Transcript BST 698 INTERIM ANALYSIS LECTURE

ADAPTIVE DESIGN FOR
CLINICAL TRIALS: PERSPECTIVE
FROM AN NIH-FUNDED
WORKSHOP
Christopher S. Coffey
Professor, Department of Biostatistics
Director, Clinical Trials Statistical and Data
Management Center
University of Iowa
ADAPTIVE DESIGNS
There may be limited information to guide initial
choices for the design of a study.
Since more knowledge will accrue as the study
progresses, adaptive designs allow these elements to
be reviewed during the trial.
An adaptive design allows for changing or modifying
the characteristics of a trial based on cumulative
information.
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ADAPTIVE DESIGNS
Recently, there has been considerable research on
adaptive designs (ADs).
The rapid proliferation of interest in adaptive designs
and inconsistent use of terminology has created
confusion about similarities and differences among
the various techniques.
For example, the definition of an “adaptive design”
itself is a common source of confusion.
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ADAPTIVE DESIGNS
PhRMA Working Group on Adaptive Designs (2006):
“By adaptive design we refer to a clinical study
design that uses accumulating data to modify
aspects of the study as it continues, without
undermining the validity and integrity of the trial.”
“…changes are made by design, and not on an ad
hoc basis”
“…not a remedy for inadequate planning.”
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ADAPTIVE DESIGNS
Infinite number of adaptive design possibilities:
Source: Coffey CS and Kairalla JA (2008). Adaptive Designs:
Progress and Challenges. Drugs in R&D, 9(4): 229-242.
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ADAPTIVE DESIGNS
Much of the research on ADs has been driven by
drug development within the pharmaceutical industry.
Many basic principles remain the same regardless of
the funding environment.
However, some specific challenges differ when
considering use of AD’s in trials funded by NIH,
Foundations, or Non-profit organizations.
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ADAPTIVE DESIGNS
As an example, justifying properties of adaptive
designs often requires conducting extensive
simulation studies.
The scope of the required simulations is generally
non-trivial, particularly for academic researchers
relying on NIH-funding.
Researchers must walk tightrope between need to
perform extensive simulations and the substantial
amount of effort required to perform simulations.
Burton et al. (2006, Stat Med) provide an excellent
description of how a protocol for a simulation study
should be developed.
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ADAPTIVE DESIGNS
Issue exacerbated by fact this is generally required
prior to submitting a grant application for funding.
Many pharmaceutical companies are developing inhouse teams primarily responsible for assisting with
such simulations.
Greater barriers exist for implementing the same type
of infrastructure within the NIH-funded environment.
Need for discussions on how to remove these
barriers to increase the use of adaptive designs.
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WORKSHOP
November 2009 - ‘Scientific Advances in Adaptive
Clinical Trial Designs Workshop’ held to advance use
of adaptive designs in publicly funded research.
50 representatives from the clinical trial community:
•
National Institutes of Health (NIH)
•
U.S. Food and Drug Administration (FDA)
•
European Medicines Agency (EMA)
•
Patients and Non-Profit Organizations
•
Professional Associations
•
Pharmaceutical Companies
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WORKSHOP
Workshop Aims:
1) To provide a forum for exploring the potential of
adaptive clinical trial designs to achieve reliable
results in shorter times with fewer resources than
required by conventional designs.
2) To provide an opportunity for participants to make
recommendations regarding next steps toward
further research, education, and coordinated
activity related to adaptive designs.
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WORKSHOP
DAY ONE (Morning): Five separate sessions:
1) Introduction to Adaptive Trial Designs, including
promises and challenges
2) Discussion of three case studies
3) Exploration of questions to guide planning of a
clinical trial with an adaptive design
4) Discussion of industry models for AD’s
5) Discussion of challenges for implementing AD’s in
NIH and other non-industry sponsored trials.
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WORKSHOP
DAY ONE (Afternoon):
•
A panel of representatives from NIH, FDA,
academia, industry, the EMA, international
organizations, and the patient community
presented their perspectives on AD’s.
DAY TWO:
•
Small group discussions devoted to open-ended
dialogue about the use and potential of AD’s in
clinical trials.
Discussions led to six formal recommendations.
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RECOMMENDATIONS
1) TAXONOMY:
More opinions should be gathered about the need
to bring a commonly understood framework to the
field of AD’s.
•
Some felt there was a need for a standardized
taxonomy for AD’s
•
Others felt that a taxonomy sets unnecessary
boundaries
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RECOMMENDATIONS
2) METHODOLOGY:
Methodology for trial adaptations should be a
priority for future research. Needs include:
•
Examining the circumstances in which AD’s would
benefit patients or save time, effort, and financial
resources
•
Discussing the optimal management of logistical issues
in an AD
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RECOMMENDATIONS
3) “ADAPTIVE BY DESIGN”:
For phase III trials, investigators should minimize
(or preferably avoid) ad-hoc changes.
•
Simulations to assess bias can only occur when the
changes are pre-specified.
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RECOMMENDATIONS
4) FUNDING:
NIH should offer more recognition and funding for
planning clinical trials that might benefit from AD’s.
•
NIH should develop a targeted program for developing
tools associated with the use of AD’s, such as software
for modeling and simulation.
•
NIH should develop a funding mechanism to examine
options for clinical trial design.
•
NIH should consider implementing flexible mechanisms
that address long-term funding of clinical trials and
commit to funding AD’s that follow their approved
protocol, even with variable durations and sample sizes.
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RECOMMENDATIONS
4) FUNDING (cont):
NIH should offer more recognition and funding for
planning clinical trials that might benefit from AD’s.
•
More opportunities for two-way discussions in the NIH
grant system should be encouraged.
•
Grant reviewers should understand how AD’s work,
when they are beneficial, and how evaluating their
progress differs from evaluating traditional trials.
•
More funding opportunities are needed for data
management specialists and systems to allow for early
availability of high-quality data.
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RECOMMENDATIONS
5) IMPACT ON DSMB:
Use of AD’s may require a different way of thinking
about the structure and conduct of DSMB’s.
•
For confirmatory AD’s, investigators should include
decision trees and triggers in trial design to minimize the
role of DSMB judgment.
•
Statisticians who serve on DSMB’s for trials that use an
AD should be familiar with theory and practice of AD’s.
•
DSMB’s should assure trial has data managers who are
knowledgeable about special needs of adaptive trials.
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RECOMMENDATIONS
6) EDUCATION:
Need for education about the use of AD’s:
•
NIH should develop programs to educate and train
researchers, reviewers, and DSMB members about use
of AD’s
•
NIH should fund efforts to train young investigators
about appropriate uses of AD’s
•
Patient advocacy groups, professional associations, and
non-profit organizations should collaborate on ways to
educate professionals, patients, family members, and
the media about AD’s
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RECOMMENDATIONS
6) EDUCATION (cont.):
Need for education about the use of AD’s (cont.):
•
NIH should develop a publication checklist for funded
researchers to encourage investigators to disclose
decision-making process in a trial involving adaptation
•
The clinicaltrials.gov registry should incorporate fields
for indicating what types of adaptations were allowed
•
The editors of CONSORT should publish definitions and
guidelines for reporting elements of an AD
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SUMMARY
In general, regulatory agencies will accept some
adaptive designs, but are cautious about others
(particularly for pivotal studies) – see FDA draft
guidelines released last year.
A misconception is that an adaptive design requires
less planning than a standard trial design.
On the contrary, an adaptive trial generally requires
much more upfront planning for design and simulation.
Furthermore, adaptive designs are NOT always better.
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SUMMARY
There are many logistical barriers that need to be
overcome before any adaptive design can be
practically implemented.
These include:
 Budget Administration
 Information Technology
 Protocol Issues
 Drug Supply
 Need for Customized Software
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SUMMARY
INFRASTRUCTURE
SCALE
High
Low
Low
High
ADAPTIVITY SCALE
Thanks to: JLP Thompson (Columbia U.)
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WORKSHOP INFORMATION
Planning Committee:
Christina Clark, Foundation for Interdisciplinary Motor Neuron Medicine
Christopher S. Coffey, University of Iowa
Peter Gilbert, National Institute of Neurological Disorders & Stroke
Bruce Levin, Columbia University
Cate Timmerman, Palladian Partners
Janet Wittes, Statistics Collaborative
Website:
www.PalladianPartners.com/adaptivedesigns
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WORKSHOP PARTICIPANTS
Keaven Anderson, Merck & Company
Irina Antonijevic, CHDI Foundation
Barbara Araneo, Juvenile Diabetes Research Foundation
Sukirti Baga, National Organization for Rare Disorders
Sarah Baraniuk, University of Texas School of Public Health
Monica Barnette, Palladian Partners
Colin Begg, Memorial Sloan-Kettering Cancer Center
Steven Bramer, National Neurovision Research Institute
Erica Brittain, NIAID
Lucie Brujin, ALS Association
Bibhas Chakraboty, Columbia University
Kathryn Chaloner, University of Iowa
Ken Cheung, Columbia University
Emory Clark, Found. Interdisciplinary Motor Neuron Medicine
Amy Comstock Rick, Parkinson’s Action Network
Jason Connor, Berry Consultants
Robin Conwit, NINDS
Jacqueline Corrigan-Curay, NIH Office of the Director
Simon Day, Roche Products, Ltd
Patrice Desvigne-Nickens, NHLBI
Kay Dickersin, Johns Hopkins University
Valerie Durkalski, Medical University of South Carolina
David Eckstein, Office of Rare Diseases Research
Brian Fiske, Michael J. Fox Foundation
Karen Furie, Massachussetts General Hospital
Wendy Galpern, NINDS
Brenda Gaydos, Eli Lilly and Co.
Nancy Geller, NHLBI
Steve Gibson, ALS Association
Steven Goodman, Johns Hopkins University
Jennifer Gorman, NIH Nobel Laureate Hall and Visitors Center
Michael Hill, University of Calgary
Karen Johnston, University of Virginia
Petra Kaufmann, NINDS
Franz Koenig, EMA
Walter Koroshetz, NINDS
Minjung Kwa, NHLBI
Michael Manganiello, HCM Strategists, LLC
Elizabeth McKenna, Foundation for Fighting Blindness
Nancy Miller, NIH Office of the Director
Stephanie Moran, Juvenile Diabetes Research Foundation
Claudia Moy, NINDS
Robert O’Neill, FDA
Yuko Palesch, Medical University of South Carolina
Michael Proschan, NIAID
Bernard Ravina, University of Rochester
Stephen Rose, Foundation for Fighting Blindness
Ira Shoulson, University of Rochester
Robert Silbergleit, University of Michigan
Robert Temple, FDA
Ronnie Tepp, HCM Strategists LLC
Peter Thall, MD Anderson Cancer Center
J.L.P. Thomson, Columbia University
Veronica Todaro, Parkinson’s Disease Foundation
Daniel van Kammen, CHDI Foundation
Phillip Wang, NIMH
Adam Wanner, Alpha-1 Foundation
John Warner, CHDI Foundation
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