1. Emerging Trends in Regulatory Biostatistics - What might be their impact ? Robert T. O’Neill Ph.D. Director, Office of Biostatistics Office of Translational Sciences, CDER Presented at the VII Graybill Conference on "Biopharmaceutical Statistics" June 12-13, 2008 ; Colorado State University Hilton Fort Collins, Fort Collins, Colorado

2. Outline u The current environment - trends u Global drug development u Guidance development - consensus building u Quantitative safety assessment u Personalized medicine - benefit / risk u Future needs

3. The current environment u Public expectations for drug regulation and monitoring u Track record for product development success u Increasing amounts of data - does it pay off and inform - is it being used u Emerging science - is statistics involved ? u Increased resources - FDA is hiring but Europe is not

4. The Environment u FDAAA and its implications u Staffing recruitment u Fellowships - Reagan Udall Foundation u New Responsibilities u Guidance development - why u Non Inferiority designs u Adaptive designs u Future - multiple endpoints, missing data u Emerging science -dealing with it u Modeling and simulation - disease modification claims u Genomics and personalized medicine u Quality by design - auditing and inspection strategies u The science of safety/risk assessment - benefit / risk - life cycle evaluation

5. http://www.fda.gov/oc/initiatives/criticalpath/

8. http://www.fda.gov/oc/initiatives/advance/reports/report0508.htmlhttp://www.fda.gov/oc/initiatives/advance/reports/report0508.html.

9. The Emerging Science of Safety

10. The medical literature and editors recognize a need to improve the reporting of safety outcomes

11. Safety First/Safe Use Overview of a New CDER Initiative

12. Rationale: New Realities in the 21 st Century u Two decades ago patients and clinicians lacked effective treatments for most major life-threatening illnesses u Congress and the President gave FDA increased resources and mandates to expedite development and patient access to new drugs [e.g., PDUFA 1992, FDAMA 1997] u Today many more treatments are available, but patterns of drug use and guiding information have shifted dramatically. Patients and clinicians need more accurate, up-to-date and understandable information to ensure safe use u Congress and the President has given FDA increased authority, resources and responsibility to oversee post-market safety and better inform patients and clinicians to enable safe use [FDAAA 2007]

13. Purpose u To ensure drug safety throughout the drug lifecycle by giving pre-marketing drug review and post-marketing safety an equal focus u To develop multiple strategies to influence the safe and appropriate use of drugs

14. The Multi-Regional Multi-center Study Increasingly used in drug product development

16. Some Experience with statistical reviews of NDA’s and Clinical Studies u Summary of review of 7 years of clinical studies involving foreign clinical data in NDA’s u 21 NDA submissions whose decisions depended upon analysis and interpretation of treatment effects in multi-regional trials u John Lawrence evaluation of large cardiovascular outcome studies

17. Of 1,926 clinical trials analyzed by OB during FY01-FY07: 41% were domestic; 50% foreign-domestic; and 9% foreign. Of all subjects enrolled in these trials: 30% were U.S.; 63% domestic-foreign; and 7% foreign.

18. Regulatory consequences u Non approvals u 4 of 22 not approved because of regional heterogeneity u 9 of 22 approvable but more information needed - regional heterogeneity u Need another study u Labeling limitations or information - Merit

19. Study Undertaken by FDA statisticians to evaluate possibility of systematic regional differences u Major cardiovascular outcome studies evaluated over the last 10 years u Overall study result statistically positive, ie. demonstrated overall effect u Region never pre-specified as a factor to be evaluated statistically u 16 independent studies

20. Estimates and confidence intervals for difference between US and Non-US treatment effects for each study J. Lawrence In 13 of 16, US log hazard above 0

21. A figure From the label

25. Among the provisions of the law, FDAAA reauthorizes user fees [PDUFA IV] and increases the resources that CDER will have available for ensuring product safety in the new drug review process, monitoring drug safety after product marketing, and reviewing consumer television ads that are voluntarily submitted to FDA. FDAAA also reauthorizes key programs for ensuring safe use of drug products in children by encouraging more research into developing treatments for children. FDA Amendments Act of 2007 FDAAA

26. Guidance Development FDA actively leading consensus and direction on critical topics u Adaptive clinical study designs u Exploratory and confirmatory u Non-Inferiority study designs u Current literature is inadequate u Missing data in clinical trials u Statistics alone cannot address it u Statistics has not added much - yet u Multiplicity u Enrichment designs, biomarkers, personalized medicine

27. Advancing Innovative Trial Design Why the need for a Guidance on Non-Inferiority Studies ? u Guidance in available documents is not sufficient u Confusion in current usage u Naïve usage u Need for direction on approaches u Clarity on when the design is appropriate

31. Statistics in Medicine Special Issue: Non-Inferiority Trials: Advances in Concepts and Methodology Volume 22, Issue 2, 2003

35. Quantitative Safety Assessment What do we mean ?

36. Emerging Science of Quantitative Safety Assessment u Causal analysis u Propensity score matching u Cumulative meta-analysis u Rare events u Prediction, prognostic, positive predictive value u Multiple recurrent event methods u Time to event analysis for risk exposure

42. Visual graphics to aid interpretation of multivariate, multiple event data (safety and efficacy), and motivate model formulation for later analysis or summary presentations Begin with the electronic chronological patient record to aid patient level interpretation (patient profile viewer) Build on this for population (group) estimates and comparisons

44. Exposure history of test treatment - time course Time of occurrence and duration of ADE’s Exposure history of concomitant medications - time course Lab data Primary outcome Patient time line graph for clinical trial data, AE’s, med. exposures, labs, outcomes Serious event

46. Display of the duration of treatment and follow up and the timing of increases in ALT for the 500 patients in a study receiving a "low" and a "high" dose treatment

52. Personalized Medicine What does that mean ?

66. Where are we going - the future u Resources - very promising for FDA u Outside of the US FDA, the picture is not as rosy - can modern product development flourish without statistical resources

68. Reagan-Udall Foundation for the Food and Drug Administration Summary of Key Provisions “The purpose of the foundation is to advance the mission of the Food and Drug Administration to modernize medical, veterinary, food, food ingredient, and cosmetic product development, accelerate innovation, and enhance product safety.” Fellowships and applied projects useful to the academic community

69. Bioinformatics Access to data, RCT and manufacturing quality assurance u Standards for clinical trial data- CDISC u Access to all clinical trials at the patient level data - not summary data in articles or websites u The quality by design concept for modern RCT’s - FDA’s mandate to monitor and inspect

70. We are looking for a few good statisticians