Introduction to the Olivieri Symposium As Chronic Fatigue, Failure to Thrive, Growth Deficiencies, Bone Deformities, a M Viens, J Savulescu and Eventually Death

INTRODUCTION 1

The Olivieri symposium haemoglobin. The abnormal haemoglo- J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from ...... bin that is produced cannot properly bind and release oxygen, and, if left untreated, can result in symptoms such Introduction to The Olivieri symposium as chronic fatigue, failure to thrive, growth deficiencies, bone deformities, A M Viens, J Savulescu and eventually death. Consequently, the primary goal of ...... treatment is to provide frequent blood Adrian Viens, Guest Editor of this Olivieri symposium, and Julian transfusions (approximately every three to six weeks) to maintain a normal Savulescu, the Editor of JME, set the scene for the symposium. haemoglobin level. As a result of the continuous blood transfusions, how- In failing...[her] when she needed in the Canadian and international news ever, there exists a progressive accumu- them most, it is now clear that some media, to changes in the governance of lation of iron in organs such as the members of the University’s Faculty public health, academic medicine, and liver, heart, and pituitary gland. Haemosiderosis, or iron overload, can of Medicine heard her muffled cries biomedical publication that have lead to hepatic fibrosis & cirrhosis,* of academic freedom from the back resulted, to the lives directly touched and altered forever, the Olivieri affair cardiomyopathy, endocrinopathies, and room, yet their response was to has had a number of wide reaching even death. serve another round of drinks and effects on a number of people. There is Thus, the secondary goal of treatment turn the music up louder. With the much to be learned from this case. is to remove the iron accumulation bombshell revelations in the...affair, Although there have been articles in using a chelator to bind to excess body the plug may have been pulled on the medical and bioethics literature iron and promote its excretion from the this business sponsored party, and discussing the Olivieri affair, this special body. For more information on the hopefully a sober re-examination of symposium represents the first sus- thalassaemias (thalassaemia major), the university’s neglected role and tained analysis of some of the central see the papers by DJ Weatherall NF responsibility toward independent ethical issues and lessons that can be Olivieri.56 inquiry and academic freedom can learned from such cases. It is hoped that Since the 1980s, Deferoxamine, also begin.1 this symposium will provide for those called DesferalH, has been the standard engaged with similar issues and cases of care to treat iron overload for patients These guys don’t get one thing— a fruitful and informative examina- with thalassaemia. Deferoxamine is we’re not going away. This isn’t a tion of professional ethics, research usually administered daily or on alter- personal vendetta. This is something ethics, academic freedom, and related nate days by subcutaneous infusion I want patients to be protected from considerations. administered over 10 to 12 hours from when I’m dead, fifty years from The Olivieri affair has raised a number a small battery operated pump. now.2 of important normative questions con- The needle is usually injected in the cerning the substance and limits of abdomen, arm, or leg and is very [The Olivieri affair is] not a mystery particular theoretical commitments and uncomfortable and can leave needle novel, but instead the latest skuldug- how ethical judgments and norms are marks, skin irritation, and scar tissue. http://jme.bmj.com/ gery at Toronto’s Hospital for Sick implemented in practice. The issues As a result of the tedious and painful Children.1 surrounding the Olivieri case are not administration and issues of body novel. Unfortunately, issues of patient image, some patients (especially adoles- The legal assaults which you have safety, conflict of interest, and academic cents and teenagers) find it difficult to endured in your battle against the freedom continue to plague many areas comply with the demanding regime. drug company, and in your battle of biomedicine. The Olivieri affair has, Given this, there was significant against the medical establishment however, gripped the attention of phy- interest in finding an iron chelator that

appear to have been fought with the sicians, researchers, and bioethicists could be taken orally to improve com- on October 1, 2021 by guest. Protected copyright. type of uncommon bravery that is around the world as a prime example pliance. While Deferoxamine had sig- rarely seen. It is for this reason that of the limitations of ethics review at nificantly improved the prognosis of our trustees have unanimously cho- multiple levels. thalassaemic patients, the prospect of sen to recognise you for this most In the introduction to this sympo- finding an efficacious alternative ther- prestigious award.3 sium, we shall begin by very briefly apy for iron overload was seen as a very explaining the disease and therapy at [The Olivieri affair resulted from] a the centre of this case. We go on to ...... provide a timeline of the most salient fundamental misreading of the issue *In addition to the cirrhosis that is caused by as a mere contractual and scientific events in the Olivieri affair. We conclude iron loading in the liver, as a result of the dispute…[it is] Canada’s worst aca- by discussing the contributions to this frequent number of blood transfusions received, demic and research scandal in symposium and how they bear on the there were also a very large number of ethical issues surrounding this case. thalassaemic patients who were more suscep- decades…[Since 1998, Olivieri tible to contracting Hepatitis C from the tainted has been] demoted, then restored, blood supply back in the 1980s and 1990s then harassed. She has been I. THALASSAEMIA AND ITS (which causes liver damage). smeared with allegations attacking TREATMENT It can also be administered intravenously. her competence, integrity, sanity Thalassaemia major, also known as While intravenous administration avoids side effects such as skin irritation, it also has other and personality….4 Cooley’s anaemia or Mediterranean anaemia, is an inherited blood disorder side effects associated with it, such as infection or thrombosis of the catheter. Patients are he Olivieri affair is one of the most caused by a mutation in the beta chain generally advised to use subcutaneous admin- important events to occur in of the haemoglobin molecule that istration, and have intravenous administration Tresearch ethics. From its dominance results in the production of abnormal as a secondary option.

www.jmedethics.com 2 INTRODUCTION

welcome and promising improvement to N 1992 encountered. Apotex requests to J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from the quality of life of thalassaemic examine the data before consent N Olivieri begins working with Dr patients. forms are changed and the Hos- Brittenham.*** Noted haematologist and researcher pital for Sick Children (HSC) at the Hospital for Sick Children and N 1993 Research Ethics Board (REB) or professor of medicine at the University N Food and Drug Administration research ethics committee is noti- 9 of Toronto, Dr Nancy F Olivieri was a (FDA) informs Drs Olivieri and fied of findings (CPSO, p5); 7 natural choice to investigate the poten- Brittenham that completion of (Olivieri report, pp 125–33). tial safety and efficacy of a new oral iron three studies—LA-01,**** LA- N In September, Dr Olivieri submits chelator in thalassaemia. As head of the 02,***** LA-03` —would be neces- separate protocol to Apotex inves- large and productive Hemoglobinopathy sary before commercial licensing tigating patients excluded from Research Program, Dr Olivieri (and of L1 could occur. LA-03 trial to observe loss of colleagues) had the research experience sustained efficacy in L1. Dr Drs Olivieri and Koren sign and expertise, and patient population, to N Olivieri also informs Apotex of contract with Apotex for LA-01 conduct such important research. her obligation to communicate trial (approximately 50% spon- her findings of reduced efficacy to sored by MRC, 50% sponsored by HSC REB. (CPSO,9 p 6); (Olivieri II. TIMELINE OF EVENTS Apotex). In the construction of this timeline report,7 11 entitled ‘‘Progress of the primarily three documents were used: N 1994 Toronto trials [LA–01 and LA–03]’’ (i) the Canadian Association of and ‘‘Concerns arising in 1995’’). N Planning for LA-02 is commenced. University Teachers’ Report of the N In October, HSC REB requires a Committee of Inquiry on the Case Involving N 1995 revised protocol for LA-03 study in Dr Nancy Olivieri, the Hospital for Sick N Research contracts are tendered to order for study to continue. Apotex Children, the University of Toronto, and Drs Olivieri and Brittenham for agrees to study patients in which Apotex Inc, hereafter referred to as the LA-02 trial. Contained within the response to L1 was suboptimal, but Olivieri Report; (ii) the report by Arnold contract is a confidentiality provi- continues to refuse to agree to Naimark, Bartha M Knoppers, and sion in which all information con- inform the REB of suboptimal Frederick H Lowy, Clinical Trials of L1 9 cerning the trial is to be kept findings. (CPSO, p 6); (Olivieri (Deferiprone) at the Hospital of Sick 7 11 confidential for three years after report, entitled ‘‘Progress of the Children: a review of the facts and circum- the termination of the trial (unless Toronto trials [LA–01 and LA–03]’’ stances, hereafter referred to as the express written consent is given to and ‘‘Concerns arising in 1995’’). Naimark Report, and (iii) the report of do otherwise). the College of Physicians and Surgeons N February 1996 of Ontario, Report of the Complaints N In April 1995, Dr Olivieri et al publish a paper in the New N Drs Olivieri, Brittenham, and Committee [complainant: Dr Lawrence Koren meet with Apotex to review Becker, respondent: Dr Nancy Olivieri] England Journal of Medicine demonstrating a ‘‘favorable effect of data from long term trial. Upon December 19, 2001, hereafter referred to 10 7–9 deferiprone on iron balance’’. examination of data, Apotex does as CPSO. ** Events not directly refer- not agree with the loss of effec- enced are thought to be of a sufficiently N Around time of publication, Drs Olivieri and Brittenham become tiveness. Apotex restates that the public nature and/or uncontroversial as claim that L1 has lost effectiveness http://jme.bmj.com/ not to require direct referencing. concerned about some patients enrolled in the LA-03 trial who in some patients should not be N 1989 display undesirable hepatic iron relayed to HSC REB or trial sub- 9 concentrations. (CPSO,9 p5); jects (CPSO, p 6); (Naimark 8 1 N Dr Olivieri (and colleagues) begin (Oliveri report,7 pp 128–9). report, entitled ‘‘Scientific dis- to examine the effectiveness of an agreement about an unexpected N In July, Drs Olivieri and Britten- oral iron chelator, deferiprone finding’’). ham request permission to estab-

(L1), in the treatment of thalasse- on October 1, 2021 by guest. Protected copyright. lish a separate trial protocol for N March 1996 mia. Research grant by Medical patients in whom L1 appears to be Research Council of Canada functioning suboptimally. Within N Dr Olivieri submits research find- (MRC) allows for L1 to be synthe- this request, it is noted that mod- ings on LA-03 cohort to HSC REB. sised in capsule form (CPSO,9 ification of patient consent forms Findings maintain that a signifi- p 3); (Olivieri Report,7 pp 104–5). would be necessary to advise cant proportion of the subjects have liver iron concentrations N 1991 patients of the negative results above clinically desirable levels N MRC renews grant for an addi- ...... and Dr Olivieri suggests that tional year (1992–3), but turns further study and observation of down Dr Olivieri’s application for ***Dr Gary Brittenham, hepatologist at Case these patients is needed to evalu- Western Reserve University, and one of funding of short term randomised Olivieri’s coinvestigators. ate the balance between risk and controlled trial to test clinical ****Prospective randomised controlled trial to effectiveness of L1. MRC suggests compare effectiveness and safety of L1 to DFO ...... that Dr Olivieri seek an industry (approximately 65 patients in Toronto and In order to assess and monitor iron loading, partner for funding of the clinical Montreal). thalassaemia major (TM) patients were trial. *****Safety study to assess particular risks required to undergo regular liver biopsies to associated with L1 (approximately 200 patients obtain tissue to assess liver histology and to be ...... in Canada, Italy, and the United States). tested to provide a hepatic iron concentration ` **The report by the College of Physicians and Continuation of the compassionate use long as a mean of evaluating total body iron stores. Surgeons of Ontario is on file with the author. It term study of L1 (approximately 25 patients). Hepatic histology and iron concentration pro- is also available on the website address given in Dr Gideon Koren, clinical pharmacologist, vide the best assessment of the safety and reference 9. HSC, and one of Olivieri’s coinvestigators efficacy of iron chelation therapy.

www.jmedethics.com INTRODUCTION 3

9 benefit associated with L1 (CPSO, Dr Olivieri giving her notice of N August 1996 J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from p 6); (Olivieri report,7 1 entitled termination of the consulting N Apotex informs Drs Olivieri and ‘‘Identification of the first risk’’). contract between her and Apotex Koren that in the process of closing for services related to the LA-02 N Apotex submits documents to the out subjects enrolled in the trial, trial. Letter also refers to the non- HSC REB representing their inter- the study drug returned by patients disclosure clause in her contact pretation of the data from LA-03 appears to be improperly issued. and threatened legal action for cohort. Dr Zlotkin****** responds Apotex informs Drs Olivieri and breaking that agreement (CPSO,9 to Apotex informing them that the Koren that such an action con- REB does not act as an intermedi- p 7); (Olivieri report,7 11 entitled stitutes a serious violation of the ary between researchers and spon- ‘‘Ongoing legal warnings’’ and ‘‘Trial ‘‘standard of good clinical prac- sors and directs Apotex to direct terminations and legal warnings’’). tice’’ (Naimark report,8 1 entitled further communications to Dr N Drs Olivieri and Koren contact the ‘‘Consequences of non-renewal of Olivieri for resolution of disagree- Canadian Medical Protection Apotex sponsorship’’). ments. (CPSO,9 p 7); (Olivieri Branch concerning Apotex’s legal report,7 1 entitled ‘‘Identification pressures. Dr Olivieri follows N Apotex informs Drs Olivieri and of the first risk’’); (Naimark Canadian Medical Protection Koren that information was report,8 1 entitled ‘‘Report to the Branch advice to inform Apotex incomplete or missing from data Research Ethics Board’’). of material she intends to disclose and records of the trial. Dr Olivieri replies to Apotex attributing pro- N April 1996 or publish (so that Apotex could exercise legal proceedings to block blemswithdrugreturnand N HSC REB directs Dr Olivieri to such disclosure/publication if they records to Apotex’s ‘‘abrupt’’ ter- amend patient information and so desire). mination of trials. consent forms to reflect findings N Drs Aberman, Olivieri, Britten- of decreased sustained efficacy of N June 1996 ham, and Apotex meet with a L1, and to inform other physicians N Dr Olivieri contacts Dr Aberman representative of the Health involved with patients receiving L1 (Dean, Faculty of Medicine, Protection Branch. and the Department of Health and University of Toronto until 1999) N Dr Spino informs Dr Olivieri that Welfare (Canada). (CPSO,9 p 7); to mediate the conflict between Apotex does not agree with data (Olivieri report,7 1 ‘‘Identification Apotex and the investigators. At analysis and interpretation in abs- of the first risk’’). the meeting, Dr Olivieri requests tracts submitted to the American N Application for a clinical trial of L1 that L1 trial continue in order to Society for Hematology for their for sickle cell anaemia is submitted study the effectiveness/loss of annual meeting. Apotex denies con- to the National Institutes for effectiveness and to ensure that sent to submit abstracts. (Naimark Health (NIH). patients who were responding report,8 1 entitled ‘‘Consequences of non-renewal of Apotex sponsor- N May 1996 favourably could continue receiving L1. Apotex did not agree to ship’’). N Dr Olivieri submits revised patient continue the trial, but did agree information and consent forms for to the emergency release of L1, and N September 1996 LA-01 and LA-03 trials to the HSC that Dr Olivieri and Apotex would N Drs Olivieri and Brittenham are

REB and Apotex. When Dr Olivieri jointly contact the Health Protec- sent the report from Apotex’s http://jme.bmj.com/ attempts to inform patients of her tion Branch. panel. Both sides reaffirm their findings (by directive of the HSC original interpretation of data. REB chair), Apotex terminates N In a subsequent meeting with a both LA-01 and LA-03 trials senior executive at Apotex, Dr N National Institutes of Health (CPSO,9 p 7); (Olivieri report,7 Aberman asks Apotex to refrain approves clinical trial of L1 for 1 entitled ‘‘Trial terminations and from threatening legal action sickle cell anaemia. 9 legal warnings’’). against Dr Olivieri (CPSO, p 7); 8 1 N November 1996 (Naimark report, entitled on October 1, 2021 by guest. Protected copyright. N Apotex write to Drs Olivieri and ‘‘Involvement of the hospital and Koren to inform them that their N Dr Spino informs Dr Olivieri that university administrations’’). research sponsorship contract has as a result of breaching contractual expired and they would not be N July 1996 obligations she is no longer a renewing it. Moreover, Drs Olivieri N Dr Spino informs Drs Olivieri and member of the LA-02 Steering and Koren are told that all infor- Koren (and HSC REB) of the Committee (thus, not entitled to mation obtained during the trials findings of an expert panel con- access data or results without are to remain secret and confiden- vened by Apotex to review the data Apotex’s consent). Dr Olivieri tial unless Apotex provide a dis- at the centre of conflict. The panel responds that such action violates closure waiver—otherwise, failure did not agree with Dr Olivieri’s regulatory guidelines and pre- to do so would result in the pursuit conclusions about L1’s efficacy11 vious agreements made with all of vigorous legal remedies (CPSO,9 (CPSO,9 p 8). membersoftheLA-02SteeringCom- p 7); (Olivieri report,7 11 entitled mittee. Apotex disagrees (Naimark ‘‘Ongoing legal warnings’’ and ...... report,8 1 entitled ‘‘Consequences of ‘‘Trial terminations and legal non-renewal of Apotex sponsor- warnings’’). The Health Protection Branch has since ship’’). been renamed the Health Products and Food N Dr Spino, pharmacist and vice Branch of Health Canada. The Health Protection N December 1996 president at Apotex, Inc, writes to Branch was a branch of government responsible for managing risks and benefits related to N Dr Olivieri presents research find- ...... health. The new organisation is responsible for ings from LA-03 at the American ******Dr Stanley Zlotkin, chair, HSC REB (until managing risks and benefits related to health Society for Hematology conference July 1996). products and food. in Orlando, Florida.

www.jmedethics.com 4 INTRODUCTION

N Around this time, Dr Brittenham and informs them of the new N Winter 1997/8 J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from informs Dr Olivieri about potential evidence. Reports of liver toxicity N Apotex continues repeated com- liver toxicity associated with L1. Dr are made to HSC REB (CPSO,9 munication with HSC REB and Olivieri arranges to receive liver p 11). with Drs O’Brodovich and Koren biopsy reports in Orlando and to request data on patients who finds that some patients in the N National Institutes for Health received L1 on compassionate long term trial did have what inquiries are made concerning grounds (to meet the requirement appears to be an accelerated pro- ethics approval of L1 trial for of regulatory bodies). A question gression of fibrosis. Upon her sickle cell anaemia patients. Dr of whether Dr Olivieri was meeting return to Toronto, Dr Olivieri O’Brodovich withdraws support her obligations—that is, providing arranges for all biopsies from LA- of L1 trial for sickle cell patients 9 data, to regulatory bodies is raised 03 trial to be assembled and (CPSO, p 11). by Apotex. (Naimark report,8 analysed (with the help of N March 1997 1 entitled ‘‘Interaction between Dr Cameron ).(CPSO,9 p9); Apotex and the hospital’’) (Olivieri report,7 1 entitled ‘‘Iden- N All patients from HSC obtain up to tification of the second risk’’). date liver biopsies. N April 1998 N Dr Koren asks for liver toxicity N Apotex continues to attempt to per- N Dr Olivieri, under increasing work- data presented at the conference. suade administrators and patients load pressures, indicates to HSC Dr Koren was surprised by the in Toronto (and the wider scien- administration that she cannot toxicity findings of the drugs and tific and regulatory communities) continue in her position under was unhappy that he was being of L1 safety and efficacy. the prevailing conditions. Dr used as a ‘‘conduit’’ for L1 for Olivieri intends to communicate N April 1997 patients still receiving the drug on the need for a change in the emergency release. He informs Dr N Apotex offers to provide new treat- prevailing conditions. However, Olivieri that he will not continue ment arrangements for Toronto her letter is interpreted by HSC as collaborative and data interpreta- patients who did not want to go a resignation. Dr Olivieri maintains tion work with her. (Koren later back to using Deferoxamine (how- that this action by HSC was an publishes findings that L1 was ever, the use of liver biopsies instance of constructive dismissal. effective and safe on a re-analysis would not be part of the monitor- (Naimark report,8 1 entitled 8 1 of data). (Naimark report, entitled ing process). Olivieri rejects propo- ‘‘Interaction between Apotex and ‘‘The question of toxicity of L1) sal and continues to phase out use the hospital’’) of L1 (Olivieri report,7 1 entitled N February 1997 N May 1998 N Dr Olivieri receives completed ‘‘Trial close-outs and another stop- N Intensity of the events surround- assessment of liver histology from page in supply of L1’’). ing the L1 trials has substantially Dr Cameron. Dr Olivieri concludes N May 1997 increased and intensive media there is evidence of liver toxicity attention begins. and accelerated progression of N Dr Olivieri writes to HSC REB to liver fibrosis caused by L1. Dr confirm that L1 is no longer being N June 1998 Olivieri recommends to patients prescribed to patients (CPSO,9 Apotex continues to attempt to http://jme.bmj.com/ that they get new liver biopsies. N p 11). secure data and a review of that Dr Olivieri informs all clinical staff data conducted by Dr Aideen involved of evidence regarding N September 1997 Moore, Chair, HSC REB (after accelerated liver fibrosis and the N Dr Olivieri expresses concerns need to inform patients (which is July 1996) and Dr Brenda Gallie, about the conflict with Apotex ophthalmologist and cancer res- done soon afterwards at a meeting and Dean Aberman’s conduct with of patients). (CPSO,9 p 10). earcher, HSC.******* Drs Olivieri University of Toronto’s vice pre- and Brittenham maintain they N Dr Olivieri meets with patients to sident of research. Dr Olivieri also have no ethical or legal obligation on October 1, 2021 by guest. Protected copyright. inform them of the evidence for explores other intra-university to provide Apotex with any further liver toxicity she has found. complaint/dispute resolution ave- data (beyond what was already N Clinical trial protocol for L1 nues. Nothing comes of it—Dr given in 1997). (Naimark report,8 1 administration in sickle cell anae- Olivieri’s complaints are found by entitled ‘‘Interaction between mia patients is submitted to HSC the University of Toronto admin- Apotex and the hospital’’). REB. istration to be not specific enough N August 1998 N While some patients in LA-01 and to merit further action (Naimark LA-03 studies continue to receive report,8 1 entitled ‘‘The role of the N Dr Olivieri et al publish findings in L1, Dr Olivieri stops prescribing L1 university’’). the New England Journal of Medicine, to patients (Naimark report,8 detailing findings of liver toxicity N November 1997 1 entitled ‘‘The question of the in patients receiving L1.12 toxicity of L1). N Abstract published in Blood by Dr N Drs Olivieri and Gallie met with Dr N Dr Olivieri meets with Drs Olivieri et al. stating that ‘‘… L1 Aberman in an attempt to finally O’Brodovich and Freed- was discontinued in all patients resolve issues surrounding L1 man for briefing of facts because of safety concerns’’. (CPSO,9 p 12)...... Pathologist, Toronto General Hospital *******Dr Gallie was also head of the blood and (now part of the University Health Network)...... cancer research section where Dr Olivieri’s Dr Hugh O’Brodovich, Paediatrician in Dr Melvin Freedman, Head, Division of haemoglobinopathy research program was Chief, HSC. Haemotology/Oncology, HSC located.

www.jmedethics.com INTRODUCTION 5

trials. Among other requests, an announces that it is referring con- N Olivieri and supporters continue to J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from independent review of the events cerns over to the College of Physi- publish articles and letters challen- which transpired, and an end to cians and Surgeons of Ontario ging the validity or accuracy of her constructive dismissal are regarding Dr Olivieri’s clinical studies demonstrating efficacy of sought. practice involving L1 patients L1. (CPSO,9 p 2); (Olivieri report,7 N European Court of Justice rules N December 1998 1 entitled ‘‘The medical advisory that Olivieri cannot challenge the N The Naimark report is published, committee proceedings’’). European drug approval agency’s reviewing the events surrounding decision to allow sale of L1. To this N March 2001 the Olivieri affair. Panel finds that point, Dr Olivieri has spent HSC staff and executives did not N University of Toronto harmonises $300,000 of her own savings to 20 act improperly.8`` its research policies with its fight approval of L1. affiliated teaching hospitals, in We have attempted to present the N January 1999 order to make it more difficult most important events concerning the for researchers to enter into con- N Dr Olivieri fired/relieved of posi- Olivieri affair. We have, necessarily, had tracts without them first being tion as head of Hemoglobinopathy to leave out a number of details in the scrutinised for conflicts of interest.19 Research Program at HSC. A group interest of length and readability. Most of scientists supporting Dr Olivieri N October 2001 of the information was obtained from are instructed by HSC not to sources in the public domain and every discuss their concerns publicly. N The Olivieri report is published, effort was taken to provide accurate 7 13 (Olivieri report, pp 225–38) report conducted by the Canadian dates and an objective accounting of N Later in the month, an agreement Association of University Teachers events. Any errors or omissions are is reached in which Dr Olivieri’s reviewing the events surrounding entirely unintentional. position is restored, her right to the Olivieri affair. The association academic freedom affirmed, and finds that Dr Olivieri did not act she is promised financial support improperly and that the University III. ETHICS IN THEORY AND in case Apotex pursue legal action. of Toronto did not do enough to PRACTICE (Olivieri report,7 pp 265–70, 505–8) protect her academic freedom and The Hospital for Sick Children and the University of Toronto initially saw the help Olivieri after it had been dispute between Dr Olivieri and Apotex N 1999/2000 alleged that she was constructively as a scientific dispute best dealt with in dismissed.7``` N After the use of forensic evidence, the scientific arenas of peer reviewed it is found that Dr Koren was the N December 2001 conferences and journals. It soon became author of a number of anonymous clearly evident, however, that it was much N The College of Physicians and letters and emails disparaging Dr more than a scientific disagreement over Surgeons of Ontario dismisses Olivieri’s (and her supporters’) the interpretation of data. complaint against Dr Olivieri by professional and personal integ- There were a number of reasons why HSC.```` (CPSO,9 p 1) The college rity. The HSC and University of the Olivieri affair took the form it did. concludes: ‘‘Dr Olivieri ceased to Toronto discipline Dr Koren for Some of the failures in this case arose administer L1 in a timely and

gross misconduct; he receives a out of simple misjudgments and errors. http://jme.bmj.com/ suspension, a chair endowed in his expedient way, and in a manner Others arose out of ignorance of the name is removed, and he is which was in the best interest of 9 gravity of what was occurring or an ordered to make some restitution. her patients’’ (CPSO, p 16). absence of full information that pre- Dr Koren is also cautioned by the N 2002/3 vented appropriate action. Some, more complaints committee of the seriously, arose out of personality con- College of Physicians and Sur- N Dr Olivieri and colleagues reach flicts and political considerations. The geons of Ontario for his unprofes- settlement of dispute with HSC, contributions to this symposium seek to

sional conduct. Veracity of Dr University of Toronto (and its explore and elucidate the issues arising on October 1, 2021 by guest. Protected copyright. Koren’s previous allegations and faculty association). Canadian from the Olivieri affair. testimony subsequently called Association of University Teachers Arthur Schafer’s contribution to this into question—for example, by the to establish a task force to review symposium provides a detailed exam- Canadian Association of University policies governing the rights of ination of the issue and historical Teachers.14 15 16 research to publish their findings context of conflicts of interest in and conflict of interest (CAUT N European Agency for the Evalua- research sponsored by private enter- press release, ‘‘Task force to inves- tion of Medicinal Products app- prise. In addition to examining the case tigate academic freedom of medical roves the use of L1 in limited cases. of Dr Olivieri, he also examines another researchers and clinical teachers’’ Dr Olivieri later requests judicial case at the University of Toronto—the 13 June 2002). review through European court case of Dr David Healy. By examining (on the basis that Apotex mis- N Series of publications from Apotex both the Olivieri and Healy cases, represented data).17 18 sponsored researchers argue that Schafer elucidates the context and L1 is safe and effective treatment norms governing partnerships between universities and private enterprise in N April 2000 for thalassaemia. academic medicine. One issue that has N HSC (via its board of directors and been central to the Olivieri affair is the its medical advisory council) ...... relationship between Apotex and the ```Individuals interested in this case are University of Toronto. In addition to ...... encouraged to read the Oliveri report. sponsoring research at University of ``Individuals interested in this case are encour- ````The complaint was not by HSC itself, but by Toronto affiliated hospitals, Apotex aged to read the Naimark report. a member of its staff, Dr Laurence Becker. was a major contributor to the

www.jmedethics.com 6 INTRODUCTION

University of Toronto—at the time of reviewed by institutional review boards correspondence, and had her named J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from the Olivieri affair, Apotex was in dis- can help to protect research subjects and dragged through the mud—the costs of cussions with the University of Toronto ethical integrity. A large source of speaking out against the academic about a multimillion dollar donation.21 22 conflict in the Olivieri affair ultimately medical complex can be great. Few In order to be competitive in the stemmed from the contract Dr Olivieri would have such conviction. academic world, universities often signed with Apotex, especially from the In addition to the Olivieri affair, require such donations to fund their confidentially clause attached to the Rhodes and Strain examine whistle- research and teaching activities. contract. Clinical study agreements that blowing in academic medicine in a However, many are rightly concerned seek to protect patients’ and researchers’ number of other cases. They point to with how such relationships could affect interests, in addition to the sponsor’s the serious and unfortunately repetitive public institutions, such as universities interest, need to be primary considera- instances of institutions that fail to and hospitals, and especially about the tions when public institutions enter into support individuals and punish those possibility of conflict of interest. For contracts with private enterprise. who seek to blow the whistle. Rhodes instance, when it was found out that the Rosamond Rhodes and James Strain’s and Strain advocate for the need to president of the University of Toronto contribution to the symposium high- attend to the failures of institutional had lobbied the Prime Minister of Canada lights the failure of academic medicine ethics in academic medicine, and also on behalf of Apotex in 1999, there was a to identify and adequately respond to for the need to create an environment in majoroutcryandfurthertalkofdistrust unethical behaviour. Rhodes and Strain which individuals feel they can do what of close ties between public institutions maintain that it is the institutional they believe is right without the fear of and corporate interests.23 See also report design of academic medicine that sys- being persecuted or punished. Bolsin, number 317 of the governing council of tematically ignores serious ethical pro- Faunce, and Chan outline practical the University of Toronto.24 blems, regards whistleblowers as strategies to train, encourage, and sup- Schafer goes on to identify two enemies of the institution and punishes port professionals to follow their con- different strategies to prevent results them, and thereby fails to provide an science and, if necessary, criticise from being biased in corporate funded ethical environment. These issues are internal regulatory decisions and pro- clinical trials. The first is a regulatory taken up by Bolsin, Faunce, and Chan. cesses, in both clinical and academic approach that emphasises managing This is, by most accounts, the experi- medicine. potential risks governing industry spon- ence Dr Olivieri (and her core set of Francoise Baylis’s contribution to the sored research at public institutions. The supporters) had.````` symposium deals with a topic of para- mount importance, which unfortunately second approach advocates sequestering After not being supported in her effort receives little attention in the litera- industry from research sponsorship at to bring forward what she found to be ture—the ethics of bioethics. In addition universities and hospitals. Schafer criti- serious ethical problems—for example, to the validity of bioethics as field of cises the regulatory approach and the need to inform research subjects of academic inquiry, the legitimacy of advances a more radical approach, possible increased risk for liver damage bioethics is often tested in situations advocating the outright elimination of associated with the study drug, Dr like that of the Olivieri affair. In the close ties currently found in corpo- Olivieri found the need to pursue alter- addition to methodological questions rate sponsorship. native and more forceful avenues to concerning the practice of applied In another contribution to the sym- protect her patients. Arguably, the ethics, how bioethicists respond to such posium, Lorraine Ferris, Peter Singer, Hospital for Sick Children and the and David Naylor have provided an ethical failings as occurred in the

University of Toronto should have sup- http://jme.bmj.com/ examination of issues regarding the Olivieri affair can also affect the dis- ported Dr Olivieri more in this regard cipline. In a self critical analysis, Baylis ethics, independence, and integrity of and protected her ability to do what she clinical research at public institution contends that bioethicists need to reflect thought (and had sufficient warrant to about the meaning and value of their sponsored by for profit enterprises. believe) was required as a morally Ferris, Singer, and Naylor elucidate work. Using the Olivieri case as an responsible researcher. Not only did illustration, Baylis is very critical of the systemic policy reforms concerning she feel the need to violate her con- the academic industry interface in the the silence of the bioethics community fidentially agreement at great personal and the countless opportunities for Toronto academic health sciences com- on October 1, 2021 by guest. Protected copyright. and professional risk, but she also felt bioethical heroism that were never plex since the Olivieri affair, and how obliged to speak out against those who such reforms have sought to strengthen undertaken. did not support her, and became per- There are many lessons to be learnt the integrity and effectiveness of human ceived as an enemy of the institutions to subject research by making ethics a from the Olivieri affair. We hope this which she belonged. As Rhodes and symposium will begin a fair and pro- more central focus in the academic Strain point out, the environment for complex. The framework outlined here ductive examination of these which will whistleblowers is very confrontational lead to better ethical evaluation and will be of great interest to those involved and adversarial. Olivieri was allegedly regulation of research, not just in North in ethics governance. dismissed, sued, received harassing America but globally. Gordon DuVal’s contribution to the symposium provides a very concrete and ...... J Med Ethics 2004;30:1–7. ````` feasible option available to researchers The experience of researchers like Dr doi: 10.1136/jme.2003.006577 and research institutions to help protect Olivieri has even served as fodder for novelists. For instance, in John le Carre´’s recent novel, ...... human subjects and the independence The Constant Gardener, he writes: ‘‘As my of investigators. Academic research Authors’ affiliations journey through the pharmaceutical jungle A M Viens, St Anne’s College, University of institutions routinely enter into research progressed, I came to realise that, by compar- Oxford, Oxford, UK; ison with reality, my story was as tame as a agreements with sponsors that fail to [email protected] holiday postcard. … I drew on several cases, meet adequate ethical standards. DuVal J Savulescu, Department of Philosophy, describes the ethical issues at stake that particularly in the North American continent, where highly qualified medical researchers University of Oxford, Oxford, UK negatively affect research integrity and have dared to disagree with their pharmaceu- academic freedom and how properly tical paymasters and suffered vilification and Correspondence to: Julian Savulescu;, structured clinical studies agreements persecution for their pains’’. [email protected]

www.jmedethics.com INTRODUCTION 7

Tonelli C Adrian Viens was one of Dr Olivieri’s research 6 Olivieri NF. The betathalassemias. N Engl J Med 13 . Sick Kids fires Olivieri as director: J Med Ethics: first published as 10.1136/jme.2003.006577 on 10 February 2004. Downloaded from assistants in the summer of 1998 and 1999. 1999;341:99–109. coworkers defy ‘‘gag orders’’ to call for In addition, Viens and Olivieri collaborated on 7 Thompson J, Baird P, Downie J. The Olivieri retraction. The Varsity, 1999 Jan 11:1. 14 Anon. Editorial. Nature Med 2000;6:364. a journal article (along with six other report: the complete text of the report of the independent inquiry commissioned by the 15 Birmingham K. No dismissal for hate mail author. coauthors) concerning iron overload and iron Canadian Association of University Teachers. Nature Med 2000;6:609–10. chelating therapy in Haemoglobin E-b Toronto: James Lorimer and Co, 2001. http:// 16 Anon. College censured over Olivieri case: board thalassemia. This collaboration was not related www.dal.ca/committeeofinquiry (accessed 1 Sept orders disciplinary review of doctor who wrote to the L1 clinical trial (see: Olivieri NF, 2003). anonymous letters. National Post 2001 Nov 22. 17 Anon. Canadian doctors announce legal de Silva S, Premawardena A, et a. Iron 8 Naimark A, Knoppers BM, Lowy FH. Clinical trials of L1 (deferiprone) at the Hospital for Sick challenge of European Commission’s approval of overload and iron chelating therapy in hae- APOTEX drug deferiprone. Canada NewsWire b Children: a review of facts and circumstances, moglobin E- thalassemia. Journal of Pediatric 1998..http://www.sickkids.on.ca/L1trials/ 1999 Nov 18. Hematology/Oncology 2000;22:593–7). revcontents.asp (accessed 1 Sept 2003). 18 European court confirms worthiness of Olivieri’s challenge. Canada NewsWire 2000 Apr 7. 9 College of Physicians and Surgeons of Ontario. 19 Clarke A. Biggest stories of 2000–2001: Nancy Report of the Complaints Committee Olivieri. The Varsity 2001 Apr 16. REFERENCES [complainant: Dr Lawrence Becker, respondent: 20 McIlroy A. Toronto doctor loses round in drug Dr Nancy Olivieri]. http://www.caut.ca/english/ battle. The Globe & Mail 2003 Dec 19. issues/acadfreedom/Olivieri_CPSO.pdf 21 Tonelli C. U of T working on $20 million donation 1 Forsdyke DR. L’Affaire Olivieri.. http:// (accessed 1 Sept 2003). from Apotex Foundation: as Hospital for Sick post.queensu.ca/,forsdyke/peerrev5.htm 10 Olivieri NF, Brittenham GM, Matsui D, et al. Iron Children research controversy continues. The (accessed 1 Oct 2003). chelation therapy with oral deferiprone in patients Varsity 2001 Oct 13. 2 Holloway K. ‘‘We’re not going away’’ vows with thalassemia major. N Engl J Med 22 Ruderman L. Critics wary of Apotex donation to U Olivieri. The Varsity, 2001 Nov 29. 1995;332:918–22. of T. The Varsity 2001 Oct 29. 3 Civil Justice Foundation. 2001 Community 11 Taylor P. A doctor takes on a drug company. 23 Luksic N. Apotex pulls out of its $20 million Champion Awards. Award citation. Washington, Globe and Mail 1998 Aug 13. promise to U of T. The Varsity 2001 Nov 9. DC: Civil Justice Foundation, 2001. 12 Olivieri NF, Brittenham GM, McLaren CE, 24 University of Toronto, the Governing Council. 4 Wente M. Medicine, morals and money. Globe et al. Long term safety and effectiveness of iron Report number 317 of the executive committee. and Mail 1999 Dec 23. chelation therapy with deferiprone for 1999 Sept 7:9. www.utoronto.ca/govcncl/bac/ 5 Weatherall DJ. The thalassaemias. BMJ thalassemia major. N Engl J Med reports/ exrep/EXrep317Sep0799pdf (accessed 1997;314:1675–8. 1998;339:417–23. 14 October 2003).

ECHO ...... Improved procedures may improve informed consent for neonatal research btaining truly informed consent for neonatal research under difficult circumstances may be more achievable with new approaches. These originate from discussions of OEuropean neonatologists, ethicists, sociologists, and legal experts—all participants in

the Euricon trial. http://jme.bmj.com/ Urgent or emergency situations when parents are asked to consent to research treatment Please visit the Journal of for their child are especially difficult. Most doctors would probably suspect that here Medical Ethics informed consent is compromised by circumstances that hinder parents absorbing and website [www. processing complex information. jmedethics. Alternatives to current process might seek consent in a stepwise or a continuous process— com] for a link with information initially given by the doctor and later chances to withhold or withdraw to the full text of this article. consent. Both would allow more time for parents to deal with complex information. A stepwise process would see parents deciding from core information, with more detailed on October 1, 2021 by guest. Protected copyright. information given later, and a continuous process with them deciding from all information given up front, repeated at later stages, sparing them the realisation that they might have withheld consent at the outset, had they understood the full picture. Importantly, parents should not assume that responsibility for their child’s welfare is theirs alone—it extends to researchers, grant awarding body, senior hospital staff, and research ethics committee. They may be reassured if they know that the research has committee approval, though this should not be allowed to interfere with their decision, and great care must be used to avoid coercive language. At worst the Helsinki declaration would permit research treatment without parental consent, but this would be a rare event, occasioned by an extreme situation. m Archives of Disease in Childhood Fetal and Neonatal Edition 2003;88:F166–F167.