'Children at Ste-Justine are not guinea pigs': Hospital defends itself in wake of suspended clinical trial

In 2016, Health Canada took the rare step of suspending a chemotherapy drug trial involving 6 terminally ill cancer patients. Pasquale Turbide of Radio-Canada's investigative program Enquête found out why.

In 2016, Health Canada took rare step of suspending cancer drug trial involving 6 terminally ill patients

Nine-year-old Léna N'guyen was diagnosed with an inoperable brain cancer in 2015. She was the first of six patients to be signed up for a phase 1 clinical trial of an experimental chemotherapy at Montreal's Sainte-Justine University Hospital Centre. (Submitted by family of Léna N'guyen)

For nine-year-old Léna N'guyen's parents, finding out about their daughter's inoperable brain cancer felt like "falling into the void."

Léna was diagnosed with the disease in 2015, and her parents, both pharmacists, had little hope for her recovery. That was until doctors at Montreal's Sainte-Justine University Hospital Centre​, Canada's largest mother-child hospital, offered them a glimmer of it.

Researchers had been working on a new last-chance chemotherapy, combining an existing drug called Decitabine with Genistein, a chemical compound derived from soy.

They called it DEC GEN, and Léna would be its first trial patient.

"You have to hope for a cure, or pray to heaven," Mai Pham, Léna's mother, said. "When you're in that void, you're trying to grab on to whatever you can — and that was the study."​

The following year, in November 2016, the study was suspended by Health Canada after it received an anonymous complaint.

Inspectors spent six days at the hospital, seizing documents, poring over computer records and interviewing employees.

Health Canada found Sainte-Justine researchers had failed to report serious side effects and the death of one of the six patients who were part of the trial. It determined medical files had been improperly kept, and staff hadn't been adequately trained. Three of the patients, including Léna, had been given expired medication.

Léna N'guyen died within weeks of being enrolled in the study, nearly a year before the trial of DEC GEN was suspended. Despite the breach in protocol, Léna didn't suffer any adverse effects from DEC GEN, and the hospital administrators say neither Léna's death nor the deaths of  the other patients in the trial were due to the treatment they received: all the participants had terminal cancer.

Still, her story — one of three told by Radio-Canada's Enquête in a lengthy investigation that revealed how the study's researchers cut corners and failed to follow their own protocols — compelled CHU Sainte-Justine to defend itself and how the clinical trial was conducted.

Patients' lives never put in danger, hospital says

In response to Enquête's investigation, CHU Sainte-Justine administrators acknowledged there were "shortfalls" in the suspended trial, but stressed that they had no impact on the health and safety of the six patients who participated in it.

"Children at Sainte-Justine are not guinea pigs," Isabelle Demers, the hospital's interim CEO, said at a news conference on Oct. 5, the day after Enquête's investigation went to air.

"They are treated with care, respect and never have their lives been put in danger. I repeat: never."

"After the suspension, we acted quickly to review our procedures according to Health Canada's recommendations," Demers said.

The hospital hired an external firm to conduct a review of its procedures and said it is in the process of implementing some of that firm's proposals.

In the future, phase one trials like DEC GEN will be subject to "external monitoring," Demers said, although the hospital acknowledged in an interview with Enquête that means future trials will be monitored by someone at the hospital who is not on the clinical research team involved in the study.

The hospital has also recruited a research quality director.

Senior officials at Sainte-Justine University Hospital Centre (CHU Sainte-Justine) vigorously defended the hospital at a news conference on Oct. 5. 'Never have [patients'] lives been put in danger,' said Isabelle Demers, the hospital's interim CEO. (CBC)

The administrators contend the Radio-Canada investigation unfairly portrayed DEC GEN and the fallout from the trial, but Marc Girard, Sainte-Justine's director of professional services, said the hospital must "obviously do better to respect procedures."

Health Canada cited 23 critical infractions

The DEC GEN trial was the first CHU Sainte-Justine had run independently, without the oversight of a pharmaceutical company.

Employees at the hospital's research centre flagged problems to hospital administrators eight months before Health Canada sent in a team of inspectors in November 2016.

"We are being asked not to follow the rules, and incidents that should be reported to Health Canada are not. The hospital's liability is at risk," they wrote in a letter.

Health Canada rarely suspends entire medical studies. Since 2012, 337 inspections have led to only five suspensions.

In the case of the DEC GEN trial, when it suspended the study, the federal ministry cited 76 violations of the Food and Drugs Act, including 23 critical infractions that threatened the health, safety and rights of the patients.

Protocol on drug's expiry ignored

Among those infractions were the expired chemotherapy drugs given to Léna and two other patients.

Léna's medical records show the study's lead researcher, Dr. Henrique Bittencourt, ordered the continuation of an infusion of medication after the drug's expiry. The drug had expired 37 minutes before the infusion ended — long enough, according to an expert consulted by Enquête, to threaten the integrity of the formula, which can curdle or otherwise change.

In Léna's case, that didn't happen, and the hospital's chief of hematology-oncology, Dr. Michel Duval, defended the doctor's decision, saying those extra minutes in a 24-hour infusion made no difference to the chemotherapy's effectiveness or toxicity.

However, Léna's parents, Mai Pham and Toan N'guyen, say they were troubled by that decision. Their experience as trained scientists taught them that for a study's results to be valid, its protocol needs to be followed to the letter.

"They are absolutely right," said Dr. Jonathan Finlay, program director of Neuro-Oncology at Nationwide Children's Hospital in Columbus, Ohio — one of the largest pediatric hospitals in the U.S.

"It calls every result into question, whether it's positive or negative."

Sainte-Justine fought trial's suspension

After Health Canada suspended the trial, Sainte-Justine vigorously fought that decision, contending the regulator's inspectors had simply misunderstood the issues with the study.

In correspondence obtained by Enquête between the hospital and Health Canada, the federal regulator repeatedly — in March, June and November, 2017 — asked researchers to explain their mistakes and change procedures to make the study better.

In its last letter to Sainte-Justine, Health Canada stood by its suspension, given the results of its inspection.

Guillaume Daraîche was five when he was diagnosed with leukemia in December 2015. He was the sixth patient to be signed up for the DEC GEN trial, in late 2016. (Submitted by the Daraîche family)

Sainte-Justine commissioned an expert from Sick Kids Hospital in Toronto to review the study and how it was followed.

That expert's findings ultimately led Health Canada to revise some of its conclusions, including that the side effects which some of the patients suffered as a result of the trial were consistent with what was described in the study's protocol and that they did not cause the patients' deaths.

However, Health Canada underscored that those side effects should still have been reported to the agency because, although they fell into a grey zone, they were "inhabitually frequent" — specifically, devastating fungal infections contracted by two of the trial's patients in their weakened state.

In the case of one of those patients, five-year-old Guillaume Daraîche, Enquête found he should never have been included in the study at all. Clinicians had enrolled him despite lab results that showed pancreatic enzyme levels that failed to meet the study's criteria.

Guillaume Daraîche developed a severe fungal infection shortly before his death of leukemia on Nov. 8, 2016, the same day Health Canada inspectors wrapped up their investigation of the DEC GEN trial. His death certificate lists both leukemia and the fungal infection as causes of death. (Submitted by the Daraîche family)

Study's flaws 'not trivial at all'

Ethics experts consulted by Enquête say Health Canada had good reasons to suspend the DEC GEN trial.

They were absolutely appropriate in shutting it down. It would have been wrong if they hadn't.- Dr. Jonathan Finlay, director of Neuro-Oncology at Nationawide Children's Hospital

"It's very serious, especially when a regulator like Health Canada intervenes and says there's a long list of problems with a study," said Bryn Williams-Jones, the director of Université de Montréal's bioethics program.

"There were too many violations," Finlay said. "They were absolutely appropriate in shutting it down. It would have been wrong if they hadn't."

Dr. Jonathan Finlay, program director of Neuro-Oncology at Nationwide Children's Hospital, in Columbus, Ohio, said Health Canada had no choice but to suspend the DEC GEN trial. 'There were too many violations,' Finlay said. (Radio-Canada)

Jonathan Kimmelman, the director of McGill University's biomedical ethics unit, said even if the study's flaws were mostly administrative, as Sainte-Justine claims, that doesn't excuse them.

"It's not trivial at all," Kimmelman said. "When you do scientific research, keeping records is absolutely critical."

"We have to be meticulous."

Parents never told of suspension

The hospital still believes the clinical study should be pursued. Sainte-Justine administrators said on Oct. 5 that researchers are looking into the possibility of resurrecting the study, although no timeline for that has been set.

If DEC GEN were to be picked back up, CHU Sainte-Justine would make sure that happens "under the most rigorous of circumstances," said Marc Girard, the hospital's director of professional services.

The N'guyen family before Léna's death in 2015. Sainte-Justine Hospital never told Mai Pham and Toan N'guyen that the trial of DEC GEN had been suspended by Health Canada. (Submitted by N'guyen family)

Léna's parents were never told by the hospital about the study's fate.

Like the parents of two other patients who participated in the study, it was Radio-Canada's Enquête team that informed them Health Canada had suspended the study, not the hospital.

The hospital's chief of hematology-oncology told Enquête they had debated informing the parents.

"Our interpretation of the facts is that we never endangered the children; [the drug trial] never had an impact on their survival," Dr. Michel Duval said. "It wasn't necessary to call the families to trouble them with that."

It's clear for Léna's parents, beyond the death of their daughter, it has been a troubling journey.

"Research is always necessary," said her father, Toan N'guyen. "But to do research properly is more important still."

Her mother, Mai Pham, says if they were to have to go through it again, "maybe we would have gone elsewhere, to another hospital."

With files from Pasquale Turbide of Radio-Canada's Enquête