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Rapid Responses: Rapid Responses published:
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Seeking the truth on deferiprone: an orphan drug for a market worth hundreds of millions.
- George J Kontoghiorghes (18 February 2004)
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Seeking the truth on deferiprone: an orphan drug for a market worth hundreds of millions.
- George J Kontoghiorghes (18 February 2004)
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Independence of local ethics review
- Mark H Wilson (9 March 2004)
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The disappearing patient
- George Constantinou (13 March 2004)
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Response to Savulescu Editorial. RE: Deferiprone
- A. Victor Hoffbrand (19 March 2004)
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To the Editor
- Nancy F Olivieri (1 April 2004)
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Abuse of patients' rights in the name of research integrity
- Panos A Ioannou (5 April 2004)
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THE TRUE ETHICS OF THE DEFERIPRONE DEBATE
- Michael Spino, Fernando Tricta (5 April 2004)
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George J Kontoghiorghes, Director Postgraduate Research Institute of Science, Technology, Environment and Medicine
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Sir, The editorial by Dr J Savulescu considers the use of deferiprone (L1 or 1, 2-dimethyl-3-hydroxypyrid-4-one) and denial of access to it in North America within the context of western medical ethics but ignores the problem in its global perspective, which is the premature death of thousands of thalassaemia patients in developing countries due to lack of iron chelating drugs [1,2]. The dispute of Dr N Olivieri and Apotex has little to do with how deferiprone has been invented and developed, but is related to the lucrative market of chelating drugs, which is estimated to be about $ 0.5 billion annual sales. There are many other academic and commercially based conflicts regarding deferiprone, deferoxamine and experimental chelators but these have not been exposed to the public [1-3]. Deferiprone has a unique history of orphan drug development and from the time of its invention (1981), survived all sorts of attacks from commercial and academic sectors. These events could be traced in the literature as long ago as 1982 [4]. Events prior to the dispute should also be examined. For example, how and why was the drug named L1 and later deferiprone? Why was the research on deferiprone terminated at the places of invention, development and original clinical trials? Why were there no publications on deferiprone between 1981 and 1985? Why was deferiprone assigned for 3 years to Ciba -Geigy (now Novartis), the producer of the competing drug deferoxamine? Why is the Greek company Vianex, which sells deferiprone at a lower price than Apotex, being sued? The first clinical trials in thalassaemia major patients using deferiprone, which clearly established the efficacy of the drug, have been published in BMJ 17 years ago and not 15 years ago as suggested by Dr Savulescu [1,5]. Most of the expenses associated with the development of deferiprone were supported by the United Kingdom Thalassaemia Society, a charitable organization. Deferiprone could be provided to thalassaemia patients that are not currently treated in developing countries at least 10 times cheaper than its present price in the west [2]. A BMJ editorial in 1991 was entitled "oral iron chelation is here". Irrespective of the various disputes, oral iron chelation is here to stay and deferiprone will be playing a leading role not only in the treatment of thalassaemia but also of other diseases. References: 1] Savulescu J. Thalassaemia major: the murky story of deferiprone. Conducting life saving research properly and quickly is a moral imperative. Br Med J 2004; 328: 538-9. 2] Kontoghiorghes GJ, Neocleous K, Kolnagou A. Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine. Drug Saf 2003; 26: 553-84. 3] Nisbet-Brown E, Olivieri N F, Giardina PJ et al. Effectiveness and safety of ICL670 in iron loaded patients with thalassaemia: a randomized, double blind, placebo controlled, dose escalation trial. Lancet 2003; 361:1597-602. 4] Kontoghiorghes GJ The design of orally active iron chelators for the treatment of thalassaemia. PhD thesis, University of Essex, Colchester UK. British Library Microfilm No D66194/86. 1982: 1-243. 5] Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV et al. Effective chelation of iron in â-thalassaemia with the oral chelator 1, 2-dimethyl-3 -hydroxypyrid-4-one. Br Med J 1987; 295: 1509-12. Competing interests: : GJK is the inventor of deferiprone or L1 or 1, 2-dimethyl-3-hydroxypyrid-4-one and chairman of the international committee on oral chelators (ICOC). |
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George J Kontoghiorghes, Director Postgraduate Research Institute of Science, Technology, Environment and Medicine
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Sir, The editorial by Dr J Savulescu considers the use of deferiprone (L1 or 1, 2-dimethyl-3-hydroxypyrid-4-one) and denial of access to it in North America within the context of western medical ethics but ignores the problem in its global perspective, which is the premature death of thousands of thalassaemia patients in developing countries due to lack of iron chelating drugs [1,2]. The dispute of Dr N Olivieri and Apotex has little to do with how deferiprone has been invented and developed, but is related to the lucrative market of chelating drugs, which is estimated to be about $ 0.5 billion annual sales. There are many other academic and commercially based conflicts regarding deferiprone, deferoxamine and experimental chelators but these have not been exposed to the public [1-3]. Deferiprone has a unique history of orphan drug development and from the time of its invention (1981), survived all sorts of attacks from commercial and academic sectors. These events could be traced in the literature as long ago as 1982 [4]. Events prior to the dispute should also be examined. For example, how and why was the drug named L1 and later deferiprone? Why was the research on deferiprone terminated at the places of invention, development and original clinical trials? Why were there no publications on deferiprone between 1981 and 1985? Why was deferiprone assigned for 3 years to Ciba -Geigy (now Novartis), the producer of the competing drug deferoxamine? Why is the Greek company Vianex, which sells deferiprone at a lower price than Apotex, being sued? The first clinical trials in thalassaemia major patients using deferiprone, which clearly established the efficacy of the drug, have been published in BMJ 17 years ago and not 15 years ago as suggested by Dr Savulescu [1,5]. Most of the expenses associated with the development of deferiprone were supported by the United Kingdom Thalassaemia Society, a charitable organization. Deferiprone could be provided to thalassaemia patients that are not currently treated in developing countries at least 10 times cheaper than its present price in the west [2]. A BMJ editorial in 1991 was entitled "oral iron chelation is here". Irrespective of the various disputes, oral iron chelation is here to stay and deferiprone will be playing a leading role not only in the treatment of thalassaemia but also of other diseases. References: 1] Savulescu J. Thalassaemia major: the murky story of deferiprone. Conducting life saving research properly and quickly is a moral imperative. Br Med J 2004; 328: 538-9. 2] Kontoghiorghes GJ, Neocleous K, Kolnagou A. Benefits and risks of deferiprone in iron overload in thalassaemia and other conditions. Comparison of epidemiological and therapeutic aspects with deferoxamine. Drug Saf 2003; 26: 553-84. 3] Nisbet-Brown E, Olivieri N F, Giardina PJ et al. Effectiveness and safety of ICL670 in iron loaded patients with thalassaemia: a randomized, double blind, placebo controlled, dose escalation trial. Lancet 2003; 361:1597-602. 4] Kontoghiorghes GJ The design of orally active iron chelators for the treatment of thalassaemia. PhD thesis, University of Essex, Colchester UK. British Library Microfilm No D66194/86. 1982: 1-243. 5] Kontoghiorghes GJ, Aldouri MA, Hoffbrand AV et al. Effective chelation of iron in â-thalassaemia with the oral chelator 1, 2-dimethyl-3 -hydroxypyrid-4-one. Br Med J 1987; 295: 1509-12. Competing interests: : GJK is the inventor of deferiprone or L1 or 1, 2-dimethyl-3-hydroxypyrid-4-one and chairman of the international committee on oral chelators (ICOC). |
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Mark H Wilson, Health Research Associates Ottawa, Canada
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According to Savulescu one can only speculate about whether the ethics committee had been more pro-active and exercised its independent status, many of the problems arising from the Olivieri affair may have been avoided. (1) While Savulescu correctly notes that research ethics committees or boards (REBs) are considered research subjects main advocate, we also need to be reminded of concerns about Canadian REBs. First, ethics review can be dominated by the majority of committee members who are often colleagues who not only review each others research but are also employed by a hospital or university which has a vested interest in research. Second, inspections of REBs in 1995 by the national council of ethics in human research raised the concern that REB independence is threatened by an expanding commercial research climate.(2) A Canadian academic claims that one large Canadian university funds its entire research ethics office from a drug company sponsor which is particularly disconcerting when the company’s research protocols are reviewed.(3) Third, a recent report which assessed the effectiveness of national governance arrangements observed that many REBs report to the university office promoting research which is a conflict of interest. (4) Finally, Health Canada has noted that serious conflicts of interest may exist within REBs and research institutions. (5) These unresolved accountability issues are worrisome given recent insider reports of REBs violating ethical guidelines in academic teaching centres and hospitals.(6) Health Canada and the US Office of Health Research Protection have also recently raised concerns about an REB at a leading Canadian University for not informing research subjects of risks in various clinical trials.(7) Against this backdrop, grounds exist to doubt whether local REBs can play the pro-active and independent advocacy role that Saulescu hopes they might. Savulescu has raised related concerns about the structure and function of local research review in other countries and has made the call to replace the local system with specialized regional ethics committees that have a more independent status.(8) That call and its underlying ethical rationale also resonate in the Canadian context. 1. Savulescu J. Thalassemia major: the murky story of deferiprone. Conducting life saving research properly and quickly is a moral imperative. Br Med J, 2004; 328: 538-9. 2. Letter to Health Canada from the President of the National Council on Ethics in Human Research, NCEHR. 1999. 3. O'Neill Patrick, "Science for Sale", Ottawa Citizen, January 29, 1999. p. A15. 4. McDonald M. The Governance of Human Research Involving Human Subjects. Ottawa: Law Commission of Canada, 2000. http://www.lcc.gc.ca/en/themes/gr/hrish/macdonald/macdonald.pdf 5. Health Canada. “A Canadian System of Oversight for the Governance of Research Involving Human Subjects.” http://www.hc-sc.gc.ca/sab-ccs/feb2002_governance_subject_e.pdf 6. Corman C., Blajchman M., Knight A. Placebo tribulations, Can. Med. Assoc. J., Sept 2002; 167: 455- 456. http://www.cmaj.ca/cgi/content/full/167/5/455-a 7. Munro M. UBC broke drug-trial rules for years, documents show. The National post, Can West News Service. February 25, 2004. 8. Savulescu J. Two deaths and two lessons: Is it time to review the structure and function of research ethics committees? J Med Ethics 2002;28: 1-2.
Competing interests: None declared |
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George Constantinou, Patient 19 The Broadway Southgate Circus N14 6PH
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To the Editor of the BMJ. The disappearing patient Julian Savulescu (1) suggests that the ethical committee is the closest advocate for patients because “no one group has the responsibility for representing the interests of all people affected by thalassaemia”. But patients have voices, there are many active Support Associations. and all concerned should keep in mind that the thalassaemia people of the 21st century are educated, married with children of their own, successful businessmen and women, scientists, doctors, active politicians, but above all very knowledgeable about the economics and politics of their treatment. The UK Thalassaemia Society (www.ukts.org) and the Cooley’s Anemia Foundation (www.thalassemia.org) are among 52 national associations under the umbrella of the Thalassaemia International Federation (TIF) (www.thalassaemia.org.cy). TIF aims to forge a global “thalassaemia community” embracing patients, families, doctors and scientists. Its activities include biennial international meetings where scientific sessions and patients’ and parents’ sessions are held side-by-side. The problem of deferiprone is far more serious for patients than Dr Savulescu visualises. Globally, approximately 43,000 children with a major beta thalassaemia are born annually, most in developing countries (2). Approximately 62% need regular blood transfusion to survive, but only about 13% of them have access to it. We estimate that Worldwide over 72,000 patients are living on regular transfusions. Without iron chelation therapy they will die from iron overload between 12 and 24 years of age (3). However less than 50% of transfused patients have access to any form of chelation therapy, and probably only 10% (including the less than 1,000 patients resident in North America) benefit from the full protocol (4). Consequently, two to four thousand patients die annually from iron overload. The Olivieri debate contributes to these deaths by subordinating medical to political issues, and imposing a narrow North American perspective on a global problem. We find it hard to understand that a hospital ethics committee in a country which barely appears on the global map of thalassaemia can be expected to make decisions with such important Worldwide consequences. Available iron chelating agents Most people with thalassaemia over 16 years of age owe their continuing survival to desferrioxamine, which became available in 1964. Its main problems are cost (about $10 per gram) and intolerability. Young children need 300 grams/year and adults need over 1 kg/year, so cost rises from $3,000 to over $10,000 per patient per year, making treatment completely out of reach for patients in developing countries. In Pakistan, where about 4,800 affected children are born annually (2), the Fatimid Foundation (a charity dedicated to voluntary blood donation) has provided regular transfusions for thousands of patients since the mid 1980s but cannot afford desferrioxamine. In Malaysia the Ministry of Health refuses to supply desferrioxamine until a thalassaemia prevention programme is in place. When it is available, desferrioxamine is taken by subcutaneous infusion using a portable syringe-driver. Deaths from iron overload continue, mainly because many adolescents and young adults find “the pump” intolerable (5,6). Techniques used at expert centres to improve acceptability (implantable infusion devices, home-delivery of prepared disposables, psychotherapy) double treatment costs, and are not risk-free. Despite these limitations the global market in desferrioxamine is worth hundreds of millions of dollars per year, and is growing. Desferrioxamine was one of Ciba-Geigy’s top earners before it merged into Novartis: a switch to a cheaper chelator, or one not produced by Novartis, will obviously be unwelcome. Deferiprone (L1) is a simple and potentially cheap oral iron chelator. The UK Thalassaemia Society supported its introduction for thalassaemia in the UK from 1987 at a total cost of £750,000 ($1,125,000). In 1992 TIF and its expert advisers requested Ciba-Geigy (then the only firm interested in iron chelation) to support clinical trials, largely because of the hope deferiprone offered for patients in developing countries. We were disappointed but not surprised when the firm declined in favour of developing a proprietary oral chelator. Without financial support for quality clinical trials, evidence would have to be collected piecemeal by dedicated professionals: the thalassaemia community seemed in for a bumpy ride – a prediction that has been amply fulfilled. Apotex now produces deferiprone (as Ferriprox) for high resource countries under orphan drugs regulations. Cipla produces it (as Kelfer) far more cheaply in India, and many Indian patients have used it regularly for more than ten years, demonstrating that it can be sold at an affordable rate in developing countries. Though authoritative reviews conclude that its safety and efficacy is well within the usual range for commonly-used drugs (7), in many low-resource countries it is still not licensed, and so is not available to patients. This is (a) because it has not been licensed by the American FDA and (b) because of professional insecurity created by the Olivieri dispute. GC has been using desferrioxamine since 1972. At that time it was presented to him as an imperfect solution, that would permit survival until research provided a better treatment. Why should patients in developing countries not have the same opportunity with deferiprone? We are not aware of a review supporting the opinion of Professors Olivieri, Nathan and Weatherall that “the safety and efficacy of deferiprone have not been established” (8), nor has any of them attended any TIF International Meeting since 1999 to engage in open scientific discussion in the presence of patients. For us the real question therefore is, how has the medical profession allowed an unsupported opinion to continue to dominate public and professional perceptions, as in Dr Savulescu’s editorial? The disappearing patient When professionals become embattled, patients vanish from the picture - especially those who live in developing countries. When we responded to an article by Nathan and Weatherall (8) by pointing out that deferiprone offers the only hope of survival for thousands of patients who cannot afford expensive drugs (9) they replied “As physicians who have treated thalassaemia for over 40 years, we completely understand the anxieties expressed by Mr Constantinou and colleagues. They desperately want an effective oral chelator: so do we. It took many years of careful clinical studies to prove that deferoxamine can save the lives of patients with thalassaemia (10))”. This response ignored our reasonable question of what these patients should do, and surprises us because (despite strong North American presence at TIF meetings) we do not know of any patient who names either author as their primary long-term carer. In addition, patients are barely mentioned in the Olivieri symposium (11). This succinctly demonstrates that in this particular case, as in any other similar occasions, conflict between the medical professionals, researchers and ethicists usually takes place in a utopian landscape where sight is lost of the single reason for the effort of doing research, namely benefiting the patients. Medical scientific research does not only harm patients if it is bad or slow (1), but also if it is a purely academic exercise or even worse a hostage between clinicians and corporations Patients can help In October 2003 we asked Professor Bernadette Modell to explain the present position to the hundreds of patients attending a TIF meeting in Sicily (12). She began with a public apology for the medical profession’s failure to manage this problem, and explained four points (13). 1. Most doctors do not assess specialist literature themselves but rely on respected experts, who normally present their assessment in critical reviews. When such eminent individuals take sides in a controversy, their research colleagues must weigh the advantages and disadvantages for patients of antagonising authoritative figures who have the ear of medical editors, grant-giving bodies and the media. Most decide to keep their heads down and concentrate on obtaining the objective evidence that normally resolves scientific disagreement. Fear of offending colleagues, being pilloried in the media and/or sued also play their part. But the patients’ perception is that doctors who remain sitting on the fence are agreeing by default. 2. The consequent “silence” has bad effects. Patients feel they have dropped out of the picture altogether. Inability to obtain answers to reasonable questions increases their perception of being abandoned, leaves them vulnerable to rumour and misrepresentation, and greatly reduces their respect for their doctors. Among professionals, lack of openness creates mistrust and suspicion, aggravated by the anonymity of peer review. The sad truth is that the thalassaemia community has been poisoned. We are no longer honest with each other. 3. TIF has also been disappointingly silent. Although it very actively promotes the best patient care, it holds back from promoting the resolution of a conflict that works against patients’ interests. Active promotion of desferrioxamine therapy (14) should be balanced with active promotion of a licensed alternative for patients who cannot access or cannot tolerate desferrioxamine therapy. 4. When professionals cannot retain objectivity they need help from patients, who have nothing to lose but their lives. We have the right to an open discussion that we can understand. We have the right to challenge opinions and ask authorities for their clinical credentials. We have the right to ask our Associations to support us and to publicise the results. Exercising these rights helps both professionals and patients. It is also facilitated by growing medical receptiveness to “expert patients” and to joint decision-making. Though some doctors may need to adjust to cope with these developments, any person who has, or who cares for someone with, a chronic condition is entitled to, and indeed should, share responsibility by negotiating their treatment options rather than merely obeying orders. This applies both for individual patients and for the patient community. To take a positive view, our present disillusionment with the medical profession may represent a painful but salutary coming of age. We hope it marks the beginning of a more equal relationship that can help communities to cope with the growing market pressures within medicine. We do not believe that new regulations, including further involvement of ethical committees, can help in such complex and fluid situations. We expect our doctors “to cure sometimes, to relieve often, to comfort always” and believe that to do so, they need closer collaboration with patients. What next? Novartis now has a new oral iron chelator (ICL670) undergoing clinical trials (14). It would not surprise us if many researchers gladly put the murky issue of deferiprone behind them and move on, with adequate financial support, to investigate a new drug unlikely to involve them in conflict. But if ICL670 proves to be safe and effective will it be any cheaper than desferrioxamine, since Novartis is competing with itself? Unless it is much cheaper, deferiprone remains the only option for patients in developing countries – who will ensure that it is accessible for them? As we see it, the deferiprone story has brought out many weaknesses of the medical research system, and of the human beings who work within it. Its message for the developing world is both depressing and challenging. It reflects the inexorable economic laws that govern drug firms, the difficulty of disentangling scientific, personal and commercial issues, and the neglect of all patients in developed and developing countries. In the meantime, the fate of patients with thalassaemia in developing countries is a continuing tragedy, about which we in the developed world may feel deeply ashamed. George Constantinou (aged 45 with thalassaemia major) UK Thalassaemia Society Committee Member, Past President of the Thalassaemia International Federation. Stavros Melides (father of Vasos Melides with thalassaemia major), UK Thalassaemia Society Regional Liaison Officer and Assistant Secretary of the Thalassaemia International Federation. Christos SOTIRELIS PhD. BEng(Hons) (Aged 39, Thalassaemia major) Air Transport Consultant References 1. Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ 2004;328;358-9. 2. Angastiniotis M, Modell B. Global epidemiology of hemoglobin disorders. Annals of the New York Academy of Sciences 1998;850:251-269. 3. Modell B, Berdoukas V. The clinical approach to thalassaemia. Grune and Stratton, New York and London. 1984. 4. Guidelines for the clinical management of thalassaemia. Thalassaemia International Federation. 2000. 5. Piga A, Longo F, Consolati A, De Leo A, Carmellino L. Mortality and morbidity in thalassaemia with conventional treatment. In Proceedings of the third international conference on bone marrow transplantation in thalassaemia. Bone Marrow Transplantation 19: Supplement 2: 1997;11-13. 6. Modell B, Khan M, Darlison M. Survival in beta thalassaemia major in the United Kingdom: data from the UK Thalassaemia Register. The Lancet 2000;355:2051-2. 7. Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood 2003;102:17-24. 8. Nathan DG, Weatherall DJ. Academic freedom in clinical research. New England Journal of Medicine 2002;347:1368-71. 9. Constantinou C, Melides S, Modell B. The Olivieri case (letter). New England Journal of Medicine 2003;348:860-1. 10. Nathan D, Weatherall DJ. Authors’ reply. New England Journal of Medicine 2003;348:862-3. 11. The Olivieri Symposium. Journal of Medical Ethics 2004;30:1-52. 12. TIF Magazine. Palermo International Conferences. December 2003. Issue No 40. 13. UKTS <Thalassaemia Matters> issue 96. Jan 04 14. Ward A, Caro JJ, Green T, Huybrechts K, Arana A, Wait S, Eleftheriou A. An international survey of patients with thalassemia major and their views about sustaining life-long desferrioxamine use. BMC Clinical Pharmacology 2002;23:3. 15. Galanello R, Piga A, Alberti D, Rouan MC, Bigler H, Sechaud R. Safety, tolerability, and pharmacokinetics of ICL670, a new orally active iron-chelating agent in patients with transfusion-dependent iron overload due to beta-thalassemia. J Clinical Pharmacology 2003;43:565-72. Competing interests: None declared |
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A. Victor Hoffbrand, Emeritus Professor of Haematology Royal Free Hospital
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British Medical Journal Publishing Group, Editorial Office, BMA House, Tavistock Square, London, WC1H 9JR. 16 March, 2004 Editor - Julian Savulescu states in his Editorial1 "We still do not know whether deferiprone harms or benefits people with thalassaemia compared with deferoxamine". Doctors now prescribe deferiprone in 32 countries where it is licensed for treating thalassaemia major patients not adequately chelated by desferrioxamine. Published data clearly show it safely removes iron from a substantial proportion of patients for whom desferrioxamine proves, for one reason or another, inadequate.2 When Olivieri and colleagues subsequent 1998 paper appeared suggesting that the drug caused liver fibrosis3, the evidence for this toxic effect was immediately criticised on scientific grounds.4,5 Subsequent review in a blinded fashion of the same biopsies did not support fibrosis as a side effect of deferiprone.6 Three year follow-up biopsies in 56 patients found no evidence for liver fibrosis induced by the drug.7 No other scientifically reviewed study has reported this complication. Uncertainties in the use of the drug that have arisen since 1998 are largely due to failure of separation of scientific evidence of the efficacy and side-effects of deferiprone from ethical issues arising from the dispute that arose between Olivieri and Apotex. Recent, albeit retrospective, studies suggest that deferiprone may be superior to desferrioxamine for removing iron from the heart8,9 although at usual doses it may be less effective at removing liver iron.3,8 On the basis that deferiprone at 75mg/kg/day may indeed not be sufficiently powerful in all thalassaemia major patients to reduce liver iron to below 15mg/gram, a level that has been suggested to be associated with cardiac damage, efforts have been made to increase the proportion for whom it is effective. Doses up to 100mg/kg daily further increase iron excretion.10 Longer term safety studies at these higher doses are in progress and so far seem satisfactory. Also combined deferiprone and desferrioxamine therapy results in substantial iron excretion for patients in whom one or other drug is ineffective.10 It is now clear that deferiprone alone or in combination with desferrioxamine, is beneficial in a large majority of thalassaemia major patients with only a small minority of patients suffering well-recognised but reversible side-effects, such as arthralgia or agranulocytosis.2 Desferrioxamine and deferiprone should not be seen as rivals as Savulescu implies but as complementary in the management of patients with thalassaemia and transfusional iron overload. REFERENCES 1 Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ 2004;328:369-1. 2 Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood 2003;102:17-24. 3 Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med 1998:339:417-423. 4 Wonke B, Telfer P, Hoffbrand AV. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998:339:1712. 5 Cohen AR, Martin MB. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1713. 6 Callea F. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1710-1711. 7 Wanless A, Sweeney G, Dhillon AP, et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 2002;100:1566-1569. 8 Anderson LJ, Wonke B, Prescott E, et al. Improved myocardial iron levels and ventricular function with oral deferiprone compared with subcutaneous desferrioxamine in thalassemia. Lancet 2002;360:516-520. 9 Piga, A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica 2003;88:489-496. 10 Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine. Br J Haematol 1998;103:361-364. Yours sincerely, Professor A.V. Hoffbrand, DM., FRCP., FRCPath., DSc. Competing interests: None declared |
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Nancy F Olivieri, Professor of pediatrics and medicine University of Toronto, Canada
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Many respected scientists and doctors in the thalassemia field are sympathetic to the confusion and frustration over the deferiprone controversy that was recently expressed by some patients 1. Like soldiers fighting for their country in an ill-advised war, many patients have been provided an ideology about deferiprone based upon ‘facts’ that are unproven, and opinions that remain resolute in the face of increasing evidence that deferiprone may not be adequately effective or safe in many patients 2, 3 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. Patients cannot be faulted for believing that there exists “insufficient evidence” against the use of deferiprone as a substitute for deferoxamine, because there has been no shortage of perspectives 15 promoting that view. The patients’ conclusion is understandable: “The fate of patients with thalassaemia in developing countries is a continuing tragedy about which we in the developed world may feel deeply ashamed.” No patients can be blamed for misunderstanding this situation. It is their advisors who should, indeed, feel deeply ashamed for misleading patients about the true priorities for thalassaemia management, and for having advanced the position that poor patients in developing countries have a ‘right’ to cheaper, potentially less effective medicine. There is considerable irony in the position of such advisors whose patients have enjoyed their prolonged survivals only because of decades of treatment with deferoxamine. Some physicians may not understand that they bear responsibility to help patients in the developing world gain access to equally safe and effective treatment. Instead, what many seem to emphasize is an apparently inalienable right of those dispossessed patients to be exposed to risks that richer patients do not need to take. In a review by three of the most vigorous proponents of deferiprone it was, at last, conceded that during deferiprone therapy iron stores “decrease in some patients, remain stable in others, and increase in some others” 15, the same conclusion to which the manufacturer of deferiprone (Apotex), responded with legal threats and the premature termination of a prospective randomized trial, eight years ago 16. Despite repeated pleas17 for the large controlled trials needed to investigate this observation, those trials were never conducted; even in their absence there is now sufficient, indeed overwhelming, evidence against the use of deferiprone as a substitute for deferoxamine 2, 3 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 -- some arising from the very doctors to whom many UK patients entrust their care 2. It is indisupted that during long-term deferiprone many patients maintain body iron burdens above the threshold for premature death. Although some investigators 15 have made efforts, post hoc, to distance themselves from those original observations 2, their data (including a 10% death rate on deferiprone) have never been retracted. And as even its advocates note15, deferiprone’s ‘protective’ effect on the iron-loaded heart must be viewed with caution: the endpoints promoted in studies of this issue remain unvalidated 18. The 10% rate of death in deferiprone-treated patients reported by the London group 2 is sharply contrasted to the experience a few miles away at University College Hospital, where deferoxamine is prescribed and where there has been no death in any deferoxamine-treated patient born after 1974 19. This is consistent with prior reports over twenty years demonstrating the remarkable survival and prevention of heart disease during deferoxamine 20, 21, 22, 23, 24, 25, 26, 27, 28. As for the claim that deferiprone does not accelerate liver damage in selected patients, this has been undermined by the inexplicable exclusion, from that publication29, of previously recognized8 evidence of rising body iron stores30, as well as by evidence of hepatocellular damage13, and progression of liver fibrosis in more small cohorts,7,12 during deferiprone exposure. Because the relationship between liver fibrosis and iron is a complex one, prospective controlled trials were suggested when sentinel concerns were raised29; seven years later, such trials are still awaited, and these concerns are not allayed. Perhaps what might assist patients is an appreciation that many arguments advanced in this controversy are self-contradictory or otherwise unsubstantiated. For example, a preliminary communication cited by ‘The disappearing patient’ 1 allegedly claims that high numbers of patients with thalassemia die, despite deferoxamine treatment 31. Not cited is a report by the same authors in the peer-reviewed literature exactly one year later 28, in which, in the large Italian study of patients receiving deferoxamine“the prevalence of heart failure at age 15 years decreased from 5% in patients born between 1970 and 1974, to 2% in patients born between 1980 and 1984”. Another paper cited 32 has purported that the risk of death during deferoxamine therapy was 50%. The discrepancy between a 50% death rate reported by these UK investigators 32 and the 2% rate of cardiac disease reported two years earlier in Italy28 is not explained. No wonder patients are confused: how deferoxamine became apparently 25-fold less effective in under two years is not easily understood. If patients believe these data, they might be influenced to abandon deferoxamine – and many have -- in favor of inadequately-studied therapy. The manner in which even the restricted European licensing for deferiprone was acquired deserves scrutiny. In 1999, I launched a challenge to the licensing of deferiprone by the EU. Although the European Court refused to consider the merits of my case (dismissing this on technical grounds) 33, it was only because I launched this challenge that I was able to learn how deferiprone came to be licensed so quickly on that continent. Documents now publicly available show that Apotex, in evidence sworn to the court, attacked my ethics and ability -- alleging that ineptitude on my part had rendered the pivotal Toronto trial non- interpretable, and that I had falsified data. (Dr. Bernadette Modell was flown to the Luxembourg court to contribute to Apotex’s case). Apotex went on to plead that as a result of my alleged incompetence, the company should be permitted to avoid the legal requirement to submit all evidence from the trial in question. Believing the company’s allegations, the European licensing body agreed. Later, because all source documents had fortunately been retained, an independent audit of the trial was able to show it to have been conducted professionally and honestly. This further confirmed what another independent review had concluded two years before: “Apotex developed and disseminated, post hoc, plainly self-serving rationalizations for terminating the trials that differed significantly from its own earlier statements as to why it terminated them” and that “attempts to discredit Dr. Olivieri had the effect of serving the interests of Apotex, an aspect of whose licensing submissions for deferiprone was an attempt to discredit her and to dispute the risks identified.” 16. During the hearing in Luxembourg in April 2003, a European Court judge did not fail to note the irony of attempts to extend deferiprone use in humans in “Old Europe” at the same time that the USA was demanding more studies in animals. The Court also discussed the growing evidence that deferiprone was being misused. Although deferiprone is licensed only for those “unable to use” deferoxamine – 12 such patients are reported in the literature -- the number of deferiprone tablets prescribed in Europe during the first full year of authorization was equivalent to 488 patient- years, and during the second year, to 1400 patient-years. Deferiprone is clearly being used beyond the category of patients “unable to use” deferoxamine, and is now administered ‘in combination’ with deferoxamine in patients (who are by definition “able to use” deferoxamine) -- although such ‘combination therapy’ is not approved under European licensing. If (as claimed) deferiprone safely controls body iron as a single agent, why does deferiprone require ‘combination’ with deferoxamine in the same patient? And if (as claimed) deferiprone does indeed safely control body iron, and is associated with improved compliance, why have there been many deaths 2, 5, 11, 10, 34 35 36, 37, 38, 39 in patients treated with deferiprone? Surely these issues merit not rhetoric, but careful study. It is hoped that such prospective, controlled clinical trials, including one of ‘combination therapy’ using valid endpoints, could be initiated, without drug company sponsorship within the North American Thalassemia Clinical Research Network. As for North America, it is correct that the American FDA has not licensed deferiprone. Indeed, that agency has demanded more studies of the drug. No one person possesses the power to prevent the licensing of a drug by the FDA. This constraint does not deny deferiprone to any patient who supposes he or she “needs” it. In the US (and Canada and Europe) any patient may choose to embark on unlicensed therapy if he or she can identify a drug company willing to provide the drug and a physician willing to supervise its use. Several patients (many enrolled in a one- year trial begun in 1995) have received deferiprone under the supervision of one US physician 40, 41, 13, while others are receiving deferiprone therapy in Montreal. The deaths and the extraordinary dropout rate, in excess of 50% 13 -- without published follow-up of those withdrawn from study -- are not the only concerns. Now, poor patients in emerging countries use deferiprone as first line therapy, based upon the restricted licensing in the EU which permits richer patients to use it only as a second line drug. Many consider this to be desirable because “more patients” are said to be able to “afford” deferiprone in “developing countries”-- opinions voiced by some doctors who visit but do not work in these countries. The truth is that most patients in many emerging countries can afford neither adequate deferoxamine nor full doses of deferiprone. The licensing of deferiprone has provided a drug ‘of uneven efficacy and uncertain toxicity’ 42 -- often at fractions of the recommended dose 43 -- to only the very few richest families, while relieving governments of their responsibilities to provide the best treatment to all their citizens. Furthermore, unlike the situation in richer countries, most centers in emerging countries are unable to monitor patients adequately to prevent the potentially fatal agranulocytosis and crippling joint disease associated with deferiprone therapy. The real solution, of course, is to work to convince these governments to provide the safest, most effective therapy to their citizens. Drs. David Weatherall and David Nathan have been criticized1 for their absence from thalassemia meetings in the past few years. In fact, these physicians, building on their considerable hands-on clinical experience with thalassemia patients over decades, are actively creating programs of treatment for thalassemia in emerging countries, and supervising the North American Thalassemia Clinical Research Network -- thereby addressing the precise needs about which many patients are concerned. But this criticism does raise a question: why do many serious scientists reluctantly attend these meetings or, like these authorities, decline to attend at all? One wonders whether the influence of commercial sponsors, and the focus of some meeting agendas, could be factors in such decisions. Without the motivation of financial or career advancement, Drs. Nathan and Weatherall have undertaken to judge the soundness of data by factual criteria (not, for example, by friendship with individual patients), to treat medical research findings as open and shared rather than secretive or proprietary (such that publication cannot be opposed with legal threats), and to form conclusions only after safety has been, not while it is being, established. Adherence to these ethical beliefs is not always in evidence at these meetings, but these values are not abusive of patient autonomy – they are respectful of it. Without those standards, “patients’ informed consent” is an empty term. Surely, most patients understand that such scientific rigor and honesty are ultimately their greatest safeguards. Finally, who is the ‘disappearing’ patient? Patients who have enjoyed the life-saving benefits of deferoxamine for decades have not disappeared. These patients can return to adequate deferoxamine should complications develop during forays into experimental therapy. Having themselves survived because of deferoxamine, some patients in rich countries seem to accept the denial of this drug to poorer patients. In contrast, many of my colleagues -- patients as well as doctors -- understand that we must organize solutions that represent the best interests of the patients in emerging countries, not only the financial interests of their governments. We do not agree that a drug is made better by being cheap. Such a belief will allow patients to truly ‘disappear.’ It is unfortunate that Dr. Julian Savulescu’s original editorial 44 confused the issues. While advancing ‘scientific’ arguments which are not his expertise, Savulescu bypassed the fundamental ethical issue of this controversy: the obligation to put the concern for patients’ safety first. Appropriate large-scale efficacy and safety trials of deferiprone could have been sponsored by Apotex when concerns were first raised in 1995 and 1996. Surprisingly, Dr. Savulescu suggests that this responsibility was that of a lone investigator who was under legal threats from Apotex, a target of gag orders and dismissals by her hospital and of harassment and defamation from a dishonest powerful senior colleague, and without effective support from her university -- then in negotiations with Apotex for a multi-million dollar donation.16 Contrary to what Dr. Savulescu suggests, the urgent need is not for fast-tracked licensing of unproven drugs, but rather for patient protection, informed consent, truly independent drug trials, and the defense of academic freedom. I join my colleagues 30 in urging doctors and patients to examine critically the data regarding deferiprone, with the help of individuals of integrity and independence 45, 17, rather than to accept opinions expressed in discussions at selected meetings (see 46.) Perhaps each of us will then better understand the moral responsibility we share for patients who are, by accident of birth, less privileged than we. Nancy F. Olivieri, MD, FRCPC Professor of Pediatrics and Medicine University of Toronto, Canada 1. Constantinou G. The disappearing patient. Rapid response to Savulescu J. Thalassaemia major: the murky story of deferiprone. Br Med J 2004;328:358 - 9 2. Hoffbrand A, Al-Refaie F, Davis B, Siritanakatkul N, Jackson B, Cochrane J, et al. Long-term trial of deferiprone in 51 transfusion- dependent iron overloaded patients. Blood 1998;91(1):295-300. 3. Tondury P, Zimmermann A, Nielsen P, Hirt A. Liver iron and fibrosis during long-term treatment with deferiprone in Swiss thalassaemic patients. Br J Haematol 1998;101(3):413-415. 4. Olivieri NF, Brittenham GM, McLaren CE, Templeton DM, Cameron RG, McClelland RA, et al. Long-Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone for Thalassemia Major. N Engl J Med 1998;339(7):417-423. 5. Mazza P, Anurri B, Lazzari G, Masi C, Palazzo G, Spartera MA, et al. Oral iron chelating therapy. A single center interim report on deferiprone (L1) in thalassemia. Haematologica 1998;83:496-501. 6. Del Vecchio GC, Crollo E, Schettini F, Fischer R, De Mattia D. Factors influencing effectiveness of deferiprone in a thalassaemia major clinical setting. Acta Haematol 2000;104(2-3):99-102. 7. Berdoukas V, Bohane T, Eagle C, Lindeman R, DeSilva K, Tobias V, et al. The Sydney Children's Hospital experience with the oral iron chelator deferiprone (L1). Transfus Sci 2000;23(3):239-40. 8. Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, et al. Absence of Deferiprone-induced hepatic fibrosis: a multicenter study. Blood 2000;96(11):606a. 9. Rombos Y, Tzanetea R, Konstantopoulos K, Simitzis S, Zervas C, Kyriaki P, et al. Chelation therapy in patients with thalassemia using the orally active iron chelator deferiprone (L1). Haematologica 2000;85(2):115 -7. 10. Lucas GN, Perera BJ, Fonseka EA, De Silva DD, Fernandopulle M, Karunatilaka DH, et al. Experience with the oral iron chelator deferiprone in transfusion-dependent children. Ceylon Medical Journal. 2002;47(4):119- 21. 11. Ceci A, Baiardi P, Felisi M, Cappellini MD, Carnelli V, De Sanctis V, et al. The safety and effectiveness of deferiprone in a large- scale, 3-year study in Italian patients. Br J Haematol 2002;118(1):330- 336. 12. Maggio A, D'Amico G, Morabito A, Capra M, Ciaccio C, Cianciulli P, et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells, Molecules, & Diseases. 2002;28(2):196-208. 13. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003;102(5):1583-1587. 14. Fischer R, Longo F, Nielsen P, Engelhardt R, Hider RC, Piga A. Monitoring long-term efficacy of iron chelation therapy by deferiprone and desferrioxamine in patients with thalassaemia major: application of SQUID biomagnetic liver susceptometry. Br J Haematol 2003;121(6):938-948. 15. Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for transfusional iron overload. Blood 2003;102(1):17- 24. 16. Thompson J, Baird P, Downie J. The Olivieri Report: The complete text of the report of the independent committee of inquiry commissioned by the Canadian Association of University Teachers. Toronto: James Lorimer & Co. Publishers, 2001. 17. Pippard MJ, Weatherall DJ. Oral iron chelation therapy for thalassaemia: an uncertain scene. Br J Haematol. 2000;111(1):2-5. 18. Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. European Heart Journal 2001;22(23):2171-9. 19. Porter J, Davis BA. Monitoring chelation therapy to achieve optimal oucome in the treatment of thalassaemia. Best Pract Res Clin Haematol 2002;15:329-68. 20. Freeman AP, Giles RW, Berdoukas VA, Walsh WF, Choy D, Murray PC. Early left ventricular dysfunction and chelation therapy in thalassemia major. Ann Intern Med 1983;99(4):450-4. 21. Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga A, Melevendi C, et al. Survival and causes of death in thalassaemia major. Lancet 1989;2(8653):27-30. 22. Freeman AP, Giles RW, Berdoukas VA, Talley PA, Murray IP. Sustained normalization of cardiac function by chelation therapy in thalassaemia major. Clin Lab Haematol 1989;11(4):299-307. 23. Aldouri M, Wonke B, Hoffbrand A, Flynn D, Ward S, Agnew J, et al. High incidence of cardiomyopathy in beta-thalassaemia patients receiving regular transfusion and iron chelation: reversal by intensified chelation. Acta Haematologica 1990;84(3):113-7. 24. Ehlers KH, Giardina PJ, Lesser ML, Engle MA, Hilgartner MW. Prolonged survival in patients with beta-thalassemia major treated with deferoxamine. J Pediatr 1991;118(4):540-5. 25. Lerner N, Blei F, Bierman F, Johnson L, Piomelli S. Chelation therapy and cardiac status in older patients with thalassemia major. Am J Pediatr Hematol Oncol 1990;12(1):56-60. 26. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331(9):567-73. 27. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, et al. Survival in medically treated patients with homozygous beta- thalassemia. N Engl J Med 1994;331(9):574-8. 28. Borgna-Pignatti C, Rugolotto S, De Stefano P, Piga A, Di Gregorio F, Gamberini MR, et al. Survival and disease complications in thalassemia major. Annals of the New York Academy of Sciences 1998;850:227-31. 29. Wanless IR, Sweeney G, Dhillon AP, Guido M, Piga A, Galanello R, et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood 2002;100(5):1566-9. 30. Brittenham GM ND, Olivieri NF, Porter JB, Pippard M, Vichinsky EP, Weatherall DJ. Deferiprone and hepatic fibrosis. Blood 2003;101:5089- 90. 31. Piga A, Longo F, Consolati A, De Leo A, Carmellino L. Mortality and morbidity in thalassaemia with conventional treatment. Proceedings of the third international conference on bone marrow transplantation in thalassaemia. Bone Marrow Transplantation 19: Supplement 2: 1997;11-13. 32. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 9220:2051- 2. 33. Dyer C. Whistleblower vows to fight on. BMJ 2004;328(7433):187. 34. Bartlett AN, Hoffbrand AV, Kontoghiorghes GJ. Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid- 4-one (L1). II. Clinical observations. Br J Haematol 1990;76(2):301-4. 35. Mehta J, Singhal S, Revankar R, Walvalkar A, Chablani A, Mehta B. Fatal systemic lupus erythematosus in patient taking oral iron chelator L1. Lancet 1991;337(8736):298. 36. Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Ramanathan J, Desai N, et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusion-dependent thalassaemia: Indian trial. Br J Haematol 1992;82:460-466. 37. Al-Refaie FN, Hershko C, Hoffbrand AV, Kosaryan M, Olivieri NF, Tondury P, et al. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haematol 1995;91(1):224-9. 38. Kersten MJ, Lange R, Smeets ME, Vreugdenhil G, Roozendaal KJ, Lameijer W, et al. Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. Annals of Hematology. 1996;73(5):247-52. 39. Pootrakul P, Sirankapracha P, Sankote J, Kachintorn U, Maungsub W, Sriphen K, et al. Clinical trial of deferiprone iron chelation therapy in B-thalassaemia/haemoglobin E patients in Thailand. Br J Haematol 2003;122(2):305-310. 40. Cohen A, Galanello R, Piga A, Vullo C, Tricta F. A multi-center safety trial of the oral iron chelator deferiprone. Annals of the New York Academy of Sciences. 1998;850:223-6. 41. Cohen A, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 2000;108(2):305-12. 42. Naylor CD. The deferiprone controversy: time to move on. Canadian Medical Association Journal. 2002;166(4):452-3. 43. Author's observations in India and Sri Lanka, 2004 44. Savulescu J. Thalassaemia major: the murky story of deferiprone. Br Med J 2004;328:358 - 9. 45. Nathan DG, Weatherall DJ. Academic freedom in clinical research. N Engl J Med 2002;347(17):1368-1371. 46. Herxheimer A. Relationships between the pharmaceutical industry and patients' organisations. BMJ 2003;326(7400):1208-10. Competing interests: None declared |
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Panos A Ioannou, A/Pr, Head, Cell & Gene Therapy Research Group Murdoch Childrens Res Inst, Univ Melbourne Dept of Paediatrics, VIC 3052, Melbourne, Australia
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Sir, The editorial by Savulescu [1] and the response by Kontogiorghes [2] highlight the moral imperative of the research community to come to a quick consensus on the place of L1 (deferiprone or 1, 2-dimethyl-3- hydroxypyrid-4-one) in the treatment of iron overload in thalassaemia. Deferiprone is probably unique among modern drugs in that its early development was almost entirely funded by a patients’ support group, the UK Thalassaemia Society. What is not surprising, however, is the subsequent exclusion of the UK Thalassaemia Society from any decisions concerning the availability of deferiprone for patient use. L1 clearly posed an immediate threat to desferal monotherapy of iron overload in the early nineties, prompting Ciba-Geigy, now Novartis, to acquire all rights for its commercial exploitation. Ciba-Geigy promptly proceeded to give L1 the “kiss of death” by pronouncing it in 1993 as unsuitable for patient use, after a questionable series of tests on non- iron loaded animals. However, the medical community was not intimidated by this pronouncement and studies on L1 in thalassaemia patients continued to expand. Dr Nancy Olivieri one of the first clinical researchers that recognised the potential benefits of L1 in reducing intracellular oxidative damage and cardiac damage [3,4], convinced Apotex to fund a series of pivotal clinical studies on L1. However, these studies were interrupted by a dispute over claims by Dr Olivieri for an increased risk of liver fibrosis in L1-treated patients. The dispute has continued to reverberate for nearly ten years, with Dr Olivieri appearing to stand up for patients’ interests and research integrity, and against interference by drug companies in sponsored research. The only definite outcome of the dispute has been the spreading of confusion in the minds of many patients and clinicians over the use of L1 and the continuation of desferal monotherapy, with all its limitations. Following a series of studies by other workers that failed to show any increased risk of liver fibrosis in L1-treated patients, L1 was approved as a second line iron chelator by the European Agency for the Evaluation of Medicinal Products, a decision that was promptly challenged by Dr Olivieri in the European Court of Justice. However, by its decision of December 18, 2003, the European Court of Justice rejected the case of Dr Olivieri. Undaunted by this decision, Dr Olivieri distributed widely a circular, dated January 13, 2004, apparently under the names of the Canadian Health Coalition and the organization of “Doctors for Research Integrity” in which she states: “You will remember that the fundamental reason that the Olivieri- Apotex-Sick Kids Hospital-University of Toronto controversy began was the protection of patients in clinical trials…” and then, “Has harm resulted from the licensing of deferiprone? Yes. Several premature deaths in patients receiving this drug have been reported over the last five years; still others have occurred but have not yet been reported. Sadly, these patients have become fatal statistics in experiments using deferiprone therapy.” I have asked Dr Olivieri in private correspondence to clarify whether her circular was approved by representative bodies of the above two organizations and to justify her claim of “premature deaths” in the absence of any such published evidence in the scientific literature. In fact, in a publication by the International Study Group on Oral Iron Chelators in 1995 in which Dr Olivieri is a co-author, it is clearly stated that “There was no treatment-related mortality” in the deferiprone- treated group of patients [3]. Although I have not received a direct response from Dr Olivieri, I have received a response from Prof David Nathan on January 25th, 2004, apparently on behalf of Dr Olivieri, which I feel morally compelled to make public [5]. In his message, Prof David Nathan offers the following explanation: “The premature deaths to which Dr. Olivieri has referred are published reports of patients who died in a very short time on L1.” One cannot help but wonder why such unsubstantiated claims are raised now by Dr Olivieri in a non-scientific circular, at a time when thousands of patients are being treated by L1 without any reports of such deaths and when evidence is mounting that L1 may actually be saving patient lives by its cytoprotective and cardioprotective effects. “The murky story of deferiprone” is clearly far from over. Research integrity and the interests of thalassaemia patients are being abused. Thousands of patients are being condemned to desferal monotherapy, while many more cannot afford the costs of current chelator therapy. Savulescu may wonder whether this affair could have developed differently “if the ethics committee in Toronto had taken a proactive and independent role in attempting to resolve the scientific dispute between Apotex and Dr Olivieri in 1996.” However, what is more important now is for the UK Thalassaemia Society, the Thalassaemia International Federation and other representative patient organizations to wrestle the initiative and work with the broad medical community towards a consensus on deferiprone at the earliest opportunity on the basis of the available evidence. Those that persist to abuse research integrity and the interests of patients will then do so at their own peril. References: 1] Savulescu J. Thalassaemia major: the murky story of deferiprone. Conducting life saving research properly and quickly is a moral imperative. Br Med J 2004; 328: 538-9. 2] Kontoghiorghes GJ. Seeking the truth on deferiprone: an orphan drug for a market worth hundreds of millions. Rapid response to Savulescu, Br Med J 2004; 328: 538-9, available online (http://bmj.bmjjournals.com.mate.lib.unimelb.edu.au/cgi/eletters/328/7436/358#50744) 3] al-Refaie FN, Hershko C, Hoffbrand AV et al. Results of long-term deferiprone (L1) therapy: a report by the International Study Group on Oral Iron Chelators. Br J Haematol. 1995; 91: 224-229. 4] Shalev O, Repka T, Goldfarb A, et al. Deferiprone (L1) chelates pathologic iron deposits from membranes of intact thalassemic and sickle red blood cells both in vitro and in vivo. Blood 1995; 86: 2008-2013. 5] Full text of correspondence with Prof N Olivieri and Prof D Nathan is available on request. Competing interests: None declared |
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Michael Spino, University of Toronto Apotex Inc., 200 Barmac Dr. Toronto, Ontario, M9L 2Z7, Fernando Tricta
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Dr. J. Savulescu has risen above the crowd by resisting the temptation to blindly support a medical investigator in her attack against industry, when she alleged foul play. Dr. N. F. Olivieri purported that she had uncovered potentially dangerous information about a drug being developed by a company, and that company attempted to prevent the dissemination of her information. Dr. Savulescu’s editorial entitled, “Thalassemia major: the murky story of deferiprone”, concludes, “One can only speculate that this whole affair may never have happened if the ethics committee in Toronto had taken a proactive and independent role in attempting to resolve the scientific dispute between Apotex and Dr Olivieri in 1996.”(1) This was the exact request made by Apotex to the Chairman of the Ethics Committee. In a letter dated, March 15, 1996, Apotex wrote to him noting it did not agree with Dr. Olivieri’s interpretation of the data and asked that the REB look into the matter. On March 25, 1996, the Chairman wrote back stating that the REB would not do this, and, without the REB ever having formally evaluated the issue, he ordered unwarranted changes in the Consent Form. The numerous ongoing difficulties in the conduct of the study, together with those changes, not supported by the other investigators, precipitated the termination of the study in Toronto, but not elsewhere. Had the REB evaluated the matter, it is most likely that they would have come to the same conclusion as did an international expert panel 2 months later when it stated that there was no basis to Dr. Olivieri’s conclusions of loss of response(2). Some may consider this matter as a disagreement simply between an investigator and a company, but that was not the case. The other investigators, studying deferiprone in their own patients, reviewed the data and all concluded that Dr. Olivieri’s allegations, even based on her own data, were untenable. At the very least, this matter should have been treated as any other serious disagreement among investigators, with an independent assessment of the data, a request rejected by the chair of the REB. However, the posturing on this event was that Dr. Olivieri was a “whistleblower”, an independent investigator fighting industry to protect patients against the avarice of industry (3); good copy for the press, but far from the truth. At no time did Apotex opt to compromise patient welfare for financial gain, but it was a message that was readily accepted by those who did not have access to the information, but were exposed to the extensive promotion employed by Dr. Olivieri in publicizing her case(4). A few, otherwise discriminating scientists, still seem to readily accept Dr. Olivieri’s allegations(5), but their lack of knowledge of the facts becomes evident in their erroneous accounts of the matter. The natural consequence of this misinformation is ill-founded conclusions, as recently revealed in the New England Journal of Medicine(6). Of even greater concern is that a supposedly unbiased academic-based committee, such as that formed by the Canadian Association of Universities Teachers (CAUT), would publish a report on the matter, having interviewed Dr. Olivieri and her supporters, but not the hospital, nor the university nor the company which she was attacking(7). It is little wonder that their treatise contains a myriad of errors. Their lack of correct information could not help but bias their view in formulating their conclusions(8). Yet the opinions of many of those involved in the discussion of the report from the Journal of Medical Ethics, to which Dr. Savulescu refers, relied upon this very document. Thus, the myth is perpetuated, unwittingly by some, because of reliance on unfounded, but highly publicized allegations. In answer to Dr. Savulescu’s other concern, “we still do not know whether deferiprone harms or benefits people with thalassemia compared with deferoxamine”, we offer the total sum of the world’s published literature on deferiprone. To date, there have been over 50 peer-reviewed published clinical studies on deferiprone in over a thousand patients as revealed in a Medline search(9). Among those, some are more positive than others, as would be expected with the study of any drug, but Olivieri’s study in 18 patients (10)is unique by suggesting that deferiprone should not be used, even in patients for whom no other iron chelators are available. It is noteworthy that her publication was accompanied by a precautionary editorial (11) and followed by a series of letters to the editor contesting its conclusions (12), (13), (14), (15), (16), (17). To answer Dr. Savulescu’s question, there is no lack of information upon which to draw a scientifically sound conclusion, but reiteration of conclusions from a single study with a flawed post-hoc retrospective analysis, has clouded the issue. Deferiprone is currently approved in > 30 countries around the world. Yet Dr. Savulescu is correct again in stating that if deferiprone is more effective than deferoxamine (or more tolerable), needless lives have been lost in those jurisdictions where the approval has not yet been granted, especially in light of the cardiac benefits which have been reported (18), (19). We know of no other orphan drug that has been as extensively evaluated for regulatory purposes, nor of a situation where a potential life-saving alternative for patients who failed the only other available treatment, is denied to patients because of allegations, largely rejected by the scientific community. More studies are always desirable, for any drug, but the available data make it unconscionable to deny deferiprone as an alternative to patients at risk of early death. This is the true ethics of the matter. REFERENCES (1) Savulescu J. Thalassaemia major: the murky story of deferiprone. BMJ 2004;328:358-9. (2) The Hospital for Sick Children Research Policy Review Task Force report. Available www.sickkids.ca/taskforcereport/default.asp (accessed March 19, 2004) (3) Valpy M. Science Friction. Elm Street Magazine 1998; Holiday Edition. (4) Undercurrents, "PR for Me," CBC, 5 March 2000. (5) Nathan DG, Weatherall DJ. Academic freedom in clinical research. N Engl J Med 2002;347:1368-71. (6) Spino M, Tricta F. The Olivieri case. N Engl J Med 2003;348:860-3. (7) Naylor CD. The deferiprone controversy: time to move on. CMAJ 2002;166:452-3. (8) Betito E. News article on report about drug researcher was biased. BMJ 2002;324:612-3. (9) PubMed: Deferiprone. (accessed March 18, 2004) (10) Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N Engl J Med. 1998 Aug 13;339(7):417-23. (11) Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone- toxicity or lack of efficacy? N Engl J Med 1998;339:468-9. (12) Cohen AR, Martin MB. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1713-4. (13) Grady RW, Giardina PJ. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1712-3. (14) Wonke B, Telfer P, Hoffbrand AV. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1712. (15) Stella M, Pinzello G, Maggio A. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1712. (16) Callea F. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1710-1. (17) Tricta F, Spino M. Iron chelation with oral deferiprone in patients with thalassemia. N Engl J Med 1998;339:1710. (18) Anderson LJ, Wonke B, Prescott E, Holden S, Walker JM, Pennell DJ. Comparison of effects of oral deferiprone and subcutaneous desferrioxamine on myocardial iron concentrations and ventricular function in beta- thalassaemia. Lancet 2002;360:516-20. (19) Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and deferoxamine on survival and cardiac disease in patients with thalassemia major: a retrospective analysis. Haematologica. 2003;88:489-96. Competing interests: We are employees of the company that manufactures deferiprone |
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