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BST 698 INTERIM ANALYSIS LECTURE

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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 ... – PowerPoint PPT presentation

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Title: BST 698 INTERIM ANALYSIS LECTURE


1
HURDLES AND FUTURE WORK IN ADAPTIVE DESIGNS
Christopher S. Coffey Professor, Department of
Biostatistics Director, Clinical Trials
Statistical and Data Management Center University
of Iowa
2
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.
3
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.
4
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.
5
ADAPTIVE DESIGNS
Infinite number of adaptive design possibilities
Source Coffey CS and Kairalla JA (2008).
Adaptive Designs Progress and Challenges. Drugs
in RD, 9(4) 229-242.
6
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 ADs in trials funded by NIH, Foundations,
or Non-profit organizations.
7
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.
8
ADAPTIVE DESIGNS
Issue exacerbated by fact this is generally
required prior to submitting a grant application
for funding. Many pharmaceutical companies are
developing in-house 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.
9
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

10
WORKSHOP
  • Workshop Aims
  • 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.
  • To provide an opportunity for participants to
    make recommendations regarding next steps toward
    further research, education, and coordinated
    activity related to adaptive designs.

11
WORKSHOP
  • DAY ONE (Morning) Five separate sessions
  • Introduction to Adaptive Trial Designs, including
    promises and challenges
  • Discussion of three case studies
  • Exploration of questions to guide planning of a
    clinical trial with an adaptive design
  • Discussion of industry models for ADs
  • Discussion of challenges for implementing ADs in
    NIH and other non-industry sponsored trials.

12
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 ADs.
  • DAY TWO
  • Small group discussions devoted to open-ended
    dialogue about the use and potential of ADs in
    clinical trials.
  • Discussions led to six formal recommendations.

13
RECOMMENDATIONS
  • TAXONOMY More opinions should be gathered about
    the need to bring a commonly understood framework
    to the field of ADs.
  • Some felt there was a need for a standardized
    taxonomy for ADs
  • Others felt that a taxonomy sets unnecessary
    boundaries

14
RECOMMENDATIONS
  • METHODOLOGY Methodology for trial adaptations
    should be a priority for future research. Needs
    include
  • Examining the circumstances in which ADs would
    benefit patients or save time, effort, and
    financial resources
  • Discussing the optimal management of logistical
    issues in an AD

15
RECOMMENDATIONS
  • 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.

16
RECOMMENDATIONS
  • FUNDING NIH should offer more recognition and
    funding for planning clinical trials that might
    benefit from ADs.
  • NIH should develop a targeted program for
    developing tools associated with the use of ADs,
    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 ADs that
    follow their approved protocol, even with
    variable durations and sample sizes.

17
RECOMMENDATIONS
  • FUNDING (cont) NIH should offer more recognition
    and funding for planning clinical trials that
    might benefit from ADs.
  • More opportunities for two-way discussions in the
    NIH grant system should be encouraged.
  • Grant reviewers should understand how ADs 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.

18
RECOMMENDATIONS
  • IMPACT ON DSMB Use of ADs may require a
    different way of thinking about the structure and
    conduct of DSMBs.
  • For confirmatory ADs, investigators should
    include decision trees and triggers in trial
    design to minimize the role of DSMB judgment.
  • Statisticians who serve on DSMBs for trials that
    use an AD should be familiar with theory and
    practice of ADs.
  • DSMBs should assure trial has data managers who
    are knowledgeable about special needs of adaptive
    trials.

19
RECOMMENDATIONS
  • EDUCATION Need for education about the use of
    ADs
  • NIH should develop programs to educate and train
    researchers, reviewers, and DSMB members about
    use of ADs
  • NIH should fund efforts to train young
    investigators about appropriate uses of ADs
  • Patient advocacy groups, professional
    associations, and non-profit organizations should
    collaborate on ways to educate professionals,
    patients, family members, and the media about ADs

20
RECOMMENDATIONS
  • EDUCATION (cont.) Need for education about the
    use of ADs (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

21
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.
22
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

23
SUMMARY
INFRASTRUCTURE SCALE
High
Low
Low
High
ADAPTIVITY SCALE
Thanks to JLP Thompson (Columbia U.)
24
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

25
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, Parkinsons 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 ONeill, 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, Parkinsons Disease
Foundation Daniel van Kammen, CHDI
Foundation Phillip Wang, NIMH Adam Wanner,
Alpha-1 Foundation John Warner, CHDI Foundation
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