Nancy Fern Olivieri

Nancy Fern Olivieri

Nancy Fern Olivieri, BSc, MD, FRCPC, is a prominent Toronto haematologist and researcher with an interest in the treatment of hemoglobinopathies.

She is best known for a protracted struggle with the Hospital for Sick Children and the pharmaceutical company Apotex about drug deferiprone.[1] Starting in 1996, Olivieri was part of a group conducting a clinical trial in order to evaluate the use of a drug in treating persons with a blood disorder, thalassaemia. During the course of the trial, Dr. Olivieri became concerned about evidence that pointed to the toxicity of the study drug and to the drug being inefficacious. Dr. Olivieri informed both the research ethics board that was monitoring the study and Apotex, the drug maker. The research ethics board instructed Dr. Olivieri to, inter alia, inform participants about her concerns. Apotex responded by noting that Dr. Olivieri had signed a confidentiality agreement as part of the drug trial and that informing participants about her concerns, the validity of which Apotex disputed, would violate that confidentiality agreement. Apotex threatened to vigorously pursue all legal remedies against her if she disclosed her conclusions to patients. Dr. Olivieri disclosed her concerns to her patients and Apotex ended the portion of the study that she was participating in.[2]

Although Dr. Olivieri was admired for tenaciously defending research integrity and academic freedom,[1] some critics characterized her as publicity-seeking and argued that she was wrongfully placed on a pedestal.[3] Nancy Olivieri's scientific findings, which sparked the controversy, have been challenged worldwide, including her data, which suggested that deferiprone led to progressive hepatic fibrosis, a finding which is disputed.[4][5][6][7] Deferiprone is currently licenced for use in over 50 countries around the globe, benefiting patients who need it, but not in Canada and the United States, possibly due to the North American media attention surrounding Dr. Olivieri.[8]

An investigation revealed that one of Dr. Olivieri's critics, Dr. Gideon Koren, had anonymously sent disparaging letters about Dr. Olivieri to the media and colleagues. Dr. Koren initially denied responsibility, but substantial DNA evidence tied him to the letters and he was reprimanded.[9] In her 2005 book, psychiatrist and ethicist Miriam Shuchman pointed out that Nancy Olivieri's actions in preventing the drug from being developed in North America caused the death of a large number of children in Canada and the United States.[10] Spokesperson for the University of Toronto, Professor David Naylor, current president of the University and then Dean of the Faculty of Medicine and Vice Provost for Relations with Health Care Institutions, and others went on record regarding Olivieri's having "advanced 'demonstrably incorrect' allegations against others" and having used “hundreds of thousands of dollars of legal fees and services” from teachers' union funds, and then being “unable to admit she made a mistake.”[11][12] Prof. Naylor also went on record citing the bias of CAUT and its Inquiry as having favored Olivieri and her Union and pointing to the lack of independence of both committees.[13]

Dr. Olivieri has advocated for greater academic freedom and called for less control of research by pharmaceutical companies.[14] This situation was publicised extensively and was investigated by The Canadian Association of University Teachers.[9] Dr. Olivieri was awarded the 2009 AAAS Award for Scientific Freedom and Responsibility for her "indefatigable determination that patient safety and research integrity come before institutional and commercial interests and for her courage in defending these principles in the face of severe consequences."[15]

On October 14, 2011, however, the basis for Dr. Olivieri's acclaim and the validity of her science were further called into question. On that date, based on further research which confirmed Dr. Koren's position, "the U.S. Food and Drug Administration approved Ferriprox (deferiprone) to treat patients with iron overload due to blood transfusions in patients with thalassemia, a genetic blood disorder that causes anemia, who had an inadequate response to prior chelation therapy... The therapy is being approved under the FDA’s accelerated approval program, designed to provide patients with earlier access to promising new drugs followed by further studies to confirm the drug’s clinical benefit. The accelerated approval program allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients...."[16] This FDA approval further strengthens author Miriam Shuchman's claim that Olivieri's efforts to block the introduction of the drug led to the premature death of many youngsters with thalassemia.[17] [18]

On the contrary, the argument that “This FDA approval further strengthens author Miriam Shuchman's claim that Olivieri's efforts to block the introduction of the drug led to the premature death of many youngsters with thalassemia”, is severely weakened by Dr Sidney Wolfe’s (PUBLICCITIZEN) detailed letter (Oct. 12, 2011), to the FDA where he concludes. “…..given the lack of data from adequate and well-controlled clinical trials demonstrating the safety and efficacy of deferiprone, as well as serious questions raised by DSl's inspection of study LA01 regarding the integrity of clinical trial data presented to the FDA by the sponsor, we urge the FDA to reject approval of NDA #021825 for deferiprone…….FDA approval of deferiprone based on such inadequate data would indeed set a recklessly dangerous precedent for drugs reviewed under an accelerated approval process in the future”.[19]

The FDA briefing notes associated with the decision reveal that the request for regular or normal approval for marketing of deferiprone was declined by the FDA following scientific review because the evidence presented in the Apotex New Drug Application failed to adequately demonstrate safety and efficacy. Also the FDA site inspection of Olivieri’s trials showed that Apotex had wrongly omitted or misrepresented 45% of the Olivieri data in its submission to FDA.

FDA then informed Apotex that additional satisfactory randomized controlled evidence and a full, detailed audit of the Olivieri trials were required if Apotex was to pursue regular approval. The company declined and instead pursued 'accelerated' approval (known as conditional approval in Canada and other jurisdictions), which requires the lowest level of evidence.

Conditional or accelerated approval usually occurs BEFORE there has been time for conclusive clinical trials to be completed on promising new drugs, not AFTER a 20 year drug development program has generated randomized, controlled evidence which fails to demonstrate safety and efficacy.

In the end, accelerated approval for last resort treatment with deferiprone was based on a single arm, non-controlled, non-randomized retrospective re-analysis of 264 patients selected from 746 patients in pooled data from studies previously conducted, showing a 20% reduction in serum ferritin in 52% of patients, the clinical significance of which is uncertain. There was "a lack of data to verify absence of a mortality disadvantage when deferiprone is used over a long period of time. The further studies to which the company must commit as part of accelerated approval are not yet described.[20][21]



See also

References

  1. ^ a b Viens A, Savulescu J (2004). "Introduction to The Olivieri symposium.". J Med Ethics 30 (1): 1–7. doi:10.1136/jme.2003.006577. PMC 1757126. PMID 14872065. http://jme.bmj.com/cgi/content/full/30/1/1. 
  2. ^ Hadskis, Michael (2007). "The Regulation of Human Biomedical research in Canada". In Downie, Jocelyn. Canadian Health Law and Policy (textbook). et. al. (Third ed.). LexisNexis. p. 304. 
  3. ^ Shuchman, Miriam, The Drug Trial, Random House, 2005. http://www.randomhouse.ca/catalog/display.pperl?isbn=9780679310846
  4. ^ Olivieri NF, Brittenham GM, McLaren CE, et al. (1998). "Long-term safety and effectiveness of iron chelation therapy with oral deferiprone in patients with thalassemia major.". New Engl J Med. 339 (7): 417–428. doi:10.1056/NEJM199808133390701. PMID 9700174.  Full Text.
  5. ^ M.A. Tanner, MRCP; R. Galanello, MD; C. Dessi, MD; G.C. Smith, MSc; M.A. Westwood, MD; A. Agus, MD; M. Roughton, MSc; R. Assomull, MRCP; S.V. Nair, MRCP; J.M. Walker, MD; D.J. Pennell, MD (2007). "A Randomized, Placebo-Controlled, Double-Blind Trial of the Effect of Combined Therapy With Deferoxamine and Deferiprone on Myocardial Iron in Thalassemia Major Using Cardiovascular Magnetic Resonance". Circulation 115 (14): 1876–1884. doi:10.1161/CIRCULATIONAHA.106.648790. PMID 17372174.  Full Text.
  6. ^ Brittenham G, Nathan D, Olivieri N, Porter J, Pippard M, Vichinsky E, Weatherall D (2003). "Deferiprone and hepatic fibrosis". Blood 101 (12): 5089–90; author reply 5090–1. doi:10.1182/blood-2002-10-3173. PMID 12788794.  Full Text.
  7. ^ Wanless I, Sweeney G, Dhillon A, Guido M, Piga A, Galanello R, Gamberini M, Schwartz E, Cohen A (2002). "Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia". Blood 100 (5): 1566–9. doi:10.1182/blood-2002-01-0306. PMID 12176871.  Full Text.
  8. ^ Savulescu J (2004). "Thalassaemia major: the murky story of deferiprone". BMJ 328 (7436): 358–9. doi:10.1136/bmj.328.7436.358. PMC 341373. PMID 14962851. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=341373.  Full Text.
  9. ^ a b Jon Thompson, Patricia Baird & Jocelyn Downie, The Olivieri Report: The Complete Text of the Report of the Independent Inquiry Commissioned by the Canadian Association of University Teachers (Toronto: James Lorimer & Co., 2001).[1]
  10. ^ Miriam Shuchman (2005). The drug trial: Nancy Olivieri and the scandal that rocked the Hospital for Sick Children. Toronto: Random House Canada. ISBN 978-0-679-31084-6. [page needed]
  11. ^ http://islet.org/forum030/messages/27664.htm Alastair Gordon, founder and president of the Islet Foundation, July 26, 2003.
  12. ^ Olivieri N (July 2002). "I beg to differ". CMAJ 167 (1): 11; author reply 11–2. PMC 116622. PMID 12137065. http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=12137065. 
  13. ^ Naylor CD (February 2002). "The deferiprone controversy: time to move on". CMAJ 166 (4): 452–3. PMC 99355. PMID 11873923. http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=11873923. 
  14. ^ Olivieri N (2003). "Patients' health or company profits? The commercialisation of academic research". Sci Eng Ethics 9 (1): 29–41. doi:10.1007/s11948-003-0017-x. PMID 12645227. 
  15. ^ http://www.aaas.org/aboutaaas/awards/freedom/freedom2009.shtml
  16. ^ FDA NEWS RELEASE: FDA Approves Ferripox (deferiprone) to Treat Patients with Excess Iron in the Body, Oct. 14, 2011 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm275814.htm
  17. ^ Gatehouse, Jonathon, Maclean’s Magazine, Toronto, May 4, 2005. http://www.macleans.ca/culture/entertainment/article.jsp?content=20050509_105255_105255
  18. ^ Miriam Shuchman (2005). The drug trial: Nancy Olivieri and the scandal that rocked the Hospital for Sick Children. Toronto: Random House Canada. ISBN 978-0-679-31084-6. [page needed]
  19. ^ http://www.citizen.org/hrg1973
  20. ^ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM271537.pdf
  21. ^ http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM271676.pdf

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