1. FDA/Industry Workshop September 14-16, 2005 Critical Path Initiative: What it means for pharmaceutical industry statisticians Walter Offen, Lilly Brenda Gaydos, Lilly José Pinheiro, Novartis

2. FDA/Industry Workshop September 14-16, 2005 2 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

3. FDA/Industry Workshop September 14-16, 2005 3 Introduction March, 2004: FDA published Innovation- Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products – http://www.fda.gov/oc/initiatives/criticalpath/w hitepaper.html (or ___. pdf) Industry has been working on a number of the issues raised Strong synergies between FDA, academia/NIH, and industry are possible March, 2004: FDA published Innovation- Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products – http://www.fda.gov/oc/initiatives/criticalpath/w hitepaper.html (or ___. pdf) Industry has been working on a number of the issues raised Strong synergies between FDA, academia/NIH, and industry are possible

4. FDA/Industry Workshop September 14-16, 2005 4 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

5. FDA/Industry Workshop September 14-16, 2005 5 Highlights of Critical Path Paper [my underlines] …the current medical product 1 development path is becoming increasingly challenging, inefficient, and costly. 1 …costs of product development have soared over the last decade. …the current medical product 1 development path is becoming increasingly challenging, inefficient, and costly. 1 …costs of product development have soared over the last decade.

6. FDA/Industry Workshop September 14-16, 2005 6 Highlights of Critical Path Paper [my underlines] Not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs. Finally, the path to market even for successful candidates is long, costly, and inefficient, due in large part to the current reliance on cumbersome assessment methods. Not enough applied scientific work has been done to create new tools to get fundamentally better answers about how the safety and effectiveness of new products can be demonstrated, in faster time frames, with more certainty, and at lower costs. Finally, the path to market even for successful candidates is long, costly, and inefficient, due in large part to the current reliance on cumbersome assessment methods.

7. FDA/Industry Workshop September 14-16, 2005 7 Highlights of Critical Path Paper The goal of critical path research is to develop new, publicly available scientific and technical tools -- including assays, standards, computer modeling techniques, biomarkers, and clinical trial endpoints -- that make the development process itself more efficient and effective and more likely to result in safe products that benefit patients.

8. FDA/Industry Workshop September 14-16, 2005 8 Highlights of Critical Path Paper …correlate early markers of safety and benefit with actual outcomes in patients. …these new technologies could provide tools to detect safety problems early, identify patients likely to respond to therapy, and lead to new clinical endpoints. …correlate early markers of safety and benefit with actual outcomes in patients. …these new technologies could provide tools to detect safety problems early, identify patients likely to respond to therapy, and lead to new clinical endpoints.

9. FDA/Industry Workshop September 14-16, 2005 9 Highlights of Critical Path Paper …much more attention and creativity need to be applied to disease-specific trial design and endpoints intended to evaluate the effects of medical products. …problems are often uncovered only during clinical trials or, occasionally, after marketing. …much more attention and creativity need to be applied to disease-specific trial design and endpoints intended to evaluate the effects of medical products. …problems are often uncovered only during clinical trials or, occasionally, after marketing.

10. FDA/Industry Workshop September 14-16, 2005 10 Highlights of Critical Path Paper Clinical testing, even if extensive, often fails to detect important safety problems, either because they are uncommon or because the tested population was not representative of eventual recipients. Conversely, some models create worrisome signals that may, in fact, not be predictive of a human safety problem.

11. FDA/Industry Workshop September 14-16, 2005 11 Highlights of Critical Path Paper Adopting a new biomarker or surrogate endpoint for effectiveness standards can drive rapid clinical development. For example, FDA adoption of CD4 cell counts and, subsequently, measures of viral load as surrogate markers for anti-HIV drug approvals allowed the rapid clinical workup and approval of life-saving antiviral drugs…

12. FDA/Industry Workshop September 14-16, 2005 12 Highlights of Critical Path Paper FDA adoption of the eradication of H. pylori as a surrogate for duodenal ulcer healing greatly simplified the path of those therapies to the market.

13. FDA/Industry Workshop September 14-16, 2005 13 Highlights of Critical Path Paper There are many important additional opportunities in the area of clinical trial design and analysis. More clinically relevant endpoints need to be developed for many diseases. Enrichment designs have the potential for providing much earlier assurance of drug activity. Bayesian approaches to analysis need to be further explored.

14. FDA/Industry Workshop September 14-16, 2005 14 Highlights of Critical Path Paper This must be a joint effort involving the academic research community, industry, and scientists at the FDA…

15. FDA/Industry Workshop September 14-16, 2005 15 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

16. FDA/Industry Workshop September 14-16, 2005 16 Overview of 8 PISC Initiatives [ PISC = Pharmaceutical Innovation Steering Committee ] 1.Improving Efficiency of Late-Stage Clinical Research (ECR) [Walt Offen] – CTs have become increasingly large and expensive in recent years; team hopes to identify means to improve efficiencies, including improved post-approval safety data collection and evaluation, study design improvements, and use of technology [ PISC = Pharmaceutical Innovation Steering Committee ] 1.Improving Efficiency of Late-Stage Clinical Research (ECR) [Walt Offen] – CTs have become increasingly large and expensive in recent years; team hopes to identify means to improve efficiencies, including improved post-approval safety data collection and evaluation, study design improvements, and use of technology

17. FDA/Industry Workshop September 14-16, 2005 17 Overview of 8 PISC Initiatives 2.Novel Adaptive Clinical Trial Design [Brenda Gaydos] –Collaborate with FDA, academia, and across the industry to develop accepted methodologies required to achieve development efficiency advantages 3.Rolling Dose Studies [José Pinheiro] – Develop and investigate dynamic CT designs with changing number of doses to efficiently and reliably characterize benefit/risk ratio of dose response. 2.Novel Adaptive Clinical Trial Design [Brenda Gaydos] –Collaborate with FDA, academia, and across the industry to develop accepted methodologies required to achieve development efficiency advantages 3.Rolling Dose Studies [José Pinheiro] – Develop and investigate dynamic CT designs with changing number of doses to efficiently and reliably characterize benefit/risk ratio of dose response.

18. FDA/Industry Workshop September 14-16, 2005 18 Overview of 8 PISC Initiatives 4.Biomarker Working Group 5.Enriched patient population trial designs 6.Data Mining Tool Validation 7.Accelerated Proof of Concept 8.Predictive Models for Safety and Efficacy Working Group 4.Biomarker Working Group 5.Enriched patient population trial designs 6.Data Mining Tool Validation 7.Accelerated Proof of Concept 8.Predictive Models for Safety and Efficacy Working Group

19. FDA/Industry Workshop September 14-16, 2005 19 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

20. FDA/Industry Workshop September 14-16, 2005 20 ECR 3 key topics: Obtaining sufficient safety data Data reduction and operational efficiency Efficient study design 3 key topics: Obtaining sufficient safety data Data reduction and operational efficiency Efficient study design

21. FDA/Industry Workshop September 14-16, 2005 21 ECR: Safety Information Goal: Increasing knowledge of safety while improving efficiency of late-stage clinical studies Rare serious AEs cannot be adequately assessed pre-approval – Phase 3 duration and sample size cannot be sufficiently extended Goal: Increasing knowledge of safety while improving efficiency of late-stage clinical studies Rare serious AEs cannot be adequately assessed pre-approval – Phase 3 duration and sample size cannot be sufficiently extended

22. FDA/Industry Workshop September 14-16, 2005 22 ECR: Safety Information Consider post-marketing LSSS (Large Simple Safety Study) – Internet based study – Relatively inexpensive, yet includes 10,000 – 100,000 exposures or more Study of large prescribing database – FDA Drug Safety and Risk Management Advisory Committee Meeting, May 18, 2005 Issue: Lack of control group, randomization Consider post-marketing LSSS (Large Simple Safety Study) – Internet based study – Relatively inexpensive, yet includes 10,000 – 100,000 exposures or more Study of large prescribing database – FDA Drug Safety and Risk Management Advisory Committee Meeting, May 18, 2005 Issue: Lack of control group, randomization

23. FDA/Industry Workshop September 14-16, 2005 23 ECR: Data Reduction and Operational Efficiency Lessen frequency of expensive procedures – e.g. lab data, lab reference ranges Reduce study monitoring Lessen frequency of expensive procedures – e.g. lab data, lab reference ranges Reduce study monitoring

24. FDA/Industry Workshop September 14-16, 2005 24 ECR: Data Reduction and Operational Efficiency Efficiency in Clinical Operations – Electronic Data Capture (EDC) – Standard database designs – Standard statistical analysis programs/tables – Internet-based trials – Handheld devices Efficiency in Clinical Operations – Electronic Data Capture (EDC) – Standard database designs – Standard statistical analysis programs/tables – Internet-based trials – Handheld devices

25. FDA/Industry Workshop September 14-16, 2005 25 ECR: Efficient Study Design Multiple co-primary endpoints PhRMA Multiple Endpoints Expert Team (MEET) has researched this problem Position paper shared with FDA and submitted to DIJ Optimal solution is medical one – reduce dimensionality to a single primary endpoint – Choose one – Create composite PhRMA Multiple Endpoints Expert Team (MEET) has researched this problem Position paper shared with FDA and submitted to DIJ Optimal solution is medical one – reduce dimensionality to a single primary endpoint – Choose one – Create composite

26. FDA/Industry Workshop September 14-16, 2005 26 ECR: Efficient Study Design Multiple co-primary endpoints Under complete null space, no upwards adjustment to nominal alpha levels is permissible Statistical adjustment under reasonable restricted null space is very modest Recent actions: – IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in CTs) – single primary endpoint for pain – Migraine AC (Aug 4) – 2-hour pain response is single primary endpoint Under complete null space, no upwards adjustment to nominal alpha levels is permissible Statistical adjustment under reasonable restricted null space is very modest Recent actions: – IMMPACT (Initiative on Methods, Measurement, and Pain Assessment in CTs) – single primary endpoint for pain – Migraine AC (Aug 4) – 2-hour pain response is single primary endpoint

27. FDA/Industry Workshop September 14-16, 2005 27 ECR: Efficient Study Design Multiple co-primary endpoints What about key secondary endpoints? – Suggest moving away from gatekeeping strategy – If academic, FDA, and industry scientists/experts can agree on a set of key secondary endpoints that help define and describe the disease, then….. – All of these should be summarized in Clinical Studies Section of product labeling (+ or -) – Helps address personalized medicine What about key secondary endpoints? – Suggest moving away from gatekeeping strategy – If academic, FDA, and industry scientists/experts can agree on a set of key secondary endpoints that help define and describe the disease, then….. – All of these should be summarized in Clinical Studies Section of product labeling (+ or -) – Helps address personalized medicine

28. FDA/Industry Workshop September 14-16, 2005 28 ECR: Efficient Study Design Non-inferiority designs Margin selection The following two paradigms lead to vastly differing size of study: – Indirect demonstration of superiority to placebo (had a placebo group been in the trial) – Preservation of a certain fraction of the active control's effect Margin selection The following two paradigms lead to vastly differing size of study: – Indirect demonstration of superiority to placebo (had a placebo group been in the trial) – Preservation of a certain fraction of the active control's effect

29. FDA/Industry Workshop September 14-16, 2005 29 ECR: Efficient Study Design Flexible dosing In such a design, patients and/or physicians are allowed to alter dose based on response Alternative to searching for the single dose which is right for all patients Diseases where response can be assessed in short period of time are candidate – e.g., migraine, acute and chronic pain In such a design, patients and/or physicians are allowed to alter dose based on response Alternative to searching for the single dose which is right for all patients Diseases where response can be assessed in short period of time are candidate – e.g., migraine, acute and chronic pain

30. FDA/Industry Workshop September 14-16, 2005 30 ECR: Efficient Study Design Flexible dosing Comparisons between dose groups is problematic – Can summarize % patients receiving available doses Separation of drug and placebo groups is maximized Mimics clinical practice Comparisons between dose groups is problematic – Can summarize % patients receiving available doses Separation of drug and placebo groups is maximized Mimics clinical practice

31. FDA/Industry Workshop September 14-16, 2005 31 ECR: Efficient Study Design Enrichment Designs Biomarkers, ____-omics, or other attribute can lead to restriction of study population to those most likely to respond to study drug Two drugs may be identical on an average basis, but one might be best for one subpopulation, the other for another subpopulation – If cant predict going into the study, a crossover design might be a candidate to evaluate this aspect Biomarkers, ____-omics, or other attribute can lead to restriction of study population to those most likely to respond to study drug Two drugs may be identical on an average basis, but one might be best for one subpopulation, the other for another subpopulation – If cant predict going into the study, a crossover design might be a candidate to evaluate this aspect

32. FDA/Industry Workshop September 14-16, 2005 32 ECR: Efficient Study Design Additional Topics Surrogate endpoints Categorization of continuous data Appropriate methods for handling missing data: Mixed Models Repeated Measures (MMRM) vs. LOCF – Lieberman et al (Neuropsychopharmacology 2005 30, pp 445-460: Contemporary approaches to handling missing data (Mallinckrodt et al, 2003, 2001) Entsuah, 1996) are highly preferable…. Pure ITT Surrogate endpoints Categorization of continuous data Appropriate methods for handling missing data: Mixed Models Repeated Measures (MMRM) vs. LOCF – Lieberman et al (Neuropsychopharmacology 2005 30, pp 445-460: Contemporary approaches to handling missing data (Mallinckrodt et al, 2003, 2001) Entsuah, 1996) are highly preferable…. Pure ITT

33. FDA/Industry Workshop September 14-16, 2005 33 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

34. FDA/Industry Workshop September 14-16, 2005 34 Adaptive Designs: Opportunity Improve quality, speed and efficiency of decision making within clinical development – Bring more winners onto market quickly – Discard losers early – Shift towards a more seamless integrated approach to clinical drug development Optimize patient treatment within a trial – Maximize patient exposure to doses/drugs that work – Minimize patient exposure to doses/drugs that dont work Improve quality, speed and efficiency of decision making within clinical development – Bring more winners onto market quickly – Discard losers early – Shift towards a more seamless integrated approach to clinical drug development Optimize patient treatment within a trial – Maximize patient exposure to doses/drugs that work – Minimize patient exposure to doses/drugs that dont work

35. FDA/Industry Workshop September 14-16, 2005 35 Adaptive Designs: What Any design which uses accumulating data to modify aspects of the trial Adaptations can include: – Sample size (stopping early, increasing sample size) – Treatment allocation ratios – Dose / Treatment arms (dropping, adding arms) – Adapting hypothesis (primary objective, primary endpoint) – Patient population (entry criteria) – Observational scheme – Test statistics – Stages of the experiment (e.g. seamless phase II/III) – Dynamic randomization based on baseline covariates Any design which uses accumulating data to modify aspects of the trial Adaptations can include: – Sample size (stopping early, increasing sample size) – Treatment allocation ratios – Dose / Treatment arms (dropping, adding arms) – Adapting hypothesis (primary objective, primary endpoint) – Patient population (entry criteria) – Observational scheme – Test statistics – Stages of the experiment (e.g. seamless phase II/III) – Dynamic randomization based on baseline covariates

36. FDA/Industry Workshop September 14-16, 2005 36 Adaptive Designs: How Facilitate understanding and implementation of adaptive designs through the deliverables of the working group Adaptive designs not yet routinely used: – Perception that there might be regulatory concerns – Additional time/upfront investment required to design/implement non-standard designs – Lack of internal/external buy-in to concept – Lack of infrastructure for timely data collection and data analysis – Lack of training and experience in best practices for adaptive design methods Facilitate understanding and implementation of adaptive designs through the deliverables of the working group Adaptive designs not yet routinely used: – Perception that there might be regulatory concerns – Additional time/upfront investment required to design/implement non-standard designs – Lack of internal/external buy-in to concept – Lack of infrastructure for timely data collection and data analysis – Lack of training and experience in best practices for adaptive design methods

37. FDA/Industry Workshop September 14-16, 2005 37 Adaptive Design: Focused Topics Rationale – when to adapt Definition and classification of adaptive designs Dose-response finding Seamless phase II/III Implementation issues Sample size re-estimation Case studies Rationale – when to adapt Definition and classification of adaptive designs Dose-response finding Seamless phase II/III Implementation issues Sample size re-estimation Case studies

38. FDA/Industry Workshop September 14-16, 2005 38 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

39. FDA/Industry Workshop September 14-16, 2005 39 Rolling Dose Studies: Why? Poor understanding of dose response (efficacy and safety) of drugs plagues clinical development Indicated by both FDA and Industry as one of leading causes of late phase attrition and post-marketing problems with approved drugs Current designs and methods for dose finding focus on selection of MED out of fixed, generally small number of doses, via hypothesis testing inefficient Poor understanding of dose response (efficacy and safety) of drugs plagues clinical development Indicated by both FDA and Industry as one of leading causes of late phase attrition and post-marketing problems with approved drugs Current designs and methods for dose finding focus on selection of MED out of fixed, generally small number of doses, via hypothesis testing inefficient

40. FDA/Industry Workshop September 14-16, 2005 40 Rolling Dose Studies: What? Flexible designs for investigating dose response, allowing dynamic allocation of patients to a larger, possibly variable number of doses Main goal: efficiently learn about dose response profiles for efficacy and safety to characterize benefit/risk over dose range Better, faster decision making on dose selection and improved labeling Emphasis on modeling and estimation, as opposed to hypothesis testing Flexible designs for investigating dose response, allowing dynamic allocation of patients to a larger, possibly variable number of doses Main goal: efficiently learn about dose response profiles for efficacy and safety to characterize benefit/risk over dose range Better, faster decision making on dose selection and improved labeling Emphasis on modeling and estimation, as opposed to hypothesis testing

41. FDA/Industry Workshop September 14-16, 2005 41 Rolling Dose Studies: How? Identify and investigate existing designs and methods for flexible dose finding Adapt current methods and develop new ones to create suite of designs and statistical methods for efficient dose response learning under various CT scenarios (e.g., availability of biomarker, single drug or combination) Evaluate potential benefits over traditional designs to make recommendations on practical usefulness of rolling dose studies Identify and investigate existing designs and methods for flexible dose finding Adapt current methods and develop new ones to create suite of designs and statistical methods for efficient dose response learning under various CT scenarios (e.g., availability of biomarker, single drug or combination) Evaluate potential benefits over traditional designs to make recommendations on practical usefulness of rolling dose studies

42. FDA/Industry Workshop September 14-16, 2005 42 Outline Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers Introduction Highlights of FDAs Critical Path Paper PhRMA initiatives to address Critical Path – Overview of 8 PISC Initiatives – Improving Efficiency of Late-Stage Clinical Research (ECR) – Adaptive Designs – Rolling Dose Studies – Biomarkers

43. FDA/Industry Workshop September 14-16, 2005 43 Biomarkers Some are useful for predicting in early phase clinical research which drugs will be successfully approved for marketing Some help identify the right patient (targeted therapeutics) – May or may not be ____-omics based Some may be elevated to become a surrogate marker Some are useful for predicting in early phase clinical research which drugs will be successfully approved for marketing Some help identify the right patient (targeted therapeutics) – May or may not be ____-omics based Some may be elevated to become a surrogate marker

44. FDA/Industry Workshop September 14-16, 2005 44

45. FDA/Industry Workshop September 14-16, 2005 45 Summary Comments FDAs Critical Path white paper has opened the door to exciting opportunities for improving the current drug development paradigm All opportunities are in need of statistical input and direction FDAs Critical Path white paper has opened the door to exciting opportunities for improving the current drug development paradigm All opportunities are in need of statistical input and direction