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. 1998 Oct 3;317(7163):945.

New drug treatment for Alzheimer’s disease

Doctors want to offer more than sympathy

Tom Dening 1,*, Claire Lawton 1,*
PMCID: PMC1113992  PMID: 9756823

Editor—Yesterday a woman with Alzheimer’s disease greeted me by asking spontaneously whether I had recovered from a cold that I had had at her last clinic appointment three months before. A man with the same condition has started to telephone his family again and is now able to go shopping for clothes. The benefits resulting from these two patients’ treatment with donepezil are not trivial as Melzer seems to suggest1—a clinical trial is scarcely required to show the improvement.

Much is to be learnt from the way in which donepezil has been launched, but, because of the reaction of health authorities hundreds of patients who would by now have benefited from taking donepezil have been denied access to a properly licensed treatment. There are two pieces of subterfuge at work. Firstly, an economic and rationing argument is presented as being a clinical one, with a campaign to raise doubts about the effectiveness of donepezil. The available evidence shows that the drug is as effective as one might expect it to be; it is, after all, only a symptomatic remedy for a progressive disease. Melzer criticises the instruments used in the trials, but the company has followed the methodological requirements of the Food and Drug Administration, so to take exception after the event is unfair. Secondly, contrary to the principles of evidence based medicine and systematic reviews, which emphasise the importance of unpublished data, in the case of donepezil only published trials may be discussed, even though other data have been available all along.

News of new treatments and the enthusiasm accompanying them should not be censored. The representation of the debate among psychiatrists specialising in conditions relating to old age is being distorted. Is it reprehensible for us to wish to offer effective treatments to our patients rather than just sympathy?

References

  • 1.Melzer D. New drug treatment for Alzheimer’s disease: lessons for healthcare policy. BMJ. 1998;316:762–764. doi: 10.1136/bmj.316.7133.762. . (7 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
BMJ. 1998 Oct 3;317(7163):945.

Effects of drugs can be variable

Raymond Levy 1

Editor—I agree with Melzer regarding the need for all evidence from trials to be published or made available before a drug is marketed.1-1 I take issue with him, however, over the question of effect size and his suggestion that it is too small to warrant using donepezil. He seems to see a small effect in all patients entering trials, whereas the evidence from trials of tacrine,1-2,1-3 velnacrine,1-4 donepezil,1-5 and other cholinesterase inhibitors suggests that the effect is extremely variable, with large improvements in some patients and none in others.

At the moment we have no foolproof way of distinguishing potential responders from non-responders. When response occurs it does so relatively quickly. The only certain way of proceeding is therefore to use the drug for, say, 12 weeks and to observe the results systematically—surely not an unusual situation in medicine. Why should Alzheimer’s disease be treated differently?

Footnotes

Competing interests: none declared.

References

  • 1-1.Melzer D. New drug treatment for Alzheimer’s disease: lessons for healthcare policy. BMJ. 1998;316:762–764. doi: 10.1136/bmj.316.7133.762. . (7 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer’s disease. Lancet. 1991;337:989–992. doi: 10.1016/0140-6736(91)92656-m. [DOI] [PubMed] [Google Scholar]
  • 1-3.Farlow M, Gracon SI, Hershey LA, Lewis KW, Sadowsky CH, Dolan-Ureno J. A controlled trial of tacrine in Alzheimer’s disease. JAMA. 1992;268:2523–2529. [PubMed] [Google Scholar]
  • 1-4.Siegfried K. Neurotransmitter-based treatment of Alzheimer’s disease: the example of velnacrine. In: Levy R, Howard R, editors. Developments in dementia and functional disorders in the elderly. Petersfield: Wrightson Biomedical; 1995. pp. 77–83. [Google Scholar]
  • 1-5.Rogers SL, Farlow MR, Doody RS. A 24-week double-blind, placebo controlled trial of donepezil with Alzheimer’s disease. Neurology. 1998;50:136–145. doi: 10.1212/wnl.50.1.136. [DOI] [PubMed] [Google Scholar]
BMJ. 1998 Oct 3;317(7163):945.

Drugs should not need to show cost effectiveness to justify their prescription

M Evans 1,2-150

Editor—Melzer’s paper is one of many that deal with the launch of donepezil and other future treatments for Alzheimer’s disease.2-1,2-2 The number of patients potentially eligible for treatment and their age seem to be the main factors leading to criticism of the cost. No other licence for a new product has been greeted with such fury. The implications for health authority budgets are serious.

The two health authorities served by Wirral and West Cheshire Community NHS Trust—South Cheshire and Wirral—have worked with the elderly mental health directorate, general practitioners, and the local branch of the Alzheimer’s Disease Society to develop a measured response, which seems to satisfy most people. Donepezil and future drugs for Alzheimer’s disease are prescribed only by the psychiatry of old age services, which has been given funding to provide extra staff and set up a central unit for diagnostic assessment with satellite follow up clinics. Drug treatment is prescribed according to strict guidelines, and the response to the drug is reviewed after three months. If the patient shows no response the treatment is stopped.

A limited budget can thus be directed to where it will be most effective. We save 17.5% of the total costs of the drugs by using prescriptions prescribed by hospital doctors and dispensed by community pharmacists. The cost is lower because VAT is charged on hospital pharmacy supplies.

We use only the 5 mg dose of donepezil as the drug companies have not shown an improvement with the 10 mg dose. Before agreement over protocols was reached and the clinic set up with an audit system in place in November 1997, donepezil was voluntarily not prescribed in our area, which allowed us to negotiate in a spirit of cooperation.

The true effect size, both clinically and economically, will be shown by the use of drugs only in clinical medicine, not in drug trials. Pilot studies for such evidence based medicine should be set up as a matter of course. Perhaps they could run at the same time as the classical double blind phase three trials; provided initial phase two work shows safety and some evidence of efficacy.

It takes so long for drugs to reach the market, and the cost of development is so high, that further delays would be counterproductive and lead to a reduction in the number of products that drug companies were willing to research. Why do these drugs need to show cost effectiveness to justify their prescription? Surely improved quality of life and delay in deterioration, such as is expected with, for example, chemotherapy, is sufficient justification.

References

  • 2-1.Melzer D. New drug treatment for Alzheimer’s disease: lessons for healthcare policy. BMJ. 1998;316:762–764. doi: 10.1136/bmj.316.7133.762. . (7 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Kelly CA, Harvey RJ, Katon H. Drug treatments for Alzheimer’s disease BMJ 1997;314:693-4. [DOI] [PMC free article] [PubMed]
BMJ. 1998 Oct 3;317(7163):945.

Information from unpublished trials should be made available

Paul Johnstone 1,3-150

Editor—Melzer’s call to end the secrecy surrounding the licensing of drugs and make available trial data for independent analysis is welcome.3-1 I have participated in preparing a systematic review on the effectiveness of drug treatment for scabies.3-2 Many important gaps in our knowledge have not been filled, not just about the effectiveness of treatments for scabies but about their side effects. Further unpublished information from drug company trials would provide valuable evidence. Yet although the companies admitted that these data existed, we were unable to obtain them. The Medicines Control Agency was similarly unhelpful. We should not forget that the original Medicines Act 1968, responsible for setting up the Medicines Control Agency to protect the public’s health, resulted from secrecy on the side effects of another drug—thalidomide.

References

  • 3-1.Melzer D. New drug treatment for Alzheimer’s disease: lessons for healthcare policy. BMJ. 1998;316:762–764. doi: 10.1136/bmj.316.7133.762. . (7 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3-2.Walker G, Johnstone P. Treating scabies. The Cochrane Library [database on disk and CD ROM]. Cochrane Collaboration; 1998, Issue 3. Oxford: Update Software, 1998. Updated quarterly.
BMJ. 1998 Oct 3;317(7163):945.

Treatment with metrifonate warrants multicentre trials

A C Zamar 1,4-150, M E J Wise 1,4-150, J P Watson 1,4-150

Editor—Meltzer addressed the problems regarding the treatment of Alzheimer’s disease with donepezil.4-1 In the absence of published data it is difficult for clinicians to make informed decisions as to whether to treat with donepezil or not, particularly because of the potential financial implications for healthcare providers.

Another cholinesterase inhibitor drug, metrifonate, has been widely used for several years in schistosomiasis. This drug is considerably cheaper than donepezil (the patent has expired) and is well tolerated. Data suggest that the only side effects of note are mild vertigo, lassitude, nausea, and colic.4-2 One double blind study compared treatment with metrifonate with placebo in 50 patients with possible Alzheimer’s disease over three months.4-3 The dose was titrated to achieve 40-60% inhibition of red cell cholinesterase activity, and outcome was measured by the cognitive subscale score of the Alzheimer’s disease assessment scale. At the end of three months the scores in the group taking metrifonate were significantly higher than those in the placebo group, by 2.6 points (P<0.01). There was a non-significant improvement in the metrifonate group of 0.75 points (P=0.15), with a significant deterioration in the placebo group of 1.10 points (P<0.02). Significant deterioration in the placebo group was recorded in the mini-mental state examination (P<0.03) and on the global improvement scale (P<0.01). Side effects were uncommon and did not necessitate changes in dose or discontinuation of treatment. Open treatment with metrifonate for up to 18 months showed a deterioration of 1.68 points a year in mini-mental state examination, as opposed to 3 points a year in Alzheimer’s disease.4-4 Metrifonate is cheap, relatively non-toxic, and it would not place a major financial burden on patient care. This warrants further multicentre trials if it is assumed that restoration of cholinergic transmission would delay deterioration in Alzheimer’s disease.

References

  • 4-1.Melzer D. New drug treatment for Alzheimer’s disease: lessons for healthcare policy. BMJ. 1998;316:762–764. doi: 10.1136/bmj.316.7133.762. . (7 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4-2.Goodman Gilman A, Wall TW, Mes AS, Taylor P. Goodman and Gilman’s pharmacological basis of therapeutics. 8th ed. New York: Pergamon; 1990. pp. 964–965. [Google Scholar]
  • 4-3.Becker RE, Colliver JA, Markwell SJ, Moriearty PL, Unni LK, Vicari S. Double blind placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease: Alzheimer Dis & Ass Disord 1996;10:124-31. [DOI] [PubMed]
  • 4-4.Katzman R, Brown T, Thal LJ, Fuld PA, Aronson M, Butters N, et al. Comparison of rate of annual change of mental status score in four independent studies of patients with Alzheimer’s dementia. Ann Neurol. 1998;24:384–389. doi: 10.1002/ana.410240306. [DOI] [PubMed] [Google Scholar]
BMJ. 1998 Oct 3;317(7163):945.

SMAC’s advice on use of donepezil is contradictory

Tony Baxter 1, David Black 1, Henry Prempeh 1

Editor—We are surprised by the contradictions between the advice of the Standing Medical Advisory Committee on the use of donepezil for Alzheimer’s disease,5-1 the committee’s principles for giving this advice, and the evidence to support the use of donepezil. The committee states that a principle of its guidance is that “resources should not be diverted to treatments whose ... cost effectiveness is not yet proven.” In its assessment of the effectiveness of donepezil the committee states that “the available evidence is not sufficient to give a clear verdict on the cost-effectiveness of donepezil.” We might therefore assume that resources should not be diverted to pay for donepezil, but the guidance to clinicians implies otherwise.

Health authorities work with local clinicians and communities to try to interpret available evidence on the effectiveness and cost effectiveness of treatments so that decision making is clear, open, principled, and fair. The committee’s guidance cannot be justified on the basis of the argument it presents and is most unhelpful.

References

  • 5-1.Standing Medical Advisory Committee. The use of donepezil for Alzheimer’s disease. London: NHS Executive; 1998. [Google Scholar]

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