Abuse of patients' rights in the name of research integrity
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.
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
Competing interests:
No competing interests
05 April 2004
Panos A Ioannou
A/Pr, Head, Cell & Gene Therapy Research Group
Murdoch Childrens Res Inst, Univ Melbourne Dept of Paediatrics, VIC 3052, Melbourne, Australia
Rapid Response:
Abuse of patients' rights in the name of research integrity
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...)
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
Competing interests: No competing interests