Adaptive Designs: The Swiss Army Knife
Among Clinical Trial Designs?
Frank Bretz (Novartis)
U Penn – April 13, 2016
Acknowledgment: Willi Maurer, Paul Gallo (Novartis)
Swiss Army Knife
 Wiktionary:
*
A tool that has many functions,
one for every perceivable need.
 Wikipedia:
The term "Swiss Army knife" has
entered popular culture as a
metaphor for usefulness and
adaptability.
2
| U Penn | Frank Bretz | April 13, 2016
*Trade Registry
Number:
CHE-105.977.463
Outline
 Adaptive designs over the years
 Role of adaptive designs in clinical trials
 Outlook
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| U Penn | Frank Bretz | April 13, 2016
Outline
 Adaptive designs over the years
• Disclaimer: In what follows, this is a (biased?) selection of references
and not meant to be exhaustive
 Role of adaptive designs in clinical trials
 Outlook
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| U Penn | Frank Bretz | April 13, 2016
Adaptive designs over the years
Historical papers
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| U Penn | Frank Bretz | April 13, 2016
Adaptive designs over the years
Cross-industry collaborations
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| U Penn | Frank Bretz | April 13, 2016
Adaptive designs over the years
Landmark trials
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| U Penn | Frank Bretz | April 13, 2016
Adaptive designs over the years
Regulatory guidance documents
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| U Penn | Frank Bretz | April 13, 2016
Adaptive designs over the years
Books
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| U Penn | Frank Bretz | April 13, 2016
Outline
 Adaptive designs over the years
 Role of adaptive designs in clinical trials
• Reference: Dette, Bornkamp, Bretz (2013) On the efficiency of twostage response-adaptive designs. Statistics in Medicine 32, 1646-60
 Outlook
10 | U Penn | Frank Bretz | April 13, 2016
Role of adaptive designs in clinical trials
Is it possible to define factors which influence whether to
select a standard, or a novel approach for a given trial?
 In a slightly narrower context:
• What are the factors leading to good trial designs?
• How can we evaluate those factors?
 In the following we elaborate further on Ph IIb Dose Finding
(DF) trials
… where until now traditional trial designs with few doses using
pairwise comparisons based on relatively few patients prevail
… while acknowledging that DF starts much earlier
- Need for incremental dose response (DR) learning at project level
requiring integrated planning and quantitative decision making
11 | U Penn
Frank Bretzto
| April
13, 2016
- | Need
design
Ph I / Ph IIa studies in view of DF (and Ph III)
Role of simulations in designing clinical trials
General considerations
 Comprehensive, simulation-based evaluations to guide
modern protocol design
 Simulations are essential to understand the operating
characteristics of a chosen trial design
• Compare different design options and / or fine tune the design
parameters
• Evaluate robustness of a design w.r.t. deviation from assumptions
 Limitations:
• Current limited availability of advanced clinical trial simulators
- Need for case-by-case implementations leading to problems of resources,
validation / reproducibility, ...
• How to summarize, visualize and communicate the results of
extensive simulation studies?
12 | U Penn | Frank Bretz | April 13, 2016
Role of analytical methods in designing clinical trials
General considerations
 Analytical results (where available) can confirm simulation
results and provide additional insight
• Use simplified settings restricted to key factors
• Allows one to “see” the relationship between the parameters and
possibly prove general results
• Overcomes numerical convergence problems often encountered in
simulation studies
13 | U Penn | Frank Bretz | April 13, 2016
Role of analytical methods in designing clinical trials
Example from Dette et al. (2013)
 Exponential model 𝑦 = 𝑒 −𝜃𝑥
with unknown parameter 𝜃
and initial guess 𝜃0
 Non-adaptive design
• 𝑁 observations according to
optimal design based on 𝜃0
 Two-stage adaptive design
• Stage 1: 𝑁0 observations with
design based on 𝜃0
• Interim: Estimate 𝜃, resulting in 𝜃1
• Stage 2: 𝑁  𝑁0 observations with
design based on 𝜃1
 Which design is more efficient and estimates 𝜃 more precisely?
14 | U Penn | Frank Bretz | April 13, 2016
Role of analytical methods in designing clinical trials
Example from Dette et al. (2013)
 Relative efficiency of these two designs depends only on
• Unknown factors:
- Parameter 𝜃
- Degree of misspecification through 𝜃0
- Variability 𝜎
• Design parameters:
- Information fraction 𝑝0 at interim
- First stage sample size 𝑁0
 Using analytical methods, one can prove that the adaptive
design is always better than the non-adaptive design for
• large sample sizes (in a broad class of models)
• small variances (in this example model)
15 | U Penn | Frank Bretz | April 13, 2016
Role of analytical methods in designing clinical trials
Example from Dette et al. (2013)
Relative efficiency of adaptive versus non-adaptive design (𝑁 = 100, 𝜃 = 1).
Efficiency > 1 indicates that the adaptive design is better.
16 | U Penn | Frank Bretz | April 13, 2016
Outline
 Adaptive designs over the years
 Role of adaptive designs in clinical trials
 Outlook
17 | U Penn | Frank Bretz | April 13, 2016
Conclusions
 There is a role for adaptive clinical trial designs and they
should be considered routinely in drug development
 No single design / method uniformly best: relative
performance depends on scenarios, assumptions, trial
objectives, ...
 Innovative approaches are multifaceted that combine
strengths from different areas, e.g. adaptive, model-based,
Bayesian, optimal design, etc.
 Individual techniques are available, but not used properly in
combination as a toolbox approach
18 | U Penn | Frank Bretz | April 13, 2016
Conclusions
 Clinical trial designs depend on a multitude of factors
 Trial design optimization requires comprehensive
simulations to
• evaluate operating characteristics and robustness of a chosen design
• compare different design options and/or finetune the design
parameters
 Analytical methods might be helpful, if available (but will
never replace simulations due to complexity of clinical trial
designs)
 Further factors not considered here will impact the choice
for or against a certain design:
• recruitment rate, time to read-out, drug supply, randomization, ...
19 | U Penn | Frank Bretz | April 13, 2016
Adaptive Designs: The Swiss Army Knife
Among Clinical Trial Designs?
 It depends ...
Simple scissor
• Optimal tool for a
specific task
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| U Penn | Frank Bretz | April 13, 2016
Swiss Army knife*
• Versatile tool that
combines several
individual functions
in a single unit
*Trade Registry Number:
CHE-105.977.463
Giant Swiss Army
knife*
• Functions for every
perceivable need
• Looks impressive
• Highly impractible
• Very expensive