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. 2001 Sep 8;323(7312):573.
Riluzole for motor neurone disease
Reply from chairman of appraisal committee at NICE
Editor—In commenting on the National Institute for Clinical Excellence's guidance on riluzole Sandercock et al show the difference between assessment and appraisal of evidence.1 One form of evidence used in an appraisal is a formal systematic review. The assessment report does not make recommendations on how the technology should be used in the NHS; that is the job of the institute's appraisal committee. The committee also receives submissions from patient and professional organisations, which provide perspectives not captured by a formal review of published evidence.
The committee takes account of the clinical need of patients and the broad balance of benefits and costs of the technology. Its conclusions are subject to consultation and can be appealed against. This is all some distance on from the original assessment of the evidence.
Sandercock et al suggest that a superficial reading of the guidance may not give an adequate understanding of the evidence base for riluzole. The institute's guidance identifies what the committee considered to be important elements of the evidence. The full assessment report is available on the institute's website (www.nice.org.uk). Neither document, however, can fully convey the depth of the committee's consideration of the evidence.
Sandercock et al advise clinicians to prescribe in accordance with riluzole's licence, say that patients offered the drug should be fully informed, and suggest further research. This is fully in accordance with the institute's guidance.
In the same cluster of letters Wheatley and Gray accuse the institute of recommending a treatment “when there is no significant evidence of benefit.”1 Although the statistical measures of benefit may not be great (we acknowledge that the relative hazard reduction for tracheostomy free survival is 12% (that is, 1.00-0.88), not 17% as quoted in the guidance), the committee is required to consider what the reported measures of clinical effectiveness of the technology actually mean to people with the disease.
Wheatley and Gray say that the guidance is contrary to the conclusions of the Sandercock report. We do not look to the authors of assessment reports for conclusions as, unlike the appraisal committee, they have neither access to the full evidence base nor the range of skills necessary to undertake an appraisal.
The institute's guidance need not deter further research into this disease or its treatment. The guidance sets out a clear research agenda, which we would encourage the manufacturer and clinicians to pursue.
References
1.Correspondence. Riluzole for motor neurone disease. BMJ. 2001;322:1305–1306. . (26 May.) [Google Scholar]
BMJ. 2001 Sep 8;323(7312):573.
Any placebo controlled trial of riluzole would surely be unethical now
Editor—We are concerned about the opinions expressed by Sandercock et al regarding the clinical efficacy of riluzole for the amyotrophic lateral sclerosis form of motor neurone disease and the appropriateness of the guidance issued by the National Institute for Clinical Excellence (NICE).1-1
Riluzole has been subject to regulatory scrutiny by the European Agency for the Evaluation of Medicinal Products and the Food and Drug Administration; an independent review by the Cochrane Collaboration1-2; and the review by the National Institute for Clinical Excellence. The health technology assessment report by Sandercock et al formed only part of the evidence based assessment by the institute; evidence from a wide range of expert clinical, research, and patient based sources was also made available.
Of particular importance are the results of two large prospective, randomised, double blind placebo controlled trials of riluzole in amyotrophic lateral sclerosis.1-3,1-4 The study by Bensimon et al (n=155) was stopped at 18 months because of a clear difference in favour of the active treatment arm.1-3 As a result, patients taking placebo were offered active treatment, which meant that the authors were unable to determine overall survival in comparison with survival with placebo. However, analysis of the study to 18 months showed that patients taking riluzole had a 28% better survival rate than those taking placebo (P=0.014).
The second study, by Lacomblez et al (n=959), reported that after adjustment for prognostic factors the risk of death or tracheostomy at 18 months was 35% lower with riluzole 100 mg/day than with placebo (P=0.002).1-4 This study also assessed the clinical efficacy and safety of different doses of riluzole and concluded that 100 mg was the optimal daily dose (P=0.003). A closer investigation of the data showed that the significant effect of riluzole was observed in earlier disease stages.1-5
These data provide the evidence that riluzole is clinically proved to extend survival in amyotrophic lateral sclerosis. In a disease with a prevalence of 4/100 000 and in which average life expectancy is 36 months, clinical trials looking at over 1000 patients1-3,1-4 over 18 months are a reliable basis on which to establish clinical effect. Sandercock et al suggest that future clinical trials should include a placebo, but we take the view that any placebo controlled trial is unethical once clinical efficacy has been clearly shown.
The important information that Sandercock et al fail to report is that riluzole is the only clinically proved treatment available to patients with amyotrophic lateral sclerosis and might extend survival.
References
1-1.Sandercock J, Burls A, Hyde C, Fry-Smith A, Barton P, Bryan S, et al. Riluzole for motor neurone disease. BMJ. 2001;322:1305. . (26 May.) [PMC free article] [PubMed] [Google Scholar]
1-3.Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med. 1994;330:585–591. doi: 10.1056/NEJM199403033300901. [DOI] [PubMed] [Google Scholar]
1-4.Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347:1425–1431. doi: 10.1016/s0140-6736(96)91680-3. [DOI] [PubMed] [Google Scholar]
1-5.Rivière M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol. 1998;55:526–528. doi: 10.1001/archneur.55.4.526. [DOI] [PubMed] [Google Scholar]
