Critical Path Initiative: What it means for pharmaceutical industry statisticians

1. Critical Path Initiative: What it means for pharmaceutical industry statisticians Walter Offen, Lilly Brenda Gaydos, Lilly José Pinheiro, Novartis

2. Outline • Introduction • Highlights of FDA’s 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. 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/whitepaper.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. Outline • Introduction • Highlights of FDA’s 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. Highlights of Critical Path Paper [my underlines] • “…the current medical product1 development path is becoming increasingly challenging, inefficient, and costly.” • “…costs of product development have soared over the last decade.”

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.”

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. 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.”

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.”

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. 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. 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. 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. Highlights of Critical Path Paper • “This must be a joint effort involving the academic research community, industry, and scientists at the FDA…”

15. Outline • Introduction • Highlights of FDA’s 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. Overview of 8 PISC Initiatives [ PISC = Pharmaceutical Innovation Steering Committee ] • 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. Overview of 8 PISC Initiatives • 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 • 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. Overview of 8 PISC Initiatives • Biomarker Working Group • Enriched patient population trial designs • Data Mining Tool Validation • Accelerated Proof of Concept • Predictive Models for Safety and Efficacy Working Group

19. Outline • Introduction • Highlights of FDA’s 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. ECR 3 key topics: • Obtaining sufficient safety data • Data reduction and operational efficiency • Efficient study design

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

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

23. ECR: Data Reduction and Operational Efficiency • Lessen frequency of expensive procedures • e.g. lab data, lab reference ranges • Reduce study monitoring

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

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

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

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”

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

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

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

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 can’t predict going into the study, a crossover design might be a candidate to evaluate this aspect

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

33. Outline • Introduction • Highlights of FDA’s 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. 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 don’t work

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

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

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

38. Outline • Introduction • Highlights of FDA’s 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. 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

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

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

42. Outline • Introduction • Highlights of FDA’s 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. 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

45. Summary Comments • FDA’s 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