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. 2

Why should we do it faster? Time Costs Efficiency Innovation 4

25 Years life-cycle of a drug Marketing starts preclinical Preclinical tox extends into clinical C Welcome Trust 5

New chemical entity approval and cost of R&D 1.3B$/Drug 6

From bench to bedside The post-genomic Bottleneck 7

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 8

Definitions of stages of clinical trials 2B studies in selected indications

Traditional controlled clinical trial TARGET POPULATION RANDOM OUTCOME TREATMENT B TREATMENT A 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

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Animal models and human PK/PD 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 Allocation Rule: how new patients will be assigned to available treatments Sampling Rule: how many subjects will be sampled at the next stage Stopping Rule: when to stop the trial 4. Decision Rule: allows for change in hypothesis, primary end-point, 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 It is not efficient It is unnecessarily complicated Too many people Involved Study design Sample size PI CROs

Patient recruitment/retention Pre-trial registries Consortiums Use of social media (twitter/facebook) New software Patients' organizations – double-edge sword