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