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The Statisticians Role in Pharmaceutical Development
Margaret Minkwitz, PhD
February 15, 2007
Steps in the process Compound delivered from Discovery Early studies
Pre Clinical Clinical
Development for market launch Regulatory Submission Approval Life Cycle Management
Organization of talk Overview of the process step Statistician’s role
Responsibilities Statistics at AstraZeneca
Discovery Step 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 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)
Provide scientific method thinking into the target evaluation process
Assess the ability to Quantify effect on target of interest 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 Cross functional team members have different
goals and needs Statistician needs to be aware of competing needs
of stake holders 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 Pharmacokinetics
Dose finding Single ascending dose Multiple ascending dose
Metabolism and elimination Drug interaction studies
Early Clinical Stage Is the compound safe
enough to dose in an effective range
What are the kinetic properties Linear dose response Accumulation on
multiple dosing
Statistical responsibilities 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 Relatively small sample sizes in studies
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 Clinical Development Plan
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
Is there something we can demonstrate value for the patient (efficacy or safety)
Aspects of development for market Proof of concept Dose selection Confirmatory studies (minimum of 2) Long term safety studies Studies based on propertied of drug
Thorough QT study for ECG changes Interaction studies based on concomitant use
or metabolic pathway
Statistical responsibilities in development phase
Study design decisions Selection of Primary
endpoints for studies Risk assessment
need to adjust for multiple comparisons?
Interim analyses
Quantification of decision criteria
Data Monitoring Boards
Challenges Statistics represented at several levels
Ensuring one voice (consistency) Regulatory guidelines in place
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 Synthesize the data Provide thorough
structure description Provide standardized
information in agreed format
Support the package Agree the label
Statistical Responsibility 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 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 Product is on the market
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
Statistician’s responsibilities 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
Statistician – usually study statistician Study Design Concept Plan to protocol
Provides link between objectives and variables Provides design and sample size justification Contributes the statistical analysis
Writes Statistical analysis plan 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
Senior Statistician Supports Project (several studies at once)
Study statistician responsibilities
Leads delivery teams – project management as well as statistical responsibilities Cross functional leadership
Mentor or coach statistician level
Statistical Positions and Roles at AstraZeneca
Principal Statistician 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
Starts to work more closely with the Global team on risk assessment and mitigation plans Uses experience and statistical knowledge to
facilitate quantification of risk
Statistical Positions and Roles at AstraZeneca
Statistician Science Director Biostatistics leadership within the company
May have research or other key initiative activities for the company
Project leadership roles Global Product Statistician Therapeutic area Global Statistician
Statistical Positions and Roles at AstraZeneca
Global Product Statistician 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
Therapeutic Area Global Statistician 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