Is Health Canada doing enough to prevent
adverse drug reactions?

ADR faxes and 'Dear doctor' letters fail to stem the rising tide
of deadly new side effects

By Marlene Busko

Vanessa had been taking the antireflux drug to treat complications from bulimia nervosa. Cisapride was first approved for sale in Canada in 1990, but was never indicated for children and was contraindicated for patients with eating disorders. By 1998, it was commonly being prescribed for gastrointestinal disorders, with more than one million scripts being written a year. Evidence of new risks, however, was accumulating. By 1999 the drug was associated with arrhythmia leading to death in 80 patients in Canada and the US. But even though the manufacturer sent out 'Dear doctor' letters in 1998 and in February 2000 to warn of rare, sudden death with cisapride, prescribing behaviour didn't change substantially. By August 2000 the drug was off the market in Canada and the US.

When Vanessa Young's story hit the headlines, the question on everyone's lips was: Is our adverse drug reaction (ADR) surveillance system working? The inquest into the teen's death responded with a resounding, 'No.' The inquest jury made 59 recommendations ? 14 of them directed straight at Health Canada ? on how the system could be improved to better inform doctors and protect Canadians about risks. So, four years later, what have we learned from the cisapride tragedy?

How to report an ADR: 1. Adverse drug reaction forms are available from: • the Compendium of Pharmaceuticals and Specialties (CPS) • online at www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/adverse_e.html your regional adverse reaction centre: phone 1-866-234-2345/fax: 1-866-678-6789 2. Fax the completed form to: 1-866-678-6789 To receive the free online quarterly Canadian Adverse Reaction Newsletter, visit www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/subscribe_e.html, enter your email address, and click 'Subscribe.'

TRIALS AND TRIBULATIONS
Some sources estimate that as many as 10,000 ADRs occur in Canada every year. These often crop up early in a new drug's life, and the companies that develop them list them when they apply for drug approval by Health Canada. But no clinical trial can predict all eventualities. "A few thousand patients are enrolled in trials ? enough to establish effectiveness but not to detect a serious side effect that might happen in one in 5000 people," says Dr Gordon Guyatt, Professor in Clinical Epidemiology and Biostatistics at McMaster University.

The Canadian Adverse Drug Reaction Monitoring Program exists to make sure these side effects are tracked. Healthcare practitioners and patients are asked to report all suspected ADRs to Health Canada, including unexpected reactions, serious reactions (unexpected or not), and all reactions to drugs marketed for less than five years. These reports are input into the Canadian Adverse Drug Reaction Information System (CADRIS) database and compared with similar information from all over the world. The data are then analysed and triggers identified for further investigation. Warning information about drug dangers is disseminated via newsletters, advisories, product monograph and labelling changes, and 'Dear doctor' letters. Finally, a drug may be pulled off the market.

WHAT WENT WRONG?
The coroner's report from the investigation into Vanessa Young's death highlighted two main shortcomings of the current system. First: "There is a serious under-reporting of ADRs, which leaves regulators ? such as Health Canada ? to rely on incomplete information in making decisions. It has been estimated that only 10% of serious reactions are reported to Health Canada's ADR program."

"Since it is not mandatory to report an ADR, there may be a series of events no one knows about," says Dr Guyatt. Dr Eric Wooltorton, a GP in Kemptville, ON, and the Health and Drug Alerts columnist for the Canadian Medical Association Journal, agrees, adding: "It's still a very passive system that depends on the goodwill of healthcare professionals to stop what they're doing and fax in a form."

Second: "It should be mandatory for healthcare professionals to forward to Health Canada information on all serious adverse drug reactions within 48 hours." The coroner's report recommended that education and policy initiatives should be undertaken to increase voluntary reporting and, if this was unsuccessful, reporting might have to be made a legal obligation.

Dr Guyatt agrees with this notion in principle. "There should be mandatory reporting and, ideally, the industry should have to perform systematic postmarketing to look for rare adverse effects," he says.

TRACKING TOMORROW'S ADRs
Although many of the recommendations from the report remain unimplemented, some progress has been made. "Although Health Canada may be a bit cautious in terms of warning people, they generally get the word out faster now and I think that's one of the big lessons that came out of cisapride," says Dr Wooltorton. Health Canada has been prompted to look at new options for monitoring ADRs. They currently have a project underway to replace CADRIS with the more powerful Adverse Event Reporting System (AERS) database used by the US Food and Drug Administration.

But Dr Wooltorton stresses that this will only address part of the problem. "You need really good data, not just more of it," he says. "Newly released drugs should be actively surveyed, because they're the ones that can cause a new set of problems. The cisapride tragedy taught us that the public should be notified sooner and warnings should be clear and not buried in a marketing message. Getting more data, better data, and a timely response will all help detect signals earlier and save lives."