central irbs: more efficient for whom? may 7, 2012 p. pearl o’rourke, m.d. partners healthcare...
TRANSCRIPT
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Central IRBs: More Efficient for Whom?
May 7, 2012
P. Pearl O’Rourke, M.D.Partners HealthCare
Boston, MA.
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Congratulations!
• You have been successfully funded as the PI of a large multi-site study– Purpose: effect of high dose Vit B on young
adults (16-26) who are HIV positive– 50 academic health centers in 35 different
states
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Your first thoughts…
Your study coordinator
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Your first thoughts…
Your study coordinator
For you
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Your next thoughts…
• I have to coordinate 50 academic health centers in 35 different states
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And on top of it…
• I have to coordinate 50 academic health centers in 35 different states
• That means 50 separate IRBs– Protocol submission to multiple local IRBs– Each IRB alters the protocol and edits the ICF– Only 50% of the sites have IRB approval on
the date of trial start
• And that is just the initial review!!
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PI of multisite clinical study
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If only I had a central IRB!
• Increased efficiency• Faster turn-around• Less cost• Avoid multiple reviews by multiple local
IRBS
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Life would be grand!
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Agenda• Local IRBs
– Advantages and disadvantages• For whom?
• Central IRBs– Perceived advantages and disadvantages
• For whom?
– Models of central IRBs
• “Costs” of central IRBs• What are they• Who pays?
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Agenda• Local IRBs
– Advantages and disadvantages• For whom?
• Central IRBs– Perceived advantages and disadvantages
• For whom?
– Models of central IRBs
• “Costs” of central IRBs• What are they• Who pays?
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Advantages of local IRBs
• For the institution– HRPP (Human Research Protection Program)
coordination – local IRB often the ‘hub’– Maximizes review of local context– Promotes awareness of what research is being
conducted and by whom (oversight and control issues)
• For the investigator– Provides a local resource – of entire HRPP– Comfort with the local system and process
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Disadvantages of local IRBs
• For the institution– Cost of infrastructure– Duplication of effort on some multi-site research
• For the investigator– For multi-site research
• Duplication• Additional time
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Advantages of Central IRBs
• For the institution– Cost savings - maybe
• For the investigator– For multi-site research
• Efficiency • No duplication
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Disadvantages of Central IRBs
• For the institution– Difficulty segregating and fulfilling IRB versus
institutional responsibilities• Possible shadow systems
– Possible erosion of cohesive HRPP– Distancing of research and researchers– Confusion with multiple systems– Possible liability issues
• For the investigator– Understanding IRB and institutional requirements– New system
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Agenda• Local IRBs
– Advantages and disadvantages• For whom?
• Central IRBs– Perceived advantages and disadvantages
• For whom?
– Models of central IRBs
• “Costs” of central IRBs• What are they• Who pays?
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Central IRBs come in different models
• Non-share model– Central IRB fulfills all IRB-regulatory
requirements
• Share model– Central IRB and local IRB share various
regulatory responsibilities
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The taxonomy of Central IRBs
Local IRB Non-share model
Share models
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The taxonomy of Central IRBs
Local IRB Non-share model
Comm
ercial
Status quo
IRBShare
NCI CIRB
VA CIRB
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The taxonomy of Central IRBs
Local IRB Non-share model
Comm
ercial
Status quo
IRBShare
NCI CIRB
VA CIRB
NeuroNEXT CIRB
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IRBshare: Vanderbilt
• Collaborative IRB Review Model– Share review documents and review process
• Supported by an Electronic Sharing Resource (eSR)– Centralized, secure web portal for sharing– Currently operated by Vanderbilt University
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How IRBshare works
• Documents available via eSR– Redacted minutes/discussion notes– Protocol– Consent form– IRB application– Product brochure– Any documents relevant to outcome of the
review
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Electronic Sharing
Resource
Site with full IRB review
Sites can consider relying on full IRB review of Site A, or do their own full IRB review
A
12
3
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How IRBshare works
• Local IRB sub-committee review by an IRB member to:– Verify and accept determination from Full Board
Review Site’s IRB– Complete review of local context to complete review
• Local IRB can decide to accept the review, or send to their own full committee
• Of note, ICF is stamped by the local IRB
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How IRBshare works
• If local IRB relies on full committee review of Institution A – then Institution A is the IRB of record for the initial review
• The local IRB then becomes the IRB of record for all subsequent IRB actions for the life of the protocol
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Electronic Sharing
Resource
Sites with full IRB review
Sites can consider relying on full IRB review from A, B or C, or do their own full IRB review
A
B
C
12
3
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NCI Model
• Current model is being reassessed
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NCI Model
• CIRB functions– Initial and continuing review– Amendments– Adverse events
• Local “IRB” functions– Facilitated review for review of local context– Development of ‘site-specific’ ICF– Review of locally occurring adverse events and
unanticipated problems– Oversight of local performance
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NCI Model
• Local site must meet eligibility criteria to enroll with cIRB
• Protocol reviewed by cIRB and results posted • Local IRB conducts a ‘facilitated review’
– If agree with cIRB, use cIRB as IRB of record– If disagree with cIRB, use local IRB as IRB or
record
CIRB is not constituted for prisoner research – local IRB retains this responsibility
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NeuroNEXT CIRB: a non-share model
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The NeuroNEXT CIRB-Background-
• NINDS grant to support a network of 25 academic centers to facilitate clinical trials in neurology
• RFA stated preferential funding to those sites that agree to use a central IRB process– RFA included three tiers
• CIRB only• Facilitated model• Local IRB
• At funding – CIRB only was selected
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The NeuroNEXT CIRB
• CIRB had to be situated at the same site as the CCC (clinical coordinating center)– Massachusetts General Hospital = CCC– Therefore, the Partners* (PHS) IRB becomes CIRB
* MGH and BWH collaborate in a singe IRB system under PHS
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The NeuroNEXT CIRB“interesting” nuance
• Presumption that 25 NeuroNEXT sites will be the study sites
• BUT – there may be involvement of additional sites:– Investigators from non-NeuroNEXT sites can propose
studies to be done by NeuroNEXT– Non-NeuroNEXT sites may be invited to join specific
studies as needed
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Steps
1. Develop the model
2. Develop a Reliance Agreement• Protocol agnostic
• To cover all NeuroNEXT member sites in NeuroNEXT studies
• Protocol-specific• To cover non-NeuroNEXT-sites participating in NeuroNEXT
studies
3. Negotiate the Reliance Agreement with all relevant sites
4. Let the fun begin!
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Steps
1. Develop the model
2. Develop a Reliance Agreement• Protocol agnostic
• To cover all NeuroNEXT member sites in NeuroNEXT studies
• Protocol-specific• To cover non-NeuroNEXT-sites participating in NeuroNEXT
studies
3. Negotiate the Reliance Agreement with all relevant sites
4. Let the fun begin!
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NeuroNEXT CIRB
• CIRB responsibility
– All IRB regulatory tasks
• Initial review• Continuing review• Amendments,
deviations, AEs
– HIPAA determination• Authorization• Waiver
• Local Site responsibility*– Site-specific context
• E.g., Local laws
– Ancillary review/s• E.g., Nursing, Rad’n safety
– HIPAA implementation– Oversight of conduct of
research– Required reporting
* Institutional NOT IRB responsibility
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Communication is KEY
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Communication is KEY
CCC-IRB Liaison
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Parent-child relationship
• Single CIRB review• PI-site submits ‘parent’ protocol for CIRB review• After approval of ‘parent’ protocol, sites are
added as amendments
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Protocol submitted via CCC
cIRB Initial
assessment to determine
‘IRB readiness’
Sites‘IRB ready’
protocol sent to sites to
identify ‘substantive’ and/or local
issues
cIRB
receives ‘substantive’ and/or local issues from each site
AND then reviews protocol
cIRB CCC sends
approved protocol to
sites
Sites communicate
decision to participate
Sites participating are added by
amendment to the cIRB approved protocol
The Basic Model
cIRB
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Protocol submitted via CCC
cIRB Initial
assessment to determine
‘IRB readiness’
Sites‘IRB ready’
protocol sent to sites to
identify ‘substantive’ and/or local
issues
cIRB
receives ‘substantive’ and/or local issues from each site
AND then reviews protocol
cIRB CCC sends
approved protocol to
sites
Sites communicate
decision to participate
Sites participating submit as an
amendment to the cIRB approved protocol
The Basic Model
cIRB
Ancillary Reviews
Ancillary Reviews
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“Parent-protocol” review
• PI submits protocol to CIRB• CIRB reviews for ‘IRB-readiness’• IRB-ready protocol is sent to all sites that are
interested in participating• Sites have 2 weeks to conduct institutional review
and submit comments – re: the protocol in general as well as local context issues
• CIRB conducts PI protocol review – Incorporates feedback from local sites
• PI coordinates ancillary review/s for PI-site and submits to the CIRB
• CIRB can then approve the protocol
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ICF:PI will develop:
– A model ICF that includes:• Locked portion, e.g.
– Study procedures– Risks and benefits
• Customizable portion, e.g.– HIPAA– COI language– Injury language– Contact persons
– A PI-site-specific ICF that includes:• Locked portion and completed customizable
portion
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“Child-protocol” review
• CIRB approved protocol is sent to each interested site
• Each site makes final decision re: participation• Each site will be reviewed as an amendment to
the ‘parent-protocol’ and must submit:– Evidence of local ancillary review/s– A completed ICF that includes:
• Locked portion• Customizable portion that includes local ICF
content
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After the protocol is CIRB approved
Continuing Review
• Anniversary date for all participating sites is tied to the initial protocol approval
• Each site PI submits site-specific continuing review data to CCC-CIRB liaison who collates and submits to the CIRB
• Investigators and study teams will not have direct access to PHS electronic IRB submission database at this time
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After the protocol is cIRB approvedAdverse events/UAPs, Deviations, Complaints, Changes to
Eliminate Immediate Hazards, Non-Compliance, and Suspension or Cessation of Study
• Each site PI submits site-specific reports to CCC-CIRB liaison who will submit to the CIRB– If an issue requires notification of all sites, the
CIRB will communicate same via the CCC
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After the protocol is cIRB approvedAmendments
• Each site PI submits site-specific amendments to CCC-CIRB liaison for submission to the CIRB– Site-specific amendments limited to:
• administrative (e.g., study staff changes) and requests for protocol exceptions;
– Any amendment that substantively changes the study must be coordinated through the PI-site and CCC
– Issues identified as a result of CIRB review of amendments requiring notification of all sites will be sent out from the CIRB via the CCC-CIRB liaison
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HIPAA
• CIRB will:– Make HIPAA determinations– Incorporate authorization language into the consent
form• Local sites can use:
– cIRB developed ICF that includes authorization – Insert their own authorization language into the ICF in
lieu of authorization language in CIRB ICF*– Use their own free-standing authorization in lieu of
authorization language in CIRB ICF*
* Final ICF and authorization must be submitted to and approved by the CIRB
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COI
• The CIRB will consider COI issues in the approval of the protocol and will include management plan/s. – E.g., disclosure in the ICF
• Each local site: – Applies local standards and processes– Can mandate more stringent management than
required by the CIRB. – Cannot implement less stringent management
• COI subcommittee of NN-Exec.Com.– Resource for the CIRB
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Compliance Investigations
• Compliance investigations will be the responsibility of each local institution
• The CIRB will have the right to initiate/conduct its own investigation in addition if necessary
• The expectation is one of collaboration and communication with the CIRB, the CCC, the DCC and the sites
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External Reporting
• Logistics of external reporting will be determined on a case-by-case basis
• Site/s and the CIRB agree upon who will report
• Drafts and final reports will be shared between the relevant site/s and the CIRB – Allows either the CIRB or individual site/s to submit
an additional report as deemed appropriate.
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CIRB Goals
• Obtain input from local sites prior to IRB full committee review of parent protocol
• Provide high quality, rapid review for multiple sites
• Work collaboratively with local sites • Streamline amendments and compliance
reporting
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Steps
1. Develop the model
2. Develop a Reliance Agreement• Protocol agnostic
• To cover all NeuroNEXT member sites in NeuroNEXT studies
• Protocol-specific• To cover non-NeuroNEXT-sites participating in NeuroNEXT
studies
3. Negotiate the Reliance Agreement with all relevant sites
4. Let the fun begin!
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Reliance Agreement
• Delineates– The process– Assignation of legal, regulatory and contractual
responsibilities
• Negotiation:– Draft Reliance Agreement sent to all prime sites for
comments– Two Webinars describing the Reliance Agreement
• Opportunity for submitted questions
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Reliance Agreements
• Prior to any protocol, all network sites must sign a reliance agreement with the CIRB– This RA will cover all NeuroNEXT studies– All RA’s ‘essentially’ identical
• CIRB required separate RA for all sites and subsites with their own FWA– Regardless of relationship or existing reliance
arrangements between Primary site and subsites.
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Prime sites and Sub-sites
A
B C
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Prime sites and Sub-sites
• Scenario 1– Prime site A and subsites B and C
• Each with their own FWA and IRB
AFWAIRB
BFWAIRB
CFWAIRB
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Prime sites and Sub-sites
• Scenario 1– Prime site A and subsites B and C
• Each with their own FWA and IRB
AFWAIRB
BFWAIRB
CFWAIRB
Three separate Reliance
Agreements
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Prime sites and Sub-sites
• Scenario 2– Prime site A and subsites B and C
• Each with their own FWA• B and C rely on IRB situated at A
AFWAIRB
BFWA
CFWA
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Prime sites and Sub-sites
• Scenario 2– Prime site A and subsites B and C
• Each with their own FWA• B and C rely on IRB situated at A
AFWAIRB
BFWA
CFWA
Three separate Reliance
Agreements
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Reliance Agreements
• Non-member sites involved in NN-research must also sign the Reliance Agreement– Details remain the same, but the agreement is limited
to a single protocol
• If non-member sites have sub-sites:– All FWA-holding sub-sites must sign their own
Reliance Agreement
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Steps
1. Develop the model
2. Develop a Reliance Agreement• Protocol agnostic
• To cover all NeuroNEXT member sites in NeuroNEXT studies
• Protocol-specific• To cover non-NeuroNEXT-sites participating in NeuroNEXT
studies
3. Negotiate the Reliance Agreement with all relevant sites
4. Let the fun begin!
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NeuroNEXT CIRB
NeuroNEXT25 Prime sites
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NeuroNEXT CIRB
NeuroNEXT25 Prime sites
BUT…more than 40 sub-sites for a grand total of
more than 60 sites
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NeuroNEXT CIRB
NeuroNEXT25 Prime sites
BUT…more than 40 sub-sites for a grand total of
more than 60 sites
Non-NeuroNEXT Sites
A B
C
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Steps
1. Develop the model2. Develop a Reliance Agreement
• Protocol agnostic• To cover all NeuroNEXT member sites in NeuroNEXT
studies
• Protocol-specific• To cover non-NeuroNEXT-sites participating in NeuroNEXT
studies
3. Negotiate the Reliance Agreement with all relevant sites
4. Let the fun begin!
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Anticipated Challenges
• Differentiating between institutional and IRB tasks
• Obtaining and addressing local context• Simple logistics of communication• Different local cultures• Developing trust• …..
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Agenda• Local IRBs
– Advantages and disadvantages• For whom?
• Central IRBs– Perceived advantages and disadvantages
• For whom?
– Models of central IRBs
• “Costs” of central IRBs• What are they• Who pays?
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Costs and Benefits of the NCI CIRB
• Survey study• CIRB associated with:
– Faster reviews (28.3 vs 62.3 days)– Less research staff time (7.9 vs 14 hrs)– Savings of $717 per initial review
• $321 for research staff• $396 for IRB staff
• Note that many sites continue some local review for amendments and continuing review
J Clin Oncol 28:662-666;2010
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What are the costs and who pays?
• Completely dependent on the model• Too early to tell• All costs are not financial
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Pandora’s Box?
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Costs of being the CIRB
• Impossible to say….but consider:– Developing and negotiating reliance agreements– New IRB panel or use an existing one?– System of communication – and persons to run said
system– FTEs that only process CIRB related tasks
• Will vary with model of CIRB and number of protocols
– Will you rely on any local site review?• If not – will need a central resource for evaluating all relevant
local laws, etc.
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Costs of relying on a CIRB
• Impossible to say….but consider:– Financial
• Is there a charge for the CIRB?• Is there facilitated review and a role for local IRBs?• Is local context review required?
– If yes, by whom?
– Nonfinancial• Loss of comfort with local research portfolio• Corrosion of Human Research Protection Program
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Final Thoughts• Variety of CIRBs makes it difficult:
– To make any generalizations– For IRBs, institutions and investigators to know what
to expect in different situations
• More guidance is needed re: – IRB versus institutional responsibilities– What responsibilities come with an FWA– Obtaining local context
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Final Thoughts• There are advantages and disadvantages to
local and central review• Advantages and disadvantages are different for:
– IRBs– Researchers– Institutions
• Hopefully our NeuroNEXT experience can help to inform the process
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Final lesson:No approach is without its snags
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Final lesson:No approach is without its snags