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Thalassaemia major: the murky story of deferiprone

BMJ 2004; 328 doi: https://doi.org/10.1136/bmj.328.7436.358 (Published 12 February 2004) Cite this as: BMJ 2004;328:358

Rapid Response:

To the Editor

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
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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
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6. Del Vecchio GC, Crollo E, Schettini F, Fischer R, De Mattia D.
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7. Berdoukas V, Bohane T, Eagle C, Lindeman R, DeSilva K, Tobias V,
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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
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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, &
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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-
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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
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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
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25. Lerner N, Blei F, Bierman F, Johnson L, Piomelli S. Chelation
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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-
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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
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36. Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Ramanathan J,
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37. Al-Refaie FN, Hershko C, Hoffbrand AV, Kosaryan M, Olivieri NF,
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38. Kersten MJ, Lange R, Smeets ME, Vreugdenhil G, Roozendaal KJ,
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39. Pootrakul P, Sirankapracha P, Sankote J, Kachintorn U, Maungsub
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42. Naylor CD. The deferiprone controversy: time to move on. Canadian
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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

Competing interests: No competing interests

01 April 2004
Nancy F Olivieri
Professor of pediatrics and medicine
University of Toronto, Canada