Friday, February 9, 2007

The Olivieri Case: She Said, They Said...

The worst nightmare of an author is that the day your book comes out, the news headlines proclaim that a basic fact, on which your book is based, has just been conclusively disproven. Fortunately this has not happened to me regarding HOOKED, but perhaps the nearest approach relates to my portrayal of the case of Dr. Nancy Olivieri of Toronto (Chapter 6, pp. 98-103).

The fly in the ointment is a newer book, by Dr. Miriam Shuchman, that tells a very different story from the accounts of the case that I relied on. I became aware of Shuchman's book only as HOOKED was going through its final round of revisions. I was able to get a footnote inserted at least to acknowledge the existence of the Shuchman book (note 2, pp. 113-14). But I had insufficient time to read and study the Shuchman volume. If I had had the time, I would probably have altered what I said about the Olivieri case.

The case, as it is generally known, is a compelling story of how the rapacious drug industry nearly ruins the career of an honest scientist who discovers a new, dangerous side effect to a potentially lucrative drug. It was so compelling that John Le Carre adapted it for his novel, The Constant Gardener. And the case appears to be impeccably documented--we have the 500-page, thoroughly referenced volume, The Olivieri Report, from the Canadian Association of University Teachers investigative team.

Shuchman, by contrast, tells quite a different story. How about: "Ambitious, vindictive scientist unfairly trashes the reputation of a good drug for a rare disease"? Dr. Olivieri comes across as a much more flawed and problematic character in the Shuchman account--one who, in all likelihood, brought a lot of her problems down around her own head. More important, according to Shuchman, are the scientific facts about the drug deferiprone (L1), used to prevent iron buildup in patients with the rare, inherited anemia, thalassemia major. Olivieri and her sympathizers, Shuchman says, have managed to persuade most US and Canadian physicians not to use the drug. But it has been widely used in Europe and elsewhere, and to date, its track record has been pretty good--far from the huge risk to patients' lives that Olivieri's research claimed it to be.

Dr. Olivieri's response to this so far has been a letter to CMAJ, the Canadian medical association journal (Olivieri N. A response from Dr. Nancy Olivieri [letter]. CMAJ 174(5):661-62, 2006). The letter is not terribly helpful; it is mostly an ad hominem attack against Shuchman, claiming that since her husband was associated with some of Olivieri's enemies, that proves that her account is flawed.

At this stage I am pessimistic that we will ever know the truth about this case. The people in a position to tell investigators what really happened and when, have divided themselves into pro- and anti-Olivieri camps; and depending on which side any new investigator appears to be on, one group will talk with her and the other will refuse to be interviewed. My tentative conclusion is that while the CAUT report is very well documented and persuasive on its face, any account of the Olivieri case based on that report will have to have an asterisk next to it, like the home run record of a baseball slugger accused of taking steroids.

Shuchman M. The drug trial: Nancy Olivieri and the science scandal that rocked the Hospital for Sick Children. Toronto: Random House Canada, 2005.

Thompson J, Baird P, Downie J. The Oliviert report: the complete text of the report of the independent inquiry commissioned by the Canadian Association of University Teachers. Toronto: John Lorimer and Company, 2001.

5 comments:

arthur said...

Professor Howard Brody is too pessimistic about our ability to assess Shuchman's book. There is ample evidence on the public record. See my review of Shuchman's book (below), published in the latest number of the journal Bioethics.
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Commentary: Science Scandal or Ethics Scandal? Olivieri Redux


A Schafer


Nancy Olivieri is famous for refusing to suppress doubts about an experimental drug with which she was treating thalassemia patients. Her principled stand, and the resulting scandal, led universities to offer researchers some protection against illegitimate drug company pressure. Medical journals changed their publication rules. Research hospitals changed their policies. She became an international icon.

By contrast, Apotex, the drug company which tried to silence her, has attracted international opprobrium. The company repeatedly threatened to sue Olivieri if she publicly revealed her fears about the inadequacy of their drug, deferiprone, and later it publicly questioned her sanity. She sued them for libeling her; they sued her for “slander of goods [their drug]”. The actions have not yet gone to trial.

Apotex claims still to believe in the virtue of deferiprone, but the company has been heavily criticized for conduct which many interpreted as placing profits ahead of patient safety. Apotex is not alone in the dock of public opinion. Every month seems to bring some new scandal involving drug company suppression of negative data: think Prozac (Eli Lilly) , Paxil (GlaxoSmithKline) and Celebrex (Pfizer) . Big Pharma is facing a crisis. Public trust in drug company sponsored research is plummeting.

Olivieri’s hospital, The Hospital for Sick Children, and her university, the University of Toronto, have also taken a public drubbing for failing to provide her with effective support as she struggled with Apotex. Actually, not only was Olivieri denied effective support, she was fired from her position as the director of the Hospital’s hemoglobinopathy programme, and both she and those colleagues brave enough to support her experienced harassment of many kinds. In the words of the CAUT Report: “Neither HSC nor the University …took effective action to defend principles of research ethics, clinical ethics and academic freedom.” When it was discovered that the university was negotiating with Apotex for a huge financial donation, well, some people drew their own conclusions, and these were not flattering to the university.

Miriam Shuchman’s recently published book The Drug Trial is the fourth book to be published on the Olivieri affair and the most troubling. The first was commissioned by the Hospital. It singled out Olivieri for special criticism but was later shown by two independent inquiries to be based upon misinformation. Next, the Canadian Association of University Teachers (CAUT) commissioned a report from three eminent academics. Their extensively documented book exonerates Olivieri, while sharply criticizing the conduct of Apotex, the U of T, and Sick Kids. Then spy novelist John le Carre joined the fray with a murder mystery, The Constant Gardener, casting an Olivieri-like character as heroic victim of drug company machinations.

Shuchman’s book, by contrast with the CAUT Report, pays little attention to the central moral issues of academic freedom and drug company censorship. She concedes that Olivieri was right to go public with her data and that Apotex was wrong to threaten her. Shuchman’s focus, however, is on Olivieri herself, as researcher, physician and person. The book attempts to demonstrate that Olivieri is a bad scientist, a bad doctor and a bad person to boot.

Shuchman, a psychiatrist and medical journalist, goes to great lengths to discredit Olivieri, portraying her as a scientist who is blind to the truth about the drug she once favoured but now criticizes. As Shuchman tells the story, the real scandal is not that a wealthy drug company attempted to suppress negative data but that Olivieri’s scientific doubts about deferiprone are not well-founded. Because of Olivieri’s allegedly irrational opposition to deferiprone and because Olivieri purportedly exercises near-mythical powers over drug licensing authorities in the United States and Canada, she is blamed for having prevented patients from gaining access to this “life-saving” drug.

In effect, Shuchman accuses Olivieri of personal responsibility for the deaths of many thalassemia patients, deaths which allegedly could have been avoided if Olivieri had not denied them access to deferiprone. Perhaps Shuchman is unaware that thousands of requests for unlicensed drugs are granted annually in Canada and the USA and that patients are not being denied access to deferiprone if they seek it.

Relying on quotations from anonymous sources, Shuchman also manages to portray Olivieri as a doctor who is so busy doing medical research and accepting humanitarian awards that she neglects her patient care duties. In case these scientific and moral sins are not deemed sufficiently wicked to warrant banishment to Siberia, Olivieri is also, Shuchman reports, a person who swears frequently at hospital administrators, is tough on colleagues and much too demanding of subordinates.

The veritable cornucopia of discredit which Shuchman heaps on Nancy Olivieri is, I’m sorry to say, standard punishment for those who have the temerity to challenge powerful vested interests. In the popular imagination David bravely slays Goliath. Alas, in the real world, the whistle-blower’s issue of principle is easily re-described as an act of private disloyalty and, worse, as evidence of professional incompetence and psychological disturbance.

For every Erin Brockovitch, rewarded with fame and fortune (when Julia Roberts was cast by Hollywood to portray her brave struggle), there are a dozen other whistle-blowers consigned by employers and colleagues to professional oblivion. Typically, those who challenge authority find that their professional competence, personal lifestyle and mental stability are all brought into question. Most whistle-blowers are also labeled malcontents and publicity seekers, as Shuchman stigmatizes Olivieri. They are duly punished with demotion, suspension, and/or dismissal. The case of Dr. Aubrey Blumsohn, recently suspended from his job by Sheffield University after he blew the whistle on one of that University’s major research funders, Proctor and Gamble, fits the same pattern.
Few whistleblowers escape this fate. Olivieri certainly didn’t, though she fought back with admirable tenacity and won some notable victories over the company, the hospital and the university.

To persuade us that Olivieri got the science disastrously wrong, which is the main thesis of her book, Shuchman quotes a large number of Apotex-funded scientists, who claim that deferiprone is safe and effective. However, Shuchman omits to inform readers of her book that the published results upon which she relies have been criticized in the scientific literature, either because the efficacy test used had not been validated, or because the investigators did not report all of their data pertaining to efficacy and safety. Moreover, Olivieri is far from being the isolated Jeremiah of Shuchman’s portrait: The world’s leading researchers on genetic blood disorders, David Nathan, former President of the Dana Farber Cancer Institute at Harvard and David Weatherall, Regius Professor of Medicine Emeritus at Oxford, both think that Olivieri got the science right. That is, both agree with Olivieri that convincing evidence does not yet exist for the safety and efficacy of deferiprone. Two subsequent studies , neither mentioned by Shuchman, have provided support for Olivieri’s published finding that patients being treated with deferiprone are at risk for progressive liver scarring.

Although desferol, the current standard treatment for thalassemia patients, requires uncomfortable nightly infusions (unlike deferiprone, which comes as a pill), desferol is both safe and effective. The course of prudence would, therefore, seem to be in the direction favoured by Drs. Nathan, Weatherall and Olivieri. Nathan and Weatherall also agree with Olivieri that it would be imprudent to license deferiprone until better evidence is available. Thus, the reluctance of licensing authorities to give approval to deferiprone would seem to be based upon legitimate scientific concerns rather than, as Shuchman suggests, the malign power of Nancy Olivieri. Indeed the European licensing authority restricts use of deferiprone to “exceptional circumstances” because, to date, “comprehensive information on the safety and efficacy of the medicinal product cannot be provided”. The licensing authorities in the United States and Canada have not issued even a restricted license for deferiprone.

Since the liver scarring associated with deferiprone is a gradual process, we may not know for years which side of this scientific controversy is correct. Because Apotex cancelled (on 24th May, 1996) the pivotal randomized comparison clinical trial which could have provided the long term data necessary to resolve the scientific dispute – a trial for which Nancy Olivieri was Principal Investigator – the risk-benefit ratio of this drug remains uncertain.

One of the many relevant features of the controversy not reported by Shuchman is that Apotex tried to discredit not only Dr. Olivieri, but also the monitoring procedure, liver biopsy, essential for assessing the efficacy and safety of iron chelation therapy. It was in data derived from this procedure, established in the medical literature and an integral part of the trial protocols (designed by Olivieri, approved by the hospital’s Research Ethics Board and agreed to by Apotex), that the unexpected risks of deferiprone were identified.

To fill out her story, Shuchman compiles a lengthy charge sheet against Olivieri. The most serious accusation is that Olivieri negligently delayed the implementation (at Sick Kids Hospital) of proper guidelines for the treatment of sickle cell patients. Shuchman claims that this delay led directly to the death of a young patient, Sanchia Bulgin. Shuchman is unmoved by the fact that Olivieri was not one of the physicians treating this patient, and that the responsible physicians were found (by two official inquiries) to have violated established guidelines which had been in place for years. It’s a bizarre accusation.

Many of Shuchman’s other allegations of ethical misconduct, directed against Olivieri, rely on the testimony of Olivieri’s leading foe at Sick Kids, Dr. Gideon Koren. Koren, then a senior scientist and scientific administrator at the Hospital, has been found guilty of and severely disciplined for both professional and research misconduct, first by the hospital and the university, and later by the Ontario medical licensing body. The hospital and the university found that his actions, including persistent “lying” in connection with his efforts to discredit Dr. Olivieri, “constitute gross misconduct and provide sufficient grounds for dismissal.”

The CAUT Report found that Dr. Koren “attempted to discredit Dr. Olivieri by dishonest means”. In the words of the Discipline Committee of the College of Physicians and Surgeons of Ontario, Dr. Koren was guilty of “conduct unbecoming a physician”. “His actions were childish, vindictive and dishonest”, authoring “vicious diatribes” contained in anonymous “poison pen letters” against Dr. Olivieri. Koren was stripped by the University of his Endowed Chair, required to arrange that his ethically suspect research be deleted from the scientific record, publicly reprimanded by the licensing body, and required to pay substantial fines by the hospital, the university and the licensing body.

Shuchman has great admiration for Koren and devotes almost a full chapter of her book to trivializing his misconduct and praising his stellar virtues and research accomplishments. Unfortunately, she omits to inform her readers of the full extent of Dr. Koren’s publicly reported misconduct. Shuchman doesn’t admire Olivieri and so, in sharp contrast, spends many pages describing the serious charges of unprofessional conduct which the Hospital made against her, charges that were based on allegations by Koren and persons closely associated with him. Then, almost sotto voce, Shuchman briefly acknowledges that the Ontario College of Physicians and other independent bodies investigated the matter and cleared Olivieri of all the charges brought against her. Indeed, the College found that Olivieri had acted in the best interests of her patients and commended her for “exemplary conduct”.

The heavily biased manner in which Shuchman assembles her material seriously undermines The Drug Trial’s credibility. Credibility is an especially important issue when evaluating the claims made in this book, because most of the hostile quotations are attributed to doctors and patients who are not identified. One of the few clearly identified patients, “Howard”, has now gone on record as saying that his words, as quoted in the book, were twisted beyond recognition. He insists that, so far from being critical of Olivieri’s patient care or ethics, he considers Dr. Olivieri to be a highly ethical doctor who is utterly dedicated to her patients. A brief excerpt from Howard’s letter of protest to Shuchman, which has now been made public, raises deep ethical concerns about the integrity of Shuchman’s journalism: "Dear Miriam: You've used a smoke-and-mirrors approach to spinning my statements to inaccurately portray Nancy by misquoting me, attributing quotes to me that I didn't make, omitting portions of my comments that would alter the effect and taking these comments out of context."

My confidence in Shuchman’s journalistic reliability, already shaken by numerous factual errors and skewed descriptions of key events was further eroded when I came across a passage in which she “quotes” from a commentary I published in The Globe and Mail. I wrote none of the words she attributes to me.

Reading The Drug Trial I was repeatedly struck by how often Shuchman’s account of events is contradicted by the findings of a series of independent inquiries – all public documents, all easily obtainable. Almost all of the anti-Olivieri “revelations” presented in Shuchman’s book are warmed-over versions of allegations already disproven by one or more of these impartial inquiries, and the others are undocumented hearsay. In short, Shuchman’s way with well-established facts would have brought a smile to the face of Procrustes.

In the end, what really matters is that once Dr. Olivieri scientifically identified deferiprone’s unexpected risks, she was ethically obliged to inform her research subjects, who were also her patients. Every research subject has a fundamental right to give or withhold informed consent to participation in a clinical trial. If information about potential risks is deliberately withheld then the right of informed consent becomes hollow. Put quite simply: patient safety is a value which trumps all others. Olivieri fulfilled her duty to warn her patients of possible risks. She did so in the face of company threats and hospital harassment. For this she is rightly honoured. Her hospital and university saw the battle as a mere “scientific dispute”. In consequence, they failed in their obligation to defend her academic freedom and her patients’ right to informed consent. They just didn’t get it. Shuchman still doesn’t.

Disclosure: The author has not received funds from any party to this dispute. He has appeared at three press conferences with Nancy Olivieri, at which his (unpaid) role was to analyse and evaluate the ethical issues raised by her dispute with Apotex, the Hospital for Sick Children, and the University of Toronto.

Arthur Schafer is Professor of Philosophy at the University of Manitoba and Director of the Centre for Professional and Applied Ethics. His article on the affair, “Biomedical conflicts of interest”, was published in 2004 by The Journal of Medical Ethics.

arthur said...

For some reason the citations and footnotes did not appear with the Commentary I just posted. Please see the journal Bioethics for these or write to me and I will send the complete article to you, with supporting citations.
schafer@cc.umanitoba.ca

Howard Brody said...

I'm pleased that Professor Schafer weighed in with his views on the Olivieri dispute. Readers of HOOKED will recognize Prof. Schafer's significant contributions to the ethical analysis I presented there, based on his earlier paper, "Biomedical Conflicts of Interest...", Journal of Medical Ethics 30:8-24, 2004. What Prof. Schafer calls the "Sequestration Thesis" in that paper was the principal source of the position that I label, in HOOKED, the "Divestment Strategy," calling for medicine to separate itself financially from the pharmaceutical industry to the greatest extent possible (HOOKED, Ch. 16).

MBP said...

the complete CAUT report on the Olivieri affair (527 pages) can be downloaded from:

http://www.caut.ca/uploads/OlivieriInquiryReport.pdf

and the supplemental report is available there as well (27 pages):

http://www.caut.ca/uploads/SupplementtoInqReport.pdf

There is an additional report somewhere of the Royal College of Surgeons findings that Dr. koren was guilty of Conduct unbecoming a doctor. It was orginally argued that the suspension and fines levied against Dr. Koren were punishment enough, but the RCPS eventually determined that he should not escape the reprimand that every other doctor in his position would have received.

Anonymous said...

Thank you, Prof. Brody, for addressing your oversight. Let us not ignore the existence of false whistle-blowing, even when based on honest error. We may never know Dr. Olivieri's motivations at every turn. We do see here, however, in these responses to your above comments, the level of energy invested in public relations, sustained by her "camp" over the past ten years possibly at the expense of children in Canada and the United States who might have benefited from the drug.