HSC Clinical Trials Controversy Continues

Research Institute for several years. When HSC clinical trials controversy continues Spino began working for Apotex, he left the staff of the hospital but became an To the editor—We write to correct inaccu- American Society of Hematology and in unpaid consultant to HSC. Since joining racies in your October issue editorial and the New England Journal of Medicine (339, Apotex, Spino has not maintained a lab- news article concerning the controversial 417; 1998). oratory at HSC, but has done collabora- clinical trial involving Nancy Olivieri, After Apotex did not renew the L-1 clin- tive research in Koren’s laboratory. Koren The Hospital for Sick Children (HSC) and ical trial contract, Olivieri wished to con- and Spino co-supervised a graduate stu- Apotex Inc. Whereas there is no question tinue to use L-1 to treat thalassemia dent and a research technician. Spino that this case is complicated and that patients at HSC and Apotex agreed to pro- was, and continues to be, a professor at there are as many interpretations of the vide the drug under the Canadian gov- The University of Toronto. facts as there are involved parties, the ernment’s Emergency Drug Release (EDR) Arnold Naimark, former dean of Medi- allegation that the HSC administration program. Later, Apotex on several occa- cine and President of the University of “completely failed to support the efforts sions contacted hospital officials request- Manitoba, has conducted a review to of Olivieri” is false and the implication ing that the hospital help them gain determine the facts and circumstances of that we did not support Olivieri’s right to access to the data generated while Olivieri this complex case. We anticipate that his publish is unwarranted. treated patients under the EDR program, report will further clarify facts in the case In a letter dated 24 May 1996, Apotex and HSC supported Olivieri in refusing and make useful recommendations for notified Olivieri (and her collaborator these requests. Olivieri’s complaint that future practice at the Hospital for Sick Gideon Koren) that they would not her data was used without her permission Children. [As Nature Medicine went to renew the contract supporting the trial of was brought to The University of Toronto press this report was released and is avail- L-1 (Deferiprone). Apotex also warned for adjudication (in keeping with the uni- able at http://www.sickids.on.ca/ HSCWeb/ Olivieri and Koren that they would pur- versity’s Procedures to Address and Manage zReview/TheReview). Further- more, a sec- sue legal remedies if they breached the Scientific Misconduct). An investigating ond-phase review is also planned to obligations in their previous three-year committee was established and reported examine current hospital policies and contract. In a letter dated 25 May, Olivieri in September 1997, dismissing the allega- procedures relating to the broader issues and Koren informed the hospital that tion and exonerating the faculty member of clinical trials and third-party funding. they had already sought legal counsel, against whom the charge was made. The outcome of these reviews may also be who had advised them to contact the The connection between HSC and of value to other institutions.

http://medicine.nature.com • Canadian Medical Protective Association Michael Spino, now a vice president of (CMPA). When Olivieri subsequently met Apotex, should be clarified. Spino was a MANUEL BUCHWALD1 & with university officials on 6 June, and member of The Hospital for Sick Children HUGH O'BRODOVICH2 with hospital representatives on 18 July, she was represented by a lawyer from DNAVEC gene therapy on course McCarthy Tetrault, the firm retained by the CMPA. It was not until the hospital In your November issue, you carried a news story (“Japan renews gene therapy ef- board of directors initiated an indepen- forts”) regarding progress on gene therapy in Japan. We think that your discussion of dent external review that Olivieri DNAVEC Research was misleading, and we would like to clarify a few points. 1999 Nature America Inc. requested legal assistance from the hospi- We disagree with your suggestion that DNAVEC has failed in its aims or is behind © tal in this matter. Olivieri has been con- schedule. Our aim is to develop new gene therapy-related technologies, to sell these tinuously represented by lawyers from to our investors and third parties and to proceed to clinical trials with companies ex- McCarthy Tetrault. perienced in clinical trials. At our inception (March 1995) and thereafter, we stated At the 18 July 1996 meeting, Olivieri our intention to invest three to five years in new vector development, followed by and her lawyer requested that the hospi- animal studies, development of the methodologies required for the initial phase of tal take a position against Apotex, back- the commercial production of vectors, and preliminary safety studies. Our develop- ing her scientific findings. The hospital’s ment of a Sendai virus-based vector is on schedule and has received favorable re- opinion was that the conflict was a sci- views from the scientific review committee of the Organization for Pharmaceutical entific dispute among Olivieri, Koren, Safety and Research, an extra-governmental organization of the Ministry of Health Apotex and several other scientists and Welfare, Japan. regarding the effectiveness of L-1 and, as Your news story failed to recognize our precise research policy—we are neither a such, should be resolved through the contract vector production facility nor a safety assessment facility. Incidentally, the scientific literature. The hospital sup- preparation to launch DNAVEC started in 1993, well in advance of the approval of ported and encouraged Olivieri’s initia- the first gene therapy clinical trial in Japan. tive to submit her findings for presentation at the December 1996 meeting of MAMORU HASEGAWA the American Society of Hematology, Managing Director which she did. She also reported her find- DNAVEC Research ings in an article in the Medical Post (Jan- 1-25-11 Kannondai, Tsukuba-shi uary 1997), in April 1997 at the Sixth Ibaraki 305 International Conference on Tha- Japan lassemia and Hemoglobinopathies, and [email protected] at the December 1997 meeting of the

1Director, The Hospital for Sick Children latory agencies. This recommendation president of Apotex, appeared on the let- Research Institute, Chief of Research, The was dismissed by the senior HSC admin- terhead of the Division of Clinical Hospital for Sick Children, Molecular and istration, who stated that “the matter Pharmacology at HSC as recently as Medical Genetics, University of Toronto, could be settled without the help of March 1998. Spino has confirmed that 2Chief of Paediatrics, The Hospital for Sick regulatory agencies.” Fortunately, the he maintained laboratory space at HSC, Children, Chairman of Paediatrics, Faculty of CMPA, recognizing that I was “subject to a fact allegedly unknown by the director Medicine, University of Toronto the ethical obligations of a physician as of the hospital’s research institute. well as the obligations imposed by the Spino’s technician confirmed in August Olivieri replies—The facts of this case are Institutional Review Board, the 1998 that work on Deferiprone was still quite straightforward. The allegation Declaration of Helsinki, and Medical ongoing in his laboratory. that the Hospital for Sick Children Research Council of Canada’s Code Finally, as is now a matter of public (HSC) and the University of Toronto of Conduct for Research Involving record, the pursuit of a $20 million do- “completely failed to support the efforts Humans,” subsequently agreed to sup- nation by Apotex to the University of of Olivieri” is absolutely true, as is the port disclosure to the Canadian Health Toronto is the ‘top’ priority of the implication that it did not support my Protection Branch. Noting that I was University of Toronto. right to publish findings about L-1 “rightly concerned about the safety and Throughout 1997 and 1998, I and sev- (Deferiprone). well-being of persons throughout the eral other concerned scientists have re- Ultimately, the only support to me for world,” the CMPA observed that such quested an independent inquiry into legal protection came from the Canadian disclosure would be “in compliance with this matter. We have refused to partici- Medical Protective Associa-tion (CMPA), statutory requirements.” That I was able pate in Naimark’s ‘review’ because of an organization that serves to protect to submit and present data at scientific grave concerns about the fairness of physicians in Canada from legal threats meetings was solely the result of support a panel appointed by one of the arising in the practice of medicine. The ultimately provided by CMPA. parties implicated in this controversy. CMPA first limited its support to the In January 1997, two abstracts endors- Therefore, presentation of the legal issue of full disclosure of the perceived ing the long-term effectiveness of records, transcripts of tape-recorded risk of Deferiprone to my Toronto pa- Deferiprone presented to a scientific messages, other communications and tients only. The CMPA declined to sup- meeting were co-authored by Apotex- unassailable facts that will not be pre- port disclosure of perceived risks to paid research fellows, a full-time em- sented to Naimark will be included in a patients in international trials (of which ployee of Apotex and two University of future full, independent and unbiased

http://medicine.nature.com

• 1,2 I was the chair of the steering commit- Toronto investigators . These abstracts inquiry. tee), to regulatory agencies (to which ap- and other subsequent communications3 plications were being made by Apotex continue to provide a favorable interpre- NANCY OLIVIERI for licensing, based in large part on ear- tation of data arising from the Toronto Professor of Pediatrics and Medicine, University lier work by us) or to the scientific com- clinical trials of Deferiprone directed by of Toronto, Canada munity. Two months after the abrupt me. The abstracts were submitted with- Scientist, Medical Research Council of Canada termination of these trials by Apotex, I out my knowledge or consent, or that of Director, Haemoglobinopathy Programs, The was unable to fulfill these last three Gary Brittenham, whose NIH-funded Hospital for Sick Children and The Toronto obligations without the risk of legal ac- laboratory generated these data. An in- Hospital 1999 Nature America Inc. tion by Apotex. The Hospital neverthe- vestigating committee at the University © less stated, unequivocally, that it would convened to investigate this conduct 1. Tricta, F. et al. Long-term chelation therapy with the orally active iron chelator deferiprone in pa- not provide legal counsel for me in this ruled, incomprehensibly, that it is ac- tients with thalassemia major. Proceedings of the matter. Written records of this refusal are ceptable practice under the current lead- 6th International Conference on Thalassemia and available. ership of the Faculty of Medicine at the the Haemoglobinopathies, April, 1997. 2. Tricta, F. et al. Randomized trial of deferiprone (L1) The HSC excused their action by say- University of Toronto for a scientist to and deferoxamine (DFO) in thalassemia major. ing it “…was a scientific dispute….” publish NIH- and MRC-funded data Proceedings of the 6th International Conference on Thalassemia and the Haemoglobinopathies, April This is alarming for an institution with without the knowledge, consent or par- 1997. a mandate to protect patients. In the ticipation of the scientists who gener- 3. Diav-Citrin, O., Atanackovic, G. & Koren, G. face of uncertainty over possible harm ated the data. Correlation between initial hepatic iron concentra- tion and response to deferiprone (L1) in patients to patients, to do nothing is a derelic- With regard to attempts by Apotex to with beta-thalassemia major. Clin. Pharm. Ther. tion of a physician’s duty by every gain access to data generated by me and 192, PII-77 (1998). international standard of ethics in med- my colleagues—data that I repeatedly re- ical research. It is also illegal under fused to provide them—Gideon Koren, LETTERS TO THE EDITOR Canadian criminal law. (Incidentally, an Apotex-paid research fellow, gained although we raised our concerns at a unauthorized access to my confidential Nature Medicine encourages brief letters to time when others were still enthusiastic patient files. This is well documented. the editor (no more than 500 words) on about the drug, we never requested that The senior HSC administration did not topics that have been reported in previous anyone at the HSC take a position reprimand Koren or Apotex, but did ad- issues or on subjects of interest to the biomedical research community. Letters against Apotex, backing our scientific vise me in writing that I should refrain should be addressed to Nature Medicine, findings.) from informing patients whose charts 345 Park Avenue South, New York, NY The HSC Institutional Review Board had been accessed without authoriza- 10010, USA, or sent by fax (212.683.5751) had, in parallel with disclosure to pa- tion. or by e-mail ([email protected]). tients, recommended disclosure to regu- The name of Michael Spino, the vice

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