The Statisticians Role in Pharmaceutical Development

1. The Statisticians Role in Pharmaceutical Development Margaret Minkwitz, PhD February 15, 2007

2. Steps in the process • Compound delivered from Discovery • Early studies • Pre Clinical • Clinical • Development for market launch • Regulatory Submission Approval • Life Cycle Management

3. Organization of talk • Overview of the process step • Statistician’s role • Responsibilities • Statistics at AstraZeneca

4. 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

5. 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

6. 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

7. 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

8. Early Clinical Stage • Pharmacokinetics • Dose finding • Single ascending dose • Multiple ascending dose • Metabolism and elimination • Drug interaction studies

9. 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

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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

16. Regulatory submission and approval • Synthesize the data • Provide thorough structure description • Provide standardized information in agreed format • Support the package • Agree the label

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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