14 February 2003
Cathie Sudlow and Carl Counsell’s contribution to the debate on disease modifying therapies (DMTs) in multiple sclerosis (MS) is welcome if sometimes misdirected. They argue the case for a randomised controlled trial comparing the licensed DMTs with the much cheaper drug, azathioprine, and with a placebo control. This trial is proposed as an alternative to the Department of Health’s Risk Sharing Scheme (RSS), which they believe to be scientifically unsound.
As independent scientific advisors on the RSS’s project management team we would like to respond to several criticisms which are valid but have already been identified and are being addressed. First, we agree that patients entering the scheme who have already been prescribed DMTs may not be representative – because of selection and other factors – and hence be a potential source of bias. Patients already on treatment at the start of the scheme will therefore be analysed separately and will contribute data only on progression between EDSS states. The cost-effectiveness evaluations will be based primarily on the incident cases. Second, ignoring outcome of treatment drop-outs would also bias assessments and so all subjects will now be followed up irrespective of compliance with therapy to allow ‘intention to treat’ analyses. Third, while EDSS is open to criticism, NICE accepted that there are no better alternatives. Blinded assessments are of little value without a concurrent control group. However, a quality assurance protocol is being developed, and further validation of EDSS against cost-utilities is planned. Fourth, it is proposed to collect data from several other series of MS patients to assess how reproducible are the outcomes in the historical control cohort of Canadian patients. Finally, the scheme does have MREC approval and it does include resources for extra clinical staff to collect the data, which should increase rather than lower levels of patient care for people with MS.
We do recognise, however, that the RSS will not provide a reliable estimate of clinical effectiveness in the absence of a randomised placebo control group, which was never the intention. The scheme evolved following the NICE appraisal concluding that the licensed DMTs were clinically effective, but did not represent cost effective use of NHS resources under the then existing arrangements for purchasing the drugs. The RSS was a compromise that sought to make the treatments available in a more cost effective manner by sharing the financial burden with industry and as such represents a ‘deal’ rather than science. While not randomised, the scheme will deliver a high level of audit of outcome and post-marketing surveillance for a complete cohort of NHS patients, who receive treatment.
How uncertainty about long-term clinical and cost-effectiveness of treatments in a chronic, and for some very disabling, neurological condition should be dealt with is a question that will arise time and again. The problem is particularly acute for previously untreatable conditions when there are no other effective therapies. Industry sponsored licensing studies, aimed at proof of efficacy over the short-term, will satisfy regulatory agencies, while leaving open the clinically important questions about worthwhile effects on long-term outcomes. In retrospect, it is regrettable that the independent UK trial of cost-effectiveness, proposed when the drugs were first licensed, was not funded and speedily implemented. Now that use of DMTs has become entrenched, denying patients the therapies at cost to the NHS until greater precision becomes available many years hence has become socially and politically unacceptable.
We encourage Sudlow and Counsell to develop plans for a comparative study as proposed and hope that it will be funded. The RSS should not be incompatible with such research studies. It may be too late, however, to include a placebo arm, as this is likely to be unpopular with clinicians and patients given that at least some effectiveness for disease modifying treatments has been established. In the meantime, we hope that they and other neurologists will support the implementation of the scheme.
Professor David Chadwick
Professor Richard Gray
© Copyright 2003, MS Trust