Sheller Quoted in “Dangers of Off-Label Drug Use Kept Secret”

The Toronto Star

2014-06-26

By: David Bruser News Reporter, Jesse McLean Investigative News reporter, Andrew Bailey Data Analyst, Published on Thu Jun 26 2014

A 15-year-old girl who wanted to clear her acne was prescribed the antibiotic minocycline. The teen developed lupus-like symptoms — her immune system attacked her own tissues and organs — and she died. The drug was not approved for this use by Health Canada.

A 23-year-old woman with “irritability” was given the anticonvulsant drug valproic acid. The medication was not approved for a patient with her condition. She developed a kidney cyst and a nervous system disorder before her kidneys failed. She died.

An 85-year-old man received the antipsychotic Seroquel to treat insomnia. Again, this was an unapproved use of a powerful drug. Neither the drug company nor Health Canada had enough scientific evidence to claim the pills could safely treat sleep disorders.

In this case, the man suffered diarrhea and nausea before dying from a heart attack, which a doctor suspected was caused by the drug.

These cases are just a few of the hundreds of recent reports of side-effects suspected to have been caused by the “off-label” prescribing of antipsychotics, anti-inflammatories and other popular drugs in Canada.

Off label means a drug is being used for a condition or age group for which it has not been approved.

An ongoing Star investigation has found Health Canada knows but does not reveal to the public that these serious, sometimes fatal side-effects are suspected to have been caused by off-label prescriptions.

Doctors across Canada are routinely giving powerful drugs to vulnerable patients, often without strong scientific evidence proving the drugs will be safe or effective, and sometimes despite warnings that such prescribing could cause serious harm.

Drug companies in the United States have been investigated for illegally promoting off-label uses to prescribers and have paid billions in fines, but Health Canada does not appear to be probing if that is happening here.

The Star had to go to the U.S. to find this crucial information about Canadian patients. We analyzed a massive trove of data found in the U.S. Food and Drug Administration’s public side-effect report database.

The FDA, which accepts side-effect reports from Canada and around the world, discloses to the public whether the drugs cited in the reports are prescribed for unapproved uses.

This means the FDA database shows that, in the case of the 15-year-old Canadian girl who died after taking minocycline, the drug was prescribed off label.

The Star’s analysis revealed nearly 400 cases from 2010 to 2013 that involve a wide and disturbing range of reported side-effects: deaths, heart attacks, strokes, birth defects, organ failures and “spontaneous” abortions.

Like the FDA, Health Canada collects this prescription data but scrubs the fact the use was off label from the reports before publishing them in its public side-effects database. This information could help doctors and patients make better prescription decisions.

Numerous doctors, top medical researchers and lawmakers interviewed by the Star had no idea Health Canada collects this crucial data until told by the newspaper.

“It’s absurd,” said Dr. Joel Lexchin, an emergency room doctor and drug safety expert who teaches at York University. “There are significant public safety implications. This is a major problem for doctors and patients alike.”

“If it’s for off-label use, then it’s never been shown to be effective and now it’s causing serious safety problems,” he said. “The job of the health regulator is to protect public health. If they’re withholding information that could do that, then they’re abdicating part of their job.”

Health Canada has been collecting this information for six years but said technical limitations with the database have prevented their public release. The regulator said it will consider making the data public.

When pressed by the Star over several months, Health Canada gave the newspaper some information on roughly 20 drugs commonly prescribed off label. The regulator has not released that information to the public.

In some cases, Health Canada is not even reviewing all the troubling data that it collects, the Star found.

On Wednesday, the newspaper published the story of at least 20 Canadian cases, found in the public U.S. database, of women who were given off-label prescriptions for the anti-nausea drug ondansetron to treat morning sickness during pregnancy and who delivered babies with defects.

Health Canada has similar reports in its internal database. The regulator said it has not done any reviews of these cases and there are currently “no emerging safety issues requiring further assessment” of the drug’s use for morning sickness.

Last year, a Senate committee investigating the issue heard the regulator did not have the analytical ability to track the consequences of off-label prescribing, according to Sen. Art Eggleton, deputy chair of the committee.

Eggleton told the Star that his committee was left with the impression the data did not exist. When told by the Star that it does, and that it is secret, he was incredulous.

“We have to go to the FDA to find out what’s happening in our own country? That’s incredible. It’s unacceptable.”

There are innovative off-label uses of drugs that have helped patients, but many off-label prescriptions are written with no solid scientific proof that the drug will be safe or effective.

In the U.S. database, the Star found more than 20 Canadian side-effect reports saying the off-label prescription was “ineffective” or “aggravated” the patient’s condition.

The Canadian cases in the FDA database likely represent just a fraction of the actual number of cases where off-label drugs are thought to be the cause of serious side-effects in Canada. Side-effects are grossly under reported, and only a small number of those from Canada make their way into the U.S. database.

Each report is the opinion of the doctor, pharmacist or patient that a particular drug has caused a reaction. Patients’ names are taken out of the reports to protect their privacy. Health regulators and researchers across the globe review side-effect reports in search of “signals” — trends or patterns that may expose unknown problems with a drug that’s already on the market.

Eggleton is frustrated that Health Canada is “not looking” to see if there is a problem with off-label prescribing. “Health Canada is not doing enough,” he said. “There are lives at stake.”

Doctors can learn of potential off-label uses of drugs from a range of sources, including published medical research and word-of-mouth from other doctors.

Health Canada says it is the responsibility of doctors to safely prescribe medications, using their expertise and experience to determine whether an unapproved use is right for a patient.

Doctors should also know a drug’s risks, and experts say side-effect reports with information about unapproved uses would help build what is known as a medication’s safety profile.

“It really doesn’t make sense (for Health Canada) to say, ‘We’re leaving it up to the doctor but we’re not going to tell you what we know,’ ” Lexchin said.

“Doctors need to be informed in their decision, and what Health Canada is saying is they’re going to exclude one of the sources of information doctors could potentially have.”

Doctors may also learn of potential off-label drug uses from pharmaceutical sales reps, though it is illegal for drug companies to promote unapproved uses of their products.

South of the border, plaintiffs’ lawyers and government investigators have aggressively pursued violators and found evidence of illegal marketing campaigns.

In 2012 alone, the U.S. government won more than $5 billion in settlements with drug companies accused of illegal promotion, including a $3-billion settlement with GlaxoSmithKline.

Investigators alleged Glaxo marketed the off-label benefits of several drugs, including the company’s brand-name version of ondansetron. The company told the Star that as part of the settlement it admitted no wrongdoing “in connection with physician prescribing of ondansetron in the U.S.”

Several companies prosecuted for illegally marketing unapproved uses in the U.S. are selling the same products in Canada.

A Health Canada spokesperson said the regulator “has not been made aware of any specific similar issue in Canada and has not received complaints concerning these companies promoting off-label uses of their products in Canada.”

Despite repeated requests, Health Canada provided no evidence it has ever investigated, prosecuted or fined a single drug company for off-label promotions, ever.

“The health regulator in Canada does nothing. I don’t know what they’re thinking up there. It’s pathetic,” said American product liability lawyer Stephen Sheller.

He said the federal and provincial governments, which spend billions of dollars on drugs under public health insurance plans, should try to recover costs from companies for inappropriate off-label prescriptions — prescriptions that may have been encouraged by illegal promotion.

Sheller, based in Philadelphia, worked alongside the U.S. Department of Justice in its case against Janssen Pharmaceuticals Inc. over its alleged off-label promotion of the antipsychotic drug Risperdal. The case was resolved in 2013 with Janssen’s parent company paying more than $2.2 billion (U.S.) in criminal fines and civil settlements.

Risperdal and its generic equivalent, risperidone, turned up in 10 Canadian side-effect reports found in the FDA files, including one in which a 15-year-old boy suffered a pulmonary embolism after he took the medication for depression. The drug is not approved for those under 18.

Janssen told the Star it only promotes its products for uses approved by Health Canada.

Sheller said the Canadian government should consult with U.S. investigators and lawyers that have successfully prosecuted companies stateside for the off-label promotion of drugs. The Canadians, he said, can use the U.S. prosecutions as a roadmap to investigate these same companies and the drugs that they also sell in Canada.

“I would be surprised if similar behaviour was not going on in Canada,” he said.

The Senate committee investigating off-label issues heard testimony from a major drug company executive that illegal promotion is “clearly not done.”

Senator Eggleton did not believe it.

“Do not tell me they are bad in the United States and they are clean here. Nothing is being done about it, and I would like an explanation,” Eggleton said to a top Health Canada official during testimony on Parliament Hill last year.

The government official, Dr. Supriya Sharma, suggested to the committee that Canada does not have a problem with off-label promotions.

“I find that hard to believe. That is not credible,’ Eggleton shot back, noting that the regulator does not police the companies and look for lawbreakers.

A 2013 study, which found a troubling pattern of off-label discussions between sales reps and Canadian doctors, suggests there is a problem.

Along with Dr. Lexchin and others, Barbara Mintzes, a drug safety expert in B.C., surveyed family doctors in Toulouse, France; Sacramento, Calif.; Vancouver; and Montreal.

The study found that in one out of every eight drug rep visits to doctors in the two Canadian cities, the reps mentioned unapproved uses of medicines during their pitches.

The drug reps, frequently toting free samples and food for the doctor and her staff, made no mention of a single harmful effect in the majority of their presentations — a possible violation under the federal law that prohibits deceptive and misleading drug promotion.

“That’s essentially saying that the norm is to breach the law,” Mintzes said.

In Canada’s regulatory vacuum, some doctors are writing off-label prescriptions despite warnings the drug could be dangerous for that treatment.

The 15-year-old girl prescribed minocycline was one of two Canadian teens who died in 2012 after they were prescribed the drug for acne and developed a “lupus-like” condition or auto-immune disorder. The other girl was 14 years old. The two girls received the prescriptions after published medical research had already linked the onset of these kinds of disorders with use of the antibiotic.

In April, the Star revealed nursing homes in Ontario are drugging thousands of helpless seniors with powerful antipsychotic drugs despite warnings on the medications’ labels that they can kill elderly patients suffering from dementia.

One of those seniors was Ethel Geraldine Anderson, sister of Order of Canada recipient Herb Carnegie. Her family blames her death on one of those antipsychotics — Zyprexa, known generically as olanzapine — given to her without consent.

The side-effect reports held by the U.S. health regulator reveal Canadian doctors are blithely handing out olanzapine to patients for a wide variety of unapproved treatments.

The drug is approved by Health Canada for the treatment of adults with schizophrenia and related psychotic disorders, as well as bipolar disorder.

Canadians received the drug for dementia, insomnia, anorexia, back pain, autism, “patient restraint” and “sexually inappropriate behavior” — often a symptom of dementia. In the case of the drug prescribed to treat back pain, the 17-year-old patient died, a doctor reported.

In each case, there is no strong scientific evidence the drug is even effective to treat the condition, according to an analysis by Dr. Tewodros Eguale, a drug safety expert currently at Harvard Medical School.

Eguale led a recent McGill University study that found 11 per cent of roughly 250,000 prescriptions given to Quebec patients from 2005 to 2009 were for off-label uses. Of those, 79 per cent lacked strong, supporting scientific evidence.

Eguale reviewed a summary of some of the Canadian side-effect reports the Star found in the U.S. FDA public database, which included olanzapine and 23 other drugs prescribed for a total of 77 different, unapproved uses.

Of 210 off-label prescriptions, just 26 were backed by solid scientific proof from medical studies or clinical trials showing the drug was effective, Eguale said.

There was no strong evidence justifying nearly 88 per cent of the prescriptions.

Jesse McLean can be reached at jmclean@thestar.ca or 416-869-4147.

David Bruser can be reached at dbruser@thestar.ca or 416-869-4282.

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