Challenges in Clinical Trials Networks

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Challenges for Clinical Trial Networks

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Modern Day Challenges in Clinical Trials

• How do we collaborate with industry?• Who controls study design? data? analysis?• Who controls which patients go to which

clinical trials? Minimize bias/conflicts• How do we control financial conflicts of

interest with human subjects research?• How do we control authorship? spin?• How do we do trials intelligently, efficiently,

cost-effectively, and ethically?

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Evolution of Randomized Clinical Trials in Retina

Evolution of Randomized Clinical Trials in Retina

21st Century: Networks for Randomized Clinical Trials in Retina

1950s: Single center trial – Patz et al

1970s: Multicenter clinical trials at university-based centers (e.g., DRS) 1970s: Multicenter clinical trials at university-based centers (e.g., DRS)

1980s: Multicenter clinical trials at university-based and community-based 1980s: Multicenter clinical trials at university-based and community-based centers (e.g., ETDRS)centers (e.g., ETDRS)

1990s: Industry sponsors randomized clinical trials (e.g., PDT trials) as 1990s: Industry sponsors randomized clinical trials (e.g., PDT trials) as other government-sponsored trials continue (e.g., AREDS, SST, CAPT)other government-sponsored trials continue (e.g., AREDS, SST, CAPT)

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When is a Network Indicated?What Should a Network Do?

• A network is of value when it is perceived likely that numerous treatments for a condition are on the horizon

• A network should have the efficiency of a common infrastructure to support multiple protocols

• A network should provide tremendous efficiency in timeline for protocol development to enrollment to completion, attractive to the public and industry

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What Is the Diabetic Retinopathy Clinical Research Network

(DRCR.net)?Dedicated to multicenter clinical research of diabetic

retinopathy, macular edema and associated disorders.

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DRCR Network Overview

• Objective:– Develop and operate a collaborative

network to facilitate multicenter clinical research on diabetic retinopathy, diabetic macular edema and associated conditions.

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Priority Initiatives

• Involvement of community-based practices, as well as academic centers

• Involve “new” investigators to train potential future leaders in randomized clinical trials

• Collaborate with industry to facilitate investigations and pursue opportunities otherwise not possible and to do so in a manner consistent with the Network’s dedication to academic integrity and optimal clinical trial performance.

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Maintaining Academic Integrity of Network: RCTs in 21st Century• Network controls study design/protocols

• Network controls budget (per NIH regs.)

• Network controls data

• Network controls publications and presentations

• Network controls organization and governance (within federal and local regulations)

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Current DRCR Network Status

• Overall Network Participation (as of January 15, 2008)

– 118 active or pending sites, 190 sites submitted application to the Network

– 75 community-based sites

– 322 total Investigators– 809 additional personnel– 33 States– >60 investigators served

on at least 1 committee

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DRCR Network Protocols (as of October 6, 2008) # of Subjects

Pilot Study of Laser Photocoagulation for DME (A) 263Randomized Trial: Intravitreal Steroids vs Focal Laser for DME (B) 693

Temporal Variation in OCT Measurements in DME (C) 107

Evaluation of Vitrectomy for DME (D) 237A Pilot Study of Peribulbar Triamcinolone Acetonide for DME (E) 113Observational Study: Development of DME After PRP (F) 155

Subclinical Diabetic Macular Edema Study (G) 82Phase 2 Randomized Trial of Bevacizumab for DME (H) 121Laser-Ranibizumab-Triamcinolone for DME (I) – Goal 701 618Laser-Ranibizumab-Triamcinolone for PDR + DME (J) – Goal 325 198Laser Response Protocol (K) 128

DRCR Network Study Subject Total 2,715

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Network Challenges

• How do you keep the investigators engaged and enthusiastic?

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DRCR Network Protocols (as of October 6, 2008) Protocol Chairs

Pilot Study of Laser Photocoagulation for DME (A) Fong

Randomized Trial: Intravitreal Steroids vs Focal Laser for DME (B) Ip

Temporal Variation in OCT Measurements in DME (C) Danis

Evaluation of Vitrectomy for DME (D) Haller

A Pilot Study of Peribulbar Triamcinolone Acetonide for DME (E) Chew

Observational Study: Development of DME After PRP (F) Brucker

Subclinical Diabetic Macular Edema Study (G) Bressler

Phase 2 Randomized Trial of Bevacizumab for DME (H) Scott

Laser-Ranibizumab-Triamcinolone for DME (I) Elman

Laser-Ranibizumab-Triamcinolone for PDR + DME (J) Googe*

Laser Response Protocol (K) Browning

DRCR Network Protocol Chair Totals 11

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Network Challenges

• How do you keep the investigators engaged and enthusiastic?– Involve investigators in “front”

(protocol development) and “back” end (writing committee) of protocols

– Keep actual day-to-day operations of clinical trial centralized

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Network Challenges

• How do you govern across wide environments, missions, cultures, personalities, at one time, and over time?

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DRCR Network Organization and Governance

DRCR Network Organization and Governance

Executive Committee (“Board of Directors”): provides oversight; sets policy; approves protocols

“Officers” Run Operations of NetworkCoordinating Center Principal Investigator (“CEO”);

Network Chair (“President”); Assistant Director (“COO”)

Investigators/staff(“Shareholders”)

NEIDSMC

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Network Challenges

• How do you implement new ideas rapidly?

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DRCR.net: From Idea to Protocol(Example of Bevacizumab for DME)

Idea Tabled:Reviewed

PeriodicallyIdea Declined

Executive Committee Reviews PRCR Reviews Monthly – Jan 2006

Disposition

Anyone may submit idea on DRCR.net Idea Form – Nov 2005

Protocol Concept Review Committee (PRCR) Reviews Ideas Monthly – Dec 2005

Idea Accepted:Protocol Development

Committee Created

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Idea Tabled:Reviewed

PeriodicallyIdea Declined

Executive Committee Reviews PRCR Reviews Monthly – Jan 2006

Disposition

Anyone may submit idea on DRCR.net Idea Form – Nov 2005

Protocol Concept Review Committee (PRCR) Reviews Ideas Monthly – Dec 2005

Idea Accepted:Protocol Development

Committee Created

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IRBs/clinicalsites need to

approve

Any industrycollaboration

may need approval

NIH External Protocol Review Committee Must Approve Protocol – Apr 2006

DSMC Must Approve Protocol – Apr 2006

Protocol Development Committee Creates Protocol – Feb 2006

Executive Committee Must Approve Protocol –Protocol Steering Committee Developed – Mar 2006

FDA or other regulatoryagencies may need

to approve


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Primary outcome complete October 2006

Follow-up completed November 2006Data finalized December 2006

Writing Committee completes draft February 2007Submitted March 2007, revised and accepted May 2007

Results published August 2007

Enrollment begins June 2006

Enrollment complete August 2006


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Network Challenges

• How do you manage multiple IRBs and contracts?– Community-based: encourage central

IRB; initial contract with amendments for each protocol

– University-based: participation only in studies enrollment anticipated to be 6 months or more if refuse central IRB and simple contract

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Network Challenges

• How do you maintain “public” support?

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Resources for the Scientific Community

• All protocols, policies, procedures, financial disclosures, and link to publications available on public www.drcr.net website

• Public documented dataset provided for use by other researchers via website when protocol complete

• Plans for access to genetic material matched to exquisitely characterized phenotypes

• Network open to community of retina specialists to participate in all aspects

• Community invited to submit protocol ideas

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Randomized Clinical Trials in Retina: From Single Center Studies in 1950 to Networks in

the 21st CenturyNew challenges in next 5 years for the DRCR Network: more protocols, international sites,

even more streamlined operations

Challenges in Clinical Trials Networks

Health & Medicine

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