Olivieri to testify against Apotex in Europe.
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Canada↗
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Generic drug maker wins right to sue for anti-competitive practices.
In December 2000, the Ontario Court of Appeal upheld the right of generic drug manufacturer Apotex Inc to sue three name-brand pharmaceutical companies for allegedly anti-competitive practices. Apotex's claim had been struck out by a lower court, but the appellate court overturned this judgment and allowed the suit to proceed. The facts alleged by Apotex, if eventually proved true, could support a court finding that the name-brand companies were in fact liable.
Acquired Immunodeficiency Syndrome↗
Ticlopidine quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study.
A rapid, sensitive and specific method to quantify ticlopidine in human plasma using clopidogrel as the internal standard (IS) is described. The analyte and the IS were extracted from acidified plasma by liquid-liquid extraction using diethyl ether-hexane (80 : 20, v/v). The extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC/MS/MS). Chromatography was performed isocratically on a Jones Genesis C(8) 4 microm analytical column (150 x 4.1 mm i.d.). The method had a chromatographic run time of 3.0 min and a linear calibration curve over the range 1.0-1000 ng ml(-1) (r(2) > 0.999427). The limit of quantification was 1.0 ng ml(-1). This HPLC/MS/MS procedure was used to assess the bioequivalence of two ticlopidine 250 mg tablet formulations (ticlopidine test formulation from Apotex do Brasil, Brazil, and Ticlid from Sanofi-Synthelabo, standard reference formulation). A single 250 mg dose of each formulation was administered to healthy volunteers. The study was conducted using an open, randomized, two-period crossover design with a 2 week washout interval. Since the 90% confidence interval for C(max) and area under the curve ratios were all inside the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that ticlopidine formulation from Apotex do Brasil is bioequivalent to Ticlid formulation with respect to both the rate and the extent of absorption.
Chromatography, High Pressure Liquid↗
The Olivieri case: lessons for Australasia.
The case of Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. vividly illustrates many of the issues central to contemporary health research and the safety of research participants. First, it exemplifies the financial and health stakes in such research. Second, it shows deficits in the ways in which research is governed. Finally, it was and remains relevant not only in Toronto but in communities across Canada and well beyond its borders because, absent appropriate policies, what happened in Toronto could have happened (and could well still happen) elsewhere. In Part One of this paper, we review the facts of the Olivieri case relevant to the issues we wish to highlight: first, the right of participants in a clinical trial to be informed of a risk that an investigator had identified during the course of the trial and the obligation of the investigator to inform participants (both her own and those of other investigators); and second, the obligation of institutions to protect and promote the well-being of research participants as well as academic freedom and research integrity, the obligations of research sponsors to inform participants, research regulators, and others about unforeseen risks, and the obligations of research regulators to ensure that participants are informed of unforeseen risks and to otherwise protect and promote research integrity. In Part Two, we relate these facts and issues to New Zealand and Australia. We also make detailed recommendations for changes to the various instruments used for the governance of research involving humans in Australasia.
Australia↗
The Olivieri debacle: where were the heroes of bioethics?
All Canadian bioethicists need to reflect on the meaning and value of their work, to see more clearly how the ethics of bioethics is being undermined from within. In the case involving Dr Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc, there were countless opportunities for bioethical heroism. And yet, no bioethics heroes emerged from this case. Much has been written about the hospital's and the university's failures in this case. But what about the deafening silence from the Canadian bioethics community? Given the duty of bioethicists to "speak truth to power", this silence is troubling. To date, nothing has been written about the silence. This article is intended as a partial remedy. As well, the article pays tribute to heretofore unsung heroes among Dr Olivieri's research colleagues.
Academic Medical Centers↗
Nasal cytology in patients with allergic rhinitis: effects of intranasal fluticasone propionate.
BACKGROUND: Nasal cytograms of patients with allergic rhinitis contain increased numbers of eosinophils and basophilic cells. Neutrophils are also more numerous in cytograms of allergic persons. Topical intranasal corticosteroid therapy for allergic rhinitis has been shown to decrease the numbers of some inflammatory cell types. Fluticasone propionate aqueous nasal spray, a potent synthetic corticosteroid preparation, is effective therapy for seasonal and perennial allergic rhinitis. METHODS: Nasal mucosal scrapings were obtained with a Rhinoprobe (Apotex Scientific, Inc. Arlington, Texas) before and after therapy with fluticasone propionate aqueous nasal spray at several doses in patients with either seasonal allergic rhinitis (2 to 4 weeks' therapy) or perennial allergic rhinitis (24 weeks' therapy). More than 1000 paired nasal cytograms obtained from patients participating in five multicenter studies were evaluated. RESULTS: The percentage of patients with nasal eosinophils (p < 0.01, most studies) and basophilic cells (p < 0.05, most studies) decreased significantly after treatment with fluticasone propionate compared with placebo-treated patients. Similar findings were observed with beclomethasone dipropionate in one study. The number of neutrophils remained relatively unchanged after treatment with the intranasal corticosteroids or placebo. CONCLUSIONS: These findings suggest that the therapeutic benefits of topical intranasal fluticasone propionate and beclomethasone dipropionate for the therapy of seasonal and perennial allergic rhinitis are reflected by the decrease in inflammatory cells in the nasal mucosa.
Administration, Intranasal↗
Orally active iron chelators in the treatment of iron overload.
Data from several trials have provided evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has now been shown to induce sustained decreases in tissue iron to concentrations that are associated with survival free of the complications of iron overload in deferoxamine-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation of the risk of this drug in patients willing and able to use deferoxamine. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy, and the United States, under corporate sponsorship by Apotex Research in Canada. The results of this study should determine the risk associated with the use of this agent and may provide the data required for a US Food and Drug Administration decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.
Administration, Oral↗
A multi-center safety trial of the oral iron chelator deferiprone.
Deferiprone, also known as L1, is an orally active iron chelator that has been studied extensively in clinical trials. The sporadic occurrence of agranulocytosis in association with deferiprone and the highly variable frequency of other possible side effects such as arthralgia have created uncertainty about the true incidence of deferiprone-related complications. A multi-center, 1-year trial was initiated to determine the safety profile of deferiprone. Using the Apotex formulation of deferiprone, 187 patients with thalassemia who were unable or unwilling to use deferoxamine were enrolled in four centers; 162 patients completed one year of therapy. Agranulocytosis (ANC < 500/mm3) occurred in one patient after 15 weeks of treatment, was not accompanied by infection and resolved following treatment with G-CSF. Nine other subjects developed less severe neutropenia (ANC 500-1500/mm3) with the lowest absolute neutrophil count reaching 500-1250/mm3. The neutropenia in these patients developed after 1-50 weeks of therapy, frequently accompanied febrile illnesses, and occurred predominantly in non-splenectomized patients. Reasons other than neutropenia for discontinuing use of deferiprone included nausea (4), voluntary withdrawal (3), high ALT (2), platelet count < 100,000/mm3 (2), low but unconfirmed ANC (1), protocol violation (1) fatigue (1), and depression (1). Mean ALT levels rose within three months of therapy and stabilized thereafter. Arthralgia and nausea and/or vomiting occurred in 6% and 24% of subjects, respectively. In this multi-center trial with weekly monitoring of blood counts, the incidence of agranulocytosis was 0.58 per 100 patient-years, and the frequency of agranulocytosis after one year was 0.5%. These findings support the safety of this formulation of deferiprone, using the careful monitoring system employed in this trial.
Administration, Oral↗
Whistleblowing in academic medicine.
Although medical centres have established boards, special committees, and offices for the review and redress of breaches in ethical behaviour, these mechanisms repeatedly prove themselves ineffective in addressing research misconduct within the institutions of academic medicine. As the authors see it, institutional design: (1) systematically ignores serious ethical problems, (2) makes whistleblowers into institutional enemies and punishes them, and (3) thereby fails to provide an ethical environment. The authors present and discuss cases of academic medicine failing to address unethical behaviour in academic science and, thereby, illustrate the scope and seriousness of the problem. The Olivieri/Apotex affair is just another instance of academic medicine's dereliction in a case of scientific fraud and misconduct. Instead of vigorously supporting their faculty member in her efforts to honestly communicate her findings and to protect patients from the risks associated with the use of the study drug, the University of Toronto collaborated with the Apotex company's "stalling tactics," closed down Dr Olivieri's laboratory, harassed her, and ultimately dismissed her. The authors argue that the incentives for addressing problematic behaviour have to be revised in order to effect a change in the current pattern of response that occurs in academic medicine. An externally imposed realignment of incentives could convert the perception of the whistleblower, from their present caste as the enemy within, into a new position, as valued friend of the institution. The authors explain how such a correction could encourage appropriate reactions to scientific misconduct from academic medicine.
Clinical Trials as Topic↗
Long-term therapy with deferiprone.
Data from several trials have provided direct and supportive evidence for the efficacy of deferiprone in the treatment of iron overload in thalassemia major. Deferiprone has been shown to induce sustained decreases in body iron to concentrations associated with survival free from the complications of iron overload in deferoxamine (DFO)-treated patients. Despite this evidence of efficacy, the risk of agranulocytosis mandates a careful evaluation in patients willing and able to use DFO. The incidence of agranulocytosis associated with deferiprone is under study in a prospective multicenter trial in Canada, Italy and the United States, under corporate sponsorship (Apotex Research, Canada). The results of this study should determine the risk associated with the use of this agent, and may provide the data required for an FDA decision regarding licensing of this agent for the treatment of iron overload, a goal supported by investigators worldwide.
Animals↗
Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulations of indometacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease.
Non-steroidal anti-inflammatory drugs (NSAIDs) vary in their propensity to cause damage in different regions of the gastrointestinal (GI) tract in laboratory animals and humans. This may depend on the type of drug formulation as well as the intrinsic pharmacological properties of the drugs. The purpose of this study was to determine the effects of NSAIDs, with cyclooxygenase 1 and 2 inhibitory activity but with different potency as inhibitors of prostaglandin production, when given orally as tablet/capsule formulations of NSAIDs for 10 days to pigs, a species that has close resemblance in structure and function of the tract to that in humans. Three capsule or tablet formulations of NSAIDs were given orally to pigs for 10 days. GI bleeding was measured by determination of radioactive iron in the faeces from (59)Fe-pre-labelled red blood cells. The blood loss was compared with the pathological changes in the GI mucosa observed at autopsy, mucosal myeloperoxidase (MPO) activity as an index of leucocyte infiltration, and plasma and mucosal concentrations of the drugs at termination assayed by high-performance liquid chromatography. Mucosal damage and bleeding varied according to the type of NSAID. Gastroduodenal ulcers and lesions occurred with the cyclooxygenase inhibitors indometacin (indomethacin) (Indocid capsules 10 or 5 mg kg(-1) day(-1) b.i.d.), aspirin (USP tablets 150 mg kg(-1) day(-1) b.i.d) and naproxen (Apotex tablets 50 or 75 mg kg(-1) day(-1) b.i.d.), and there was an increase in the cumulative (i.e. 10-day) blood loss at higher doses of indometacin and naproxen, and with aspirin. There was no statistically significant increase in gastric or intestinal mucosal MPO activity in the non-damaged mucosa with these drugs and this was confirmed by histological observations in non-lesioned areas of the mucosa. Indometacin produced focal ulcers in the caecum but this was not observed with the other drugs. All the NSAIDs produced significant blood loss coincident with gastric ulceration but no increase in gastric or intestinal MPO activity. Plasma concentrations of the non-aspirin NSAIDs were within the range encountered therapeutically in humans. The mucosal concentrations of indometacin in the gastric and intestinal mucosa correlated with mucosal injury. These findings show that: (i) NSAIDs vary in their propensity to produce mucosal injury in different regions of the GI tract according to their pharmacological properties and formulation; (ii) mucosal injury from some NSAIDs may not directly relate to blood loss at low doses of NSAIDs and this may depend on inhibition of platelet aggregation; and (iii) the occurrence of caecal ulcers uniquely observed with indometacin treatment may be relevant to the development of intestinal pathology (e.g. diaphragm-like structures) seen occasionally in humans. These results suggest that the pig model employed in the present studies may be useful for investigations of GI damage from NSAID tablets/capsules, especially in regions that are generally inaccessible to routine endoscopic investigations in humans (e.g. the proximal regions of the large intestine).
Administration, Oral↗
Royal Society of Chemistry--sixth international symposium on applied bioinorganic chemistry.
This was the sixth in a series of symposia that began in Beijing, China in 1986. Approximately 100 chemists, environmental and biomedical scientists from 25 countries attended the meeting and presented some 80 papers on topics ranging from cancer chemotherapy to the production of paper. About half the papers presented could be broadly described as having medical implications, and of these, approximately half related directly to the use of platinum and the potential uses of other metals, such as palladium and the lanthanides, as anticancer agents. Many of these papers provided valuable insights into mechanisms of action and offered pointers for future research, but only rarely did they point to potential new drugs that might find early exploitation in clinical medicine. Two of the more exciting clinical developments were the introduction of the insulin-mimetic bis(maltolato)oxovanadium(IV) (KP-102; Kinetek Pharmaceuticals Inc/University of British Columbia) into clinical trials in the UK for the treatment of Type II diabetes, and the increasing importance of the orally active agent 3-hydroxy-pyridin-4-one-deferiprone (Apotex Inc/Cipla Ltd), in the treatment of iron overload in thalassemia.
Journal Article↗
Patients' health or company profits? The commercialisation of academic research.
This paper is a personal account of the events associated with the author's work at the University of Toronto's Hospital for Sick Children on a drug, deferiprone, for the treatment of thalassaemia. Trials of the drug were sponsored by the Canadian Medical Research Council and a drug company which would have been able, had the trials been successful, to seek regulatory approval to market the drug. When evidence emerged that deferiprone might be inadequately effective in a substantial proportion of patients, the drug company issued legal threats when the author proposed informing her patients and the scientific community. Until protests were made by international authorities in her field of research, the hospital and university did not adequately support the author's academic freedom and responsibilities as a medical practitioner. It is argued that underlying cause of this, and of other similar cases, is the political philosophy which is driving the commercialisation of universities and bringing about the deregulation of drug approval procedures. Together these changes constitute a serious threat to the public good.
Biomedical Research↗
The Olivieri Report--a compelling study of the growing tensions in clinical research.
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Clinical Trials as Topic↗
Canadian panel calls for review of drug-trial confidentiality agreements.
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Biomedical Research↗
Canadian whistleblower row prompts broader code of conduct.
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Biomedical Research↗
Inquiry into clinical trial scandal at Canadian research hospital.
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Biomedical Research↗
A duty to publish.
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Biomedical Research↗