Problem Prescriptions

When a patient has a serious adverse reaction to a prescribed drug, she probably–and logically–believes her experience will have a meaningful impact on the health care system. Unfortunately, the reality is quite different.

People who experience adverse reactions to prescription medicine are often left alone to search for information about the drug that may have caused the reaction, as well as the reaction itself, whether it might have been expected, for example, or whether others have had similar experiences.

But adverse drug reactions are a serious problem, responsible for death and illness among Canadians at levels that may shock people. In Canada it is estimated that up to 10,000 hospital deaths each year are the result of adverse reactions to prescribed drugs. Across Canada an estimated 220,000 more experience serious adverse reactions to prescription drugs that are approved by Health Canada.

In 1999 Duncan Hunter and Namrata Bains, in the Canadian Medical Association Journal, estimated that an average of 16,344 hospital admissions each year in Ontario between 1992 and 1993 and 1996 and 1997 were for adverse drug reactions. Despite these high numbers, public awareness is almost nonexistent; Canada’s monitoring system is poorly funded and has languished in the shadow of drug industry-supported efforts to get more drugs to the market more quickly.

Going to Market

Before a drug can be marketed in Canada, all information about it must be submitted by the manufacturer to Health Canada, including reports of unexpected harms detected during clinical trials. Health Canada reviews the information to determine whether a drug, in controlled circumstances, produces the desired effect in treating or preventing a specific medical condition.

Health Canada then decides whether the clinical benefits outweigh the risks of harm that the drug might cause. But Health Canada only has access to limited safety data from the drug company applying for permission to market a drug. In addition, while safety data are collected, the drug has usually been tested in too few people to identify less common problems associated with it.

Postmarket Scrutiny

The Marketed Health Products Directorate (MHPD) of Health Canada is responsible for coordinating postmarket surveillance, the term used to describe the monitoring of a drug’s safety and effectiveness after it is approved for the market. This is a vital step in the regulatory process, in part because clinical drug trials typically are conducted on far fewer people than will actually use the drug, and usually for less than 90 days.

By contrast, many approved drugs will be used in therapy for much longer periods, while others may be used over a lifetime by those with chronic conditions. Thus, the full range of harmful effects of any given drug after approval may not be immediately known.

Once a drug is on the market, those who use it may have multiple medical conditions being treated with other drugs, some of which may interact with one another. In addition, those who will actually use a drug may differ significantly from those who have participated in clinical trials, both in terms of the number and diversity of people receiving treatment, the dose, and duration of therapy they may require.

A drug may be prescribed for children, the elderly, women of childbearing age, or women generally–all groups which are often under-represented or not represented at all in clinical trials. Consequently, different benefits and harms may be observed postmarket than were seen in controlled research environments.

Keeping Track of Problems

While manufacturers are required to report all serious adverse drug reactions (ADR) to Health Canada, the regulator currently does not have any legislative authority to require drug companies to conduct postmarketing trials.

Physicians, health professionals, and consumers all report adverse side effects on a voluntary basis. All in all, only about 5 percent of all such reports actually make their way onto the record–and even that estimate might be overly optimistic.

While it is Health Canada’s job to regulate pharmaceutical products–both before and after they reach the market–its resources are mainly dedicated to drug approvals, not monitoring safety after drugs are on the market. Further, its job isn’t limited to the 22,000 prescription and over-the-counter (OTC) drugs and the 40,000 medical devices currently on the market.

In January 2004 natural health products–vitamins and minerals, herbal remedies, Chinese and other traditional medicines, probiotics, amino acids, and fatty acids–also came under federal regulations that cover everything from product labelling to adverse drug reaction reporting. By next year, all natural health products will have to be licensed and assigned product numbers before they’re sold.

Canada’s modern system of postmarket drug regulation was developed in the early 1960s in response to the thalidomide disaster. Thalidomide was used by pregnant women in Canada from 1959 to 1962 to prevent morning sickness (it was not granted FDA approval in the US and was only distributed on an “investigational basis” under the trade name Kevadon, starting in early 1960). Its use in North America and Europe prompted a wave of regulatory reform after the drug was found to cause peripheral neuropathy and severely malformed limbs in many thousands of newborns. In 1965 Canada established its first program to track consumer experiences with prescription medicines after they reached the market.

Since then, the drug industry has maintained a consistent level of pressure on Health Canada to speed up approvals of prescription medicines. The introduction of the User Fee Act in 1994 and its application to drug approvals has led to charges by industry critics that Health Canada is tilted in favour of the industry and that this may compromise patient safety. If the targeted timelines in the Act for approvals are not met, Health Canada suffers a financial penalty, a de facto incentive to approve. (There are, of course, no safety targets.)

According to Dr. Joel Lexchin, an emergency physician at the University Health Network (Toronto) and associate professor at the School of Health Policy and Management, York University, the fact that “there was a correlation between the level of user fees and approval times and the percent of positive approvals lends support to the proposition that there may be a causal relationship.” Like many others concerned about the links between user fees and approvals, Lexchin has called for more research and greater transparency in the approval process.

Throughout the 1990s, the Health Protection Branch was struggling to survive budget reductions of more than 50 percent and the closure or downsizing of laboratories across the country. As a consequence, the MHPD has been forced to stop routinely trying to assign causality when evaluating ADR reports. In 2003 to 2004 the finance ministry allocated an additional $31.2 million to speed up drug approvals, but gave only $2.5 million to the MHPD.

Between 1998 and 2003 ADR reports from the five regional centres run by MHPD to collect consumer and health professional reports began to decline, as the number from manufacturers significantly increased.

But a growing number of advocacy groups are working in tandem to reverse this trend and to bring pressure on Health Canada to develop and implement strategies that will significantly increase what is being termed “direct-from-consumer-reporting” of ADRs.

Consumers Must Report

Advocates of strategies to increase awareness among the public about ADR reporting assert that consumers have unique perspectives and experiences that often are not reflected in Health Canada’s database and are unknown to both those who prescribe and those who use medicines.

The problem is that consumers may not know about Canada’s ADR monitoring program and their ability to directly report adverse side effects. Such consumer reporting would provide early warnings to regulators, manufacturers, physicians, health professionals, and other consumers about side effects, thereby increasing the effective and safe use of medicines. Early signals about drug safety can invigorate more research or a more careful reassessment of the use of particular drug products, both of which are needed.

The scientific literature is just beginning to accumulate, but there are indications that consumer reports may provide meaningful and important insights into the experiences that people actually have with medicines and thus provide important insights for those prescribing, selling, or using prescription drugs.

One powerful example of this is a 2002 study assessing the quality of information in the UK Yellow Card scheme, the drug safety monitoring program that is widely regarded as one of the best postmarket surveillance systems in the world.

Charles Medawar and Andrew Herxheimer, the study’s authors, compared the quality of the information in the Yellow Card scheme to reports obtained directly from patients in 862 messages that had been sent to a website discussion forum between 2000 and 2002. Added to these messages were almost 1,400 emails sent to the BBC after a television documentary on Paxil was broadcast. Their analysis of the direct-from-consumer reports found previously unrecognized experiences that coincided with dosage increases and withdrawal from therapy.

This report suggested that “the collective weight of the patient accounts of experiences with [Paxil] therapy was profound.” Researchers found that “reports from users and relatives–especially with respect to behavioural effects–communicated information that professional reporters can never be expected to provide. They were far richer, and described suicidality and withdrawal symptoms much more clearly and intelligibly than the Yellow Card reports.”

Finally, the researchers’ analysis of “over a decade’s worth of Yellow Card reports suggests that miscoding and flawed analyses by regulators led to an underestimation of the risk of suicidal behaviour” during treatment with Paxil.

In this example, reports from consumers had a major impact on an international re-think of the safety and efficacy of certain antidepressants and, in particular, the link to suicidality and addiction.

A Prescription for Change

Health Canada has taken some positive steps toward opening up the reporting system to consumers, but they have not done nearly enough. Much greater public education and awareness about the potential side effects associated with drugs are needed.

A re-orientation of Canada’s postmarket monitoring system is needed to empower the public and involve them in the decisions about prescription drugs. Many groups have emerged over the last century to represent people who have only one thing in common: the medicines they took that injured or harmed them, their children, or other loved ones. They often view these events as part of an unjust system that serves the interests of manufacturers well, but fails the public. They are fighting for a drug approval system that puts patient safety first, and for a system that safeguards the interests of the public once drugs are approved for the market by Health Canada. That includes an early warning system that tells us when approved medicines may not be working properly.

The current system of postmarket surveillance is inadequate and underfunded. More resources and funding are required to raise awareness about the ability of consumers to report their experiences with prescription medicines and about the key role that citizens can and should play in our system of prescription drug approvals and postmarket surveillance.

Consumers need a stronger system to protect them from harmful drugs. This means increased resources to the Marketed Health Products Directorate, which is responsible for monitoring drugs once they’re on the market.

But citizens also have a role to play to ensure the drugs that get to the market in the first place are tested properly and that objective information about them is available to consumers. Public funding is needed to support an independent citizens’ network that represents the public interest in a system of drug safety, a network that does not have to rely on the pharmaceutical industry for its bread and butter.

The Drug Approval Matrix

Health Canada’s mandate is to ensure that the medicines flowing to the market are well tested, safe, and effective. The department has a number of tools at its disposal, including:

• Food and Drugs Act
• Health Products and Food Branch (HPFB)
• Therapeutic Products Directorate (TPD)
• Biologics and Genetic Therapies Directorate (BGTD)
• Natural Health Products Directorate
• Marketed Health Products Directorate (MHPD)

In the past these functions were referred to as the Health Protection Branch.

Keeping Tabs Following Approval

A system of postmarket surveillance is vital to:

• protect the health and safety of Canadians
• determine with greater accuracy whether the benefits of a drug continue to outweigh the risks
• ensure labels and product information remain current and up-to-date
• inform Canadians about adverse drug reactions so they themselves can make informed choices about what’s in their medicine cabinets­­­­

How to Protect Yourself

All drugs have side effects and not all people react in the same way to medicines. To help minimize the risk of an adverse drug reaction (ADR) to a medication prescribed by your doctor, make sure you have all the facts about the drug, vaccine, or medical device. You can do this by reading the product monograph, which you can obtain from the manufacturer. This will tell you what adverse drug reactions were detected during clinical trials and whether it may interact with other drugs you are currently using.

If You have an Adverse Drug Reaction, here are a Few Steps to Follow:

1. Contact Health Canada

Health Canada has a toll-free number that connects you to a regional Adverse Drug Reaction Centre. The number is 1-866-234-2345. Consumers and others can also visit Medeffect, Health Canada’s ADR website at hc-sc.gc.ca/dhp-mps/advers_react_neg/index_e.html to report adverse effects or to find out more about Canada’s system of postmarket surveillance.

2. Tell Your Doctor

Always report an adverse drug reaction to your physician or to the pharmacist who sold you the drug. This information should go on your medical record so you won’t be prescribed the same drug again.

3. Tell the Manufacturer

Manufacturers are the only group required by law to report serious adverse drug reactions. It’s important that they hear from you, but you should also report to Health Canada.

4. Get Involved–Educate Yourself

There are a growing number of consumer groups focused on prescription medicines. Now that natural health products are also coming under similar regulations as prescription drugs, consumers will want to make sure that their interests are being served. Some excellent non-industry- funded groups include:

• Women & Health Protection (whp-apsf.ca)
• Psychiatric Medication Awareness Group (psychmedaware.org)
• The Society for Diabetic Rights (diabeticrights.ca)
• Healthy Skepticism (healthyskepticism.org)
• Media Doctor, Canada (mediadoctor.ca)