Multicentre trials

A data set consisting of a series of results by treatment for a number of centres is closely analogous to one consisting of a number of results by treatment for a number of trials. Accordingly, many similar issues to those that arise in meta-analysis arise in the analysis of multicentre trials, although traditions in the two cases are rather different. Hence, there may be some value in studying this chapter and Chapter 16 on meta-analysis together. 

1 Patient numbers per centre should be roughly equal 

This point of view is often propounded. It is maintained that it is the sign of a bad trial that the numbers of patients per centre are unequal. There are perhaps two reasons why this is believed to be the case. First, it is argued that we ought to wish to treat 

Statistical Issues in Drug Development, 2nd Edition. Stephen Senn 2007 John Wiley Sons, Ltd. ISBN 978-0-470-01877-4 

When describing the relative variability of a distribution, however, it is not the ratio of variance to mean which is important but that of standard deviation to mean. This feature is a useful one which can be exploited given an appropriate attitude. The sum of a number of independent Poisson variables is also a Poisson variable, so that if we had four centres each with a mean (Poisson) arrival rate of 9 patients per six months overall, we should have a trial where arrival was described by a Poisson distribution with mean of 36 per six months. Now, since the standard deviation is the square root of the variance, the ratio of standard deviation to mean for a Poisson with mean 36 is 6/36 = 0.17, whereas for a Poisson with mean 9 it is 3/9 = 0.33. 

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Wallenborn J, Gelbrich G, Bulst D et al (2006) Prevention of postoperative nausea and vomiting by metoclopramide combined with dexamethasone randomised double blind multicentre trial. Br Med J 333 324-327... 

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In multicentre trials, it is usual to use a separate randomisation procedure within each centre to ensure that there is balance - or at least near balance within each centre. In such circumstances ICH E9 (Section 2.3.2) recommends that the randomisation be performed centrally, with several blocks allocated to each centre. This procedure is a simple form of stratified randomisation. 

The EU Clinical Trials Directive contains specific provisions regarding the conduct of clinical trials, including multicentre trials, on human subjects. It defines clinical trial as any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to... 

There is one CTN form for each site conducting the same clinical trial, such as multicentre trials. In some cases a composite site can be notified where a single HREC and approving authority have responsibility for all sites conducting the trial, such as a general practice network. 

Saunders MI, Dische S, Barrett A, et al. Continuous hyperfractionated accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer. A randomized multicentre trial. Lancet 1997 350 161-165. 

Levi F, Zidani R, Misset JL. Randomized multicentre trial of chronotherapy with oxaliplatin, fluorouracil, and folinic acid in metastatic colorectal cancer. Lancet 1997 350 681-686. 

In large trials it could be argued that block randomisation is unnecessary. In one sense this is true, overall balance will be achieved by chance with an unrestricted randomisation list. However, it is usually the case that large trials will be multicentre trials and not only is it important to have balance overall it is also important to have balance within each centre. In practice therefore we would allocate several blocks to each centre, for example five blocks of size four if we are planning to recruit 20 patients from each centre. This will ensure balance within each centre and also overall. 

As indicated in the ICH E9 guideline there are two reasons why we conduct multicentre trials ... 

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WHO Special Programme of Research, Development and Research Training in Human Reproduction. The WHO multicentre trial of the vasopressor effects of combined oral contraceptives 1. Comparisons with IUD. Task Force on Oral Contraceptives. Contraception 1989 40(2) 129 15. 

Gogarten W, Van de Velde M, Soetens E, et al. A multicentre trial comparing different concentrations of ropivacaine plus sufentanil with bupivacaine plus sufentanil for patient-controlled epidural analgesia in labour. Eur J Anaesthesiol. 2004 21 38M5. 

Petroni ML, Jazrawi RP, Pazzi P, et al. Ursodeoxycholic acid alone or with chenodeoxycholic acid for dissolution of cholesterol gallstones a randomized multicentre trial. The British-Italian Gallstone Study group. Aliment Pharmacol Ther. 2001 15 123-128. 

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Jamrozik K, Anderson CA, Stewart-Wynne EG (1994). The role of lifestyle factors in the etiology of stroke. A population-based case-control study in Perth Western Australia. Stroke 25 51-59 Jespersen CM, Als-Nielsen B, Damgaard M etal. (2006). Randomized placebo controlled multicentre trial to assess short term clarithromycin for patients with stable coronary heart disease CLARICOR trial. British Medical Journal 332 22-27 Jorgensen HS, Nakayama H, Raaschou HO etal. (1994). Stroke in patients with diabetes. The Copenhagen Stroke Study. Stroke 25 1977-1984... 

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Battezzati, P.M., Podda, M., Bianchi, F.B., Naccarato, R., Orlandi, F., Surrenti, C, Pagliaro, L., Manenti, F. Ursodeoxycholic acid for symptomatic primary biliary cirrhosis. Preliminary analysis of a doubleblind multicentre trial. J. Hepatol. 1993 17 332-338... 

R. Long-term effects of ursodeoxycholic acid in primaiy bihary cirrhosis results of a double-blind controlled multicentric trial. J. Hepatol. 2000 32 561-566... 

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