Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Eyes tightly shut
- Abhijit Chaudhuri, Peter O Behan (14 February 2003)
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Cost-effective provision of effective MS therapies
- Jacqueline C Napier, Richard Francis, Glyn Wright (15 February 2003)
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MS Risk Sharing Scheme
- David W Chadwick, Richard Gray (15 February 2003)
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The Pharmaceutical Industry
- Malcolm R Macleod (18 February 2003)
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Consumer view!
- David Lloyd (18 February 2003)
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Response from the MS Monitoring Study
- Mark Pickin, Mike Boggild, Jackie Palace, Cindy Cooper, Jenny Roberts, and Jon Nicholl. (18 February 2003)
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Problems with the MS Risk sharing scheme
- Christopher J. McCabe, Jim Chilcott, Paul Tappenden, Anthony O'Hagan, Karl Claxton, Keith Abrams, Nicola Cooper (19 February 2003)
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A CONSUMER'S APOLOGY
- David Lloyd (19 February 2003)
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Randomised controlled trials in MS
- John Zajicek, David Wright, Principal Lecturer in Statistics, University of Plymouth (21 February 2003)
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The outcome measures used will determine the success of the risk sharing scheme for MS treatment
- Michael H Johnson, Helen Ford (27 February 2003)
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The Risk Sharing Scheme - more problems
- Charles P Warlow (5 March 2003)
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The MS risk sharing scheme - authors' reply
- Carl E Counsell, Cathie L.M. Sudlow (14 March 2003)
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Abhijit Chaudhuri, Senior Lecturer in Clinical Neurosciences University of Glasgow, Peter O Behan
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We thank Sudlow and Counsell for criticising the risk-sharing scheme for beta-interferon and glatiramer in multiple sclerosis (MS) for its impracticality and poor evidence base (1). The clinical and scientific flaws in using these and the other anti-inflammatory or immunosuppressive agents in MS have been cogently addressed in a recent review on MS (2). The authors are correct in suggesting that the efficacy of azathioprine is probably similar to that of beta-interferon or glatiramer; however, all three are ineffective in preventing long term disability due to MS as evident from the existing data and collective physician experience. In our opinion, investing in a long-term randomised trial of “beta-interferon or glatiramer versus azathioprine versus no treatment” will be as wasteful as the current cost-sharing scheme. This is due to several reasons, not the least of which is the fact that the characteristic side-effect profiles of the individual treatments will limit effective double blinding, a fact recognised in the Cochrane review of the beta-interferon trials. Before committing precious resources to any long term trial in MS involving several thousand patients as proposed (1), we have to be absolutely clear what is the primary end-point and how this is likely to be achieved by the chosen treatment(s). The end-point of any long-term clinical trial in MS can only be the prevention of significant neurological disability rather than arresting short-term fluctuations due to the relapses. What the authors have failed to address in their paper is the fact that progressive neurological disability in MS is due to axonal transection and neuronal loss, not autoimmunity(2). Epidemiological studies have clearly established a biological dissociation between relapses and progressive disability once an EDSS score of 4-4.5 is reached (3). Results of all immunotherapy trials in MS, including the recently published natalizumab trial (4), have indicated that although such treatments may reduce relapse rates, they do not modify disability or progressive loss of function. Azathioprine is not an exception to this rule. That the disability progression in MS is independent of its relapses and the inflammatory changes claimed to be responsible for these events is supported by the natural history of MS during pregnancy (5). Recent neuroimaging data, some of which have been reviewed in our paper(2), confirm this view. The emerging evidence clearly indicates that widespread axonal damage is always present even at the earliest clinical stages of MS and this is essentially independent of the inflammatory changes (6). A recent trial of glatiramer in 900 patients with primary progressive MS has been stopped prematurely because of total lack of efficacy (the PROMISE trial); that no immunological treatment has ever worked in sufficient number of patients for sufficient length of time is because progressive MS (primary or secondary) is due to neurodegeneration, the rate of which may be determined metabolically and not by autoimmunity (2). In our opinion, resources for MS should be currently used to provide better level of social care, support and rehabilitation for those affected and to provide funding for treatment trials for the continuing symptoms of fatigue and pain that disable a vast majority of MS patients irrespective of their EDSS scores. Specific treatment trials in the future should be based on metabolic strategy (2) and neuroprotection(6)in MS rather than on autoimmunity as has been proposed (1). However, this is unlikely to be achieved in the short-term because it requires a better understanding of MS that will not be possible if the minds as well as the eyes are kept tightly shut. References: 1. Sudlow CLM, Counsell CE. Problems with UK government’s risk sharing scheme for assessing drugs for multiple sclerosis. BMJ 2003; 326: 388-92 2. Behan PO, Chaudhuri A, Roep BO. Pathogenesis of multiple sclerosis revisited. J R Coll Physicians Edinb 2002; 32: 244-65. 3.Confraveux C, Vikusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med 2000; 343: 1430-8. 4. Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15- 23. 5. Confraveux C, Hutchison M, Hours MM, Cortinovis-Tournaire P, Moreau T and the Pregnancy in Multiple Sclerosis Group. Rate of pregnancy related relapse in multiple sclerosis. N Engl J Med 1998; 339: 285-91. 6. Fillipi M, Bozzali M, Rovaris M, et al. Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis. Brain 2003; 126: 433-37. Competing interests: None declared |
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Jacqueline C Napier, Associate Medical Director Schering Health Care Ltd, The Brow, Burgess Hill, West Sussex RH15 9NE, UK, Richard Francis, Glyn Wright
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Editor Sudlow and Counsell suggested that the UK Government’s risk sharing scheme for the provision of disease modifying MS therapies (beta interferons and glatiramer acetate) may be flawed . We are surprised at the content of this paper from a number of aspects, and we would like to support the statements issued today by Professor David Chadwick, Professor Richard Gray, and the MS Trust, in response to Sudlow and Counsell’s assertions. Firstly, the risk-sharing scheme was introduced precisely to ensure that the disease modifying therapies in question are acquired by the NHS in a cost-effective manner which will be reviewed by the DoH at scheduled time points with the required adjustments being made to ensure the agreed cost-effectiveness threshold is maintained. Secondly, pivotal, randomised, placebo-controlled studies lasting for up to 5 years already demonstrate that these therapies are effective and well tolerated. The longer-term outcome is less certain, although evidence both from observational studies and more than 15 years of clinical practice in the US, suggests that efficacy continues and there have been no unexpected safety issues. We agree there is a need to collect additional robust long-term data on lifetime cost effectiveness of MS therapies and this is what the risk sharing scheme sets out to achieve. Most importantly, it is vital that it is recognised that cost effectiveness of treatments that delay disease progression can only be properly measured over the long term, 20 years or more. However, suggesting that this can only be done in a new placebo- controlled study would be naïve, unethical and in practice, unworkable. Such a study would deny many patients access to licensed treatments that have already been shown to deliver clinical benefit and which are used routinely in most other developed countries. Thirdly, we are surprised that unlicensed drug therapies or other forms of therapy are being suggested at this stage as alternatives to beta interferons or glatiramer. Azathioprine was not widely used before the disease modifying therapies were licensed and to our knowledge there have been no new data published in the past 10 years to suggest improved efficacy or risk/benefit profile in comparison to the licensed treatments being used in the risk-sharing scheme. Working together with patient support groups and professional bodies involved in neurology and the Health department we are at last seeing some progress in delivering access to cost-effective treatment for people with MS. In comparison to the situation in other countries, the UK has for many years neglected and under-served people with MS and their families. We are very proud to be working co-operatively to re-dress this imbalance. Yours sincerely Dr Jackie Napier, Associate Medical Director, Schering Health Care Limited Richard Francis, Country Manager UK & Ireland, Biogen Limited Glyn Wright, General Manager, Teva Pharmaceuticals Limited 1. Sudlow, C and Counsell, C., Problems with UK government’s risk sharing scheme for assessing drugs for multiple sclerosis. BMJ; 326: 388 -392 Feb 2003 Competing interests: The authors are employees of pharmaceutical companies involved in MS research and the risk share scheme |
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David W Chadwick, Professor of Neurology University of Liverpool, Walton Centre, Lowere Lane, Liverpool, L9 7LJ, Richard Gray
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Dear Sir, 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). 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 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 may not provide a reliable estimate of clinical effectiveness in the absence of a randomised placebo control group. 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 is not 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 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. David Chadwick
Professor Richard Gray,
Competing interests: None declared |
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Malcolm R Macleod, Research Fellow Natl Stroke Res. Inst., Australia VIC 3081
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The rapid rebuttal from the pharmaceutical industry to the article from Sudlow and Counsell - worthy of Alistair Campbell and Millbank at their worse - serves to underline a basic and often forgotten truth. Pharmaceutical companies exist to maximise profits for their shareholders, and also for those - including Napier et al - who are stakeholders in those companies. Any other asserted role, such as providing cost effective treatments to the NHS, come a poor second. We should therefore interpret views expressed by pharmaceutical companies in the same way that we should use new drugs - with caution, and with evidence. Behind their rhetoric, Napier et al do not even claim a benefit of their products over azathioprine. Yet they state that it would be unethical to do the very trials which are required to tell us whether their treatment actually works. Perhaps the answer lies in their files of unpublished data? Prescription of so-called disease modifying treatments in the UK remains in a muddle, a muddle which is not in the interests of patients with multiple sclerosis. Future generations may well look back on our decisions and wonder how we could have been so daft as to go ahead on the basis of such flimsy evidence. Competing interests: None declared |
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David Lloyd, Retired Consultant anaesthetist BB9 6HH
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Dear Sir, Much of the emphasis of this paper is upon azathioprine as an alternative to interferon or glatiramer acetate – why stop here? Why ignore mitoxantrone and what about campath or the statins currently under review? As a Welcome Trust clinician scientist wrote the paper and azathioprine is manufactured by Welcome perhaps we have the answer. Does this not count as a competing interest? The authors seem to be forgetting about the patients involved in this search for their idealised pharmaceutical study. It is already known that it is a progressive disease and I fail to see how allowing several thousand people go without treatment can in anyway be considered ethical and what gain is there for this forgotten group? Rather than viewing the risk sharing scheme as a full scientific study perhaps it should be viewed for what it is - a way of attempting to bring new (expensive) treatments to as many people as possible who may benefit, whilst at the same time holding the pharmaceutical industry responsible for their claims about effectiveness. Is this ideal? - No. Does it offer a better deal for MS sufferers than the current postcode lottery? - Yes. The cost for follow up reviews will be demanding, but is this not a reflection on how poor current provision for MS sufferers is and how understaffed politicians and managers have allowed Neurology departments to become. Perhaps all MS reviews should already include expanded disability status scores to monitor progress and offer treatment and care on a proactive basis rather than the current situation where many have been lost to follow up until severe problems arise. My own view is that the proposed 10 year study will be hard to complete because as new drugs become available with (hopefully) more clinical/cost effectiveness patients will “ethically” need to be changed to these, but providing these drugs until this occurs will be the role of this scheme. Finally, I agree any additional resources are welcome but why should having one treatment exclude another from the overall care package? I have yet to see a smoking arteriopath refused respiratory care because they have use up their budget on cardiovascular drugs! (And quite rightly so.) Why should MS patients be treated any differently? Doctors need to decide whether they are there to promote the interests of their patients or to act as financial gatekeepers as both roles are clearly becoming mutually exclusive. Yours faithfully, Dr David Lloyd
Competing interests: Diagnosed with relapsing remitting MS in 2000. Retired from my post of Consultant Anaesthetist following year (aged 35). Had several cycles of Mitoxantrone over 9 months whilst waiting for funding for glatiramer acetate, which I currently take. |
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Mark Pickin, Clinical Senior Lecturer University of Sheffield, S1 4DA, Mike Boggild, Jackie Palace, Cindy Cooper, Jenny Roberts, and Jon Nicholl.
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Sir The key uncertainties about the cost-effectiveness of Interferon Beta and Glatiramer Acetate in Multiple Sclerosis (MS) are around their long- term benefits. Clinical trials of these agents undertaken to date have typically lasted no more than 2-3 years, however it is results at 10-20 years which matter. With this clear the arguments put forward by Sudlow and Counsell (1) against the risk-sharing scheme and for another randomised controlled trial (RCT) are neither helpful nor well conceived. A further long-term, placebo controlled RCT in primarily relapsing forms of MS is not feasible or indeed ethical. As the authors are well aware two previous attempts to set up such a study within the UK have failed. Further analysis of the available data, which the authors suggest, ignores the fact that both the National Institue for Clinical Excellence (NICE) and the Cochrane MS review group (2) have undertaken such an analysis and concluded that the treatments provide modest clinical benefit. It is not this, but their cost-effectiveness which is disputed. We are well aware of the potential weaknesses of the data collected within the risk-sharing scheme as proposed and acknowledge the points raised about the assumptions needed to model the cost-effectiveness of therapies in chronic diseases such as MS. To improve these assumptions and estimates we will be collecting new data on costs and utilities, as well as disability progression for those who cease therapy. We will also be undertaking extensive further work to validate the natural history control group against a number of similar data sets. The risk-sharing scheme offers the opportunity to monitor outcome for a group of up to 7000 patients, starting disease modifying therapy in accordance with well developed clinical guidelines, over 10 years. The Association of British Neurologists has encouraged UK Neurologists to support this scheme and its success requires the dedication and cooperation of many hard working clinicians and MS Nurse Specialists. The only alternative in the present climate would be no study and no long term data. If comparison with natural history data does prove a workable means of assessing long-term treatment effect for expensive new therapies in chronic diseases such as MS, and if shared-risk schemes lead to appropriate price adjustments, this model – though born perhaps of political expedience - has much potential. We would suggest that a positive attitude, aiming to collect good quality data with full follow-up will give this scheme the best potential to succeed. Finally we would also argue, and believe that there is already evidence, that rather than being relevant to only the minority of patients - as the authors suggest - implementation of the scheme will lead to the rapid development of MS services within the UK to the benefit of the majority. Dr Mike Boggild, Consultant Neurologist, Liverpool Dr Jackie Palace, Consultant Neurologist, Oxford Dr Mark Pickin, Clinical Senior Lecturer, ScHARR, University of Sheffield Dr Cindy Cooper, Senior Research Fellow, ScHARR, University of Sheffield Dr Jenny Roberts, Senior Lecturer, ScHARR, University of Sheffield Professor Jon Nichol, Director of the Medical Care Research Unit, ScHARR, University of Sheffield. 1. Sudlow CLM, Counsell CE. Problems with UK government’s risk sharing scheme for assessing drugs for multiple sclerosis. BMJ 2003; 326: 388-92 2. Filippini G, Munari L, Incorvaia B, Ebers G, Polman C, D’Amico R, Rice G. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 2003; 361: 545-52 Competing interests: The authors are part of a consortium appointed to monitor the risk sharing scheme. |
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Christopher J. McCabe, Senior Lecturer in Health Economics ScHARR, University of Sheffield, Regent Ct. 30 Regent St. Sheffield S1 4DA, Jim Chilcott, Paul Tappenden, Anthony O'Hagan, Karl Claxton, Keith Abrams, Nicola Cooper
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We were very interested to read Sudlow and Counsell's paper reviewing the cost effectiveness analysis which we undertook for the National Institute for Clinical Excellence (NICE), as part of the appraisal of beta interferons and glatiramer acetate.(1) Whilst we have some sympathy with the broad arguments of their paper, there are some observations which we believe would aid the debate on this issue. The authors state that the model 'has several unavoidable flaws'. We would argue that the quality of the evidence for effectiveness of treatment, the lack of long term placebo controlled trials and lack of evidence about what happens when patients stop treatment are flaws in the evidence base which the construction of the model highlighted. They are not flaws in the model per se. It is important to remember 'all models are wrong, but some models are useful'.(2) We believe that the model we constructed falls in to this category. Our model allows the incorporation of the uncertainty, which derives from the poor quality of the evidence base, and the estimation of the value of reducing that uncertainty. (3) The problem facing decision makers is the quality of the evidence on the long term impact of the disease modifying therapies, and this is acknowledged by most of the companies involved in the risk sharing scheme. (4) Even though some of the trials began in the early 1990s there would appear to be no long term data on the trial participants. Either this data was not collected, which strikes us as naïve given the chronic nature of the condition, or it was but has not entered the public domain. Since NICE has extremely limited legal powers regarding disclosure, compared to the drug licensing agencies, we have no way of knowing which. The risk sharing scheme offers an opportunity to collect these long term outcome data, and it is important that all patients in the scheme are followed up, even after they have ceased therapy. It is also important that the risk sharing scheme takes the opportunity to improve the evidence on the costs and quality of life in multiple sclerosis. The evidence base in this regard is equally important for establishing long term cost effectiveness (4); and is currently as weak as that relating to the medium and long term effectiveness of these therapies. (5) We do have some concerns about the choice of outcome measure being used in the scheme. For the purposes of the scheme, only progressions at EDSS 4.0 and above will be counted as progressive events. (6) If patients are treated early in the disease process, as some clinical evidence indicates may be the best strategy, (7), then the scheme's outcome measure will be insensitive to real changes in the disability of the patients. The greater the proportion of patients at EDSS 3.5 and below, the longer it will take the scheme to provide substantial evidence on the cost effectiveness of these therapies, using this outcome measure. Sudlow and Counsell's paper proposes that azathioprine should have been included in the analysis and should now be included in the risk sharing scheme.(6) Whilst azathioprine was identified as a disease- modifying drug in the Health Technology Assessment review of disease- modifying drugs for multiple sclerosis, it was not referred to NICE for appraisal. (8) That is why it was not included in the economic evaluation we undertook for the NICE appraisal. With hindsight, we agree that it would have been desirable to consider azathioprine within the analysis. Given that NICE have not reviewed azathioprine and have certainly not recommended against its use, there is nothing to stop clinicians using it in practice. However, it would be interesting to know how cost effective its use would be. To facilitate an informed debate on this issue we have undertaken a brief cost effectiveness analysis of azathioprine compared to placebo and compared to the disease-modifying therapies considered in the original evaluation. Using the relative risk of relapse from the meta-analysis by Sudlow and Counsell, in the cost effectiveness model constructed for NICE, the model estimates that azathioprine is cost saving to the NHS, and produces moderate quality of life gains; i.e. that azathioprine dominates no -treatment. However, the quality of the data is again such there is large uncertainty surrounding these estimates. Using public domain estimates of effectiveness, the estimated cost effectiveness ratios of the other disease modifying therapies compared to azathioprine, using a 20 year time horizon, are: Beta Interferon 1a (Avonex, Biogen) £45,500 per QALY Beta Interferon 1a 22mcg (Rebif, Serono) £67,000 per QALY Beta Interferon 1a 44mcg (Rebif, Serono) £77,200 per QALY Beta Interferon 1b in RRMS (Betaferon, Schering) £55,600 per QALY Glatiramer Acetate (Copaxone, TEVA) £116,000 per QALY Beta Interferon 1b in RR and SPMS (Betaferon, Schering) £48,700 per QALY It is important to note that these cost effectiveness estimates are subject to the same high degree of uncertainty as the original cost effectiveness estimates for each therapy compared to placebo.(3) It seems reasonable to conclude that, on current evidence, azathioprine may be a better choice of therapy than glatiramer acetate as the small difference in efficacy does not appear to justify the large price differential. Given the similarity in the effectiveness of these therapies, according to the meta-analysis in Sudlow and Counsell, and the great uncertainty around the estimates of effectiveness, there may be some value in a randomised trial comparing these two therapies. However, unless there is evidence of a potential impact of azathioprine on progression, it is unlikely that a randomised controlled trial comparing it with the beta interferons would be justified. An RCT to examine the long term efficacy of the beta interferons would be desirable to substantially reduce the uncertainty in the evidence base for these products. However, such a study would require a degree of equipoise in the clinical community, which according to submissions to the NICE appraisal process, does not exist. ( 1) Sudlow CLM and Counsell CE Problems with UK government's risk sharing scheme for assessing drugs for multiple sclerosis BMJ 2003;326:388-92 (2) Box GEP, Hunter WG, Hunter JS Statistis for Experimenters: an introduction to Design, Data Analysis and Model building New York: John Wiley and Sons 1978 (3) Tappenden P. et alCost effectiveness of beta interferons and glatiramer acetate in the management of multiple sclerosis. Final Report to National Institute for Clinical Excellence, July 2001. www.NICE.org.uk (4) Napier JC et al. Cost effective provision of MS Therapies http://bmj.com/cgi/eletters/326/7385/388#29656 accessed 19/02/03 (5) Filippini G et al Inteferons in relapsing remitting multiple sclerosis: a systematic review Lancet 2003;361:545-52 (6)Department of Health Cost effective provision of disease modifying therapies for people with multiple sclerosis. Health Service Circular 2002/004 February 2002 (7) PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon B-1a in relapsing/remitting multiple sclerosis. The Lancet 1998;352:1498-504. (8) Clegg A. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review Health Technol Assess 2000;4(9) Competing interests: We constructed the cost effectiveness model used in the NICE appraisal of these drugs and the MS Risk Sharing Scheme. Chris McCabe has previously undertaken cost effectiveness analyses of beta interferon on behalf of Serono who produce one of the beta interferon products. |
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David Lloyd, retired BB9 6HH
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Dear Sir, Since writing my original response, I have come across further information regarding the association between the Wellcome trust and Glaxowellcome (1). From this it is obvious that the remaining link is very small, because in 1995 most of the Wellcome shares were sold to Glaxo (apart from owning a residual 4.7% of Glaxowellcome shares as of 1998.) I am unable to access any more up to date data on this. I apologise to all concerned for seeing a conflict of interest when none existed, but stand by the rest of my comments. Yours faithfully, Dr David Lloyd (1)http://www.kcl.ac.uk/kis/schools/life_sciences/biomed/bscb/newsletter/summer98/wellcome.html Competing interests: MS Patient |
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John Zajicek, Reader in Neurology Peninsula Medical School, PL6 8BX, David Wright, Principal Lecturer in Statistics, University of Plymouth
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Sudlow & Counsell highlight the problems of the current UK risk- sharing scheme for interferon beta and glatiramer acetate for relapsing- remitting MS. They also repeat many of the arguments associated with the published trials in this field. There have been several previous attempts at producing an independent UK National trial of these treatments in MS, all of which failed to be funded for various reasons ranging from difficulties with outcome measures, to a perceived reluctance of patients to take part in placebo- controlled trials of treatments which already had a licence for use in relapsing-remitting disease. A further proposal is currently being considered by the MRC for a study of these drugs, this time at the beginning of the MS clinical disease process. The UK Early MS Study (UKEMS) would randomise patients to active treatment or control following their first clinical manifestation, with follow-up for 10 years. There are already two published studies for this clinical indication, which form the basis of licensing applications by manufacturers. This provokes a considerable sense of déjà vu. The UKEMS study is possibly the last opportunity to perform a long-term randomised controlled study of these treatments, but once again may fail over cost issues. If these drugs are licensed and used for this new indication, we estimate that the NHS costs will increase from £50m to £100m per annum, yet clinical trials costs will be a fraction of this amount. There are strong arguments for testing these expensive treatments in the context of long-term randomised controlled trials before we get to the stage of risk- sharing schemes. Can the country now afford not to invest in these trials and will we be rehearsing these same arguments in another ten years time? Competing interests: Authors are collaborators in the UK Early MS (UKEMS) study |
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Michael H Johnson, Consultant Neurologist St. James's University Hospital leeds St. James's University Hospital, Beckett Street Leeds LS9 7TF, Helen Ford
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Sir,
We welcome the critical analysis of the Dept of Health's Risk Sharing Scheme (RSS) by Sudlow and Counsell(1) which coincided with the publication of another meta-analysis of recombinant interferon trials in relapsing-remitting multiple sclerosis (MS), the conclusion being that any effect after the first year was modest and not clearly demonstrated in completed trials.(2) Our concern is that monitoring of patients in the RSS is based on the annual assessment of the Expanded Disability Status Scale (EDSS) and does not include a measure of quality of life. We have shown that the EDSS is insensitive to change in this population which means that real effects, both good and bad, will be missed. We have prospectively assessed all patients treated with interferon beta and glatiramer acetate in the West Yorkshire MS Treatment Programme using a disease specific measure of quality of life, the Leeds MS Quality of Life measure, (LMSQoL), and a disease-specific measure of disability, the Guy's Neurological Disability Scale (GNDS) in addition to the EDSS. The LMSQoL score improved significantly at one year and this improvement was maintained at 2 years. There was no significant change in the EDSS (Table 1). The responsiveness to change of the LMSQoL was greater in those who were maintained on treatment by treating clinicians. Effect size Effect size Maintained on treatment (n=53) Treatment stopped(n=16) LMSQoL 1.12 0.69 GNDS 0.30 0.53 EDSS 0 0 Table 1. Responsiveness to change of the LMSQoL, GNDS and EDSS in a prospective cohort treated with interferon beta (n=73) The LMSQoL has also been shown to be more responsive to change than the MSQoL-54, a measure of health status and the EuroQoL in a study of patients with acute relapses due to MS treated with intravenous steroids. (Table 2).
Effect size Effect size
Improved Unchanged/deteriorated
LMSQoL 0.843 0.434
MSQOL-54 0.039-0.997 0.07-0.32
(range of subscales)
EUROQoL 0.322 0.021
Table 2 Responsiveness to change of the LMSQoL, MSQoL-54
and EuroQoL in a prospective cohort of acute relapsing patients (n=50)
Many other problems with the RSS have been identified, most notably issues of selection. The patients included are selected by the patchy availability of resources in different areas, in particular access to neurology services. Previous years of postcode prescribing have resulted in areas like Leeds having many actively relapsing and remitting patients already on treatment with other areas with no previous prescribing having large populations of drug-naïve patients. Patients already on treatment can be included at this stage but those that started and have now stopped or changed to other treatments will not be included. It is also open to patients to decline consent for the RSS while still being given treatment. It is very unlikely that long-term(10+years) double blind controlled trials of treatments such as interferons, glatiramer or azathioprine are possible. As Sudlow and Counsell point out, blinding is extremely difficult to maintain, and drop-outs amount to about 20 % over the first 5 years. Furthermore, azathioprine is likely to be used in different types of patients than interferons and glatiramer and clinicians may feel unhappy to randomise patients between these two treatments. Patients are also reluctant to consider placebo treatment when licensed drugs are available. After an experience of 5 years using these treatments, we feel that the interferons and glatiramer are of short-term benefit in patients with severe and frequent relapses and we would support a study in which these treatments are compared one with another and possibly with azathioprine so long as the study utilised established outcome measures which capture some of the potential benefits of these treatments. The particular and unique difficulties posed in MS should not deter us from attempting to find solutions to the difficulties of clinical trials and the NHS is an ideal organisation through which long-term efficacy can be measured. Michael Johnson Helen Ford Department of Neurology, St James's University Hospital, Leeds, LS9 7TF. References 1. Sudlow CL, Counsell CE. Problems with UK government's risk sharing scheme for assessing drugs for multiple sclerosis BMJ 2003;326:388-92 2. Filippini G et al. Interferons in relapsing remitting multiple sclerosis: a systematic review.Lancet 2003;361:545-52 3. Ford HL, Johnson MH, Fear J. A multi-district model for the management of disease-modifying treatments in multiple sclerosis B J Clinical Governance 2002;7:267-272 Competing interests: Dr Johnson and Dr. Ford have received grants from pahrmaceutical companies involved in the risk sharing scheme in order to attend multiple sclerosis meetings. Dr Johnson has served on advisory panels for Schering and Teva pharmaceuticals. |
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Charles P Warlow, Professor of Medical Neurology Department of Clinical Neurosciences, Western General Hospital, Edinburgh, EH4 2XU
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Dear Sir, The Risk Sharing Scheme cannot evaluate the cost-effectiveness of disease modifying drugs in multiple sclerosis (MS). Although a non- randomised study such as this allows costs to be assessed, it cannot measure effectiveness reliably because of the inevitable biases. The prognosis of MS is too difficult to predict, effectiveness needs to be measured over years not months (a substantial challenge), the validity of the outcome selected is suspect, those who measure the outcome are not blinded to the treatment, not just one drug is involved but four, and patients may switch between these drugs. Piloting such a scheme by studying a single drug in a disease which leads to death in a matter of months (such as riluzole for motor neurone disease) might have had a better chance of success. However, there is a silver lining, and so opportunities. The Scheme will at least provide a huge cohort of MS patients which should allow better definition of groups of patients (but not individuals) in different strata of expected outcome. This will be useful in future practice when high risk or high cost treatments can be applied to those most likely to do badly without them, and in designing randomised trials. But to succeed the Scheme must be funded properly by the Department of Health. After all, it will be by far the largest and longest cohort study ever attempted by UK neurologists. Unfortunately, there are threats, to other patients and to future research. Because the Scheme is so expensive, and will take up the time of so many neurologists, it seems very likely that patients with other neurological disorders (and those with MS who are ineligible for the Scheme) will be disadvantaged. And already the existence of the Scheme has prejudiced the chance of MRC funding of a proposed trial to get what we really need - more randomised evidence for beta interferon, at least in the earliest stages of the disease, something which MS patients really need to know. History is repeating itself. Nearly 10 years ago, both the MRC and the Department of Health turned down - not just once but three times - a large randomised trial which they themselves asked me and others to design to sort out the effectiveness of beta interferon in relapsing and remitting MS. If they had funded it, the Risk Sharing Scheme may not have been necessary – we would already have the necessary randomised evidence on long term effectiveness and from that could have sorted out cost-effectiveness. Yours sincerely Charles Warlow Competing interests: The first author of the article 'Problems with the UK government's risk sharing scheme for assessing drugs for multiple sclerosis' is my partner. |
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Carl E Counsell, Clinical Senior Lecturer in Neurology University of Aberdeen, Cathie L.M. Sudlow
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We would like to thank all those who took time to respond to our article. The UK risk sharing scheme (RSS) will provide a large modern cohort of patients with relapsing-remitting and secondary progressive-relapsing multiple sclerosis (MS)treated with beta-interferon and glatiramer in whom observational data on long term outcome and costs can be collected. However, as recognised by both the independent scientific advisors and the monitoring group, the use of a historical control group cannot provide reliable evidence about whether these drugs actually provide any worthwhile benefit in the long-term by reducing the progression of disability. Surely this is what patients, doctors, health economists, and politicians want and need to know. No amount of “validating” the historical control group will ensure that those in it had the same baseline prognosis as those entering the RSS. The only way to achieve this is through randomisation. The monitoring group suggests that there is no place for further analyses of existing data. This fails to acknowledge the substantial added value of analyses based on unrestricted access to individual patient data. No systematic review has been able to include all of the relevant data, since the pharmaceutical companies have not made these available. However, even if these data were available, there is still a lack of information beyond two to three years. Extension of follow-up in some trials was too biased by large numbers of losses to follow-up to be informative about the effects of treatment. We acknowledge that a trial including an untreated control group might be unpopular but do not think it is unethical. For all but those few patients with very frequent and severe relapses, the reduction in short-term relapse rate with treatment is small in absolute terms (and is likely to be overestimated due to various biases [1]) whilst the long-term effect (benefit or harm) is completely unknown. Given that we do not know if we are exposing patients to long-term side-effects without long-term gain, we (and others [1]) believe it is ethical to randomise most patients between treatment and no treatment. The choice of a clinically relevant and sensitive outcome measure is not a new problem in MS research and should not hold back such a trial. A simplified expanded disability status scale score as required by the RSS combined with a quality of life score should satisfy most people. We welcome the fact that others are trying to establish a trial with a control arm in early disease and consider it most unfortunate that the RSS as it stands may hamper such research. The inclusion of azathioprine in our proposal was on the basis that its short-term effects appear similar to those of the newer agents at a fraction of the cost. Like many, we are unsure of the long-term effects of both azathioprine and the newer agents (not least because of the unclear association between demyelination and axonal degeneration), but the few trials that assessed disability progression with azathioprine found similar reductions to the interferon trials (2). Chaudhuri’s argument that neither azathioprine nor the newer agents merit further long -term trials misses the point: the newer agents are now in clinical use and yet we do not know their long-term effects (good, bad, or none). We are also not convinced that the RSS will provide substantial benefit to most patients with MS. Extra resources are welcome and will allow those with suspected MS to be seen more quickly. However, many patients who do not fulfil treatment criteria, particularly those with progressive disease, mainly require access to good rehabilitation and social services and there is no provision for increased funding for these services in the scheme. It also remains unclear whether the increased resources will be sufficient to meet the increase in workload without impacting on services to patients with other neurological diseases who are just as deserving as MS patients. Finally, we believe the RSS sets the unfortunate precedent of bypassing the need for long-term randomised controlled trials (RCTs) in slowly progressive neurodegenerative conditions such as MS, dementia, and Parkinson’s disease. This was/is an opportunity to develop a strategy whereby promising treatments are introduced to eligible patients throughout the country in the context of a simple, independent, long-term RCT. However, in the future pharmaceutical companies will be able to push for similar schemes for other expensive neuroprotective drugs which have gained a licence on the basis of company sponsored trials showing short- term benefits on outcomes chosen more for their likelihood of showing statistical significance than for their clinical relevance. We, like all other neurologists, want the best for present and future generations of MS patients as well as the best use of resources for all patients with neurological diseases in the UK. Rather than offering this, we feel that the RSS is a politically expedient solution in the face of a poor evidence base and overwhelming pressure from the pharmaceutical companies and patient support groups. We hope our concerns are proved wrong. Yours sincerely. Carl Counsell, Cathie Sudlow. (1). Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C, D'Amico R, Rice GPA. Interferons in relapsing remitting multiple sclerosis: a systematic review. Lancet 2003;361:545-552. (2). Yudkin PL, Ellison GW, Ghezzi A, Goodkin DE, Hughes RAC, McPherson K, et al. Overview of azathioprine treatment in multiple sclerosis. Lancet 1991; 338: 1051-1055. Competing interests: None declared |
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