Overview

In 1996 Toronto hematologist Dr. Nancy Olivieri identified an unexpected risk of a drug she was studying in industry-sponsored clinical trials involving patients with thalassemia, an inherited, potentially fatal blood disorder.  When she moved to inform patients, the drug's manufacturer Apotex Inc. prematurely terminated the trials.  Simultaneously, the company issued warnings of legal action against her should she disclose the risk to her patients or anyone.  Several months later, she identified a second, more serious risk through review of patients' charts, and the company again issued legal warnings against disclosure.  Despite the possible legal action by the company and the lack of effective assistance from her university and hospital, Olivieri informed her patients and the scientific community of the risks she had identified. 

The dispute became public in 1998 when Dr. Olivieri published her findings on the drug's risks in a leading scientific journal.  Since then, she has been subjected to a continuing series of public criticisms attempting to discredit her -- by the hospital, by Apotex and by individuals.

The dispute has received international attention since 1998, largely because it vividly illustrates fundamental problems regarding public safety in matters of health care.  Some aspects relevant to the case are: the changing international political economy of the past quarter century; the rapid growth of the pharmaceutical industry; the deteriorating financial circumstances of universities and hospitals; the failure of government agencies and universities to revise their research policies to address these new circumstances; and the remoteness of clinical faculty from the improvements in employment procedures gained by other professors during the past half century.

Although the case itself has led to settlements, the problems it illustrates have not yet been satisfactorily resolved across the country or elsewhere.  However, it has had a useful role in raising public awareness of adverse corporate influences on universities and hospitals.  It also has been a catalyst to stimulate progress on improving measures to protect the safety of the public at the local, national and international levels. The general public awareness of the case was instrumental in stimulating resolutions of  the local disputes that arose in the case itself.

We became involved in this case in 1999, when the Canadian Association of University Teachers (CAUT) commissioned us to undertake an independent inquiry.  We conducted the inquiry without remuneration, and the CAUT covered expenses and published our report in 2001.[1]  The report has been discussed in national and international science and bioethics journals, and became a factor in several positive developments.  Thus it, too, has become part of the context for issues related to protection of clinical trial participants and preventing suppression of information by sponsors of research.

Context for the Case

The general background for events of the case is the neo-conservative political economy that became dominant from the 1980s onward, first in the USA and UK and then in much of the rest of the world, including Canada.  In the early 1970s several American foundations undertook a massive, sustained propaganda campaign to discredit the liberal social programs introduced in the 1960s and the political economy that gave rise to them.  The campaign included funding several works that became the 'handbooks' of a new era.[2] It also included funding conservative think-tanks that generated articles and tracts promoted by the corporate-dominated mass media. Government services and works -- with the exception of the Pentagon which channels vast sums of public money into a relatively small number of private hands -- came under increasing attack.

Once in power, neo-conservative governments began reducing taxes (mainly for the wealthy) and in the USA especially, increasing military expenditures (mainly benefiting large corporations).  These actions helped drive up government deficits, which in turn led to cuts in government spending on public services, privatization of state resources, weakening of government health and environmental regulatory agencies, and deregulation in the private sector.[3]

During the same period, universities and their affiliated hospitals were becoming increasingly important to the general economy -- due in substantial measure to the large public investment made in them in the 1950s and 1960s.  The advances in science and technology, to which they themselves contributed, made these institutions increasingly expensive to operate, while their public funding declined in the changing political climate of the subsequent decades.  These developments were also influenced by the passage of the Bayh-Dole Act by the American Congress in 1980.  This act allowed universities and hospitals to patent results of government-funded research, and hence derive revenue from research.  Also at that time, government research agencies began to offer financial incentives for university-industry partnerships -- in Canada as well as in the USA.  As the publicly derived budgets of universities decreased, they also became more dependent on corporate donations for infrastructure, scholarships and even salaries for some prominent faculty.

There were beneficial effects from these developments, such as economic growth and accelerated progress in science.  However, along with benefits came problems, because the goals of business are not the same as the goals of the university; the partners may have conflicts in their interests.  However, no significant changes in the policies of research institutions, or the relevant government agencies, had been made to ensure continued protection of university autonomy, academic freedom, public safety or scientific integrity in this new environment.  No significant steps were taken to ensure that individual or institutional conflicts of interest would be promptly identified and properly managed.  In some disciplines and in some institutions, "production-driven research cultures" developed, in which increasing numbers of publications and resulting increased funding became ends in themselves.[4]  These factors led to corrupt practices entering into some scientific endeavours, with not merely unfortunate, but tragic consequences.[5]

Another striking contextual aspect is the enormous growth in bio-medicine: in its scientific disciplines, in medical treatments and diagnostic methods, and in its economic impact.  This growth was driven by two factors.  One factor was the recognition that bio-medicine could become a generator of economic expansion, especially if governments assumed part of the research and development risks while the private sector reaped all of the profits.  Research granting agencies, such as the National Institutes of Health in the USA, would provide government funding in a manner similar to defence research agencies for electronics and aeronautics during the Cold War period.

The other factor was the importation into the health-care sector, without change, of successful business practices from more traditional sectors of the economy.  With advertising and sales promotion for treatments and drugs targeted both at medical practitioners and the public, the human condition itself has become 'medicalised'. The impression has been created that no one need feel, look, smell or perform badly, because there is a drug, surgery or other treatment that could eliminate any such embarrassment.[6]

There have been many advances in the treatment of very serious illnesses during this period, for example the iron chelation drug deferoxamine manufactured by Novartis.*  However, the majority of new drugs are simply variants of existing ones, developed in order to acquire 'market share'.[7]  In some cases, a drug is invented and an advertising campaign is then undertaken to establish a 'medical' condition purportedly treatable by this drug.[8]  Ironically, this 'economic opportunity' was in significant measure created by changes to the USA Food and Drugs Act passed in 1962 in response to the thalidomide tragedy.[9] 

More recently, with neo-conservatism ascendant, such powers that food and drug regulatory agencies have had to protect the public interest have been eroded through reductions in funding and privatisation, as a result of political and ideological pressure to be 'industry-friendly'.  This has been a factor in several public health scandals involving regulatory agencies and industry, ranging from suppression of risk data concerning anti-inflammatories such as Vioxx or antidepressants such as Prozac, to the spread of Creutzfeldt-Jakob disease ('mad cow disease').  These developments occurred in the same time period as scandals in the private sector fueled by deregulation and lax accountability standards, for instance those involving Enron, Worldcom and Hollinger International.

The manufacturers of many 'health-care products' rely on physicians to promote or prescribe their wares, and so actively court the medical profession.  Physicians are subjected to corporate influences throughout their careers, as recipients of free lunches, free dinners and free trips to attend company-sponsored conferences.  "In 2001, drug companies paid over 60% of the costs of continuing medical education [in the USA], and that fraction has increased since then."[10]  Although some physicians deny being influenced, "Pharmaceutical companies would hardly spend $2 billion every year sponsoring lectures and other forms of education for physicians if these efforts did not boost sales."[11]

In addition to the medical profession, pharmaceutical manufacturers also rely on influencing patient support groups and medical charities through donations and sponsorships.  Representatives of such organizations have assisted companies in efforts to get their products licenced.[12]

Medical research is now also heavily dependent on corporate sponsorship.  It shows similar signs of corporate influence, with recent studies showing statistically significant bias in publications in favor of corporate research sponsors' products, when compared to publications resulting from publicly funded research on medical or health-care products.[13]  Medical research articles are now frequently ghost written: company staff draft 'scientific' articles that are then submitted to journals listing as authors professors of medicine who may not have had access to all of the relevant study data, or may not even have had any direct involvement in the study.  One recent estimate is that "at least 50% of academic publications in therapeutics is now ghost written, in particular that in the most prestigious medical journals."[14]

Another standard business principle imported into medical research and practice is protection of trade secrets, the objective of which is to protect the profit-making ability of the company.  This transfer into the medical realm is inapporpriate as the objective here should be to improve treatment.  However, many government research agencies, universities and hospitals have not changed their policies to protect the welfare of patients, especially those enrolled in clinical trials.  Although participants must give informed consent to their participation in a trial, some universities and hospitals still allow their researchers to sign contracts that permit corporate sponsors to prevent or delay disclosure of information they may consider injurious to the reputation of their products, and hence to their profits.

During the past forty years, university professors have made great strides in protecting academic freedom as well as employment rights.  However, this has not been the case for most clinical professors in medical faculties.  There are several reasons for this, a principal one being that clinical professors typically receive most of their salaries not from their universities, but from their hospitals or from intermediate agencies.  Thus they are usually not included in faculty unions or associations.  Their colleagues in such fields as mathematics, history or economics have established rights to publish their work and to criticize university or government policy, and they can rely on strong unions to help them in the exercise of their rights.  Clinical professors are usually not in the same favorable position.

The Olivieri case occurred in Ontario during a time when provincial governments were sharply reducing funding to universities and hospitals, partly in response to radical deficit cutting measures by the federal government.  Hospitals and treatment programs were being required to undergo 'rationalisation' to reduce costs. Universities were turning increasingly to corporate sponsors, and some corporations were prepared to give multi-million dollar donations in return for 'naming opportunities' and other considerations.[15] 

The dispute between Apotex and Dr. Olivieri erupted in 1996.  At around the same time, a disagreement between the administration of the Hospital for Sick Children and Dr. Olivieri developed when the Hospital proposed that treatment of her largest patient group, those with sickle cell disease, be 'rationalised' by outsourcing their care to a suburban hospital.  Patients' families and Dr. Olivieri objected on the basis that patients with this very complex disease should be treated in tertiary hospitals with leading specialists on staff.  Also around this time, the University of Toronto and Apotex were in negotiations over a major donation.  In 1998, when the Olivieri case became public, the University and Apotex had reached agreement in principle to what would then have been the largest donation ever received by the University -- $20 million for the university and an additional $10 million for affiliated hospitals.

Features of the Olivieri Case

From 1996 onward, Dr. Olivieri was subjected to a series of strongly adverse actions, by senior Hospital staff, the Hospital Board of Trustees, officers of Apotex and others, some of them highly public.  The actions could have resulted in her medical practice licence being revoked, with the consequent loss of her positions at the Hospital and at the University, and the end of her career.  The University publicly acknowledged an obligation to defend her academic freedom, yet provided no effective support to her until more than two and a half years after Apotex first issued legal warnings to her.  It was only after the combined interventions of the CAUT, the local faculty association and two of the world's leading authorities in thalassemia that the University began to provide effective support to Dr. Olivieri.

A critical juncture came in 2000 when legal counsel for Dr. Olivieri (provided to her through the faculty association) obtained access to testimony given against her behind closed doors by senior Hospital staff.  The testimony was false, inaccurate or otherwise misleading, but she had heretofore been unable to rebut it for the simple reason that it had not been disclosed to her -- she had had no reasonable opportunity to respond.  Grave actions were taken against her by the administration and Board of the Hospital on the basis of this testimony.

Dr. Olivieri was later completely vindicated through a series of reports by independent inquiries.  Our inquiry was the first and its report was published on October 26, 2001.  The Hospital immediately contracted to have a rebuttal prepared by consultants it had previously employed in this case.  Ironically, the Hospital's rebuttal was posted on its website just prior to publication of the second independent inquiry report, by the College of Physicians and Surgeons of Ontario (CPSO) on December 19, 2001.  The CPSO report confirmed our findings and termed Dr. Olivieri's conduct "commendable".[16]  The Dean of Medicine then also dismissed similar charges against her brought to the University by the Hospital.  The Hospital subsequently removed its rebuttal from its website.

Our report was discussed in articles in The New England Journal of Medicine, Nature Reviews and Science in 2002.  In addition to policy changes at all levels, the report had recommended redress for Dr. Olivieri.  In November 2002, Dr. Olivieri reached a mediated settlement with the Hospital and the University, providing her with substantial redress for her grievances over unfair treatment.

The principal witness against Dr. Olivieri in the Hospital proceedings, Dr. Gideon Koren, was publicly disciplined in 2000 by the Hospital and the University for dishonest actions in connection with his attacks on her.  He was publicly disciplined by the University again in 2002, for research misconduct in connection with an article he published favorable to Apotex's drug.  In 2003, the CPSO publicly disciplined him for misconduct.

Apotex has continued efforts to have deferiprone licenced for prescription sale in the USA and Canada.  However, the American regulatory agency FDA required it to undertake further toxicity studies in animals, as the company acknowledged in a court proceeding in Europe in 2003.*

A major new attack on Dr. Olivieri was launched at the beginning of May 2005, with the publication of a book criticizing her as a person, a physician and a researcher.[17]  The book repeats allegations by Dr. Koren and others, already proven false (it devotes many pages to repeating discredited allegations, and only mentions in a brief paragraph that Olivieri has been exonerated).  The book's conclusion is that Apotex's deferiprone should be licenced by the FDA.  The book was launched in the same week that Novartis made application to the FDA for licencing of its newer, rival oral iron chelation drug ICL 670 (exjade).  Exjade was promptly granted Priority Review status and after a hearing on September 29, 2005, the FDA's scientific panel unanimously recommended licencing.  A formal decision by the FDA on whether it will licence exjade is expected soon.[18]

Significance of the Case

The Olivieri case was a catalyst for the University of Toronto and its affiliated teaching hospitals to change their policy on industry-sponsored research.  The new policy ensures that in matters of human health, scientists can no longer be prevented from disclosing risks to patients in a timely manner.  The Toronto lead should be followed elsewhere.

The presidents of the three Canadian government research granting councils referred recommendations in our report to a panel considering revisions to the Tri-Council Policy Statement: Ethical Conduct of Research Involving Human Subjects -- "The Olivieri Reference".  The work of this panel is proceeding and draft recommendations are expected to be released for public discussion in the near future.

In response to the Olivieri case, several other highly publicized cases, and the findings alluded to earlier that scientific publications may be biased, the editors of the leading international bio-medical journals have imposed new standards for authorship.  Authors must have access to the raw data from clinical trials, must have substantial involvement in the work, must not be impeded by contractual agreements from freely publishing their findings, and must disclose all potential conflicts of interest.[19]

Following publication of our report, the CAUT commissioned a report by a Task Force of senior clinical scientists from across Canada on protecting academic freedom, and protecting employment rights in medical schools.  This report was released in December 2004.[20]  The CAUT is also assisting clinical faculty to organize effective associations.

Much remains to be done, not least being the strengthening of the independence of, and resources for, government regulatory agencies.  Many view these as having been 'captured' by the pharmaceutical industry so that they have come to view the companies rather than the public as their 'client'.  A thorough review of the criteria used by such agencies may also be required.  Restoring (in real terms) public funding for universities and hospitals will also be important.

International agreements also will be necessary.  This is because as public pressure builds on governments and regulators in developed countries for improved defence of the public interest, drug manufacturers are moving trial sites to impoverished developing countries.  In such countries it is very difficult to enforce proper standards of ethical conduct and research integrity because of their weak infrastructure.[21] It is of note that the recent novel The Constant Gardener by John Le Carré and the subsequent motion picture of the same title, as well as the television documentary Dying for Drugs by the British production company Truevision TV, are each based on events both in the Olivieri case and in Africa.

We in the developed world are fortunate in still being free to discuss societal problems, address unfair conduct by large institutions or organizations, and advocate changes in public policy.  However, we should bear in mind the observation made forty years ago by C.B. Macpherson, "tell your politicians that the free way of life depends, to an extent they have not yet dreamed of, on the Western nations remedying the inequality of human rights as between ourselves and the poor nations".[22]

* Thalassemia patients are severely anemic and must have regular blood transfusions, which result in toxic levels of iron accumulating in major organs.  The iron must be removed by chelation therapy.  Deferoxamine is effective and safe in proper dosages, but treatment with it is unpleasant and uncomfortable, requiring many hours of subcutaneous infusion.  Thus development of a safe, effective orally active chelator would be an important advance – it had been hoped both by Dr. Olivieri and Apotex that deferiprone would prove to be such.

* Apotex was granted a marketing authority for deferiprone in Europe in 1999, but one that restricted its use to exceptional circumstances. The European Public Assessment Report on the drug explained that the restriction was imposed "because of the fact that in the present state of knowledge, comprehensive information on the safety and efficacy of the medicinal product cannot be provided".