Correspondence
The Olivieri Case
N Engl J Med 2003; 348:860-863February 27, 2003
- Article
To the Editor:
In their article on the dispute over the iron-chelating agent deferiprone (Oct. 24 issue),1 Nathan and Weatherall focus on the ethical implications for the relationships among scientists, their institutions, and industry. Their article ignores recent evidence on the safety and efficacy of the drug2-5 and does nothing to resolve the uncertainty that has made deferiprone unavailable to the majority of patients with thalassemia worldwide.
This very public controversy has generated fear, uncertainty, and doubt among such patients and their physicians, fomented mistrust among clinicians and researchers, and undermined patients' confidence in their doctors. Such doubts have been heightened by the high respect in which North American science is held. The Food and Drug Administration has not licensed deferiprone, since its decisions are made in a North American context and cannot remain uninfluenced by such a high-profile dispute. Consequently, regulatory authorities in many countries have also declined to license deferiprone. As a result, although it has been used safely by thousands of patients for as long as 10 years and is marketed cheaply by Cipla in India, doctors in neighboring countries have been unable to use it, despite the fact that it offers the only hope for their patients with thalassemia. For every year this situation continues, at least 2000 to 3500 patients with thalassemia who receive regular transfusions die worldwide from untreated iron overload — more than the total number of such patients living in North and South America combined. Patients cannot wait 10 years for a better iron-chelating agent. They need deferiprone now because it is affordable, tolerable, and adequately safe and effective.
5 ReferencesGeorge Constantinou
Stavros Melides
United Kingdom Thalassaemia Society, London N14 6PH, United Kingdom
george@constantine58.freeserve. co. uk Bernadette Modell, Ph.D., F.R.C.P.
University College London, London N19 5LW, United Kingdom1
Nathan DG ,Weatherall DJ . Academic freedom in clinical research. N Engl J Med 2002;347:1368-1371
Full Text | Web of Science | Medline2
Wonke B ,Wright C ,Hoffbrand AV . Combined therapy with deferiprone and desferrioxamine. Br J Haematol 1998;103:361-364
CrossRef | Web of Science | Medline3
Giardina PJ ,Grady RW . Chelation therapy in β-thalassaemia: an optimistic update. Semin Hematol 2001;38:360-366
CrossRef | Web of Science | Medline4
Wanless IR ,Sweeney G ,Dhillon AP , et al. Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassaemia. Blood 2002;100:1566-1569
CrossRef | Web of Science | Medline5
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;360:516-520
CrossRef | Web of Science | Medline
To the Editor:
Nathan and Weatherall misrepresent facts related to Apotex and deferiprone. Moreover, one of the authors failed to disclose his relationship with a company that is developing a competing drug1 and, in so doing, violated recent Journal guidelines for authorship and accountability.2 We take issue with many of the statements made by Nathan and Weatherall.
The facts as seen by Apotex are as follows. In 1992, Olivieri and a coinvestigator requested that Apotex support the development of deferiprone (L1), advocating the need for this oral drug in treating iron overload in patients with thalassemia major. Although it was needed by patients, deferiprone would not be viewed by a pharmaceutical company as a profitable investment because there are fewer than 700 patients with thalassemia major in the United States, there is a risk of agranulocytosis, and there would be patent protection for only a short time. Notwithstanding these limitations, Apotex made a commitment to develop deferiprone because of its potential for enhancing the survival of a segment of the population of patients with thalassemia major.
In 1993, Apotex initiated a program to determine the safety and efficacy of deferiprone, leading to its evaluation in more than 800 patients in Europe, North America, and other parts of the world. In 1995, Olivieri and a colleague of hers in Toronto expressed concern about a loss of response in six of their patients.3 The scientists at Apotex reviewed the data and concluded that they did not support this interpretation. To obtain an independent assessment, Apotex distributed the raw data to all the other investigators studying deferiprone. The investigators were unanimous in their disagreement with Olivieri's interpretation. Apotex then convened an international committee of experts to review the raw data and Olivieri's interpretation. The committee concluded as follows: “Specifically, the Committee does not find a trend toward a loss of effectiveness of therapy in patients treated with L1 [deferiprone] on a long-term basis. There are no sudden, unexpected changes in regard to failure of therapy.”4
By that time, Apotex had decided not to renew Olivieri's contract and discontinued the study in Toronto, while continuing the studies at all other sites. Nathan and Weatherall characterize the termination of Olivieri's contract as an attempt to stop her from divulging her views, but the systematic approach to disclosure and review demonstrates that such a perspective is invalid.
Three months after her contract had been terminated, Olivieri submitted an abstract for presentation at a scientific conference,3 not disclosing that a review of the data had been conducted and that two committees had rejected her conclusions. Only after her contract had been terminated did she allege that the use of deferiprone might be associated with an increase in the risk of hepatic fibrosis.5 We think these claims have been disproved.6
Nathan and Weatherall demonstrate a lack of current knowledge regarding the clinical safety of deferiprone, its efficacy, and its role in the treatment of thalassemia major. Readers who wish to learn about deferiprone may refer to recent reports from independent6-10 and Apotex-sponsored11 studies. Deferiprone, now approved in 24 countries, is the only lifesaving alternative for patients with thalassemia major who will not or cannot take deferoxamine and for whom no other treatment is approved; Nathan and Weatherall would deny them this treatment.
In addition, Nathan and Weatherall falsely contend that within “a few years” after Apotex stopped the trials, “two lawsuits totaling over $20 million were formally lodged against” Olivieri. At no time did Apotex initiate any lawsuit against Olivieri. The truth may be found in the records of the Court of Ontario. It was Olivieri who filed numerous lawsuits against those who disagreed with her actions, including other scientists, the media, and Apotex. As part of its defense, Apotex filed a counterclaim.
In summary, the record shows a picture remarkably different from that portrayed by Nathan and Weatherall. What is academic freedom, and what evidence can an author hide from a journal or the scientific community? Is it acceptable to suppress the fact that conclusions have been challenged, particularly when extensive peer review has resulted in the rejection of the author's conclusions? What are the responsibilities that accompany academic freedom, and how are the patients' interests best served? There is a responsibility that comes with the right to academic freedom, and that is the duty of full disclosure and scientific objectivity.
11 ReferencesMichael Spino, Pharm.D.
Fernando Tricta, M.D.
Apotex, Toronto, ON M9L 1T9, Canada
mspino@apotex.com 1
Nisbet-Brown E ,Olivieri NF ,Giardina PJ , et al. ICL670a, a tridentate orally-active iron chelator, provides net negative iron balance and increased serum iron binding capacity in iron-overloaded patients with thalassemia. Blood 2001;98:747a-747a abstract.
Web of Science2
Davidoff F ,DeAngelis CD ,Drazen JM , et al. Sponsorship, authorship, and accountability. N Engl J Med 2001;345:825-827
CrossRef | Web of Science | Medline3
Olivieri NF . Long-term followup of body iron in patients with thalassemia major during therapy with the orally active iron chelator deferiprone (L1). Blood 1996;88:Suppl 1:310a-310a abstract.4
Schwartz E, Blumer J, Corey M, Wonke B. Report: expert advisory panel on L1 efficacy. Toronto: Hospital for Sick Children, July 12–23, 1996.
5
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
Full Text | Web of Science | Medline6
Wanless IR ,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
CrossRef | Web of Science | Medline7
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;360:516-520
CrossRef | Web of Science | Medline8
Ceci A ,Baiardi P ,Felisi M , et al. The safety and effectiveness of deferiprone in a large-scale, 3-year study in Italian patients. Br J Haematol 2002;118:330-336
CrossRef | Web of Science | Medline9
Maggio A ,D'Amico G ,Morabito A , et al. Deferiprone versus deferoxamine in patients with thalassemia major: a randomized clinical trial. Blood Cells Mol Dis 2002;28:196-208
CrossRef | Web of Science | Medline10
Hershko C ,Link G ,Konijn AM ,Huerta M ,Rosenmann E ,Reinus C . The iron-loaded gerbil model revisited: effects of deferoxamine and deferiprone treatment. J Lab Clin Med 2002;139:50-58
CrossRef | Medline11
Cohen AR ,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;108:305-312
CrossRef | Web of Science | Medline
Author/Editor Response
As physicians who have cared for patients with thalassemia for more than 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 thalassemia.1,2 Before patients and governments in developing countries give up this drug and accept deferiprone as an effective agent for treating thousands of patients, a long-term trial must be performed to prove that it can control body iron levels. Sadly, as we understand it, the only study of this kind was stopped by the manufacturers of deferiprone six years ago. Had it not been stopped, we would have this information by now; there are no shortcuts to assessing control of the slow accumulation of iron in patients with thalassemia.
Although the current Apotex lawsuit against Olivieri may be defensive, Spino and Tricta fail to mention that their company threatened her repeatedly with legal action if she publicized her concerns about the efficacy and safety of deferiprone and even threatened the American Society of Hematology in the same way if it allowed her to present her results at its annual meeting. Furthermore, if the company's advisors were so confident that Olivieri was incorrect and that body iron levels were being controlled, why did they immediately stop the trial? Had they not done so, or had they at least ensured that adequate data on iron levels were made available from the toxicity studies that were continued, we would now have this vital information.
Spino and Tricta also suggest that we are denying the drug to those “who will not or cannot take deferoxamine.” Patients in whom deferoxamine results in adequate control of the level of iron accumulation should survive for a long time without cardiac or other complications.1,2 We ask only that similar controlled data be collected for deferiprone. In fact, a recent, peer-reviewed article reviewing the field of chelation concluded, on the basis of currently available evidence, that deferiprone does not control iron accumulation in a substantial number of cases.3 Although the more recent studies of toxicity and cardiac function cited by Spiro and Tricta are interesting, ultimately it is iron accumulation that kills patients with thalassemia. Very few “cannot” take deferoxamine on medical grounds; those who “will not” should be reminded of the uncertainty of the long-term efficacy of deferiprone.
Finally, Spino and Tricta call into question the objectivity of our review by suggesting that one of us has a conflict of interest, presumably because of recent work on an oral chelator manufactured by Novartis. We would remind them, however, that we first asked for adequately controlled trials of deferiprone in 19954 — long before this new agent was on the scene — and have asked many times since. We have never had a financial interest in Novartis (Novartis Oncology has made a grant to the Dana–Farber Cancer Institute for the development of kinase inhibitors for cancer; it has nothing to do with chelation research, and we are not supported by it).
Our review of the Olivieri case was written because we are concerned about problems at the interface between academia and industry and about the importance of open scientific debate and academic freedom.5 The fact that Spino and Tricta choose to interpret the article as the expression of a wish on our part to deny patients lifesaving drugs suggests that our fears are well founded.
5 ReferencesDavid G. Nathan, M.D.
Harvard Medical School, Boston, MA 02115David J. Weatherall, M.D.
University of Oxford, Oxford OX3 9DS, United Kingdom1
Olivieri FN ,Nathan DG ,MacMillan JH , et al. Survival in medically treated patients with homozygous β-thalassemia. N Engl J Med 1994;331:574-578
Full Text | Web of Science | Medline2
Brittenham GM ,Griffith PM ,Nienhuis AW , et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994;331:567-573
Full Text | Web of Science | Medline3
Porter JB . Practical management of iron overload. Br J Haematol 2001;115:239-252
CrossRef | Web of Science | Medline4
Nathan DG . An orally active iron chelator. N Engl J Med 1995;332:953-954[Erratum, N Engl J Med 1995;332:1315.]
Full Text | Web of Science | Medline5
Thompson J, Baird P, Downie J. Report of the Committee of Inquiry on the case involving Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. Toronto: Canadian Association of University Teachers, 2001.
- Citing Articles (2)
Citing Articles
1
Katherine H. Thompson, Cheri A. Barta, Chris Orvig. (2006) Metal complexes of maltol and close analogues in medicinal inorganic chemistry. Chemical Society Reviews 35:6, 545
CrossRef2
Aurelio Maggio, Gennaro D'Amico, Alberto Morabito. (2004) Independent clinical trials. The Lancet 363:9414, 1080
CrossRef
