Clinical Trials Methodology

The ECTU medical statistics, trial management, health economics and IT specialist teams also engage in clinical trials methodology research which aims to improve the quality and efficiency of trial design, analysis, conduct and reporting.

Activities in these four areas of trials methodology include:                              

Trial design
  • Supporting the use of efficient model-based designs (e.g. continual reassessment method) for early phase trials, instead of traditional algorithm-based “A+B” designs
Love SB, Brown S, Weir C, Harbron C, Yap C, Gaschler-markefski B, Matcham J, Caffrey L, Mckevitt C, Clive S, Craddock C, Spicer J, Cornelius V. (2017) Embracing model-based designs for dose-finding trials. British Journal of Cancer 117:332-339. doi:10.1038/bjc.2017.186  
  • Review and development of statistical methods for the evaluation of potential surrogate outcome measures in clinical trials

Ensor H, Lee RJ, Sudlow C, Weir CJ. (2015) Statistical approaches for evaluating surrogate outcomes in clinical trials: a systematic review. Journal of Biopharmaceutical Statistics, published online 21 September 2015. DOI: 10.1080/10543406.2015.1094811

Ensor H, Weir C. (2017) Two categorical endpoints.  In: Applied surrogate endpoint evaluation methods with SAS and R. Alonso, A. (ed.). Boca Raton: Chapman and Hall/CRC, pp. 145-155.

  • Highlighting advantages and practical implementation of efficient trials with an adaptive design
ECTU Methodology

Pallmann P, Bedding AW, Choodari-Oskooei B, Dimairo M, Flight L, Hampson LV, Holmes J, Mander AP, Odondi L, Sydes MR, Villar SS, Wason JMS, Weir CJ, Wheeler GM, Yap V, Jaki T. (2018) Adaptive designs in clinical trials: why use them, and how to run and report them. BMC Medicine 16:29. doi:10.1186/s12916-018-1017-7

Holm Hansen C, Warner P, Parker RA, Walker BR, Critchley HOD, Weir CJ. (2017)  Development of a Bayesian response-adaptive trial design for the Dexamethasone For Excessive Menstruation (DexFEM) study. Statistical Methods in Medical Research, 26:2681–2699. DOI: 10.1177/0962280215606155

Weir CJ. (2015) Adaptive clinical trials and their potential to improve drug development efficiency. Clinical Investigation, 5:359-361. DOI: 10.4155/cli.14.134

  • Development of novel outcome measures
Handforth, C., Hall, P., Marshall, H. and Seymour, M., 2013. Overall treatment utility: A novel outcome measure to convey the balance of benefits and harms from cancer treatment. Journal of Geriatric Oncology, 4, p.S49.
  • Development of improved methods for the economic evaluation of diagnostic tests, in collaboration with the NIHR MedTech and In Vitro Diagnostics Cooperatives

Longo R, Baxter P, Hall P, Hewison J, Afshar M, Hall G, McCabe C. Methods for identifying the cost-effective case definition cut-off for sequential monitoring tests: an extension of Phelps and Mushlin. PharmacoEconomics. 2014 Apr 1;32(4):327-34.

Smith AF, Messenger M, Hall P, Hulme C. The Role of Measurement Uncertainty in Health Technology Assessments (HTAs) of In Vitro Tests. PharmacoEconomics. 2018 Mar 3:1-3.

  • The use of early Health Economic modelling to improve research design and relevance of outputs for Health Care decision making

Hall PS, McCabe C, Brown JM, Cameron DA. Health economics in drug development: efficient research to inform healthcare funding decisions. European Journal of Cancer. 2010 Oct 1;46(15):2674-80.

Hall PS, Edlin R, Kharroubi S, Gregory W, McCabe C. Expected net present value of sample information: from burden to investment. Medical Decision Making. 2012 May;32(3):E11-21.

Trial conduct
  • ECTU is registered with Trial FORGE, a collaboration undertaking a series of “Studies Within a Trial” (SWATs) to evaluate important aspects of trial conduct such as methods for recruiting and retaining trial participants.  SWAT activity is embedded within ongoing clinical trials and at ECTU is led by the trial management team.  
  • One example of a SWAT was PRIME, which evaluated a complex intervention: the combination of support from a recruitment coordinator with use of bespoke reports based on national audit data to provide investigators with lists of potentially eligible patients for the RESTART trial.  

Link: Trial FORGE

Maxwell AE, Parker R, Drever J, Rudd A, Dennis M, Weir C, Salman R. (2017) Promoting Recruitment using Information Management Efficiently (PRIME): a stepped wedge cluster randomised trial of a complex recruitment intervention embedded within the RESTART or Stop Antithrombotics Randomised Trial (RESTART). Trials 18:623. doi:10.1186/s13063-017-2355-z  
  • Developing guidance for the anonymising and sharing of individual patient data following the completion of a clinical trial.
Keerie C, Tuck C, Milne G, Eldridge S, Wright N, Lewis SC. (2018) Data sharing in clinical trials - practical guidance on anonymising trial datasets. Trials 19:25. doi:10.1186/s13063-017-2382-9
  • Ongoing work includes the development of Good Clinical Practice training, tailored to specific topics relevant to clinical trials statisticians

 

Trial analysis
  • Presenting guidelines for the content of clinical trial Statistical Analysis Plans
Gamble C, Krishan A, Stocken D, Lewis S, Juszczack E, Doré C, Williamson PR, Altman DG, Montgomery A, Lim P, Berlin J, Senn S, Day S, Shanahan D, Barbachano Y, Loder E. (2017) Guidelines for the content of Statistical Analysis Plans in clinical trials. JAMA 318(23):2337-43. doi:10.1001/jama.2017.18556
  • Review of statistical methods for recovering mean or standard deviation values not reported in clinical trial publications, so that those studies may still be included in meta-analysis
Weir CJ, Butcher I, Assi V, Lewis SC, Murray GD, Langhorne P, Brady MC. (2018)  Dealing with missing standard deviation and mean values in meta-analysis of continuous outcomes: a systematic review. BMC Med Res Methodol. 18(1):25. doi: 10.1186/s12874-018-0483-0.
  • Development of improved and standardised methods for the measurement of healthcare costs in the context of clinical trials and cost-effectiveness analysis
Hall PS, Hamilton P, Hulme CT, Meads DM, Jones H, Newsham A, Marti J, Smith AF, Mason H, Velikova G, Ashley L. Costs of cancer care for use in economic evaluation: a UK analysis of patient-level routine health system data. British Journal of Cancer. 2015 Mar;112(5):948.
Trial reporting
  • Investigation of how the function of Trial Steering Committees in clinical trials is reported, and recommendations regarding standards of reporting of Trials Steering Committee activity
Conroy EJ, Arch B, Harman NL, Lane, JA, Lewis SC, Norrie J, Sydes MR, Gamble C. (2017) A cohort examination to establish reporting of the Remit and Function of Trial Steering Committees in Randomised Controlled Trials. Trials 18:590. doi: 10.1186/s13063-017-2300-1  
  • Collaborating on development of an extension to the CONSORT reporting guidance for clinical trials which have an adaptive design
Dimairo M, Todd S, Julious S, Jaki T, Wason J, Hind D, Mander A, Weir C, Koenig F, Altman D, Hamasaki T, Proschan M, Scott J, Walton M, Ando Y, Biggs K, Pallmann P & Coates E (2017) Journeying through the development of an adaptive designs reporting guidance: findings from Delphi process. CEN ISBS Vienna 2017 (pp 94-94), 28 August 2017 - 1 September 2017.
Implementation studies
  • Development of new models of technology adoption and policy making to allow improved implementation of the results of clinical trials

Edlin R, Hall P, Wallner K, McCabe C. Sharing risk between payer and provider by leasing health technologies: an affordable and effective reimbursement strategy for innovative technologies? Value in Health. 2014 Jun 1;17(4):438-44.

McCabe C, Edlin R, Hall P. Navigating time and uncertainty in health technology appraisal: would a map help? Pharmacoeconomics. 2013 Sep 1;31(9):731-7.

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