Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
There are no winners and losers in a case that involves the only drug treatments available for people with dementia
- Andrew Ketteringham (24 August 2007)
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The Alzheimer's Society and public trust
- Iain Chalmers (26 August 2007)
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Alzheimers society and drug promotion
- Miranda Mugford (28 August 2007)
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Role of Alzheimer Society
- Hugh Rickards (31 August 2007)
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Meaningful Trial Outcomes
- Arun S. Nanivadekar (15 September 2007)
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NICE cost-effectiveness models should be open to scrutiny
- Chris D Poole, Samir Agrawal, and Craig J. Currie (24 September 2007)
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Obtaining the evidence - new opportunities for clinical trials in neurodegenerative diseases
- John Zajicek, Jeremy Hobart and Methodology Special Interest Group (26 September 2007)
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Andrew Ketteringham, Director of External Affairs Alzheimer's Society, SW1P 1PH
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In this week’s BMJ, Iain Chalmers makes inaccurate claims about the Alzheimer’s Society’s campaign for access to drug treatments that a simple call to the Society would have laid bare.
Sir Iain says that four simple steps would restore his confidence in us. The Society would like to reassure him that all of these steps have already been taken. That the Alzheimer’s Society should clearly declare on its website the sources and amount of support it receives from its work. That the Society makes clear what alternative distribution of limited resources it regards as more appropriate and why. That we campaign for treatments for dementia to be evaluated using the outcomes that are meaningful to patients. That the Society call for data from clinical trials to be published. Implied and outright allegations that the Alzheimer's Society has pleaded an irresponsible case, while in the back pocket of drug companies are mischievous, misleading and insulting. Representing people with dementia and their carers, the Society raised separate legal arguments with independent council. The public, wanting their voice to be heard, funded the Alzheimer’s Society challenge. To suggest an alliance with drug manufacturers is an insult to the thousands of people across the nation who took to the streets in support of the campaign. The only alliance the Alzheimer’s Society has in this case is with over 30 patient and professional organisations that opposed NICE’s decision under the banner of the Action on Alzheimer’s Drugs Alliance. The judicial review was not the victory for NICE Sir Iain suggests. Beneath the spin NICE was found guilty of having breached the Disability Discrimination Act and the Race Relations Act and was ordered by the court to substantially amend its guidance. This is an extremely serious finding and why it was ordered to pay 40% of the drug company costs in addition to its own costs. The 40% of people with Down’s Syndrome who go on to develop dementia in later life, others with learning difficulties and those who do not speak English as a first language will now have equal access to drugs. The Alzheimer’s Society gave a voice to these people when it threatened to go unheard. But, there are no ‘winners’ in a case that involves the only drug treatments available for people with dementia and NICE. The Alzheimer’s Society has long supported the role of a public rationing body such as NICE. The controversy over the drugs guidance masks the very positive work NICE has done on the Dementia Care Guideline which is a far more important step forward. We have already had discussions with NICE about how to encourage implementation of the most important and positive aspects of the guideline. But it remains the case that NICE’s guidance on treatment for Alzheimer’s Disease is against patient experience and clinical sense. Sir Iain can rest assured that the Alzheimer’s Society has and will continue to campaign in the best interests of people with dementia and carers with integrity, transparency and commitment. Competing interests: The Alzheimer's Society acted as an interested party in the Judicial Review of the NICE appraisal of Alzheimer's drug treatments. |
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Iain Chalmers, Coordinator James lind Initiative , Middle Way, Oxford OX2 7LG
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As the Director of External Affairs at the Alzheimer's Society suggests that I have insulted the Society and its supporters it seems that I need to reiterate the words used by the Society in its reaction to the legal judgement exonerating NICE in respect of five of the six charges brought against it. The Society’s website contains (25 August 2007) the following statement: "NICE failed to listen to the views of thousands of carers who told them drug treatments make a huge difference to their lives. It is deeply disturbing that a public body, required to use rigorous standards of evidence based decision making, can simply guess at vital data. This is simply unacceptable . . . To retain its authority as a public body it must command the confidence of the public. The result of this case must call into question whether NICE has lost that confidence." These were the insulting words that prompted me to submit my personal view for publication. How dare the Society claim that NICE “failed to listen to the views of thousands of carers”? How dare it suggest that NICE “simply guess[es] at vital data”? And on what extraordinary logic does the Society conclude that the court’s exoneration of NICE on five of the six charges brought against it by the Society and drug firms “must call into question whether NICE has lost [public] confidence?” As someone who is at above average risk of developing Alzheimer’s disease I am reassured to learn that the Society is already doing some of the things that I believe it should be doing. But it is not yet doing so with the transparency to which it claims to be committed. Importantly, for example, the Society’s website does not make clear the sources and amount of support it receives for its work. Indeed, if it did do so, I would have expected its Director of External Affairs to have provided the link to help me and other readers to substantiate his assertion. This issue is important because of increasing concern over the lack of transparency about the extent to which patients’ groups are being funded by industry (1). The Society should be taking advantage of the opportunity to reassure the public by trumpeting the fact that only 0.5 per cent of its money comes from pharmaceutical companies. The Society’s website provides an opportunity for it to draw attention to the steps that it is taking to address the challenges I posed to it. I shall hope that transparency there - drawing attention to the evidence supporting its assertions - will help to restore my former substantial respect for the Society. Iain Chalmers 1. Herxheimer A. Relationships between the pharmaceutical industry and patients' organisations. BMJ 2003; 326: 1208- 1210; doi:10.1136/bmj.326.7400.1208. Competing interests: I am a member of the NICE research and development advisory committee and provided written evidence challenging the charge that NICE's assessment and consideration of the AD2000 study (of donezepil in Alzheimer's disease) was irrational. |
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Miranda Mugford, Professor of Health Economics University of East Anglia,
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The Alzheimer's Society has funded some excellent research on health of carers of people with dementia, and much else. For this reason I was very happy to subscribe to a direct debit donation to the Society. As a health economist, I am committed to fair and open allocation of health care resources for the people of the UK, so that each pound spent by the government gains as much benefit as it can for people in need. I have had a growing unhappiness about the way that the Alheimer's society has 'marketed' the drug, and has raised unrealisable hopes and expectations among many I know for its value to potential users and to society. I have now decided to withdraw my donation as long as the charity's funds are being used to assist sales of a drug of very marginal effectiveness. The fact that the company manufacturing the drug has not paid for this campaign seems to imply that donors to the Society are happy to promote the drug. I am not. If successful, this campaign could very well (unintentionally of course) result in poorer social services, which are currently struggling to provide the very help that is so lacking at present for people with dementia. I might take a different view if the Alzheimers Society were campaigning for a lower price for this drug, which is apparently helpful to some for a while. Competing interests: Close relative just died following dementia. I am an academic health economist. I am a Quaker. |
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Hugh Rickards, Consultant in Neuropsychiatry B15 2QZ
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I was relieved to read Iain Chalmers' article as it articulated what I had been thinking. It is appropriate for Societies to actively lobby on behalf of their members but is also important to preserve a balance in their views, to reflect the diversity of the membership, and to be above any suspicion of conflicts of interest. The impression is that the Alzheimer's Disease Society have formed a political alliance with the Pharmaceutical industry and have launched a personal attack on NICE. This impression is damaging to the credibility of the Society and may not be in the long term interests of its members. I have never been a member of the ADS, my only interest is that of a clinician. Competing interests: None declared |
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Arun S. Nanivadekar, Medical Research Consultant C-2, Flushel Apts, 21 Rd, Bandra West, Mumbai 400050, India
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I wish to emphasize the importance of Sir Ian's third point, namely, "... using outcomes that are meaningful to patients and carers". Working at the interface of drug-makers and regulators, I am increasingly becoming aware that mega trials are being driven more by what regulators would accept for granting a claim, and the statistical techniques available to achieve those outcome measures, disregarding what is materially important to patients and their carers, both in nature and size. I believe if a benefit outcome is important and large enough, as predefined by patients, carers, and their support groups, then that ought to be the focus of any trial, whether sponsored by a government, an industry, an academic body, or a regulatory agency. And it should be done on patients who resemble the patients to whom the conclusions are to be applied. These are essential requirements which can only be fulfilled by patients and their physicians, not by statisticians or regulators in isolation. Competing interests: None declared |
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Chris D Poole, Director Pharmatelligence LLP, Cardiff MediCentre, Heath Park, Cardiff, CF14 4UJ, Samir Agrawal, and Craig J. Currie
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Dear Sir, With respect to the recent ruling by Mrs Justice Dobbs in favour of the NICE decision over donezepil[1], we wish comment on the current adversarial system of medicines evaluation in general in the UK, and the adequacy of providing only ‘read-only’ versions of the cost-effectiveness models for the purposes of reviewing health economic decisions by NICE. This issue has been raised before[2]. We have previously requested access to fully executable versions of cost-effectiveness models used to inform Final Appraisal Determinations (FADs), without success[2,3]. Andrew Dillon’s (Chief Executive of NICE) oft repeated assertion that “[NICE] is not in a position to deal with the reality of restrictions being placed on [the models] by those who supply them"[1] is not defensible. The commissioners of the systematic reviews should quite reasonably be expected to specify terms and conditions which allow full disclosure of what after all is publicly funded research. If the current academic Health Technology Assessment groups are unwilling to accept these terms and conditions then NICE should turn to HTA groups willing to do so; there is an abundance of equally competent organisations in the private sector. Furthermore, in our view it can be argued reasonably that they should be disclosed under the Freedom of Information Act[4]. This could be from either NICE directly, or from the specific university groups who developed them. Prevention of disclosure here could be defended if disclosure can in some way be interpreted as being against the public interest. Recently, the Sheffield HTA group published a correction to their own cost-effectiveness model for multiple sclerosis treatments caused by a coding error that was not identified in any of the review procedures in the original project5. Intelligence from this model underpinned a high profile and novel ‘shared risk’ policy6. Our own previous experience in evaluating others’ cost-effectiveness models has shown the ease with which serious computational errors can go unnoticed through the entire appraisal process. Given that even the simplest spreadsheet-based deterministic models are likely to consist of thousands of calculations, each of which is coded manually by one individual, errors are hardly surprising. More sophisticated simulation models often employ ‘hard-coded’ computational routines, the detail of which is rarely, if ever, scrutinised. It could be reasonably argued that the responsibility of NICE to quality-assure these models cannot be adequately discharged under the current contractual arrangements with the academic HTA community. The current adversarial system of economic assessment for new health technologies is not acceptable to key stakeholders as the Eisai vs. NICE case has illustrated. Development of cost-effectiveness cases acceptable to all sides demands an open and fair means of consensus including the ability of all parties to scrutinise and approve the proposed computational methods. This could easily be achieved by appointment of a single agency (selected by competitive tender) to produce cost- effectiveness models for a given appraisal under the joint direction of both NICE and the manufacturer. Such a consensus-based system would reduce cost and potentially lengthy appeals procedures thereby hastening access to effective health technologies that all agree are good value for money. An alternative way of improving confidence would be to have two models developed independently by NICE and their findings compared. Even this would present difficulties. Recent evidence from a deliberate comparison of alternative, widely utilised diabetes cost-effectiveness models resulted in highly varied findings7. Under the existing system of drug evaluation, NICE’s craving for secrecy is simply to protect themselves from periodic embarrassment and potentially expensive litigation. Litigation is undesirable and should be prevented. We have broadly agreed with NICE’s previous decisions; however, the process can still be improved, and openness to scrutiny of their key decision making process is imperative. Yours sincerely, Dr Chris Poole, Pharmatelligence LLP, Cardiff MediCentre, Cardiff Dr Samir Agrawal, Department of Haematological Oncology, St. Bartholomew's Hospital, London Dr Craig J. Currie, Department of Medicine, Cardiff University References 1. <http://www.bailii.org/ew/cases/EWHC/Admin/2007/1941.html> 2. Currie C. Open drug testing models to scrutiny by more agencies. Financial Times [London 1st ed]. London (UK): Nov 22, 2006. pg. 18 3. NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE. Appraisal of erythropoeitins for the treatment of cancer-treatment induced anaemia. Decision of the Appeal Panel. 4th September 2006. <http://guidance.nice.org.uk/download.aspx?o=360061> 4. <http://www.ico.gov.uk/Home/what_we_cover/freedom_of_information.aspx> 5. Corrections. Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis. Correction for Chilcott et al., BMJ 326 (7388) 522. BMJ 2007;334 (24 March), doi:10.1136/bmj.39155.488704.BE 6. Sudlow CL, Counsell CE. Problems with UK government's risk sharing scheme for assessing drugs for multiple sclerosis. BMJ 2003;326:388-92 7. The Mount Hood 4 Modeling Group. Computer modeling of diabetes and its complications. A report on the Fourth Mount Hood Challenge Meeting. Diab Care 2007;30:1638-1646 Competing interests: Drs Currie and Poole have previously worked for several pharmaceutical companies assisting in the preparation of NICE submissions. Dr Agrawal has represented the Royal College of Pathologists in previous NICE Appeal proceedings. |
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John Zajicek, Chair DeNDRoN methodology special interste group Peninsula Medical School, PL6 8BX, Jeremy Hobart and Methodology Special Interest Group
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The observed increase in neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s disease (PD), accompanying our aging population poses major challenges to health care systems worldwide. Although considerable time, energy and financial resources have been devoted towards slowing disease progression, no treatments exist that convincingly alter the natural history of neurodegeneration. Why? Are all the compounds showing promise in the laboratory ineffective when translated to human use, perhaps due to false positive findings(1), or are there flaws in the way we test these medicines? Has the pace of basic laboratory science, and the complexity of studying humans, outstripped our ability to design clinical trials for the 21st century? Iain Chalmers’ recent personal view(2) highlights some major issues in this area. Although we have numerous outcome measures (predominantly rating scales) for AD and PD, we know little about their meaningfulness to patients and carers. Also, we don’t know what level of change on most of these measures is clinically significant. It is, therefore, impossible to power clinical trials meaningfully. Even if we have some idea of the importance of specific changes, this may vary across the disease process and measurement continuum. More fundamentally, many scales are based on poor basic principles, with little qualitative grounding to really understand what they measure. Vitally, the numbers generated by most scales are not equal across the range of the continuum, so changes measured at different stages of the disease course may not be directly comparable. The ADAS-cog, for example, which is the US FDA recommended measure for licensing cognitive enhancing medication, was originally developed from data on only 27 patients, and demonstrates limited input from established rating scale science (psychometrics)(3). It is noteworthy (very) that scientific methods of rating scale construction and evaluation have advanced substantially in the last 40 years. Methods now exist for constructing “ruler-like” linear measurements from ordinal rating scale data(4), and for explicitly determining the nature of the abstract clinical variables we seek to measure(5). These methods, poorly appreciated and often misunderstood(6), offer an opportunity to accurately measure clinical change across the course of a disease and spectrum of severity. The problems in designing trials to alter the course of neurodegeneration are not confined to outcome measurement. There are also major problems in separating symptomatic and disease modifying effects, though the distinction may be of little concern to patients should they have a sustained treatment benefit. These issues are exemplified in the DATATOP study of selegiline in PD(7). This trial was initially hailed as demonstrating neuroprotection until it was realised that the drug has significant symptomatic benefit, confounding any potential long-term disease modifying effect. Many different trial designs have been suggested to separate symptom relief from long-term disease slowing. These include randomised delayed treatment initiation, randomised withdrawal, time to event, or slope analysis. All of these strategies are associated with potential problems including long (often unknown) wash-out periods of the symptomatic drug action, and difficulties keeping people in long-term studies when they are deteriorating. One suggested has been to seek biomarkers associated with known pathological processes – for example atrophy on sequential magnetic resonance scanning for AD, or radio-isotope imaging (PET or SPECT) of dopaminergic neurones in PD. Whilst surrogate outcomes may be helpful (especially in phase 2 studies), and encouraged by licensing authorities, there is little prospect of their replacing well constructed and validated clinical measures. Results can also be significant but counter-intuitive, which further complicates interpretation, such as occurred in the amyloid immunisation trial in AD(8). Ultimately we are treating people, not scans or biochemical tests, so there will always be a need for scientifically rigorous clinical measures. But what if the clinical measures are found wanting? A recent £100m new investment in NHS research infrastructure (http://www.ukcrn.org.uk/index.html) and re-engineering of NHS research organisation offer a unique opportunity to address some of these issues. The formation of topic specific research networks such as the Dementia and Neurodegenerative Disease Research Network (DeNDRoN) provides the infrastructure to enable well-designed studies to become adopted with access to resources to facilitate that research. Independent special interest groups such as the DeNDRoN methodology group, have an opportunity to go back to basics with regard to outcome measurement and trial design. However, whilst the new networks provide infrastructure access, they do not provide research costs. There is a requirement to work with industry, charities, other funding bodies and the licensing authorities to develop new ways of measuring the impact of neurodegenerative disease on people’s lives. An example of such a collaboration is the AD Neuroimaging Initiative (ADNI)(9). Although the philanthropic motivations of commercial, academic and government organisations may differ, we currently have an opportunity to develop robust methods to test new treatments, incorporating newly developed clinical measurements with research in surrogate measures (including an evaluation of genetics on drug responsiveness)(10) for the benefit of our patients. John Zajicek, Jeremy Hobart and the DeNDRoN Methodology Special Interest Group. (full membership list at : http://www.dendron.org.uk/cr/methodology_sig.html) 1. Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P et al. Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007; 334:197 2. Chalmers I. The Alzheimer’s Society, drug firms and public trust. BMJ 2007; 335: 400 3. Rosen G, Mohs RC, Davis K.L. A new rating scale for Alzheimer’s disease. Am J psychiatry 1984; 141: 1356-1364. 4. Hobart, JC, Riazi A, Thompson AJ, Styles IM, Ingram W, Vickery PJ, et al., Getting the measure of spasticity in multiple sclerosis: the Multiple Sclerosis Spasticity Scale (MSSS-88). Brain 2006; 129: 224-234. 5. Stenner, AJ, Burdick H, Sanford EE, Burdick DS. How accurate are lexile text measures? J Appl Meas 2006; 7: 307-322. 6. Andrich, D, Controversy and the Rasch model: a characteristic of incompatible paradigms ? Med Care 2004; 42: I7 - I16. 7. Stocchi F and Olanow CW Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003; 53 suppl 3 : 97-99 8. Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L et al. Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease. Neurology 2005;64:1563-72. 9. Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack CR Jaqust W, et al. Ways towards an early diagnosis in Alzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative (ADNI). Alzheimers Dement 2005; 1: 55-66. 10. O'Toole M, Janszen DB, Slonim DK, Reddy PS, Ellis DK, Lequalt HM et al. Risk Factors Associated With Beta-Amyloid(1-42) Immunotherapy in Preimmunization Gene Expression Patterns of Blood Cells. Arch Neurol 2005; 62: 1531-1536 Competing interests: None declared |
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