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

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

Introduction • March, 2004: FDA published “Innovation. Stagnation: Challenge and Opportunity on the Critical 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 FDA/Industry Workshop September 14 -16, 2005 3

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

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

Highlights of Critical Path Paper [my underlines] • “Not enough applied scientific work has 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. ” FDA/Industry Workshop September 14 -16, 2005 6

Highlights of Critical Path Paper • “The goal of critical path research is to 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. ” FDA/Industry Workshop September 14 -16, 2005 7

Highlights of Critical Path Paper • “…correlate early markers of safety and benefit with 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. ” FDA/Industry Workshop September 14 -16, 2005 8

Highlights of Critical Path Paper • “…much more attention and creativity need to be 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. ” FDA/Industry Workshop September 14 -16, 2005 9

Highlights of Critical Path Paper • “Clinical testing, even if extensive, often fails to 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. ” FDA/Industry Workshop September 14 -16, 2005 10

Highlights of Critical Path Paper • “Adopting a new biomarker or surrogate endpoint for 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 CD 4 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…” FDA/Industry Workshop September 14 -16, 2005 11

Highlights of Critical Path Paper • “FDA adoption of the eradication of H. pylori 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. ” FDA/Industry Workshop September 14 -16, 2005 12

Highlights of Critical Path Paper • “There are many important additional opportunities in the 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. ” FDA/Industry Workshop September 14 -16, 2005 13

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

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

Overview of 8 PISC Initiatives [ PISC = Pharmaceutical Innovation Steering Committee ] 1. 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 FDA/Industry Workshop September 14 -16, 2005 16

Overview of 8 PISC Initiatives 2. Novel Adaptive Clinical Trial Design [Brenda Gaydos] – 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. FDA/Industry Workshop September 14 -16, 2005 17

Overview of 8 PISC Initiatives 4. Biomarker Working Group 5. Enriched patient population trial 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 FDA/Industry Workshop September 14 -16, 2005 18

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

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

ECR: Safety Information • Goal: Increasing knowledge of safety while improving efficiency of late-stage 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 FDA/Industry Workshop September 14 -16, 2005 21

ECR: Safety Information • Consider post-marketing LSSS (Large Simple Safety Study) – Internet based 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 FDA/Industry Workshop September 14 -16, 2005 22

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

ECR: Data Reduction and Operational Efficiency • Efficiency in Clinical Operations – Electronic Data 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 FDA/Industry Workshop September 14 -16, 2005 24

ECR: Efficient Study Design Multiple co-primary endpoints • Ph. RMA Multiple Endpoints Expert Team ECR: Efficient Study Design Multiple co-primary endpoints • Ph. RMA 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 FDA/Industry Workshop September 14 -16, 2005 25

ECR: Efficient Study Design Multiple co-primary endpoints • Under complete null space, no upwards 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 FDA/Industry Workshop September 14 -16, 2005 26

ECR: Efficient Study Design Multiple co-primary endpoints • What about key secondary endpoints? – 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” FDA/Industry Workshop September 14 -16, 2005 27

ECR: Efficient Study Design Non-inferiority designs • Margin selection • The following two paradigms 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 FDA/Industry Workshop September 14 -16, 2005 28

ECR: Efficient Study Design Flexible dosing • In such a design, patients and/or physicians 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 FDA/Industry Workshop September 14 -16, 2005 29

ECR: Efficient Study Design Flexible dosing • Comparisons between dose “groups” is problematic – 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 FDA/Industry Workshop September 14 -16, 2005 30

ECR: Efficient Study Design Enrichment Designs • Biomarkers, ____-omics, or other attribute can lead 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 FDA/Industry Workshop September 14 -16, 2005 31

ECR: Efficient Study Design Additional Topics • Surrogate endpoints • Categorization of continuous data 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 FDA/Industry Workshop September 14 -16, 2005 32

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

Adaptive Designs: Opportunity • Improve quality, speed and efficiency of decision making within clinical 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 FDA/Industry Workshop September 14 -16, 2005 34

Adaptive Designs: What • Any design which uses accumulating data to modify aspects of 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 FDA/Industry Workshop September 14 -16, 2005 35

Adaptive Designs: How • Facilitate understanding and implementation of adaptive designs through the deliverables 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 FDA/Industry Workshop September 14 -16, 2005 36

Adaptive Design: Focused Topics • Rationale – when to adapt • Definition and classification 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 FDA/Industry Workshop September 14 -16, 2005 37

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

Rolling Dose Studies: Why? • Poor understanding of dose response (efficacy and safety) of 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 FDA/Industry Workshop September 14 -16, 2005 39

Rolling Dose Studies: What? • Flexible designs for investigating dose response, allowing dynamic allocation 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 FDA/Industry Workshop September 14 -16, 2005 40

Rolling Dose Studies: How? • Identify and investigate existing designs and methods for flexible 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 FDA/Industry Workshop September 14 -16, 2005 41

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

Biomarkers • Some are useful for predicting in early phase clinical research which drugs 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 FDA/Industry Workshop September 14 -16, 2005 43

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

Summary Comments • FDA’s Critical Path white paper has opened the door to exciting 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 FDA/Industry Workshop September 14 -16, 2005 45