meeting of the
full IRB to approve a protocol pending resolution of requested modifications
(contingent approval) if the requested modifications are non-substantive
changes that are not relevant to the determinations required by the IRB under
the Common Rule or its subparts (45 C.F.R. part 46) or, as applicable, FDA
regulations (21 C.F.R. part 56).
Contingent approval also is permitted in situations
where the IRB stipulates specific revisions requiring simple concurrence from
the investigator.
If substantive clarifications or modifications
regarding the protocol or informed consent documents are required as a
condition of approval, approval must be deferred pending subsequent review by
the convened IRB of responsive material (See, Section IV.C, below)
2. If a protocol is approved pending resolution of requested
modifications, the IRB office will notify the investigator of those
modifications and instruct the investigator that he or she must respond to
these requests according to IRB directions.
3. For the protocol to be approved, the investigator must comply with the
request for modifications according to the IRB’s directions.
4. An IRB member(s) reviews the investigator’s response and either
a. approves it, or
b. if the investigator’s response is not
consistent with the IRB’s directions, sends the response back to the full IRB.
If a staff reviewer process is used to review an
IRB’s request for modifications, the staff reviewer works with the investigator
to obtain the modifications requested by the IRB. The staff reviewer then
forwards the investigator’s response to an IRB member(s) for review along with
a staff report and recommendation as to whether the investigator’s response has
satisfied the IRB’s request for modifications. The IRB member(s) reviews both
the investigator’s response and the staff report and recommendation before
deciding to approve the protocol or to send it back to the full IRB as per
Section IV.B.4.
5. The full IRB will be provided, on a routine basis, a list of research
protocols approved by the full IRB pending resolution of requested modifications
that were subsequently granted final approval by an IRB director or IRB
member(s) designated by the IRB chair to conduct expedited reviews. All IRB
members shall be provided access to the IRB files for any research study in
which they may have a concern.
6. Notice to investigators of requested modifications.
a. SBS IRB and ED IRB: At intervals of 60 and
120 days from the date the modification request was first sent to the
investigator, the electronic protocol management system automatically sends a
reminder to the investigator of the need to respond to modification requests
and obtain IRB approval of the research before research can begin. If a
response is not received from the investigator within 180 days of the first
request for modifications, the electronic protocol management system
automatically sends a notice to the investigator that the protocol has been
closed and will need to be re-submitted for reconsideration before the research
to proceed.
b. HS IRB or MR IRB: The HS IRB and MR IRB do
not send out automatic reminders. However, if they fail to receive a response
from the principal investigator to any modification requests, then the protocol
is terminated.
C. To defer a protocol until additional information is obtained:
1. The IRB must defer approval of a protocol if, to approve the protocol,
the IRB requires substantive clarifications or modifications of the protocol or
informed consent documents that are relevant to the determinations required by
the IRB under the Common Rule or its subparts (45 C.F.R. part 46) or, as
applicable, FDA regulations (21 C.F.R. part 56).
2. The IRB will notify the investigator of the substantive clarifications
or modifications needed to allow approval of the research.
3. The investigator may supply the substantive clarifications or
modifications or provide a rationale for not doing so.
·
For SBS IRB and ED IRB protocols, if the full IRB has determined
in its deferral that the protocol is eligible for expedited review, the review
of additional information supplied by the investigator may be done by an IRB
subcommittee.
·
If a staff reviewer process is used to review an investigator’s
response to an IRB’s request for substantive clarifications or modifications,
the staff reviewer works with the investigator to obtain the substantive
clarifications or modifications requested by the IRB. The staff reviewer then
forwards to the IRB the investigator’s response along with a staff report and
recommendation as to whether the investigator’s response has satisfied the
IRB’s request for substantive clarifications or modifications. The IRB reviews
both the investigator’s response and the staff report and recommendation before
deciding whether to approve the protocol.
5. Notice to investigators of the substantive clarifications or
modifications needed to allow approval of the research.
a. SBS IRB and ED IRB: At intervals of 60 and
120 days from the date the modification request was first sent to the
investigator, the electronic protocol management system automatically sends a
reminder to the investigator of the need to respond to modification requests
and obtain IRB approval of the research before research can begin. If a
response is not received from the investigator within 180 days of the first
request for modifications, the electronic protocol management system
automatically sends a notice to the investigator that the protocol has been
closed and will need to be re-submitted for reconsideration before the research
to proceed.
b. HS IRB or MR IRB: The HS IRB and MR IRB do
not send out automatic reminders. However, if they fail to receive a response
from the principal investigator to any modification requests, then the protocol
is terminated.
D. If an IRB decides to disapprove an application for change of protocol,
the IRB gives the investigator an opportunity to respond in person or in
writing.
E. An IRB decision to disapprove or defer an application for change of
protocol may be addressed by the investigator by re-submission of the
application to the original IRB, accompanied by a cover letter detailing
changes made or a justification of why recommended revisions were not made.
The full IRB will approve or disapprove all responses.
F. An application for change of protocol that has been disapproved,
deferred or for which modifications have been requested by an IRB cannot be
resubmitted to a different IRB for review as an alternative to following the
procedures as set forth in this Section.
V. IRB Records on Change of Protocol Applications
A. The full IRB’s discussion and decision on each application for change
of protocol is documented in the minutes for each meeting.
B. Votes for and against approval of each application for change of
protocol and the name of any IRB member abstaining from the vote on each
protocol or leaving the room before the vote due to a conflict of interest
with a protocol are recorded in the meeting minutes. IRB meeting minutes are
available from the IRB Office for review by the Institutional Official at his
or her request.
