Critical Path Initiative: What it means for
pharmaceutical industry statisticians
Walter Offen, Lilly
Brenda Gaydos, Lilly
José Pinheiro, Novartis
FDA/Industry Workshop
September 14-16, 2005
Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
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Introduction
• March, 2004: FDA published “InnovationStagnation: Challenge and Opportunity on
the Critical Path to New Medical Products”
– http://www.fda.gov/oc/initiatives/criticalpath/w
hitepaper.html (or ___ . pdf)
• Industry has been working on a number of
the issues raised
• Strong synergies between FDA,
academia/NIH, and industry are possible
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
4
Highlights of Critical Path Paper
[my underlines]
•“…the current medical product1
development path is becoming
increasingly challenging, inefficient,
and costly.”
•“…costs of product development have
soared over the last decade.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
[my underlines]
•“Not enough applied scientific work
has been done to create new tools to
get fundamentally better answers
about how the safety and effectiveness
of new products can be demonstrated,
in faster time frames, with more
certainty, and at lower costs.”
•“Finally, the path to market even for
successful candidates is long, costly,
and inefficient, due in large part to the
current reliance on cumbersome
assessment methods.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“The goal of critical path research is to
develop new, publicly available
scientific and technical tools -including assays, standards, computer
modeling techniques, biomarkers, and
clinical trial endpoints -- that make the
development process itself more
efficient and effective and more likely
to result in safe products that benefit
patients.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“…correlate early markers of safety
and benefit with actual outcomes in
patients.”
•“…these new technologies could
provide tools to detect safety problems
early, identify patients likely to
respond to therapy, and lead to new
clinical endpoints.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“…much more attention and creativity
need to be applied to disease-specific
trial design and endpoints intended to
evaluate the effects of medical
products.”
•“…problems are often uncovered only
during clinical trials or, occasionally,
after marketing.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“Clinical testing, even if extensive,
often fails to detect important safety
problems, either because they are
uncommon or because the tested
population was not representative of
eventual recipients. Conversely, some
models create worrisome signals that
may, in fact, not be predictive of a
human safety problem.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“Adopting a new biomarker or
surrogate endpoint for effectiveness
standards can drive rapid clinical
development. For example, FDA
adoption of CD4 cell counts and,
subsequently, measures of viral load as
surrogate markers for anti-HIV drug
approvals allowed the rapid clinical
workup and approval of life-saving
antiviral drugs…”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“FDA adoption of the eradication of H.
pylori as a surrogate for duodenal
ulcer healing greatly simplified the
path of those therapies to the market.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“There are many important additional
opportunities in the area of clinical
trial design and analysis. More
clinically relevant endpoints need to be
developed for many diseases.
Enrichment designs have the potential
for providing much earlier assurance
of drug activity. Bayesian approaches
to analysis need to be further
explored.”
FDA/Industry Workshop
September 14-16, 2005
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Highlights of Critical Path Paper
•“This must be a joint effort
involving the academic
research community,
industry, and scientists at
the FDA…”
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
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Overview of 8 PISC Initiatives
[ PISC = Pharmaceutical Innovation Steering
Committee ]
1. Improving Efficiency of Late-Stage
Clinical Research (ECR) [Walt Offen]
–
CTs have become increasingly large and
expensive in recent years; team hopes to
identify means to improve efficiencies,
including improved post-approval safety data
collection and evaluation, study design
improvements, and use of technology
FDA/Industry Workshop
September 14-16, 2005
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Overview of 8 PISC Initiatives
2. Novel Adaptive Clinical Trial Design
[Brenda Gaydos]
– Collaborate with FDA, academia, and across
the industry to develop accepted
methodologies required to achieve
development efficiency advantages
3. Rolling Dose Studies [José Pinheiro]
–
Develop and investigate dynamic CT designs
with changing number of doses to efficiently
and reliably characterize benefit/risk ratio of
dose response.
FDA/Industry Workshop
September 14-16, 2005
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Overview of 8 PISC Initiatives
4. Biomarker Working Group
5. Enriched patient population trial designs
6. Data Mining Tool Validation
7. Accelerated Proof of Concept
8. Predictive Models for Safety and Efficacy
Working Group
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
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ECR
3 key topics:
•
Obtaining sufficient safety data
•
Data reduction and operational efficiency
•
Efficient study design
FDA/Industry Workshop
September 14-16, 2005
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ECR: Safety Information
•
Goal: Increasing knowledge of safety
while improving efficiency of late-stage
clinical studies
•
Rare serious AEs cannot be adequately
assessed pre-approval
–
Phase 3 duration and sample size cannot be
sufficiently extended
FDA/Industry Workshop
September 14-16, 2005
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ECR: Safety Information
•
Consider post-marketing LSSS (Large
Simple Safety Study)
–
Internet based study
–
Relatively inexpensive, yet includes 10,000 –
100,000 exposures or more
•
Study of large prescribing database
–
•
FDA Drug Safety and Risk Management
Advisory Committee Meeting, May 18, 2005
Issue: Lack of control group,
randomization
FDA/Industry Workshop
September 14-16, 2005
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ECR: Data Reduction and Operational
Efficiency
•
Lessen frequency of expensive
procedures
–
•
e.g. lab data, lab reference ranges
Reduce study monitoring
FDA/Industry Workshop
September 14-16, 2005
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ECR: Data Reduction and Operational
Efficiency
•
Efficiency in Clinical Operations
–
Electronic Data Capture (EDC)
–
Standard database designs
–
Standard statistical analysis programs/tables
–
Internet-based trials
–
Handheld devices
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Multiple co-primary endpoints
•
PhRMA Multiple Endpoints Expert Team
(MEET) has researched this problem
•
Position paper shared with FDA and
submitted to DIJ
•
Optimal solution is medical one – reduce
dimensionality to a single primary
endpoint
–
Choose one
–
Create composite
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Multiple co-primary endpoints
•
Under complete null space, no upwards
adjustment to nominal alpha levels is
permissible
•
Statistical adjustment under reasonable
restricted null space is very modest
•
Recent actions:
–
IMMPACT (Initiative on Methods,
Measurement, and Pain Assessment in CTs)
– single primary endpoint for pain
–
Migraine AC (Aug 4) – 2-hour pain response
is single primary endpoint
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Multiple co-primary endpoints
•
What about key secondary endpoints?
–
Suggest moving away from gatekeeping
strategy
–
If academic, FDA, and industry
scientists/experts can agree on a set of key
secondary endpoints that help define and
describe the disease, then…..
–
All of these should be summarized in Clinical
Studies Section of product labeling (+ or -)
–
Helps address “personalized medicine”
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Non-inferiority designs
•
Margin selection
•
The following two paradigms lead to vastly
differing size of study:
–
Indirect demonstration of superiority to
placebo (had a placebo group been in the trial)
–
Preservation of a certain fraction of the active
control's effect
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Flexible dosing
•
In such a design, patients and/or
physicians are allowed to alter dose
based on response
•
Alternative to searching for “the single”
dose which is right for all patients
•
Diseases where response can be
assessed in short period of time are
candidate
–
e.g., migraine, acute and chronic pain
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Flexible dosing
•
Comparisons between dose “groups” is
problematic
–
Can summarize % patients receiving
available doses
•
Separation of drug and placebo groups is
maximized
•
Mimics clinical practice
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Enrichment Designs
•
Biomarkers, ____-omics, or other
attribute can lead to restriction of study
population to those most likely to
respond to study drug
•
Two drugs may be identical on an
“average” basis, but one might be best
for one subpopulation, the other for
another subpopulation
–
If can’t predict going into the study, a
crossover design might be a candidate to
evaluate this aspect
FDA/Industry Workshop
September 14-16, 2005
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ECR: Efficient Study Design
Additional Topics
•
Surrogate endpoints
•
Categorization of continuous data
•
Appropriate methods for handling
missing data: Mixed Models Repeated
Measures (MMRM) vs. LOCF
–
•
Lieberman et al (Neuropsychopharmacology
2005 30, pp 445-460: “Contemporary
approaches to handling missing data
(Mallinckrodt et al, 2003, 2001) Entsuah,
1996) are highly preferable….”
“Pure” ITT
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
33
Adaptive Designs: Opportunity
• Improve quality, speed and efficiency of
decision making within clinical development
– Bring more winners onto market quickly
– Discard losers early
– Shift towards a more seamless integrated
approach to clinical drug development
• Optimize patient treatment within a trial
– Maximize patient exposure to doses/drugs that work
– Minimize patient exposure to doses/drugs that don’t
work
FDA/Industry Workshop
September 14-16, 2005
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Adaptive Designs: What
• Any design which uses accumulating data
to modify aspects of the trial
• Adaptations can include:
– Sample size (stopping early, increasing sample size)
– Treatment allocation ratios
– Dose / Treatment arms (dropping, adding arms)
– Adapting hypothesis (primary objective, primary endpoint)
– Patient population (entry criteria)
– Observational scheme
– Test statistics
– Stages of the experiment (e.g. seamless phase II/III)
– Dynamic randomization based on baseline covariates
FDA/Industry Workshop
September 14-16, 2005
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Adaptive Designs: How
• Facilitate understanding and
implementation of adaptive designs through
the deliverables of the working group
• Adaptive designs not yet routinely used:
–
Perception that there might be regulatory concerns
–
Additional time/upfront investment required to
design/implement non-standard designs
–
Lack of internal/external buy-in to concept
–
Lack of infrastructure for timely data collection and data
analysis
–
Lack of training and experience in best practices for
adaptive design methods
FDA/Industry Workshop
September 14-16, 2005
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Adaptive Design: Focused Topics
• Rationale – when to adapt
• Definition and classification of adaptive
designs
• Dose-response finding
• Seamless phase II/III
• Implementation issues
• Sample size re-estimation
• Case studies
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
38
Rolling Dose Studies: Why?
• Poor understanding of dose response
(efficacy and safety) of drugs plagues
clinical development
• Indicated by both FDA and Industry as one
of leading causes of late phase attrition
and post-marketing problems with
approved drugs
• Current designs and methods for dose
finding focus on selection of MED out of
fixed, generally small number of doses, via
hypothesis testing  inefficient
FDA/Industry Workshop
September 14-16, 2005
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Rolling Dose Studies: What?
• Flexible designs for investigating dose
response, allowing dynamic allocation of
patients to a larger, possibly variable
number of doses
• Main goal: efficiently learn about dose
response profiles for efficacy and safety to
characterize benefit/risk over dose range
• Better, faster decision making on dose
selection and improved labeling
• Emphasis on modeling and estimation, as
opposed to hypothesis testing
FDA/Industry Workshop
September 14-16, 2005
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Rolling Dose Studies: How?
• Identify and investigate existing designs
and methods for flexible dose finding
• Adapt current methods and develop new
ones to create suite of designs and
statistical methods for efficient dose
response learning under various CT
scenarios (e.g., availability of biomarker,
single drug or combination)
• Evaluate potential benefits over traditional
designs to make recommendations on
practical usefulness of rolling dose studies
FDA/Industry Workshop
September 14-16, 2005
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Outline
• Introduction
• Highlights of FDA’s Critical Path Paper
• PhRMA initiatives to address Critical Path
– Overview of 8 PISC Initiatives
– Improving Efficiency of Late-Stage Clinical
Research (ECR)
– Adaptive Designs
– Rolling Dose Studies
– Biomarkers
FDA/Industry Workshop
September 14-16, 2005
42
Biomarkers
• Some are useful for predicting in early
phase clinical research which drugs will be
successfully approved for marketing
• Some help identify the “right patient”
(targeted therapeutics)
– May or may not be ____-omics based
• Some may be elevated to become a
surrogate marker
FDA/Industry Workshop
September 14-16, 2005
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FDA/Industry Workshop
September 14-16, 2005
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Summary Comments
• FDA’s Critical Path white paper has opened
the door to exciting opportunities for
improving the current drug development
paradigm
• All opportunities are in need of statistical
input and direction
FDA/Industry Workshop
September 14-16, 2005
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