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European Statistical meeting on Oncology Thursday 24 th , June 2010

European Statistical meeting on Oncology Thursday 24 th , June 2010. Introduction - Challenges in development in Oncology H.U. Burger, Hoffmann-La Roche. Some challenges in Oncology. Early developments: Dose determination for safety and/or efficacy Proof of concept study designs

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European Statistical meeting on Oncology Thursday 24 th , June 2010

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  1. European Statistical meeting on OncologyThursday 24th, June 2010 Introduction - Challenges in development in Oncology H.U. Burger, Hoffmann-La Roche

  2. Some challenges in Oncology • Early developments: • Dose determination for safety and/or efficacy • Proof of concept study designs • Late development: • PFS versus OS as endpoint • Go-No Go decisions for phase III • Personalized health care strategies

  3. Early Developments in Oncology • Since about 10 years the paradigm of developing oncology drugs has changed • More and more biological treatments are developed for oncology indications • Targeted therapies play a larger role (pathway and mechanism of actions) • Balance between safety and efficacy more important with more effective treatments available • Therefore, aspects which have not been so important in the past become more dominant. This concerns • Proof of concept for biologics or combination regimen • Dose finding using alternative approaches (e.g. model-based approaches)

  4. The Classical development paradigm in Oncology • Phase I: Dose escalation to define the dose for development as the highest tolerable dose (MTD, 3+3 design classically based on ~ 20 to 40 patients) • Phase II: Proof of concept: “One” responder is sufficient to prove anti tumor activity and to move into phase III (based on ~ 40 patients) • Phase III: Large randomized clinical trial to confirm efficacy versus standard or in combination with standard versus standard

  5. Challenge: Proof of concept • Classically, proof of concept for a cytotoxic therapy was based on a single arm monotherapy study in phase IIwhere some tumor responses were sufficient to warrant the compound to go into phase III • What triggers today proof of concept ? • For biologics, responses not necessarily expected • For combination therapies, responses can originate from the combination partner => Proof of concept more and more based on randomized studies including time to event endpoints; increasing role of the biomarker data

  6. Challenge: Dose finding • Dose finding originally based on MTD trials for safety • CRM methods introduced with the potential to improve the precision of such studies to determine a dose with a certain toxicity threshold • More flexible two-parameter Bayesian logistic models developed to better characterize the dose-toxicity relationship • For most of biologic therapies in oncology, maximal tolerated doses become irrelevant as therapeutic effects are already achieved at lower doses  Optimal biologic dose or dose range leading to phase II dose finding studies

  7. Late Developments in Oncology • Go-No Go decisions become more complex • More sophisticated methods used in early development. Efficacy assessment not based on single responses observed anymore • More competitive environment requiring new risk-benefit assessments • Discussion around phase III endpoints never ending story • Overall survival (OS) clinically most relevant but sometimes difficult to observe and frequently leads to long studies • What are suitable surrogate endpoints for OS • Response rates ? • MRD (minimal residual disease) ? • Progression-free survival ?

  8. Late Developments in Oncology • Targeted therapies: Personalized health care major development challenge in the future • Three types of development scenarios • New treatment for all comers • New treatment only for a subset of patient (defined by biomarker) • Right population unknown upfront • For last case challenges in development potentially huge

  9. Today's Session 08:45-09:15 Registration Chair: Hans-Ulrich Burger (Hoffmann-La Roche) 09:15-09:30 Introduction – Challenges in early phase development of Oncology, Hans-Ulrich Burger (Hoffmann-La Roche) 09:30-10:10 Understanding Progression-free Survival, Bertil Jonsson, MD (Medical Products Agency) 10:10-10:50 IRESSA: A Journey of Experience from Broad to Biomarker Populations, Claire Watkins (AstraZeneca) 10:50-11:15 CoffeeChair: Pierre Verweij (Merck and EFSPI) 11:15-11:55 Adaptive Bayesian Designs for Phase I Oncology Trials,Stuart Bailey (Novartis) 11:55-12:35 Oncology Dose Finding – A Case Study, Jonas Wiedemann (Hoffmann-La Roche)

  10. Today's Session 12:35-13:35 Lunch Chair: Nigel Howitt (PRA International and EFSPI) 13:35-14:15 Bayesian Hierarchical Modelling of Clinical Response in NSCLC Subpopulations, Simon Wandel (Novartis) 14:15-14:55 The Time to Progression Ratio for Phase II Trials of Personalized Medicine, Marc Buyse (IDDI and University of Hasselt) 14:55-15:20 CoffeeChair: Hans-Ulrich Burger (Hoffmann-La Roche) 15:20-16:00 Optimal Cost-Effective Go-No Go Decisions in Late-Stage Oncology Drug Development, Cong Chen (Merck) 16:00-16:40 Panel Discussion

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