- Email: [email protected]
Interferon beta in multiple sclerosis
Interferon beta in multiple sclerosis Sir—Alastair Compston (May 15, p 1 7 1 0 ) 1 highlights the lack of resources and wide geographical inequalities that characterise the treatment of people with multiple sclerosis in the UK today. However, I would like to challenge some of his assertions. The only interferon beta licensed for the treatment of secondary progressive multiple sclerosis is interferon beta-1b, and not interferon beta-1a as stated. Despite the extension of the licence, it is most unlikely that uptake of the drug will approach 50% of the population of patients with multiple sclerosis. Experience in other countries where prescription has been according to clinical need, indicates that no more than 20–30% will be both eligible and keen to proceed. Given that 20% of patients with multiple sclerosis in the UK have already been identified as suitable for interferon beta by the Association of British Neurologists, 1 it is most unfortunate that the UK funds treatment for just 1·5%, the lowest rate in Europe by a wide margin. The issue of a national trial of interferon beta in multiple sclerosis remains a practical and ethical nightmare. Such a trial has been attempted twice, and was successful only in delaying decisions about funding treatment. In the event of the resurrection of the trial, potential participants need guarantees that it will go ahead and that prescribing decisions for patients unwilling to take part will not be delayed in the interim. It would be unacceptable for patients to be forced into a placebo-controlled trial as their only chance of receiving a licensed drug. Finally, Compston makes several references to the high cost of interferon beta. The development and licensing of these products is a highrisk undertaking that requires the investment of hundreds of millions of pounds over a decade or more. For every product that reaches the market, many more fail to meet the high standards demanded. The return on such an investment is moderate in its context. Low-volume, high-tech, expensive products, such as interferon beta, are easy targets for criticism. The total UK market for all three types of interferon beta is less than £10 million per year. Multiple sclerosis costs the UK over £1·2 billion per year, of which only 12·8% are NHS costs. 2 Most of this burden is carried by other UK Government
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departments and by the individual patients and their families. It is time that people with multiple sclerosis had fair access to the right treatment, wherever they live. Jacqueline C Napier Schering Health Care, Burgess Hill, West Sussex RH15 9NE, UK 1
2
Compston A. Provision of treatment of multiple sclerosis. Lancet 1999; 353: 1710–11. Holmes J, Madgwick T, Bates D. The cost of multiple sclerosis. Br J Med Econ 1995; 8: 181–93.
Sir—Alastair Compston’s comments1 on interferon beta and multiple sclerosis, raise some interesting and complex issues. I thoroughly agree with his statement that, “more resources are required for the management and treatment of multiple sclerosis and, as promised in the White Paper, these must be spread evenly so that geographical inequities are eliminated.” However, multiple sclerosis is seriously under funded in the UK and has been for some time. The number of neurologists who work in the UK is also much lower than in other developed countries. This serious imbalance has made patients with multiple sclerosis an easy target for politicians and others swept along on the wave of cost-effectiveness. Patients with multiple sclerosis are being discriminated against by a government that has just announced that it plans to enforce the Disability Discrimination Act (1995) on all businesses, but it seems to exclude itself in the provision of treatment for patients with multiple sclerosis. Four trials now show benefit sufficient to have convinced regulators to license use of interferon beta.2–5 There is a need to identify those who respond well to the drug from those who do not, but further placebocontrolled trials will be difficult, because of the question of consent and the Declaration of Helsinki’s recommendation that the “wellbeing of the subject” should take priority over the interests of society. Subgroups are already identified with regard to interferon beta (patients must be older than 18, able to walk a certain distance, and to have had two relapses in the previous 2 years). There would need to be reassurance from the UK Government that any new subgroups identified from new trials would be more likely to be given interferon beta than those already identified. It is only in the UK that the development of the first treatment for multiple sclerosis has been regarded as a financial embarrassment.
Compston may not like the concept of pharmaceutical companies making profit. Profit means tax and reinvestment, and government, I suspect, likes both. For the moment, at the sharp end of clinical practice, purchasing health authorities are using the foundation of the National Institute for Clinical Excellence (NICE) as the means to refuse funding. I hope NICE, when it considers the case of interferon beta, will look not just at the scientific evidence and price, but also the moral, ethical, and legal issues involved. Value-added benefit, for example, has been achieved with the excellent network of specialist nurses. In my own unit, many hundreds of multiple sclerosis sufferers have benefited already from this programme, irrespective of whether they are candidates for interferon beta. Michael Gross Department of Neurology, Royal Surrey County Hospital, Guildford, Surrey GU2 5XX, UK 1
Compston A. Provision of treatment for multiple sclerosis. Lancet 1999; 353: 1710–11. 2 PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon b-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498–504. 3 OWIMS, Freedom MS, et al. 123rd Annual Meeting of American Neurological Association. 9ANA0, Oct 18–21, 1998, Montreal, Quebec, Canada. 4 Jacobs LD, Cookfair DL, Rudrick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing remitting multiple sclerosis. The Multiple Sclerosis Collaborative Research Groups (MSCRG0). Ann Neurol 1996; 39: 285–94. 5 Knobler RL. IFN-b 1a. J Neurol Neurosurg Psych 1996; 13: 333–40.
Author’s reply Sir—I called for guidelines on the use of interferon beta that are clinically appropriate yet pragmatic, a general increase in resources for people with multiple sclerosis, geographical equity in their distribution, and a solution to the issue of managed entry for expensive but moderately effective drugs in the UK national health service, for which a range of options was suggested. My purpose was to stimulate debate. Jacqueline Napier challenges several of my assertions. My original letter referred to interferon beta-1b, not interferon-beta-1a; Napier correctly identifies a printing error that went unnoticed at proof stage (see p 518). The original guidelines for interferon beta-1b applied to around
THE LANCET • Vol 354 • August 7, 1999
20% of patients (Napier’s figure, based on my own previous estimate) 1 to which can now be added around 30% who have secondary progressive multiple sclerosis and score 6·5 or below on the Kurtzke expanded disability status scale. Hence, about 50% of patients are now potentially eligible for treatment, leaving aside those outside these limits who also want treatment. The fact that interferon beta is reaching only 1·5% of patients throughout the UK, with low take-up even in places where prescribing is apparently unrestricted, has several explanations that are unrelated to eligibility. Michael Gross restates most of my points and adds that I may not like the concept of pharmaceutical companies making profit. Napier offers some economic advice. The point that a company must price its licenced products at a level that not only covers the costs of production, marketing, and distribution, but also recoups investment on the many drugs discovered that do not make it to market is elementary. The issue of whether, having failed to capture the perceived market, one option (in addition to coaxing more funds out of the system, on the desirability of which we are both agreed) is to review the price is also not economically challenging. The annual cost of interferon beta-1b in the UK is about US$15 500. In Europe, to which my comment on profits referred, the price ranges from $11 200 (Spain) to about $20 600 (Finland). Roughly the same differential applies to interferon beta1a. These figures do not accurately reflect profit margins, since substantial differences exist between brands in the recommended dose and frequency of administration. Self-evidently, factors other than what the market will stand determine local price, but at a time when strenuous efforts are being made to increase the availability of treatment for patients who have something to gain from interferon beta, it is disappointing to learn that Schering Health Care Limited does not seem to consider the price of interferon beta-1b a topic for discussion. Maybe the companies who market interferon beta-1a will prove more flexible in maximising the effect of future expenditure for people with multiple sclerosis. Alastair Compston University of Cambridge Neurology Unit, Addenbrooke’s Hospital, Cambridge C B 22 Q Q , UK 1
Compston DAS, ed. McAlpine’s multiple sclerosis, 3rd edn. London: Churchill Livingstone, 1998: 469–86.
THE LANCET • Vol 354 • August 7, 1999
Future of minimally invasive surgery Sir—In his discussion of future directions in minimally invasive surgery in your surgery supplement, David Rattner (suppl I, p 12) 1 mentions several surgical procedures that are currently done under videoscopic guidance by most of the surgeons. He did not mention that it is now possible to perform splenectomy by a laparoscopic approach. Since laparoscopic splenectomy was first successfully performed in 1992 by Carroll and colleagues 2 in Los Angeles, this approach has been adopted by several centres in the USA and in Europe for the removal of normal sized spleens. Laparoscopic splenectomy has been performed mostly for haematologic diseases— chronic idiopathic thrombocytopenic purpura, which accounts for at least 60% of all laparoscopic splenectomy cases reported in the literature, followed by hereditary spherocytosis, haemolytic anaemia, and less frequently leukaemia or lymphoma. More than 700 cases have b e e n reported in the literature. Data from a recent national survey i n I t a l y 3 revealed that 37% of surgical centres with special interest in surgery for haematological disease have now adopted laparoscopic splenectomy. Although a definite learning curve exists, most reports point out that laparoscopic splenectomy results in shorter and less complicated postoperative course with better cosmetic results and more rapid return to full activity.4,5 According to a recent review of the literature,3 the procedure carries a mortality of 0·8%; surgicalrelated morbidity was 12% and postoperative stay averaged 3 days. Moreover, evidence is growing that immune function is better preserved after a minimally invasive approach than after open surgery, a fact that might hold advantages in several malignant haematological diseases that require splenectomy. Laparoscopic splenectomy is currently regarded as the first-line procedure for the removal of normal sized spleens in many centres with advanced laparoscopic surgery programmes.3 Controversies still exist about the laparoscopic approach to massive enlarged spleens, mostly because of high risk of bleeding and difficult manipulation of the spleen. The improvement of new laparoscopic instruments, such as the ultrasonic dissector and atraumatic grasper, might help to expand the pool of
patients who can benefit from a minimally invasive approach. *Umberto Baccarani, Giovanni Terrosu, Annibale Donini, Andrea Risaliti, Fabrizio Bresadola Department of Surgery, University Hospital, 33100 Udine, Italy (e-mail: [email protected]) 1
Rattner DW. New technologies: future directions in innovative minimally invasive surgery. Lancet 1999; 353 (suppl I): 12–15. 2 Carroll BJ, Phillips EH, Semel CJ, Fallas M, Morgenstern L. Laparoscopic splenectomy. Surg Endosc 1992; 6: 183–85. 3 Baccarani U, Terrosu G, Donini A, Zaja F, Bresadola F, Baccarani M. Splenectomy in hematology: current practice and new perspectives. Haematologica 1999; 84: 431–36. 4 Friedman RL, Hiatt JR, Korman JL, Facklis K, Cymerman J, Phillips EH. Laparoscopic or open splenectomy for hematologic disease: which approach is superior? J Am Coll Surg 1997; 185: 49–54. 5 Glasgow Re, Yee LF, Mulvihill SJ. Laparoscopic splenectomy: the emerging standard. Surg Endosc 1997; 11: 108–12.
“Doctor, is wine good for my heart?” Sir—In their May 29 commentary,1 Katherine Bradley and Joseph Merrill conclude that physicians should warn their patients about the risks of drinking wine for their health, and argue that our “current understanding of the relation between alcohol and health comes exclusively from observational studies”. This statement seems somewhat surprising. It ignores a wealth of trial data on alcohol consumption in human beings.2–5 Bradley and Merrill are probably right in stating that no patients should be advised to start drinking or increased alcohol consumption. Nevertheless, it seems counterproductive not to consider the evidence from controlled clinical trials, most of which show that alcohol consumption has relevant positive effects on many health-related endpoints. E Ernst Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter EX2 4NT, UK 1
Bradley KA, Merrill JO. Doctor, is wine good for my heart? Lancet 1999; 353: 1815–16. 2 Suter PM, Schutz Y, Jequier E. The effect of ethanol on fat storage in healthy subjects. N Engl J Med 1992; 326: 983–87. 3 Hendriks HFJ, Veenstra J, Velthuis-te Wierik EJM, Schaafsma G, Kluft C. Effects of moderate dose of alcohol with evening meal on fibrinolytic factors. BMJ 1994; 308: 1003–06. 4 Gorinstein S, Zemser M, Berliner M, et al. Moderate beer consumption and positive biochemical changes in patients with
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departments and by the individual patients and their families. It is time that people with multiple sclerosis had fair access to the right treatment, wherever they live. Jacqueline C Napier Schering Health Care, Burgess Hill, West Sussex RH15 9NE, UK 1
2
Compston A. Provision of treatment of multiple sclerosis. Lancet 1999; 353: 1710–11. Holmes J, Madgwick T, Bates D. The cost of multiple sclerosis. Br J Med Econ 1995; 8: 181–93.
Sir—Alastair Compston’s comments1 on interferon beta and multiple sclerosis, raise some interesting and complex issues. I thoroughly agree with his statement that, “more resources are required for the management and treatment of multiple sclerosis and, as promised in the White Paper, these must be spread evenly so that geographical inequities are eliminated.” However, multiple sclerosis is seriously under funded in the UK and has been for some time. The number of neurologists who work in the UK is also much lower than in other developed countries. This serious imbalance has made patients with multiple sclerosis an easy target for politicians and others swept along on the wave of cost-effectiveness. Patients with multiple sclerosis are being discriminated against by a government that has just announced that it plans to enforce the Disability Discrimination Act (1995) on all businesses, but it seems to exclude itself in the provision of treatment for patients with multiple sclerosis. Four trials now show benefit sufficient to have convinced regulators to license use of interferon beta.2–5 There is a need to identify those who respond well to the drug from those who do not, but further placebocontrolled trials will be difficult, because of the question of consent and the Declaration of Helsinki’s recommendation that the “wellbeing of the subject” should take priority over the interests of society. Subgroups are already identified with regard to interferon beta (patients must be older than 18, able to walk a certain distance, and to have had two relapses in the previous 2 years). There would need to be reassurance from the UK Government that any new subgroups identified from new trials would be more likely to be given interferon beta than those already identified. It is only in the UK that the development of the first treatment for multiple sclerosis has been regarded as a financial embarrassment.
Compston may not like the concept of pharmaceutical companies making profit. Profit means tax and reinvestment, and government, I suspect, likes both. For the moment, at the sharp end of clinical practice, purchasing health authorities are using the foundation of the National Institute for Clinical Excellence (NICE) as the means to refuse funding. I hope NICE, when it considers the case of interferon beta, will look not just at the scientific evidence and price, but also the moral, ethical, and legal issues involved. Value-added benefit, for example, has been achieved with the excellent network of specialist nurses. In my own unit, many hundreds of multiple sclerosis sufferers have benefited already from this programme, irrespective of whether they are candidates for interferon beta. Michael Gross Department of Neurology, Royal Surrey County Hospital, Guildford, Surrey GU2 5XX, UK 1
Compston A. Provision of treatment for multiple sclerosis. Lancet 1999; 353: 1710–11. 2 PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon b-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498–504. 3 OWIMS, Freedom MS, et al. 123rd Annual Meeting of American Neurological Association. 9ANA0, Oct 18–21, 1998, Montreal, Quebec, Canada. 4 Jacobs LD, Cookfair DL, Rudrick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing remitting multiple sclerosis. The Multiple Sclerosis Collaborative Research Groups (MSCRG0). Ann Neurol 1996; 39: 285–94. 5 Knobler RL. IFN-b 1a. J Neurol Neurosurg Psych 1996; 13: 333–40.
Author’s reply Sir—I called for guidelines on the use of interferon beta that are clinically appropriate yet pragmatic, a general increase in resources for people with multiple sclerosis, geographical equity in their distribution, and a solution to the issue of managed entry for expensive but moderately effective drugs in the UK national health service, for which a range of options was suggested. My purpose was to stimulate debate. Jacqueline Napier challenges several of my assertions. My original letter referred to interferon beta-1b, not interferon-beta-1a; Napier correctly identifies a printing error that went unnoticed at proof stage (see p 518). The original guidelines for interferon beta-1b applied to around
THE LANCET • Vol 354 • August 7, 1999
20% of patients (Napier’s figure, based on my own previous estimate) 1 to which can now be added around 30% who have secondary progressive multiple sclerosis and score 6·5 or below on the Kurtzke expanded disability status scale. Hence, about 50% of patients are now potentially eligible for treatment, leaving aside those outside these limits who also want treatment. The fact that interferon beta is reaching only 1·5% of patients throughout the UK, with low take-up even in places where prescribing is apparently unrestricted, has several explanations that are unrelated to eligibility. Michael Gross restates most of my points and adds that I may not like the concept of pharmaceutical companies making profit. Napier offers some economic advice. The point that a company must price its licenced products at a level that not only covers the costs of production, marketing, and distribution, but also recoups investment on the many drugs discovered that do not make it to market is elementary. The issue of whether, having failed to capture the perceived market, one option (in addition to coaxing more funds out of the system, on the desirability of which we are both agreed) is to review the price is also not economically challenging. The annual cost of interferon beta-1b in the UK is about US$15 500. In Europe, to which my comment on profits referred, the price ranges from $11 200 (Spain) to about $20 600 (Finland). Roughly the same differential applies to interferon beta1a. These figures do not accurately reflect profit margins, since substantial differences exist between brands in the recommended dose and frequency of administration. Self-evidently, factors other than what the market will stand determine local price, but at a time when strenuous efforts are being made to increase the availability of treatment for patients who have something to gain from interferon beta, it is disappointing to learn that Schering Health Care Limited does not seem to consider the price of interferon beta-1b a topic for discussion. Maybe the companies who market interferon beta-1a will prove more flexible in maximising the effect of future expenditure for people with multiple sclerosis. Alastair Compston University of Cambridge Neurology Unit, Addenbrooke’s Hospital, Cambridge C B 22 Q Q , UK 1
Compston DAS, ed. McAlpine’s multiple sclerosis, 3rd edn. London: Churchill Livingstone, 1998: 469–86.
THE LANCET • Vol 354 • August 7, 1999
Future of minimally invasive surgery Sir—In his discussion of future directions in minimally invasive surgery in your surgery supplement, David Rattner (suppl I, p 12) 1 mentions several surgical procedures that are currently done under videoscopic guidance by most of the surgeons. He did not mention that it is now possible to perform splenectomy by a laparoscopic approach. Since laparoscopic splenectomy was first successfully performed in 1992 by Carroll and colleagues 2 in Los Angeles, this approach has been adopted by several centres in the USA and in Europe for the removal of normal sized spleens. Laparoscopic splenectomy has been performed mostly for haematologic diseases— chronic idiopathic thrombocytopenic purpura, which accounts for at least 60% of all laparoscopic splenectomy cases reported in the literature, followed by hereditary spherocytosis, haemolytic anaemia, and less frequently leukaemia or lymphoma. More than 700 cases have b e e n reported in the literature. Data from a recent national survey i n I t a l y 3 revealed that 37% of surgical centres with special interest in surgery for haematological disease have now adopted laparoscopic splenectomy. Although a definite learning curve exists, most reports point out that laparoscopic splenectomy results in shorter and less complicated postoperative course with better cosmetic results and more rapid return to full activity.4,5 According to a recent review of the literature,3 the procedure carries a mortality of 0·8%; surgicalrelated morbidity was 12% and postoperative stay averaged 3 days. Moreover, evidence is growing that immune function is better preserved after a minimally invasive approach than after open surgery, a fact that might hold advantages in several malignant haematological diseases that require splenectomy. Laparoscopic splenectomy is currently regarded as the first-line procedure for the removal of normal sized spleens in many centres with advanced laparoscopic surgery programmes.3 Controversies still exist about the laparoscopic approach to massive enlarged spleens, mostly because of high risk of bleeding and difficult manipulation of the spleen. The improvement of new laparoscopic instruments, such as the ultrasonic dissector and atraumatic grasper, might help to expand the pool of
patients who can benefit from a minimally invasive approach. *Umberto Baccarani, Giovanni Terrosu, Annibale Donini, Andrea Risaliti, Fabrizio Bresadola Department of Surgery, University Hospital, 33100 Udine, Italy (e-mail: [email protected]) 1
Rattner DW. New technologies: future directions in innovative minimally invasive surgery. Lancet 1999; 353 (suppl I): 12–15. 2 Carroll BJ, Phillips EH, Semel CJ, Fallas M, Morgenstern L. Laparoscopic splenectomy. Surg Endosc 1992; 6: 183–85. 3 Baccarani U, Terrosu G, Donini A, Zaja F, Bresadola F, Baccarani M. Splenectomy in hematology: current practice and new perspectives. Haematologica 1999; 84: 431–36. 4 Friedman RL, Hiatt JR, Korman JL, Facklis K, Cymerman J, Phillips EH. Laparoscopic or open splenectomy for hematologic disease: which approach is superior? J Am Coll Surg 1997; 185: 49–54. 5 Glasgow Re, Yee LF, Mulvihill SJ. Laparoscopic splenectomy: the emerging standard. Surg Endosc 1997; 11: 108–12.
“Doctor, is wine good for my heart?” Sir—In their May 29 commentary,1 Katherine Bradley and Joseph Merrill conclude that physicians should warn their patients about the risks of drinking wine for their health, and argue that our “current understanding of the relation between alcohol and health comes exclusively from observational studies”. This statement seems somewhat surprising. It ignores a wealth of trial data on alcohol consumption in human beings.2–5 Bradley and Merrill are probably right in stating that no patients should be advised to start drinking or increased alcohol consumption. Nevertheless, it seems counterproductive not to consider the evidence from controlled clinical trials, most of which show that alcohol consumption has relevant positive effects on many health-related endpoints. E Ernst Department of Complementary Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter EX2 4NT, UK 1
Bradley KA, Merrill JO. Doctor, is wine good for my heart? Lancet 1999; 353: 1815–16. 2 Suter PM, Schutz Y, Jequier E. The effect of ethanol on fat storage in healthy subjects. N Engl J Med 1992; 326: 983–87. 3 Hendriks HFJ, Veenstra J, Velthuis-te Wierik EJM, Schaafsma G, Kluft C. Effects of moderate dose of alcohol with evening meal on fibrinolytic factors. BMJ 1994; 308: 1003–06. 4 Gorinstein S, Zemser M, Berliner M, et al. Moderate beer consumption and positive biochemical changes in patients with
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