Researchers enjoying a pharmaceutical industry bounty because of their willingness to engage in applied research to increase the effectiveness of existing drugs, sometimes find themselves legally cornered because of the "confidentiality agreements" they have signed.
A 1998 case at the Toronto Hospital for Sick Children involved the trial of a modified form of a drug (Deferiprone) which promised the advantage that it could be given orally, rather than intravenously. Having published the results of a preliminary study in the New England Journal of Medicine, it was then found that certain patients showed signs of toxic liver damage. Rather than give up and allow the funds to be diverted to other avenues, it was proposed to try to find ways of predicting which patients would benefit, and which would respond adversely.
To discriminate between the two groups of patients required that administration of the drug be continued, rather than stopped. Accordingly the researcher approached the sponsoring pharmaceutical company seeking permission to change the consent form which experimental subjects were required to sign in order to inform them of the new risk. The pharmaceutical company (Apotex: research director, Michael Spino) refused, and threatened the investigator with legal action if she divulged her findings to her patients.
After bathing in the glory of having a paper by one of its researchers published in the prestigious New England Journal of Medicine, the Hospital now refused to back the researcher, and pressed her to resign. A usual tactic in such cases is to brand the alleged offenders as persistent "trouble makers", or to dismiss the matter as a "personality conflict" between people with big scientific egos. The Hospital's President, Michael Strofolino, characterized the dispute as what Globe & Mail Editor Margaret Wente describes as "a spat propelled by a small group of troublemaking malcontents". She further observed that evidently Strofolino "had sold this version of events to the trustees, who, when last heard from, declared it none of their business."
With the support of some colleagues (Brenda Gallie, Helen Chan, John Dick, Peter Durie), the researcher "went public", and pressure mounted for a full enquiry. One commentator noted in a letter to to Toronto Globe & Mail:
The modern research system being structured to promote competition rather than collaboration, it is noteworthy that Nancy Olivieri had supportive colleagues. Such colleagues depend on the institution for advancing their careers (research space, funds, etc.). At an individual level there is more to gain by backing one's Administration rather than one's colleague.
Thus, the decision to support a colleague is not lightly made. There may be days and weeks of soul-searching, dealing with worries about getting another appointment if there are dismissals, worries about the hum-drum details of life such as where the next mortgage payment and school bill will come from if justice does not prevail.
Thus, not surprisingly, many colleagues were not supportive. Prominent among these was professor and head of the hospital's division of clinical pharmacology, Dr. Gideon Koren, a recent recipient of the first Canadian chair in child health research, the result of a $2-million gift from the Canadian Imperial Bank of Commerce to the hospital. Another was Dr. Sergio Grinstein, holder of the University of Toronto Pitblado Chair in Cell Biology and, until recently, a member of the Gairdner Foundation Committee which adjudicates Canada's equivalent of Nobel Prizes.
Koren went into action at the early "soul searching" stage to undermine the support which Olivieri so needed.
Usually, in such cases, a little light lobbying in corridors, well out of ear-shot of others, is sufficient to shepherd the waverers back to the fold. But, being MDs with the possibility of clinical practice to fall back on financially, some of Olivieri's colleagues were not so vulnerable. So Koren had to institute an anonymous "poison pen" letter writing compaign. It was not until late 1999, following the hiring of a private detective and the testing of DNA attached to postage-stamps, that Koren was identified as author of at least four such letters. Reporters Krista Foss and Andrew Mitrovica of The Globe and Mail (Tuesday, December 21, 1999) described this as: "not a mystery novel, but instead the latest skullduggery at Toronto's Hospital for Sick Children".
In the letters, supportive colleagues were referred to as "unethical" and "a group of pigs", and at least one was advised to leave the hospital. One letter was sent to as many as 40 people in the hospital, according to Dr. Durie, who was told that he should leave the institution, and that he was a British version of a "foul air balloon."
"How did you ever get yourself in the middle of this group of pigs? Or did you think that their shit won't touch you?," the same letter asked. A final letter, received by Dr. Durie says he is "contaminating our air and fabric" and then refers to his candidacy for a job at another hospital.
This final revelation gave the story sufficient momentum to propel it beyond Canadian media, ... to 60 Minutes and The New York Times.
Dr. Durie informed several people at the hospital about the letters he was receiving, including the President. He asked for an investigation of the individual he suspected was sending them, but the Hospital declined. Accordingly, Olivieri's colleagues had to spend around $300,000 to get the overwhelming evidence, leading to Koren's confession.
DNA evidence was also used to catch Grinstein, according to reporter Karen Birmingham in the May 2000 issue of Nature Medicine (6, 485). A Canadian expert on drug development and drug regulatory law, Dr. Michele Brill-Edwards, who had worked at the Bureau of Human Prescription Drugs at the Health Protection Branch, Ottawa, wrote an article in September 1998 for the Toronto Globe & Mail "calling for the Hospital for Sick Children administration to admit its failings and resign." This provoked a personal signed letter from Grinstein in October 1998, which said that Brill-Edwards has "...cast a shadow over the hospital...", and urged her to redress "...the damage you may have done to the Hospital and its community of scientists and administrators."
Brill-Edwards received an anonymous note in July 1999 shortly after she had attended a regulatory meeting on the safety and efficacy of Deferiprone. The note read:
The note was wrong on two counts. Deferiprone had not received FDA approval, and Olivieri had not left the HSC. Brill-Edwards found the note "intimidating" and having had Grinstein's DNA identified and obtained his confession, reported the matter to David Naylor, the Dean of the Faculty of Medicine at the University of Toronto.
In an article entitled "Medicine, Morals and Money" Margaret Wente described the failure of correct administration action as resulting from "a fundamental misreading of the issue as a mere contractual and scientific dispute (Globe & Mail. Thursday, December 23, 1999). It was also noted that, since 1998 Olivieri has been "demoted, then restored, then harassed. She has been smeared with allegations attacking her competence, integrity, sanity and personality, ...".
Meanwhile, the Head of Apotex, Barry Sherman, was raising the stakes with some sweet philanthropic offerings ($20 million) to the University of Toronto, which is affiliated with the Hospital for Sick Children. In return, then University President, Robert Pritchard, lobbied the Government to extend the period of review of drug patent protection regulations.
The drug in question in the Olivieri affair was to be Apotex's first patented, non-generic drug, and it was potentially worth hundreds of millions (see Krista Foss & Nicola Luksic, Globe & Mail. September 16th 1999). When interviewed by Correspondent Leslie Stahl in 60 Minutes, Sherman referred to Olivieri as "nuts". When asked to delete the remark, Stahl replied: "Yeah, but you know, we're reporters. We're not your pals." (See also Krista Foss. Globe & Mail. 22nd December 1999).
However, some reporters still seem unaware of the depth of the problem. Margaret Wente in "Medicine, Morals and Money" (see above), referring to the Olivieri affair as "Canada's worst academic and research scandal in decades", gives the impression that otherwise all is well. Although, information in the area is difficult to obtain, it is the impression of the author of this web-page on the failings of the peer review system that the Olivieri scandal may be far from "Canada's worst". It may be the tip of a much more ominous iceberg, as hinted at by John LeCarre in the epilogue of The Constant Gardner. It is receiving public attention,
Whatever else one might say, Gideon Koren and Sergio Grinstein displayed remarkably bad judgement. Yet, they had been for many years, and probably still are, major participants in the peer review process in Canada and elsewhere. In 2001 Grinstein was still on the Editorial Board of the Journal of Experimental Medicine.
A further article by Karen Birmingham (2000. Nature Medicine 6, 609-610) summarized the 9 page Report of a panel investigating Gideon Koren, which was signed for the University of Toronto by the President, Robert Prichard, and for the Hospital for Sick Children by its CEO, Michael Strofolino:
The President of the University of Toronto Faculty Association commented:
Sergio Grinstein may have faired even better. The Hospital investigated his conduct as "an internal matter." A spokesperson says "the Hospital has investigated Grinstein's conduct and taken the appropriate action."
Although the possible penalties have been mitigated by "Koren's hitherto unblemished career record," the Report notes that "specific allegations of alleged research misconduct remain outstanding" and have been referred to the Dean of the Faculty of Medicine. There is also an "open verdict" on allegations that Koren submitted false evidence. The case is still open also on the possibility that certain letters, dated 18th December 1996 and 8th February 1997, were actually prepared at a later date to buttress Koren's submission to the Naimark inquiry (see below) and to discredit Olivieri.
A "International Safety Committee" consisting of 9 scientists coordinated by Dr. George Sweeney (McMaster University) and "all receiving support from Apotex," "found no evidence" that oral Deferiprone "increased liver fibrosis" (K. Foss Globe & Mail 25th November 2000).
When asked by the reporter for her opinion, Olivieri pointed to defects in the study. This prompted an attack by Dr. S. Macleod (McMaster University)on Dr. Olivieri's integrity (28th November; letter to Globe & Mail).
Dr. Brill-Edwards promptly replied: "Dr. Sweeney touted the study as vindicating the drug. The Globe, doing its job, sought and received Dr. Olivieri's response. In meeting her public obligation to respond, Dr. Olivieri pointed to a potential fatal flaw in the claimed victory. The study results that purport vindication account for only a small fraction of the patients studied."
Olivieri was not unscathed materially. In June 2001 Nature Medicine (7, 644) reported that "Olivieri's lab was closed down in 1998 and the administration has not provided her with new space." The University of Toronto Faculty Association President noted in an open letter that: "UTFA alleges that the University failed utterly in its duty to act to protect Dr. Olivieri, her academic freedom, the academic freedom of all of us and the fundamental rights of the public which we in the University have the duty to uphold."
However, Nature Medicine reports that: "the Hospital for Sick Children ... has refused to allow the grievance panel to access relevant documents." Happily, "Olivieri was selected ... as a recipient of the 2001 award by the Civil Justice Foundation in Washington," which noted:
For more on this, please go to the web-site of the University of British Columbia's Centre for Health Services and Policy Research and download Tales from the Other Drug Wars (Click Here), which includes a fine article by Michele Brill-Edwards entitled "Canada's Health Protection Branch: Whose Health, What Protection?"
Or, on a lighter note, read John Le Carré's novel The Constant Gardener. The author's note at the end states:
On June 4th 2003, Gay Abbate
reported in the Toronto Globe and Mail
Whether or not, down the line it is shown that deferiprone is safer than supposed, is irrelevant to many of the issues raised by the Olivieri affair. In 2005 Random House published Miriam Shuchman's book The Drug Trial: Nancy Olivieri and the Science Scandal that Rocked the Hospital for Sick Children. This was reviewed by D. J. Weatherall in The Lancet (vol. 366, 455-456). Declaring "no conflict of interest," A. V. Hoffbrand responded (vol. 366, 1432-1433):
Donald Forsdyke October 2005
Donald Forsdyke, March 2006
Donald Forsdyke May 2015
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This page was established circa 1999 and was last edited 11 May 2015 by Donald Forsdyke