Unlicensed drug harmed patients, study finds
Canada’s largest hospital permitted patients to suffer “persistent toxicity and adverse effects” resulting in elevated incidents of diabetes and liver dysfunction — along with a death — after being treated with an unlicensed drug for six years, says a co-author of a study being published Wednesday.
Dr. Brenda Gallie, a professor of medical biophysics and ophthalmology at the Hospital for Sick Children, says the new data provide clear evidence that the drug deferiprone — sold as Ferriprox by generic pharmaceutical maker Apotex — poses serious health risks that hospital administrators were told about years ago.
“These patients were sold a bill of goods that has impacted their health,” she says of patients given deferiprone, a drug used to treat hereditary blood disorders such as thalassemia.
“It is a human experiment and I can’t imagine how it went on and on and on.”
The peer-reviewed study, obtained exclusively by the Star, is being published in Public Library of Science Journal.
The study concludes that deferiprone showed “significant toxicity in most patients” over the six-year study of 41 patients — findings that demand an “urgent, transparent review of current standards of patient protection, informed consent, and medical practice.” The findings document a 17 per cent incidence of new diabetes and new liver dysfunction in 65 per cent of patients who were given deferiprone between 2009 and 2015. A woman in her 30s died in 2013, 13 months after being placed on the drug, the study found. Only two of the 41 patients fared well on deferiprone, said Gallie, who authored the study with Dr. Nancy Olivieri, a senior scientist at the University Health Network (UHN) who has been in a 22-year legal and academic dispute over the health impacts of deferiprone.
Dr. David Nathan, an international expert in thalassemia and professor of pediatrics and medicine at Harvard University, calls the findings “very striking.”
“Patients fared far worse on deferiprone. The world is going to have to look at this. It looks like credible science to me. It’s been reviewed up and down the line. I think its terribly important. It’s a lesson.” Separately, on Monday, Health Canada issued a safety review warning of a potential link between Ferriprox and neurological disorders in children following two international case reports.
The agency said it will update current warnings in the safety information and will take “appropriate and timely action if or when new health risks are identified.”
Apotex responded to questions from the Star in a written statement Tuesday. It says the UHN study relies on selected data from a small sample of patients from one hospital, which poses a “risk of bias” and could lead to “erroneous conclusions.”
“This limitation may have contributed to the contrasting results with, for example, a recent study in more than 500 patients from 68 treatment centers,” reads the statement from Dr. Fernando Tricta, vicepresident of medical affairs for Apotex subsidiary ApoPharm.
That 2018 study, published in the British Journal of Haematology, found a greater reduction in cardiac iron with deferiprone than with competing drug deferasirox.
“What the thalassemia com- munity knows is that patients receiving deferiprone have less iron toxicity and are living longer,” the statement reads. In response to Monday’s Health Canada safety review, the Apotex statement says the company agrees with the regulator’s assessment of cases where two children on the drug had difficulty with walking or co-ordination.
“Twenty years of post-market experience and drug exposure … support the regulators’ view that deferiprone is safe and effective in the treatment of iron load in patients with thalassemia. Nonetheless, we encourage vigilance in detection of adverse events, regardless of how rare they may be.”
UHN officials declined interview requests for this story. In a written statement, the hospital said deferiprone has been the subject of “ongoing attention for many years” and that the study is “an addition to the literature on the subject” providing clinicians and scientists “additional information about this drug which has been in regular use around the world for many years.”
Because of the “potential quality concerns” noted in the study, UHN will “review the cases involved in the research and UHN has requested that the investigators provide this patient data as soon as possible.” The drug was approved by Health Canada in February 2015 as a “third line” therapy for the treatment when other “therapies do not work well enough,” according to Health Canada’s website. At the time, according to Apotex, Ferriprox had been approved for use in 65 countries as treatment for patients “whose current therapy is unsatisfactory.”
Between 2009 and 2015, onethird of patients transfused at UHN were switched from licensed drugs to then unlicensed deferiprone, the study says, apparently using Health Canada’s “special access program” that permits the use of an unlicensed drug when conventional therapies are inadequate.
The use of an unlicensed drug raises serious ethical questions, says bioethicist Arthur Schafer, founding director of the Centre for Professional and Applied Ethics at the University of Manitoba.
“I think it’s a frightening scandal,” said Schafer, who is writing a paper on the ethics of the case. “How and why did this particular thalassemia program come to be treating such a large percentage of its patients with an unlicensed drug when drugs proven safe and effective were available? How would any patient agree to be a research subject when they might be given deferiprone when their condition is potentially life threatening when Health Canada and the FDA and the European drug authority have all licensed other drugs as safe and effective?”
The researchers reviewed every clinical entry of all 41 patients between 2009 and 2015, Gallie says.
“We could not identify any patient who was failing both licensed, first-line, proven-effective therapies which Health Canada demands to allow a switch to unlicensed deferiprone. In fact, most patients appeared to be responsive to both licensed drugs, and were doing well on one or the other licensed therapy.”
It is not known what the patients were told about deferiprone, Olivieri said in an email.
“One can never confirm, patient by patient, the information the patients received, or did not receive, at the time each was switched from first-line therapy to deferiprone between 2009 and 2015,” she said. “I cannot think of another situation in which this happened. ‘What were the patients told?’ is the most critical question of all.”
In interviews with the Star, Olivieri and Gallie said they brought their early study findings and concerns to UHN officials as early as 2009.
A 2012 letter to Olivieri from a senior UHN official said, “The appropriateness of the clinical use of deferiprone at UHN has been exhaustively reviewed in the relatively recent past and has been completely validated.”
“The issue to which I keep coming back to is how could an administration not regard as serious my warnings and concerns for 10 years, and later, those of Dr. Gallie? The issue I am focused on is, why was UHN silent for all those years? What kept this going?”
“The issue to which I keep coming back to is: How could an administration ignore these warning and concerns for 10 years while a patient died, and many others developed irreversible complications?” said Olivieri.
“Why was UHN silent for all those years? What kept this going?”
On May 8, 2015, Gallie wrote to the UHN president and CEO, Dr. Peter Pisters, warning of “the harm to patients, including death” related to the drug.
It says the two spoke about the problems two months earlier — on March 17, 2015 — and that Pisters “undertook to identify the ‘correct’ path to report the patient harm that is evident” in the early student results.
“It is clear to me that NOW we must move to fully deal with these issues, before they are out of your control. Since the trouble is so deep and complex in the UHN, I think that it needs your personal attention first, then a very careful plan to manage the UHN institutional processes.”
There is a “very real potential” that the issues will emerge in the media, Gallie wrote.
“None of us wants this outcome, but it is inevitable that it will reach public view at some time. The best for all (for a bright safe future world) would full disclosure when the UHN has both the conflicts of interest and the patient harm addressed.”
“Respectfully, we present to you an opportunity to actualize the UHN’s commitment to ‘reduce preventable patient harm to zero.’ Can we please arrange a time for you and I to discuss next steps, at your earliest convenience?”
The same day, Pisters responded in an email to Gallie that reads: “I want you to know how seriously I take these concerns and that I have rearranged my schedule in order to meet next week.”
Gallie says no action was taken.
“When we presented the executives of UHN with data that patients with thalassemia were showing dangerous iron overload first in 2015, we were summarily dismissed and no action was taken to assure safety of patients.”
Gallie says that during a meeting with Olivieri, Pisters and two other UHN administrators in February, 2017, she informed the executives that “people had been exposed and patient safety risks.”
The two researchers asked for data on deferiprone held by the hospital but were told UHN could not provide it to them.
In its written statement, UHN said Olivieri and Gallie made former senior leaders at the hospital aware of their intent to publish their research “about two years ago.”
“Requests were made of the researchers at that time to share the paper in draft form because of the concerns the investigators expressed about the drug. The paper was received by current UHN executive leadership on February 12, 2019,” the statement reads.
Calling the case “deeply troubling,” Dalhousie University health law expert Jocelyn Downie, who reviewed the study for the Star, said UHN should “immediately commission an independent review” to determine whether patients gave informed consent and whether the standard of care was met. She said Health Canada should also investigate whether the hospital ensured conventional treatments had failed, were unsuitable, or were unavailable before turning to deferiprone.
The study’s publication provides the latest chapter in a high-profile battle reaching back to the mid-1990s that has pitted Olivieri against generic pharmaceutical giant Apotex and the University of Toronto.
Olivieri, a specialist in haematology and internal medicine, first conducted a small trial on deferiprone in 1988 to determine its efficacy and safety. It showed promising short-term findings. She began in 1993.
But in 1995, adverse findings began to emerge.