Transcript New types of trials: Smaller, faster, cheaper etc.
Traditional vs novel trial designing . Giuseppe M.C. Rosano, MD, PhD Why should we do it faster? From 2000 to 20010, the top 10 pharma companies started more than 1700 new projects/year Loscalzo J (2012) Circulation 125:638-645. Why should we do it faster? • • • • Time Costs Efficiency Innovation 25 Years life-cycle of a drug New chemical entity approval and cost of R&D 1.3B$/Drug From bench to bedside Reasons for termination of clinical development program on NCEs C. K. Atterwill; M. G. Wing Molecular and Cellular Approaches to Lead Optimization in Pharmaceutical Development Definitions of stages of clinical trials 2B studies in selected indications Traditional controlled clinical trial TARGET POPULATION RANDOM TREATMENT A TREATMENT B OUTCOME OUTCOME STATISTICAL COMPARISON Traditional trial designs Traditional trial designs Traditional trial designs Scheme for a prototypical n-of-1 trial modified from Zucker et al. 2006 Animal models and human PK/PD 1. More than 25% of drug entering CTs fail because of “poor pharmacology” 2. Animal data are useless to indicate the effective dose in humans (1/100th of the therapeutic dose in animals) • Animal models are only required to test safety. Efficacy should be either tested in big animals or should be directly tested in humans 3. Animal studies • Kill promising drugs (may work at therapeutic concentrations) • Promote drugs that are ineffective Can we skip earlier phases of clinical drug development? • Aloperidol • LCZ696 Adaptive trial designs • A decision-oriented, sequential learning process • At any stage, the data may be analysed and next stages redesigned taking into account all available data from the trial, or even from outside, based on predefined rules 1. Allocation Rule: how new patients will be assigned to available treatments 2. Sampling Rule: how many subjects will be sampled at the next stage 3. Stopping Rule: when to stop the trial 4. Decision Rule: allows for change in hypothesis, primary endpoint, statistical method or patient population design Adaptive trial designs Drop-Loser Adaptive Study Design Learning phase Confirmatory phase Adaptive Licensing: the way forward Basic principle Make innovative drug access easier through an early approval and acknowledgement of uncertainty of data... …but not of the risk! (a) Current scenario (b) AL scenario Eichler et al. Clin Pharmacol Ther. 2012 Mar How to streamline clinical trials • Duration • Costs Study design Sample size • It is not efficient • It is unnecessarily complicated PI • Too many people Involved CROs Patient recruitment/retention 1. Pre-trial registries 2. Consortiums 1. Use of social media (twitter/facebook) 2. New software 3. Patients' organizations – double-edge sword