Transcript Slide 1

Michael Thomas, CIP
Assessment Manager, HRPP
[email protected]
415-476-9837
Megan Sullivan
Assistant Coordinator,
Assessment Team, HRPP
[email protected]
415-502-6880
Melanie Mace, MA, CIP
Education Coordinator, HRPP
[email protected]
415-476-9839
July 16, 2009
Human Research
Protection Program
Training
CHR Training: Modifications and
Renewals
Renewals Overview
Re-review of all projects involving human subjects
is required at least annually (see 45 CFR 46.109(d)
(DHHS) and 21 CFR 56.109(d) (FDA))
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Modification Overview
All changes to a study, even minor ones, must
receive CHR approval before they are
implemented.
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Modification Approval Exception
• The only exception to the requirement for prior CHR
review and approval is when the changes are
“necessary to eliminate apparent immediate
hazards to the subject” (45 CFR 46.103.b.4, 21
CFR 56.108.a).
• In such cases, the actions taken should be reported
to the CHR within 5 working days, and approval
should be sought for permanent changes to prevent
the hazards in the future.
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Types of Modifications
• Administrative Modifications
• Minor Modifications
• Major Modifications
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Administrative Modifications
are Minor Modifications or changes that do not affect
study participants (subjects) in any way.
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Administrative Modifications Examples
• Changing procedures that do not affect participants (e.g., method
of shipping samples)
• Fixing typographical, grammatical, or spelling errors
• Changing personnel (but PI and Co-PI stay the same) if no
participant-contact documents are affected.
• Not changing procedures that affect participants
• Not changing risks
• Not changing information on the CHR application form or protocol
beyond fixing typographical, grammatical, formatting, or spelling
errors
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• Not changing CHR consent form beyond fixing typographical,
grammatical, formatting, or spelling errors
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What to submit
Administrative Modifications
1 set of the following:
• Cover letter (optional)
• CHR Modification Request for Minor and Administrative
Changes
• Revised Versions of All Previously Submitted Documents
that Contain Information Affected by the Modification
• Additional Documents Needed to Explain or Implement the
Modifications
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Administrative Modifications:
Type of Review
• Noted and approved in database
• No Approval Letter sent
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Minor Modifications
to previously approved research are changes in which
• any increase in risk to participants is no more than
minimal
and
• all additional activities or procedures would be
eligible for review using the expedited procedures if
submitted as part of new research
and
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• either the research itself involves minimal risks or the
changes do not significantly alter the study design.
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Minor Modification Examples
for Full Committee Studies
• Changing minor procedures (e.g., adding small-volume blood
draws, ultrasounds, visits with noninvasive procedures)
• Reducing risks
• Adding minor risks (e.g., risks of small blood draws)
• Changing wording in CHR consent form, application, or other
documents
• Revising questionnaires
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unless the new questions are more likely than the old ones to evoke
responses that would reasonably place subjects at risk of criminal or civil
liability or be damaging to the subjects' financial standing, employability,
insurability, reputation, or be stigmatizing if the answers became known
outside of the study context
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Minor Modification Examples (cont.)
for Full Committee Studies
• Adding or changing advertisements or notices
• Changing or deviating from eligibility criteria if the change
creates no serious risks to participants
• Changing the Principal Investigator or Co-Pl
• Changing other Key Personnel (in some circumstances)
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Minor Modification Examples
for Expedited Studies
• Changing major procedures or activities without adding more-thanminimal risks
(e.g., adding participant contact to a record-review study, adding a
new round of participant contact and interviews, changing from
review of past patients’ records to review of current patients’
records)
• Changing study design without adding more-than-minimal risks
• Changing method of contacting participants
• Changing, adding, or deleting approved drugs, devices, or other
standard treatments that are being used in standard ways
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• Adding vulnerable populations (e.g., minors, patients unable to
consent) as long as risks remain minimal and other criteria for
expedited review are still met. Adding prisoners is almost always a
major modification requiring full committee review.
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Minor Modification Examples
for Expedited Studies (cont.)
• Changing wording in CHR consent form, application, or
other documents
• Changing or adding questionnaires or other study
instruments
• Adding or changing advertisements or notices
• Changing or deviating from eligibility criteria if the change
itself creates no more than minimal risks to participants
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• Changing Principal Investigator or Co-PI
• Changing other Key Personnel (in some circumstances)
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What to submit
Minor Modifications
6 identical collated sets of the following:
• Cover letter (optional)
• CHR Modification Request for Minor and Administrative
Changes
• Revised Versions of All Previously Submitted Documents
that Contain Information Affected by the Modification
• Additional Documents Needed to Explain or Implement the
Modifications (including application supplements [e.g.
Surrogates, Minors, Prisoners, Stem Cells], consent and
assent documents, questionnaires, advertisements, HIPAA
documents, letters of support, etc.)
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What to submit
Minor Modifications (cont)
2 copies of the following (ONLY if revised):
• Questionnaire/Instruments/Focus Group Guides
1 copy of the following (ONLY if revised):
• Sponsor’s protocol (or “full” or “multicenter” protocol)
• Investigator’s Brochure
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Additional Instructions for all
Modifications
• To facilitate review, specific changes in the modified
application (or Cover Page and Protocol, if originally
submitted using those forms), consent form(s), and other
documents must be bolded, highlighted, or struck through
as appropriate.
• All revised documents should be based on the version most
recently approved by the CHR.
• All revised documents should include a new version date.
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Additional Tips:
• Make double-sided copies of large
documents (e.g., sponsor’s protocol,
investigator brochures, exceptionally long
surveys or questionnaires).
• Please use a single staple in collating the
copies of the submission.
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• DO NOT edit documents using
“balloons.” You can turn balloons off in
the “Track Changes” tab in “Options”
under the “Tools” pull down menu.
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Minor Modifications:
Type of Review
• Reviewed by a subcommittee (using
“expedited” review procedures)
• Approval letter sent when approved
• Expiration date does not change
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What would you do if…
you currently have an expedited (no subject contact)
application approved for a study that involves
retrospective medical record review of patients visiting
the ER. The PI now wants to modify the study to
include a survey that will be sent to a small subset of
patients. The survey does not include any questions
that might increase risk to the subjects.
• What type of modification request would you
submit?
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• What would you need to include in your
submission?
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What would you do if…
you currently have an approved Full Committee study
that involves a Phase I drug. The PI now wants to add
key personnel who will consent research subjects.
• What type of modification request would you
submit?
• What would you need to include in your
submission?
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What would you do if…
you currently have an approved expedited review
study that involves conducting anonymous surveys
at fast food restaurants. The PI now wants to
include subjects under 18 years of age.
• What type of modification request would you
submit?
• What would you need to include in your
submission?
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Major Modifications
to previously approved research are changes in which
• Any increase in risk to participants is more than
minimal
or
• any additional activity or procedure would not be
eligible for expedited review if submitted as part of
new research
or
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• the research itself involves more than minimal risks
and the changes significantly alter the study design.
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Major Modification Examples
for Full Committee Studies
• Changing, adding, or deleting drugs, devices, or other
treatments being studied (significant alteration of design of
study)
• Adding or deleting major procedures or diagnostic tests
(e.g., adding bronchoscopy or spinal tap; doubling duration
of treatment; deleting adjuvant chemotherapy; deleting
diagnostic MRI or liver function test)
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• Increasing major risks or discomforts (e.g., risks from new
procedures, deleted safety measures, or newly discovered
serious risks; risks that are serious by themselves do not
become minor even if subjects already have a terminal
disease)
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Major Modifications Examples
for Full Committee Studies(cont.)
• Changing study design
(e.g., eliminating 1 arm of a multi-arm study or going from
placebo-controlled to open-label)
• Adding serious privacy risks
(e.g., asking subjects about abusive behavior or illegal
activities)
• Adding vulnerable populations
(e.g., minors, prisoners, patients unable to consent)
• Re-starting study after a hold for safety concerns
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• If sponsor or cooperative group specifically requires full
committee review
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Major Modifications
for Expedited Studies
• Any change that:
• Makes the study have more than minimal risks for
participants
or
• Makes the study no longer fit one of the Expedited
Review Categories
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Major Modifications
for Expedited Studies: Examples
• Adding invasive procedures other than small-volume blood draws
• Adding use of experimental drugs or devices
• Adding serious privacy risks (e.g., asking participants about
abusive behavior or illegal activities)
• Revising questionnaires if the new questions are more likely than
the old ones to evoke responses that would reasonably place
subjects at risk of criminal or civil liability or be damaging to the
subjects' financial standing, employability, insurability, reputation,
or be stigmatizing if the answers became known outside of the
study context
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• Changing retrospective record review of standard care to
randomized test of two standard regimens
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Renewals
Re-review of all projects involving human subjects is
required at least annually (see 45 CFR 46.109(d)
(DHHS) and 21 CFR 56.109(d) (FDA))
• even if no changes are made,
• even if the only study activity is patient followup, and
• even if the only study activity is data analysis.
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• The CHR may require more frequent review.
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Renewals (cont.)
If Approval Expires, ALL ACTIVITIES INVOLVING
SUBJECTS MUST STOP.
• The only exception is that activities needed for
participant safety should continue.
• No new subjects may be enrolled.
• You should notify the CHR before any such
research activities are done
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What to submit
Major Modifications / Renewals:
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REQUIRED - 6 identical collated sets of the following:
• CHR Status Report for Renewals and Major Modifications
(Continuing Review)
• CHR Full Committee or Expedited Review Application (if using
current forms) or CHR Cover Page, Protocol, and HIPAA
supplement (if originally submitted using those forms).
• CHR Application Supplements that have been previously
submitted or are now needed for proposed modifications
• All Consent Documents
• All Recruitment Letters
• All Flyers/Ads (only if revised)
• Adverse Event Summary Log (if applicable)
• Other Reports: serious or unexpected AERs, violations, incidents
(if not previously submitted)
• Audit or Data and Safety Monitoring Board Report (if a report was
issued)
• Other supporting documents if new or revised
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What to submit for Major Modifications
and Renewals (cont):
2 copies of the following (ONLY if revised):
• Questionnaire/Instruments
1 copy of the following (ONLY if revised):
• Sponsor’s (or “full” or “multicenter”) protocol
• Investigator’s Brochure
OPTIONAL: Include with the 6 identical sets:
•
Cover letter
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Major Modifications / Renewal:
Type of Review
• Full Committee Review
– ALL major modifications
– Full Committee studies with ongoing subject contact
• Expedited Review
– Expedited studies
– Full Committee studies that qualify for expedited review
• Approval letter sent when approved
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• New expiration date is given
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Full Committee Studies Renewed
through Expedited Review:
Studies Initially Reviewed as Full Committee can be
reviewed under the Expedited Review procedures if one
of the following apply:
• The research is permanently closed to the enrollment of
new subjects and the research remains active only for longterm follow-up such as medical records review and
telephone follow-up. (If one of the research follow-up
procedures is an intervention such as a blood draw or an xray, the renewal is not eligible for expedited review).
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• No subjects have ever been enrolled and no additional risks
have been identified since the last Full Committee IRB
review.
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Renewals – Data Analysis Only:
Studies Being Renewed for Data Analysis Only undergo
expedited review
• Submit 6 copies of the CHR Status Report for Renewals
And Major Modifications (Continuing Review)
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What would you do if…
you have a currently approved Full
Committee study and the P.I. receives an
updated sponsor's protocol that identifies
additional minimal risks to the study?
• What type of modification request would
you submit?
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• What would you need to include in your
submission?
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What would you do if…
you currently have a Phase II/III study approved. It is a
randomized 3 arm study - Arm A is a higher dose of an
experimental drug; Arm B is a lower dose of the same
experimental drug; and Arm C is placebo. A scheduled interim
analysis concludes that while Arm A has more frequent and
severe side effects, there is no statistical difference in efficacy
over Arm B. The study sponsor has revised the protocol to
eliminate Arm A. All new subjects will be randomized to either
Arm B or placebo, and all subjects originally randomized to
Arm A will be switched to Arm B.
• What type of modification request would you submit?
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• What would you need to include in your submission?
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What would you do if…
you currently have a Phase III study approved. It is
a randomized study comparing an experimental
drug versus placebo. The study has reached its
accrual goal and preliminary data suggests that the
experimental drug provides a benefit. The study
sponsor wants to modify the protocol to an openlabel extension study so that the experimental drug
is available to all participants.
• What type of modification request would you
submit?
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• What would you need to include in your
submission?
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What would you do if…
you currently have an approved study that
takes place at Parnassus and Mt. Zion. The
PI now wants to add the VAMC as a study
site.
• What type of modification request would
you submit?
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Protection
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• What would you need to include in your
submission?
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5 Common Problems with
Modification Submissions:
• Changes are not bolded or highlighted and
deletions are not struck through.
• Version dates are not revised
• The wrong version(s) is modified
• Affected documents are not submitted with
modification request form
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• Not all changes are stated explicitly in the
modification request form
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5 Common Problems with
Renewal Submissions:
• Subject numbers do not add up and no clear
explanation is given in the status report.
• Study status (page 2 of the status report) is wrong
• Modifications approved since the last renewal are
not listed in Section J.1 of the status report
• If the study has expired or is about to expire,
assurance that no study activity will occur is not
given or the status report doesn’t fully discuss
approval lapse including a corrective action plan.
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• Required supplements are not included
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Remember!
IRB Review is required before initiating,
modifying or extending any research project
that uses human subjects
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Questions?
www.research.ucsf.edu/chr/
• Ask your PI or Mentor
• Call or email the CHR and ask for a
screener of modifications and
renewals
• Main CHR Line: 415-476-1814
• Main CHR Email: [email protected]
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HRPP Training: Upcoming Sessions
• Post-Approval Event Reporting
– Tuesday, August 11, 10-11:30 a.m., N-225
– Lisa Voss, Assistant Director, HRPP Quality
Improvement Unit
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Protection
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