The Unit exists to develop and evaluate novel statistical methods of study design and data analysis relevant to pharmaceutical companies and medical research institutes. We undertake methodological research, often in direct collaboration with companies, and provide professional development courses and a consultancy service.
Our main areas of research and expertise are:
Statistical Methods for Dose-Finding Studies
Our work concerns first-in-man studies of new drugs, both in the setting of oncology where subjects are patients and responses are toxicities, and more generally where subjects are healthy volunteers and responses are pharmacokinetic and pharmacodynamic assessments. Research has centred on the development of Bayesian decision procedures, and on phase I/II designs in which both adverse events and (surrogate) measures of benefit are assessed. Also of interest is the identification of the optimal doses for more than one drug in combination therapies.
- Whitehead, J., Thygesen, H., Whitehead, A., ( 2011 ). Bayesian procedures for phase I/II clinical trials investigating the safety and efficacy of drug combinations . Statistics in Medicine 30, 1952-1970
- Whitehead, J., Zhou, Y., Patterson, S., Webber, D., Francis, S., ( 2001 ). Easy-to-implement Bayesian methods for dose-escalation studies in healthy volunteers . Biostatistics 2, 47-61
- Zhou, Y., Whitehead, J., Korhonen, P., ( 2008 ). Implementation of a Bayesian design in a dose-escalation study of an experimental agent in healthy volunteers . Biometrics 64, 299-308
Analysing Pharmacokinetic and Pharmacodynamic Data
This is an area on which a new professional development course has been prepared. Most work to date has concerned non-compartmental estimation of pharmacokinetic parameters such as the area under the concentration versus time curve for sparse sampling schemes. Recent work is also looking at extrapolation for pediatic development programmes.
- Jaki, T., Pallmann, P., Wolfsegger, M. J., ( 2013 ). Estimation in AB/BA cross-over trials with application to bioequivalence studies with incomplete and complete data designs . Statistics in Medicine. 32(30):5469-5483
- Wolfsegger, M. J., Jaki, T., ( 2005 ). Estimation of AUC from 0 to Infinity in Serial Sacrifice Designs . Journal of Pharmacokinetics and Pharmacodynamics 32, 757-766
- Jaki, T., Wolfsegger, M. J., ( 2012 ). Non-compartmental estimation of pharmacokinetic parameters for flexible sampling designs . Statistics in Medicine. 31(11-12), 1059-1073.
We are interested in both Bayesian and frequentist approaches to the determination of sample size for phase II studies. Such studies may be conducted to make a go/no go decision for a single treatment, or to select one or more treatments or doses for further study. It is often desirable to include an interim analysis within the design, although less common to need more than one. Futility analyses are very sensible at this early stage of clinical evaluation. Often the decision to proceed has to be taken on the basis of an early endpoint that will not be suitable for later phase III studies: the sample size for such a trial should be related to the eventual treatment effect desired in terms of the definitive long-term outcome.
- Stallard, N., Whitehead, J., Cleall, S., ( 2005 ). Decision-making in a phase II clinical trial: a new approach combining Bayesian and frequentist concepts . Pharmaceutical Statistics 4, 119-128
Adaptive Designs for Clinical Trials
There is substantial experience within MPS of developing and implementing group sequential designs for clinical trials, and we are currently involved in the conduct of interim analyses for several trials that we have previously designed. We have also worked on methods for sample size reviews and their implementation. Current research includes designs with a single interim analysis conducted to detect a treatment by factor interaction. The factor might concern the presence of a biomarker, which might be genetic. The choices following the interim analysis are to continue the trial with all subjects, restrict recruitment to those who are bioassay positive, or stop the study due to futility. The overall type I error and a form of power are specified.
- Magirr, D., Jaki, T., Whitehead, J., ( 2012 ). A generalized Dunnett Test for Multi-arm Multi-stage Clinical Studies with Treatment Selection . Biometrika. 99(2), 494-501.
- Whitehead, J., Whitehead, A., Todd, S., Bolland, K., Sooriyarachchi, M. R., ( 2001 ). Mid-trial reviews for sequential clinical trials . Statistics in Medicine 20, 165-176
- Whitehead, J., ( 1997 ). The Design and Analysis of Sequential Clinical Trials . Revised Second Edition, Chichester: Wiley.
Ordered Categorical Data
One strand of our current research concerns the correlation between the score statistics for comparing two treatments when these are based on different ordinal assessment scales. For example, in stroke trials the assessment scales might be the Barthel index, the modified Rankin score and the NIH stroke scale. One approach is to use generalised estimating equations, but we are seeking an alternative that is more robust when prognostic factors with many levels (such as treatment centre) are to be fitted. Another interest is repeated assessments of patients on an ordinal scale, with the primary response being the last of them. During interim analyses, some patients will have only short-term assessments. We are building on our work with binary data, and developing methods which allow the inclusion of these patients, without the need to assume any longitudinal model.
- Whitehead, A., Sooriyarachchi, M. R., Whitehead, J., Bolland, K., ( 2008 ). Incorporating intermediate binary responses into interim analyses of clinical trials: a comparison of four methods . Statistics in Medicine 27, 1646-1666
- Dark, R., Bolland, K., Whitehead, J., ( 2003 ). Statistical methods for ordered categorical data based on a constrained odds model . Biometrical Journal 45, 453-470
- Sooriyarachchi, M. R., Whitehead, J., Whitehead, A., Bolland, K., ( 2006 ). The sequential analysis of repeated binary responses . Statistics in Medicine 25, 2196-2214
As for ordinal data, the correlation between different score statistics for comparing the same two treatments is of interest. In the context of survival data, the score statistics will be logrank statistics or their counterparts from a Cox’s proportional hazards regression model adjusting for prognostic factors. The different score statistics will correspond to different waiting times, such as time to death and time to disease progression, or time to loss of sight in the right eye and time to loss of sight in the left eye. Correlations are needed to enable bivariate or multivariate analyses to be made or global tests to be performed. One possible approach is to use the Wei-Lin-Weissfeld method, but that is difficult to understand and does not reduce to a simple logrank analysis in the case of a single endpoint.
- Branson, M., Whitehead, J., ( 2002 ). Estimating a treatment effect in survival studies in which patients switch treatment . Statistics in Medicine 21, 2449-2463
- Whitehead, J., ( 2001 ). Predicting the duration of sequential survival studies . Drug Information Journal 35, 1387-1400
Meta-Analysis of Clinical Trials
MPS has a long standing interest in developing methodology for meta-analysis, particularly individual patient data approaches, and in the conduct of such analyses. Recent work has included meta-analyses of studies in which repeated observations have been made on subjects at different time points across studies. The problems arise when only summary data from published papers are available, and involve the handling of correlation between time points and of missing observations. The properties of cumulative meta-analyses, and the problems of inflating type I error are also of interest.
- Whitehead, A., Perdomo, C., Pratt, R.D., Birks, J., Wilcock, G.K., Grimley Evans, J., ( 2004 ). Donepezil for the symptomatic treatment of patients with mild to moderate Alzheimer’s disease: a meta-analysis of individual patient data from randomised controlled trials . International Journal of Geriatric Psychiatry 19, 624-633
- Whitehead, A., ( 2002 ). Meta-analysis of Controlled Clinical Trials . Wiley: Chichester
- Oliver, D., Connelly, J.B., Victor, C.R., Shaw, F.E., Genc, Y., Vanolli, A., Martin, F.C., Gosney, M.A., ( 2006 ). Strategies to prevent falls and fractures in hospitals and care homes and effect of cognitive impairment: systematic review and meta-analyses . Online: Brit Med Journal, DOI: 10.1136/bmj.39049.706493.55
Statistical Methods in Pharmacogenetics
We are interested in the relationship between the human genome and the risk of adverse drug reactions. We devised a sequential procedure to identify such an association governed by a limit on type I error which was valid even though the genome itself comprises thousands or hundreds of thousands of separate but possibly correlated SNPs. Work is now centred on what to do following the discovery (or suspicion) of such a relationship. In particular, can an exclusion criterion be devised so that subjects whose genome suggests an excessive risk of an adverse drug reaction do not enter clinical studies, and the risk of subsequent ADRs is reduced. A Bayesian formulation is being used and the repeated review of the exclusion rule is being considered.
- Kelly, P., Stallard, N., Zhou, Y., Whitehead, J., Bowman, C., ( 2006 ). Sequential genome-wide association studies for monitoring adverse events in the clinical evaluation of new drugs . Statistics in Medicine 25, 3081-3092