Transcript The Statisticians Role in Pharmaceutical Development

The Statisticians Role in
Pharmaceutical Development
Margaret Minkwitz, PhD
February 15, 2007
Steps in the process
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Compound delivered from Discovery
Early studies
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Pre Clinical
Clinical
Development for market launch
Regulatory Submission Approval
Life Cycle Management
Organization of talk
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Overview of the process step
Statistician’s role
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Responsibilities
Statistics at AstraZeneca
Discovery Step
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Targeted development
Clinical unmet medical
need
Seek series of molecules
that hit target
Select candidates which
have desired activity
Test molecules to
quantify effect on target
Target identification
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What is needed?
What features are
desired?
What is acceptable in
terms of risk?
Cross functional team
comes up with a
Target Product Profile
Statisticians Role (high level, experienced)
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Provide scientific method thinking into the target
evaluation process
Assess the ability to Quantify effect on target of
interest
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Does animal model translate into human
How will effective dose be identified
Provide critical input into quantification of risk
Assist in establishing go/no go decision criteria
Challenges
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Cross functional team members have different
goals and needs
Statistician needs to be aware of competing needs
of stake holders
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Clinical – elegant science, meeting patient needs
Commercial – optimum product to sell
Business – speed to market
Translational science may be in infancy, signal in
animal model not validated in human disease
Early Clinical Stage
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Pharmacokinetics
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Dose finding
Single ascending dose
 Multiple ascending dose
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Metabolism and elimination
Drug interaction studies
Early Clinical Stage
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Is the compound safe
enough to dose in an
effective range
What are the kinetic
properties
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Linear dose response
Accumulation on
multiple dosing
Statistical responsibilities
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Review of margins from animal data
Agree criteria for stopping dose escalation
Plan for Go/No go decision
Ensure program assesses areas of potential
safety risk identified in animal tox studies
Challenges
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Relatively small sample sizes in studies
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Decisions based more on clinical judgment
than statistics
Study designs critical at this stage
Need to get buy in for decision rules put in
place
Development for Market Launch
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Clinical Development Plan
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What needs to be done to support desired
claims in world markets (Regulatory
requirements)
What trials, which drug interaction studies
What are the competitors and their profiles
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Is there something we can demonstrate value for
the patient (efficacy or safety)
Aspects of development for
market
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Proof of concept
Dose selection
Confirmatory studies (minimum of 2)
Long term safety studies
Studies based on propertied of drug
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Thorough QT study for ECG changes
Interaction studies based on concomitant use
or metabolic pathway
Statistical responsibilities in
development phase
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Study design decisions
Selection of Primary
endpoints for studies
Risk assessment
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need to adjust for
multiple comparisons?
Interim analyses
Quantification of
decision criteria
Data Monitoring Boards
Challenges
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Statistics represented at several levels
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Regulatory guidelines in place
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Ensuring one voice (consistency)
Can change during development
Differ across regions
Need to be aware of the environment
High visibility – failures due to incorrect
assumptions are a problem
Clinical and Commercial input may differ
Need good negotiation skills
Regulatory submission and
approval
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Synthesize the data
Provide thorough
structure description
Provide standardized
information in agreed
format
Support the package
Agree the label
Statistical Responsibility
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Provide plan to synthesize the data across the
program
Ensure that the data is clearly reported and
statements are supported by appropriate statistical
analysis
Prepare for questions which may come during
review
Prepare presentation for Advisory panel if needed
Review label language and address regulatory
issues in label
Challenges
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Work as integral part of a larger team – need to
reach consensus on issues
Commercial and drug safety have more influence
in this stage – need to be able to clarify the
statistical issues for non-statisticians
Need to be able to provide information in a way
that facilitates the benefit/risk assessment
In labeling negotiations need to be aware of who
the target audience for the label is
Life Cycle Management
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Product is on the market
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How to we maximize it’s value
Broaden the indications for use
 Identify patients currently not treated
 Look for ways to demonstrate the strength of the
product compared to others
 Look for economic or quality of life benefits
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Statistician’s responsibilities
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Review of Ideas for studies supplied by
outside researchers
Mine registration data to identify scientific
questions we have a reasonable chance of
addressing
Assist in developing plan for new clinical
indications
Evaluate the development risks
Statistical Positions and Roles at AstraZeneca
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Statistician – usually study statistician
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Study Design Concept Plan to protocol
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Writes Statistical analysis plan
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Provides link between objectives and variables
Provides design and sample size justification
Contributes the statistical analysis
detail document for data handling and analysis
Performs analysis and supports the interpretation of
results
Contributes to Study report and publications and
presentations of the data
Statistical Positions and Roles at AstraZeneca
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Senior Statistician
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Supports Project (several studies at once)
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Leads delivery teams – project management
as well as statistical responsibilities
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Study statistician responsibilities
Cross functional leadership
Mentor or coach statistician level
Statistical Positions and Roles at AstraZeneca
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Principal Statistician
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Supports Program (several studies at once)
Oversees the work of Study statistician delivering
a program of work
 Provides Analysis Plan for project level as
template for individual studies
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Starts to work more closely with the Global
team on risk assessment and mitigation plans
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Uses experience and statistical knowledge to
facilitate quantification of risk
Statistical Positions and Roles at AstraZeneca
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Statistician Science Director
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Biostatistics leadership within the company
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May have research or other key initiative activities
for the company
Project leadership roles
Global Product Statistician
 Therapeutic area Global Statistician
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Statistical Positions and Roles at AstraZeneca
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Global Product Statistician
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Input into the Clinical Development Plan
Review responsibilities for all study protocols,
statistical analysis plans, and documents sent to
regulatory authorities
Represent statistics for a product in any regulatory
interactions
Strategic review of data as it comes in to identify
aspects of the drug (risk or benefits)
Support the Commercial function by providing
scientific approach and clarity around messages
Statistical Positions and Roles at AstraZeneca
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Therapeutic Area Global Statistician
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Input into the early stage compounds
Keep abreast of the literature to ensure that
advice is appropriate
Look at the data in the industry landscape to
assess development risks
Support the Commercial function by
providing scientific approach and clarity
around possibilities given current knowledge