Traditional vs novel trial designing. Giuseppe M.C. Rosano, MD, PhD.

Traditional vs novel trial designing

Giuseppe MC Rosano MD PhD

Loscalzo J (2012) Circulation 125638-645

Why should we do it faster

From 2000 to 20010 the top 10 pharma companies started 1113090more than 1700 new projectsyear

Why should we do it faster

bull Time

bull Costs

bull Efficiency

bull Innovation

25 Years life-cycle of a drug

New chemical entity approval and cost of RampD

13B$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

TARGET POPULATION

RANDOM

OUTCOMEOUTCOME

TREATMENT BTREATMENT A

STATISTICAL COMPARISON

Traditional controlled clinical trial

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 PKPDAnimal models and human PKPD

1 More than 25 of drug entering CTs fail because of ldquopoor pharmacologyrdquo

2 Animal data are useless to indicate the effective dose in humans (1100th of the therapeutic dose in animals)

bull 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

bull Kill promising drugs (may work at therapeutic concentrations)

bull Promote drugs that are ineffective

Can we skip earlier phases of clinical drug development

bull Aloperidol

bull LCZ696

Adaptive trial designs bull A decision-oriented sequential learning process

bull 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 end-point statistical method or patient population design

Adaptive trial designs

Drop-Loser Adaptive Study Design

Learning phaseLearning phase Confirmatory phaseConfirmatory phase

Adaptive Licensing the way forward

(a) Current scenario(b) AL scenario

Basic principleMake innovative drug access easier through an early approval and acknowledgement of uncertainty of data

Eichler et al Clin Pharmacol Ther 2012 Mar

hellipbut not of the risk

bull DurationDuration

bull CostsCosts

bull It is not efficientIt is not efficient

bull It is unnecessarily complicatedIt is unnecessarily complicated

bull Too many people InvolvedToo many people Involved

How to streamline clinical trialsHow to streamline clinical trials

Study design

Sample size

PI

CROs

Patient recruitmentretention

1 Pre-trial registries

2 Consortiums

1 Use of social media (twitterfacebook)

2 New software

3 Patients organizations ndash double-edge sword