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