TORONTO - When Dr. Nancy Olivieri presented clinical trial results at a recent hematology meeting, she was risking litigation by the drug's manufacturer for contravening a confidentiality agreement concerning her findings.
When the trial began, Dr. Olivieri, director of the hemoglobinopathy program at Toronto's Hospital for Sick Children and a Medical Research Council career scientist, was tremendously excited about the new agent, an oral iron chelation drug that promised to save the lives of many young people who rely on transfusions to battle blood disorders like sickle cell anemia and beta thalassemia.
But now, Dr. Olivieri is sufficiently concerned about the agent, called L1 or deferiprone, that she has gone directly to Health Canada's Health Protection Branch with her findings and presented the data in the public forum of a large medical meeting, despite the assertion by the drug's manufacturer, Apotex Inc., that she would contravene their confidentiality agreement by doing so.
"In 1995, Dr. Olivieri published a paper in the New England Journal of Medicine which had a very optimistic view of L1, because she began the clinical trials in 1991 and it looked positive," said Steven Mason, a lawyer with Toronto firm McCarthy Tetrault and Dr. Olivieri's legal counsel.
"Her views on L1 are now dramatically different. It was those views that she felt necessary to report to the scientific community, and it was those views that Apotex threatened her against reporting."
Dr. Olivieri did sign the confidentiality agreement with the company, he said. But based on her findings, "she was not satisfied that her ethical and moral duties would be discharged," if the information was not made available, Mason said. Patients in other centres continue to be treated with L1, largely on the basis of her previous positive publications. No litigation has been undertaken to date, Mason said.
The drug is manufactured by Apotex Inc., Weston, Ont., part of an expansion by the company from making generic drugs to developing drugs of its own.
Contacted about this issue, spokesperson Elie Betito, director of public and corporate affairs for Apotex, read a prepared statement: "Data from our clinical trials support the safety and efficacy of the drug, and we are proceeding with international regulatory filings for marketing approval."
No one else was available for comment, Betito said, and he declined to answer further questions.
According to Mason, data on the Toronto patients were reviewed by a panel appointed by Apotex, who disagreed with Dr. Olivieri's interpretation. It is perhaps on the basis of this assessment that Apotex is going forward with development of the drug.
Dr. Olivieri's dilemma raises a wider issue both for researchers and for the public at large. With less and less peer-reviewed funding available, many researchers and academic institutions are trying to forge partnerships with pharmaceutical companies in the private sector.
From the drug company's standpoint, the maintenance of confidentiality is critical to keeping a competitive edge over other companies, protecting patent rights and ultimately remaining commercially viable as a company.
Accordingly, scientists often sign agreements to maintain the confidentiality of what they have found when partnering with commercial concerns. But what are the options for a researcher when they feel the data should be available on the grounds of what they perceive as patient safety concerns?
In blood disorders such as sickle cell anemia and beta thalassemia, the disorder itself can be managed effectively with blood transfusions. However, with each transfusion comes iron, which is difficult to clear from the system.
Instead, the body stores it, mostly in organs. Over time, magnetic resonance imaging shows hearts, livers, kidneys, blackened and ultimately made useless by iron stores. Without intervention, thalassemia patients, for example, predictably die in their 20s.
The problem is currently treated with deferoxamine, an iron chelation agent that binds iron from the serum and tissues, and allows the body to excrete it. However, the drug has to be given using a subcutaneous pump, and infused over a 12-hour period every day.
Perhaps not surprisingly, compliance with deferoxamine, or Desferal as it is known commercially, is "lousy," Dr. Olivieri told The Medical Post in 1991.
L1 (deferiprone) is an iron chelating agent as well, but it can be given orally. Not only would this be much more acceptable from a compliance standpoint, Dr. Olivieri pointed out, but it would allow treatment to be offered in third world countries where these diseases are common but the funds and facilities for subcutaneous pumps are not.
Initial studies showed iron excretion induced by L1 was similar to that seen with deferoxamine at much lower doses. Since effectiveness is a measure of efficacy and compliance together, they felt the improved compliance with the oral agent would result in it being just as effective as deferoxamine.
"We haven't seen any complications with L1, so we're very hopeful," Dr. Olivieri said at that time. "But the long-term results are obviously what counts."
The trial reported here was begun in 1993, a randomized comparison of oral L1 and subcutaneous deferoxamine in patients with thalassemia major.
Patients were originally recruited from a single site, the Toronto Hospital for Sick Children and The Toronto Hospital, and the triad was supported by the Medical Research Council of Canada and Apotex. A second study site, the Montreal Children's Hospital, was added in 1995, with seven patients, bringing the total to 66.
In May 1996, Dr. Oliviere's preliminary analysis showed that over time, iron stores were climbing in the L1 treated group despite extraordinary compliance of more than 90%. Dr. Olivieri reported her concern about these findings both to Apotex and to the research ethics board at the Hospital for Sick Children.
The research board recommended the informed consent forms for the trial be altered to reflect this new information.
The new forms were also forwarded to the company for their approval.
Apotex stopped the trial at the Toronto site the same week, Mason said, and Dr. Olivieri's consultancy contract was terminated. She was also unilaterally removed from the steering committee of an ongoing Italian trial of the drug.
Dr. Olivieri then elected to present the data at the recent American Society of Hematology meeting in Orlando, Fla., and contacted scientific program committee chairman Dr. Kenneth Kaushansky, professor of medicine and biochemistry at the University of Washington in Seattle.
Dr. Kaushansky was also contacted by Dr. Michael Spino (PhD), head of research and development at Apotex. Rather than adjudicate the situation themselves, he said, the ASH executive decided to allow the abstract Dr. Olivieri submitted to be judged by the program committee on its scientific merit as any other abstract would, without disclosing the controversy between the two parties. The paper was accepted for oral presentation.
For her part, Dr. Olivieri is following the advice of her counsel, and declined comment for this article. However, her assessment of the agent, presented to hematology colleagues gathered in Orlando, was plain:
"Iron balance, in conclusion, achieved with deferiprone was less than that induced by deferoxamine at a dose of 40 mg/kg/day administered an average of 22 days per month," she concluded.
"In most deferiprone-treated patients, after two years on the study, body storage iron exceeded concentrations associated with long-term survival free of the complications of iron overload."
"These results raise concern that long-term therapy with L1 may not provide adequate control of body iron in a substantial proportion of patients with thalassemia major," the abstract concluded.
Data presented were on 26 of the 66 patients who had received two years of assigned therapy, and had hepatic iron concentrations determined before Aug. 31, 1996.
Results showed hepatic iron increased in the L1-treated patients, and was in the optimal range in only 7%, or one of 15 patients, over the course of the trial.
Over the same two-year period, mean hepatic iron concentrations did not change significantly in the deferoxamine-treated patients, and was in the optimal range in 64% or seven of 11 patients in that group.
This was despite compliance of between 90% and 95% with L1, significantly better than 73% compliance in the deferoxamine group.
"Neither compliance, nor transfusion index explain the difference between effectiveness and changes in tissue iron in these patients," Dr. Olivieri noted.
A separate British paper presented at the ASH meeting also found inadequate control of iron stores using L1.
Of 14 patients with various transfusion-dependent disorders, only six had liver iron levels below the threshold for cardiac damage at the trial's end.
"We conclude that long-term iron chelation with L1 alone is successful at maintaining body iron at a 'safe' level in only a minority of transfusion-dependent patients," their abstract concluded.
Dr. Victor Hoffbrand, who presented findings on behalf of colleagues at Whittington and Royal Free Hospitals in London, England, pointed out that because the drug is investigational, it is often given only to patients who have failed treatment with deferoxamine or have been noncompliant with that treatment.
He raised the possibility that if the drug were given earlier, before iron stores have built up to dangerous levels, results with Ll may be better. He also suggested some combination regimen using L1 and deferoxamine may be useful. They are going ahead, he said, investigating the use of higher doses of L1.
What seems clear is that no one wants to give up on this drug yet, and that includes Dr. Olivieri, Mason said. With no other oral chelator on the horizon, doctors at the Orlando meeting also urged further investigation be done with the drug.
"In our experience, deferoxamine compliance is dismal, and I still think any hope for an oral chelator should be pursued," noted one researcher.
"We quite agree," Dr. Olivieri responded. "We do think the first priority, of course, is patient safety and effectiveness."
A second member of the audience pointed out that similar problems were seen during the development of deferoxamine, now the standard of care:
"I'd like to congratulate Nancy on this study, and on her courage in presenting it under somewhat difficult circumstances, because I think what happened in the Desferal era was that we had very clear dissemination of information. All the groups got together and we sorted out this problem."
Copyright © 1997 Maclean Hunter Publishing Limited
Reprinted with permission.
Internet Mental Health (www.mentalhealth.com) copyright © 1995-2011 by Phillip W. Long, M.D.