Thalassaemia major: the murky story of deferiprone

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

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

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).