Statistical Innovations in Clinical Trials
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London Area Symposium: Statistical Innovations in Clinical Trials at Amgen (Uxbridge) in collaboration with Cytel
Speakers are Peter Colman (UCB) Cyrus Mehta (Cytel), James Wason (MRC Biostatistics Unit, Cambridge), Kevin Carroll (kjcstatistics)
9am Arrival and Coffee
9:30am – 11am : Statistical and Operational Challenges of VALOR, an Adaptive Phase-3 Trial for Acute Myeloid Leukemia. Cyrus Mehta, Cytel Inc.
The recently completed VALOR trial comparing vosaroxin to cytarabine in acute myeloid leukemia (ASH 2014) accrued 711 patients, and comprises the largest body of evidence for AML from a randomized phase 3 clinical trial. This adaptive event driven trial was designed with an interim analysis that allowed for early efficacy stopping, early futility stopping, unblinded sample size re-estimation, or continuation as planned. The sample size re-estimation option was implemented. We will present top-line results from the trial and discuss the operational, regulatory and statistical challenges that were faced along the way. To our knowledge this is the first phase 3 confirmatory oncology trial in which unblinded sample size re-estimation was implemented.
Cyrus Mehta is President and co-founder of Cytel Corporation and Adjunct Professor of Biostatistics, Harvard University. Cytel is a leading provider of software and services for the design, interim monitoring and implementation of adaptive clinical trials. Dr. Mehta consults extensively with the biopharmaceutical industry on group sequential and adaptive design, offers workshops on these topics, and serves on data monitoring and steering committees for trials in many therapeutic areas including oncology, cardiology, neurology and metabolic disease. He has led the development of the StatXact, LogXact and East software packages that are widely used in the biopharmaceutical industry and at academic research centers. He publishes his methodological research in leading statistics journals and is a past co-winner of the George W. Snedecor Award from the American Statistical Association. He is a Fellow of the American Statistical Association and an elected member of the International Statistical Institute. He was named Mosteller Statistician of the Year by the Massachusetts Chapter of the American Statistical Association in 2000, and Outstanding Zoroastrian Entrepreneur by the World Zoroastrian Chamber of Commerce in 2002.
11am-11:15am – Coffee break
11:15am – 12:45am: Innovative Considerations on a Phase 2a Dose-Finding Strategy Using Bayesian Methods and MCP-Mod. James Wason (MRC Biostatistics Unit, Cambridge, UK), Julian Zhou (Roche Products, Shanghai, China)
Early phase clinical trials in patients who are currently on treatments may be difficult to recruit for. Owing to this limited availability of patients they often require the use of smaller numbers of patients and more innovative statistical methods. Often single agents, developed for the same disease of interest are not sufficient and may need be used in combination to be effective. Appropriate decsisions may also have to be made for doses, treatment duration and combinations with other compounds.
The plan for the twelve-week phase 2a study in one such population will involve an early futility look at week 2 based on a biomarker, using Bayesian posterior probabilities. This will be followed by using MCP-Mod at the end of study on a clinical response, in order to investigate the dose response.
At week 2, a biomarker is measured to see if there is a clinically meaningful effect at the target for appropriated doses. If not then new doses may need to be added. The posterior probability of the meaningful effect will be used in the decision criteria.
At the end of the study MCP-Mod will be used in order to investiagate the dose response. MCP-Mod involves pre-specifying candidate dose-reponse models followed by statistical testing for dose-response signal whilst controlling the type I error. The best fitting model is then selected, and the target dose estimated, which is then recommended for phase 2b and phase 3 studies. The method has been qualified by the EMA as an efficient method of dose finding.
Simulations have been conducted to investigate the futility and dose finding decisions in phase 2a and understand the operating characteristics, and comparisons made to a traditional dose finding paradigm, which might involve fewer doses compared to a control using pairwise comparisons. Dr James Wason
is a senior investigator statistician at the MRC Biostatistics unit (BSU) in Cambridge. He has been there since doing his Ph.D. in 2006. Since 2009 he has worked in the BSU’s Hub for Trials Methodology Research, directed by Adrian Mander. His main research interests are adaptive designs for clinical trials, efficient analysis of composite endpoints, and the use of biomarkers in clinical trials. He is also the co-lead of the MRC Hub for Trials Methodology’s stratified medicine working group.
12:45 noon- 1:45pm – Lunch
1:45pm – 3:15pm: Defining, Understanding and Communicating Decision Criteria in Early Clinical Development. Peter Colman (UCB)
It is not uncommon to investigate multiple indicators of potential clinical efficacy in an early study in patients. A broad swathe of biomarkers may be nominated to ensure that evidence of activity on the projected biochemical pathway is acquired and additional biomarkers may indicate the precursors of clinical benefit. Registration endpoints, surrogates thereof or less-qualified biomarkers of efficacy may also be captured. The number of endpoints may easily exceed the number of subjects in the study and so it is vital that the properties of any decisions are well understood and consistently communicated. We discuss one approach which elicits views on the combinations of results that would be considered positive or encouraging and seeks to assess the likely false-positive rates associated with the consequent decision criteria. We illustrate the ideas with some real examples.
Peter spent the first 29 years of his statistical career with Pfizer at their UK research site in Sandwich. During this time he worked in Animal Health, Clinical Pharmacology and Early Clinical Development. He also experienced a phase III project for 6 months. For several years, he led a group of statisticians focussing on PK-PD Modelling & Simulation, Genetics, Clinical Technology and Outcomes Research. He returned to mainstream, hands-on project work and also contributed to a number of European collaborations (e.g. IMI SAFE-T). In 2011, upon closure of the Sandwich site, Peter moved to AZ at Alderley Park, where he worked on safety data and as a manager of statisticians in the oncology and anti-infectives area. He joined the UCB early development statistics team at UCB in 2013 where he contributes to the design of studies in the immunology and neuroscience areas. In his spare time he plays classical double bass and he is currently the chair of Maidstone Orchestral Society.
3:15pm – 3:30pm – Coffee Break
3:30pm – 5pm: Tackling Real Problems in Multi Regional Clinical Trials. Kevin Carroll (KJCStatistics)
MRCTs are an increasingly necessary feature of modern drug development. In areas like diabetes and cardiovascular disorders, or early adjuvant oncologic disease settings, or where there is a regulatory requirement to rule out small, but important safety issues such as in the ongoing cluster of trials investigating long acting beta agonists in the treatment of asthma, the demand for very large trials drives the need for MRCTs. Such trials are needed to provide the power to address the underlying hypothesis of interest, but can only do so under the assumption of no true regional heterogeneity. This talk will address the implications of true regional differences in MRCTs and will illustrate the real statistical and regulatory challenges faced by reference to recent case studies, including the 18,000 patient ‘PLATO’ trial in acute coronary syndromes.
Kevin Joseph Carroll, PhD, CStat, CSci, Honorary Senior Lecturer Medical Statistics is an Independent Statistical Consultant and owner of KJCStatistics Ltd. Kevin has 26 years drug development of experience across all trial phases and multiple therapeutic areas including Oncology, CV, Metabolism, Respiratory, CNS and GI. Most recently Kevin held the positions of VP Statistics and Chief Statistician at AstraZeneca Pharmaceuticals and Expert Statistician with Boehringer-Ingelheim. Kevin has extensive experience in the design, conduct, analysis and reporting of clinical trials. As a Consultant, Kevin has gained experience in helping both small and large pharma and biotech companies tackle statistical issues in development, including the application of innovative statistical approaches to trial design and analysis and regulatory product license applications. This includes the use of Bayesian decision-based designs to expedite effective decision making, and the use of complex staged designs in pivotal Phase II/III and Phase III trials to expedite overall development times. Kevin retains a strong technical interest in areas such as parametric survival modelling, group sequential analysis, adaptive designs and large outcomes trial design, and a growing interest in the statistical issues associated with health economic analyses and network meta-analyses.