FDA highlights importance of simulation and alternative design strategies to improve trial outcomes
Monday, November 9th, 2009
By Tom Parke
The US Food and Drug Administration (FDA) end-of-Phase 2a (EOP2A) meeting guidance issued on the September 2009 emphasises the value of the greater use of trial simulation and alternative design strategies in the clinical trials design process. The FDA’s primary purpose of an EOP2A meeting is to select the dosing regime and design “informative dose-response trials”.
The guidance is to encourage sponsors to consider the design of their subsequent phases carefully. Poor dose selection for Phase II and III trials is one area that can lead to the study failing and, given the rate of attrition through these stages, the industry is seeking to improve planning and design. “Dose selection for phase 2 and phase 3 trials is a challenge in many drug development programs, and poor choice may lead to trial failure,” write the FDA. In fact, it is said that some very high profile failures in phase 3 and even post registration have been due to poor choice of dose during drug development.
In particular the FDA is encouraging the use of modelling and simulation in the planning for phase 2b and beyond: “the FDA recognizes trial planning may be improved by clinical trial simulations that employ quantitative models of drug exposure-response, effects in placebo group, and disease progression.” Allowing the EOP2A to be focused on interpreting results and discussing dosage and trial design issues. Amongst the possible topics for the meeting they include: “Contrasting alternative trial design strategies (e.g., parallel, cross-over, adaptive, randomized withdrawal) and analyses (e.g., Bayesian)”.
There are broadly two different uses of modelling and simulation at this stage in drug development and both are important. One is to model and simulate the pharmacokinetics and the pharmacodynamics of the compound and study population, and the other is to simulate the trial design. The first allows decisions about the dosing, study population and patient follow-up timetable to be explored and the latter allows decisions about study size, recruitment rate, number of treatment arms, the nature of the statistical analysis and any pre-planned trial adaptations to be explored.
Simulation is often the only way to bring together and understand the many strands of pre-clinical information and allow informed trial design decisions to be made and tested before running the actual trial.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079690.pdf
Tom Parke
Tom Parke is head of clinical trial solutions at Tessella and has been working at Tessella for over ten years. For a large part of that time he has been working on Adaptive Clinical Trial projects particularly with Dr Mike Krams (first at Pfizer and now at Wyeth) and Don and Scott Berry at Berry Consultants.
Tom has helped implement numerous adaptive phase 2 dose finding trials that are now complete, for a range of pharmaceutical companies across a range of indications. For these trials, he managed the development of simulation tools, systems to support the running of the trials and the integration of adaptive algorithms with existing IVRS and EDC systems.
He is currently working on his 12th adaptive dose finding trial, and consulting with a number of companies to help them define the software systems they require to move adaptive clinical trials into their mainstream activities.
Before working at Tessella, Tom had worked at Praxis (part of Deloitte & Touche) most notably managing projects for part of the air traffic control system at Heathrow Airport, and control software for imaging systems for GE Medical Systems and Varian Oncology.
tom.parke@tessella.com
