Academic freedom, scientific integrity, and conflicts of interest: Lessons learned from the University of Toronto

To steal a memorable line up front: “Accounts of the Olivieri-Apotex-Sick Kids Hospital- University of Toronto controversy have multiplied and divided to the point where they would now over-fill the shelves of a reasonably sized library.” (1) But in the many contradictory accounts of this saga, none disagree about one point: that my colleagues and I, over these ten years, have opposed very influential forces. Those forces included: a powerful drug company; two successive Presidents and two successive Deans of Medicine (one of whom is now University of Toronto’s President) at Canada’s largest university; and the Boards and Administrations of a formerly highly prestigious children’s hospital.

Readers of Hypothesis might be forgiven for knowing nothing of the above controversy. Many were in high school when it was being fought — in boardrooms of beleaguered administrators at the University of Toronto and Hospital for Sick Children; on the front pages of national newspapers. The issues surrounding the saga, referred to as “the greatest academic scandal of our time,” rapidly reached international attention despite (arguably, aggravated by) efforts by local bureaucrats to claim all had been quickly resolved (2). By contrast, knowledgeable academics (1, 3-12) appreciated that the inappropriate influences of the pharmaceutical industry on the university community are pervasive, and that mere “mov[ing] on” (2) was a highly inadvisable strategy.

The story raised overdue questions about how biomedical research is funded, and about the duty of individual scientists to protect the core values of research integrity, academic freedom and (in the case of clinical research) patient safety. Surely few scientists — probably fewer citizens — would deny that a duty to defend these core values, and to resist inappropriate influences which may distort or imperil them, falls to those in the university community. But in practice, defending these values often means challenging the hierarchy of a university whose administrators perceive a necessity to rely on large donations from the corporate world. In the space provided, I have room only to offer some brief advice “from the trenches” – a far-from- comprehensive primer on what to expect if one commits actively to a defense of the principles of research ethics and academic freedom.

The heart of the controversy

  1. In 1995, I came to believe, based on scientifically credible preliminary evidence, that the drug administered in a clinical trial I had supervised since 1989, might cause harm to some patients. The trial had, from its onset, been publicly supported by the Medical Research Council of Canada. Later, additional support was provided by a drug company. The drug was being tested in potentially fatally ill patients, some children, for whom another safe licensed drug was and is available.
  2. Because “the life and health of the patient must be (a physician’s) first consideration” I was duty-bound to disclose my concerns about this experimental drug (8).
  3. In response to my signal that I wished to disclose these concerns, the sponsoring drug company threatened “all legal remedies” should I do so, and abruptly terminated the clinical trials. Those legal warnings were issued on the basis of a “confidentiality” clause in the research contract (co-signed by the Hospital for Sick Children’s Associate Director of Research, three years previously). The Medical Research Council, which was continuing to support the trials, issued no comment on their premature termination.
  4. I fulfilled my ethical obligations, despite the legal warnings.
  5. The Hospital for Sick Children and the University of Toronto “did not provide effective support either for my rights, or for the principles of research and clinical ethics, and of academic freedom, during the first two and a half years of this controversy. After the controversy became public in 1998, the University stated publicly that it had provided effective support for my academic freedom, but this was not true.” (3)

Instead, both the University and Hospital “took actions that were harmful to [my] interests and professional reputation, and disrupted [my] work” (3). The institutions’ administrators attempted to characterize the conflict as a “scientific dispute,” to be resolved primarily between the parties themselves. Then, it was discovered that the University of Toronto was negotiating a twenty million dollar donation from the drug company in question, with additional millions promised for the University’s affiliated hospitals. As a result, “some were led to speculate that the University’s failure to recognize and support [my] academic freedom might not have been unconnected to its eagerness to secure financial support for its proposed Molecular Medicine Building project”(1). When it was then revealed that the University’s president Robert Pritchard had lobbied the Government of Canada (through a private letter to the Prime Minister) on behalf of the same drug company, “the lengths to which the University was prepared to go in appeasing a company’s interests were…revealed” (1).

What to expect
If one takes on a battle like this it is probably best to anticipate that one’s job is in jeopardy; indeed, it is a rare person in such situations who is not fired. In my case, I was dismissed repeatedly from (and once I invoked legal defenses, repeatedly restored to) my position as Director of the Hemoglobinopathy Program at Sick Kids’ Hospital. (The Hospital denied strenuously that these repeated “firings” were in any way related to the controversy). Financial pressures will also serve to discourage those who would take on such a battle. The estimates of my colleagues’ and my legal and other expenses arising from this matter easily exceeded a million dollars. I was required to defend against threats of legal action and an expensive “countersuit” from the drug company, after I issued libel proceedings for public defamation. However, the most unexpected source of legal action against my colleagues and me arrived in a lawsuit from the Deans of Toronto’s Faculty of Medicine (Dr. David Naylor, Dean from 1999-2005; and Dr Arnold Aberman, Dean from 1992-1999) in 2002. The Deans sued us after the inadvertent posting, on the website of our organization Doctors for Research Integrity, of a Toronto Star article critical of them. While legal action is often the only available approach to a controversy, justice might be seen to be somewhat imbalanced if one side must seek their own funding to defend a lawsuit brought by bureaucrats of powerful public institutions.

Financial ruin is not the only cost of such a battle. Almost as soon after this scandal reached the press, the Hospital for Sick Children financed the “Naimark Report” — which “took several hundred pages to document its claim that if anyone was at fault in this sorry tale, it was Dr. Nancy Olivieri” (1). By contrast, authors Arnold Naimark, Bartha Knoppers and Fred Lowy directed no criticism towards Sick Kids’ or the University for their effective failure to support my academic freedom (13). Although “significant parts of the testimony on which Naimark et al. based their findings were later shown to be incorrect, it took some time for the historical record to be authoritatively established. In the interim, because of the adverse findings of the Naimark Report, [I] was charged with “professional misconduct” and “research misconduct” and referred, amidst great publicity, first to the Medical Advisory Committee of [The Hospital for Sick Children], and subsequently to the College of Physicians and Surgeons of Ontario.” (1)

Research misconduct was not the only allegation. Damaging rumours also circulated of my alleged incompetence, dishonesty, unethical medical practices, and promiscuity. To this year, I remain the target of character assassination, with anonymity the primary strategy: a recent attack strings together several anonymous accusations from “unnamed” sources, long proven false by independent inquiries, and attacks my family, friends and supporters as well as my character, motivations and personality. In a review of this recent attack, it was observed that “… [this] apparent readiness to twist the truth in … attempt[s] to pillory Olivieri is troubling. [The essential destructiveness] of the inaccuracies and distortions … lies in the context of two ongoing political debates … the first debate relates to criticisms the pharmaceutical industry has recently faced for a number of long-standing practices. The second debate relates to increasing threats to the academic freedom of university-associated clinicians and researchers. [So [i]f Olivieri was biased and intransigent, then perhaps we are making too much of concerns about drug toxicity, and the industry’s suppressing and ignoring toxicity. If Olivieri is a harridan, self-serving and nasty, then perhaps the same is true of other clinician-scientists claiming their academic freedom is being violated. If that is the case, then our concern about the direction in which medical schools and their associated hospitals are drifting may be unwarranted.” (14).

The sources of other damaging accusations were also anonymous — at least temporarily. Anonymous hate mail sent to my colleagues and me in 1998-9 urged us to “stop poisoning the air and fabric” of “decent people” at Sick Kids’ and mocked the ethnic origins of one of us. The author, a prominent senior Sick Kids’ physician and chair of children’s research, was uncovered after months of denial during which he blamed others, through DNA left on a licked stamp (15). A second anonymous letter was also later traced to another senior scientist, recipient of the Pitblado Chair at Sick Kids’, through DNA on a stamp (16). This bizarre story appeared to engage the imagination of John le Carré in The Constant Gardener, which details – fictionally, of course — activities of some pharmaceutical companies (17). (Le Carre describes the sending of anonymous hate mail to a researcher at a Canadian university, urging her to stop “poisoning decent people’s lives.” Its author is identified through DNA on a licked stamp).

Returning to reality, after my referral by Sick Kids’ to the Ontario College of Physicians, the College exonerated me of all charges and found my conduct to have been “exemplary.” Dean Naylor then withdrew the charges against me of “research misconduct” – accusations he had accepted from the Sick Kids’ hate mailer. Unfortunately, the highly publicized referral to the College, “together with repeated attempts to dismiss me, forced [me] to endure years of public humiliation before the charges of unprofessional conduct were exposed as baseless.” (1) But the CPSO’s findings made it likely that Sick Kids and the University would move towards a settlement with my colleagues and me, reached in 2002, “six years after the conflict became a national and international cause célèbre” (1).

Lessons learned?
The lessons arising from this saga are important. Restrictive provisions in University-industry contracts represent a threat to academic freedom and to patient protection in clinical trials (3). But the University of Toronto is no longer an isolated example of what can go wrong in interactions between academia and industry.

In a 2005 survey of contracts between industry and academic institutions, 82% of institutions surveyed reported disputes during interactions with industry sponsors (18). Three or more disputes, and a “great pressure to compromise,” on contracts with industry were reported by 24% of institutions. Academic freedom appears to be losing in these disputes: 80% of institutions allowed the corporate sponsor (usually a drug company) to “own” all the data arising out of a clinical trial conducted at those institutions. Fifty percent of institutions allowed the corporate sponsor to alter the design of a study, including its primary endpoints, after an agreement was signed. An equal proportion of institutions, 50%, permit the drug company to write up the data for publication (but “allow” the academic investigators to “review” and “suggest” changes to the industry’s manuscripts). And secrecy clauses are still permitted in 41 to 66% (depending on the definition of secrecy) of institutions.

There is empirical evidence that such heavy involvement of industry in biomedical research may negatively influence scientific integrity (11). In one recent survey, 15% of respondents reported a willingness to “select, omit, or fabricate data to win a grant or publish a paper” (19). The design of industry trials may also be influenced by commercial pressures: in 98% of industry-sponsored research, the new drug being evaluated reflects favorably on an older comparator drug (20). Much of the data arising out of industry-sponsored trials — including findings adverse to commercial interests — remain unpublished. The results of 21% of clinical trials are not published; in 28% reportedly because “the results did not favor the new drug” (21). This may change as legal action against those who conceal data becomes more common (4).

Solutions?
The idea of an independent agency to conduct drug testing and other applied research has been advanced by many experts and deserves consideration (4-7). Under such an arrangement, drug companies would contribute revenues not tied to individual drugs in which they have a commercial interest, and truly independent researchers would be contracted to conduct the trials. The proposal that disclosure of conflict of interest in the case of individual scientists is any panacea should be rejected, and conflict of interest should be expressly forbidden.

The other lessons learned may, possibly, be inspirational to a new generation of scientists. This — “an ethical struggle of international proportion” – [called out] for someone “to take a principled stand in the face of serious wrong, in order to protect the interests of research participants and the integrity of the research process” (10). By contrast to the “deafening silence from the Canadian bioethics community” (10) (with the exception of Professor Schafer) four distinguished scientists, all then also at Sick Kids’ – Drs. Helen Chan, John Dick, Peter Durie and Brenda Gallie – risked their careers, health, and finances to defend the principles central to this controversy: research integrity, academic freedom, informed consent, and patient safety. These scientists’ ‘‘courage to take a stand in the face of serious wrong, and courage to persevere in the face of seemingly constant setbacks, weariness, difficulties and dangers” (22) can be described as truly heroic.

Summary
The principles at stake in this case – research integrity, academic freedom, informed consent, and patient safety – are often obscured by rhetoric, but (as written about a similar case, that of Dr. Kern at Brown University) the facts of this case, and its ethical implications “are so straightforward as to be almost uninteresting” (23). The stakes at play, the preservation and protection of the profitable relationship between the pharmaceutical industry and the academic medical community, are enormous. The industry’s influence in all spheres of academic research and drug development, from Deans of Medicine and University presidents (7) to individual scientists and doctors, from journal editors and “patient organizations” (many merely fronts for the pharmaceutical industry) to regulatory agencies, is not declining. This story can happen again.

References

1. Schafer A. Biomedical conflicts of interest: a defence of the sequestration thesis—learning from the cases of Nancy Olivieri and David Healy. The Olivieri Symposium. J Med Ethics 2004;30:8–24

2. Naylor CD. The deferiprone controversy: time to move on. CMAJ 2002; 166: 452-3

3. 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. Lorimer Press, 2001

4. Angell M. The Truth about the Drug Companies: How They Deceive Us, And What to do About It. Random House, 2004

5. Kassirer J. On The Take: How Medicine’s Complicity with Big Business Can Endanger Your Health. OUP, 2004

6. Krimsky S. Science in the Private Interest. Rowman and Littlefield, 2004

7. Washburn J. University Inc. Basic Books, 2005

8. Bok D. Universities in the Marketplace. Princeton University Press, 2003

9. Nathan DG, Weatherall DJ. Academic freedom in clinical research. N Engl J Med 2002; 347:1368–70.

10. Baylis F The Olivieri debacle: where were the heroes of bioethics? J Med Ethics 2004; 30: 44–9

11. Bodenheimer T. “Uneasy Alliance – Clinical Investigators and the Pharmaceutical Industry” N Engl J Med 2000;342:1539-44

12. Lewis et al “Dancing with the porcupine: rules for governing the university-industry relationship” CMAJ 2001; 165 (6) 783

13. Naimark A, Knoppers BM, Lowry FH. Clinical trials of L1 at The Hospital for Sick Children: a review of the facts and circumstances, released December 9, 1998

14. Guyatt G. Private attack, political weapon. Newsletter of the Medical Reform Group Issue 134. Volume 25, Number 2, Summer 2005 Pages 1-2

15. Bonetta L. Hate-mail author trapped by DNA Nature Med 2000; 6: 364

16. Birmingham K. Second Hospital for Sick Children researcher sends anonymous ‘Olivieri’ note. Nature Med 2000; 6 (5): 485

17. Le Carré J. The Constant Gardener. Penguin Press, 2001

18. Mello M et al. “Academic Medical Centers’ Standards for Clinical-Trial Agreements with Industry” N Engl J Med 2005; 352:2202-10

19. Evans S. “Research Misconduct: How Common Is It?” Proc R Coll Physicians Edinb 2000; 30: 9-12

20. Cho MK, Bero LA. “The Quality of Drug Studies Published in Symposium Proceedings” Ann Int Med 1996; 124:485.

21. Dickersin R. “The Existence of Publication Bias and Risk Factors for Its Occurrence” JAMA 1990; 263:1385-9

22. Baylis F. A profile of the health care ethics consultant. In: Baylis F (ed) The health care ethics consultant. Totowa, NJ: Humana Press 1994

23. Frumkin H. Right, wrong, and occupational health: lessons learned. International Journal of Occupational & Environmental Health 1998; 4(1):33-4

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