Post-Market¹ Surveillance of Therapeutic Drugs in Canada

By Colleen Fuller and Diane Saibil
February 2005

Introduction

Regulation of prescription drugs is critically important in protecting the health and safety of citizens. It is the job of the Canadian government to regulate prescription medicines, from the clinical trial phase through to approval and the marketing and selling of the drugs. Even the most rigorous government approval process for new drugs cannot possibly predict the full extent of harmful or unexpected effects of a drug once it is on the market. For that reason, all countries, including Canada, need a post-market surveillance system for therapeutic drugs.

However, partly due to inadequate funding, the current Canadian post-market surveillance system does not adequately detect harmful or unexpected effects of drugs in a timely manner. Delays in identifying harm caused by drugs result in corresponding delays in appropriate follow-up actions, such as providing additional information and warnings to health professionals and consumers, revising or adding information to a product’s label, restricting use or withdrawing a product from the market.

The harmful effects of therapeutic drugs are often under-emphasized and dismissed. Commonly used terms such as “adverse drug reaction” or “side effect” imply a single event, such as an allergic rash, rather than a condition like lymphoma that may be a long-term result of using a drug. This terminology makes the effect seem incidental or unrelated rather than part of what the drug does. It may be more honest to refer instead to “harms caused by drugs”.

In this paper, we argue that greater consumer involvement would considerably improve the effectiveness of the post-market surveillance system.

The critical importance of an effective post-market surveillance system

Before a new therapeutic drug can be marketed in Canada, it must be approved by Health Canada. To get approval, the manufacturer must submit for review all information about the drug, including any individual reports of unexpected harm and the results of clinical trials. The process is primarily designed to find out whether a drug, in controlled circumstances, produces the desired effect in treating or preventing a specific medical condition. Health Canada also collects and tabulates all reported harm associated with the drug. The Health Canada reviewer then makes a judgement about whether the anticipated clinical benefit outweighs the risk of any harm that the drug might cause. Regrettably, when Health Canada reviews an application by a drug company for permission to market a drug in Canada, it only has access to limited safety data. Clinical trials are primarily designed to test for "efficacy"2. While safety data are collected, often the drug has been tested in too few people to identify less common problems associated with it. Moreover, attributing harmful effects to a drug is a judgement call that is subject to reviewers’ biases.

Once a new drug is on the market, actual population exposure to the drug differs significantly from clinical trials, both in terms of the number and diversity of people receiving treatment and the dose and duration of therapy. General population exposure may include people with multiple medical conditions taking multiple other medications, children, the elderly, women in general and women of childbearing age in particular. It is often the case that individuals from these groups are represented either inadequately or not at all in clinical trials. As a result, different benefits and harms are likely to be observed post-marketing than were seen in research conditions. Furthermore, the duration of clinical trials can vary, but it is typically less than 90 days. By contrast, a drug may be used in therapy for a far longer period, sometimes over a lifetime for those with chronic conditions. Therefore, it is not possible to know what the full range of harmful effects of any given drug may be on the basis of clinical trials alone. In essence, when a new drug comes onto the market, it continues to be “experimental”3. Heavy use of newly approved drugs in unstudied populations is significantly driven by promotion – both to health professionals and to consumers.

Another factor that must be considered when assessing harms is the use of approved drugs to treat conditions for which they have not been authorized, known as “off-label” use. Health Canada reviews a drug’s efficacy in relation to a particular use by a particular population. Approval is granted for treatment of specific conditions and sometimes only in a specified population. However, Canadian physicians are not legally constrained from broader or off-label prescribing of a drug once it is available for another approved use. In off-label use, doctors are prescribing drugs for people and for conditions either for which Health Canada has rejected evidence of efficacy or safety or for which no evidence was submitted in the first place. This practice is particularly noteworthy in paediatric medicine but is also very common in the use of hormones in women.

There have been too many instances of drugs approved for therapeutic use that have subsequently been found to cause serious harm, including long-term illnesses and sometimes death. Recent examples include hormone replacement therapy and Vioxx. Hormone replacement therapy (HRT) was prescribed to millions of women worldwide for several decades before scientists and medical professionals, under pressure from women’s health and consumer groups, finally carried out clinical trials which established that it was causing more harm than benefit to most; its use increased women’s risk of heart disease, strokes, invasive breast cancer and blood clots. Vioxx, a pain-killer and arthritis drug, was withdrawn from the world market in the fall of 2004 when the manufacturer acknowledged research evidence showing that Vioxx increases users’ risk of cardiovascular disease. Here the problem was less a matter of clinical trials that were too short or too small, but rather a situation where the manufacturer interpreted information in such a way as to minimize the harms associated with the drug.

The above are but two of many examples of how our current drug approval system does not and, in fact, cannot catch many of the harmful and unexpected effects of new drugs that will become evident once they are on the market and being used by a large, diverse population for periods of time significantly longer than in clinical trials.

Problems with the current post-market surveillance system

Once a drug is licensed for use, regulators invest what many feel to be inadequate resources for gathering or analysing reports of serious harmful effects.4 The Marketed Health Products Directorate no longer has sufficient resources to routinely determine the likelihood that a particular drug has caused a reported adverse effect. The post-market surveillance system relies exclusively on voluntary reporting by health professionals and consumers, although reporting by health professionals may become mandatory in the near future. These voluntary reports can be submitted either to the drug manufacturer or directly to Health Canada’s Adverse Drug Reaction Monitoring Programme (CADRMP). CADRMP maintains a computerized database, the Canadian Adverse Drug Reaction Information System (CADRIS), of reports filed with them. Manufacturers have a legal responsibility to submit reports of serious harm within 15 days of receiving them. Health Canada advises manufacturers that a report of harm suspected to be caused by a drug is “reportable” if “the minimum reporting criteria are met and the report is considered relevant by a medical professional in the industry.”5 To meet minimum reporting criteria, a report must identify: that a patient existed; the suspect product; the suspect reaction; and the reporter.6

Most experts estimate that, overall, only between 1% and 5% of harmful effects are reported to Health Canada. This low rate of reporting makes it impossible for CADRMP’s database to accurately reflect the extent of harm caused by any given drug. Because of this low rate of reporting, CADRMP does not have enough data to effectively monitor drug effects and therefore appropriate action is delayed, although they do participate in the international system for ADRs that is run by the WHO which can help in some measure to augment Canada’s data base.

In this environment, where doctors, manufacturers and Health Canada are all doing an inadequate job of watching over the safety of medications, the burden of identifying and reporting harmful effects to Health Canada falls on the people receiving drug therapy. But minimal resources exist to provide consumers with information regarding their right to report directly to Health Canada and how to go about doing so.

What has made the system work better?

Sometimes the reporting system has worked more effectively; that is, a higher percentage of harmful effects have been reported. For better or for worse, there is evidence that media and regulatory attention regarding a particular drug can significantly increase the number of reports of harm. A case in point is the story of Diane-35, a drug approved in Canada only for the treatment of women with severe acne who had failed to respond to one or more other acne treatments, and who had signs of androgenization (or excess male hormones). As explained by Barbara Mintzes in a recent case study,

“From April 1998 to December 2002, during nearly five years, there were only 25 reports of adverse drug reactions in which Diane-35 was the suspected cause, including one death. About three-quarters of these reports were of serious adverse events according to the World Health Organization definition: life-threatening, leading to hospitalization or prolonged hospital stay, or resulting in ongoing disability, cancer or birth defects.

Health Canada posted a first safety advisory about Diane-35 on December 23, 2002, [a] CBC documentary was aired on January 14, 2003, and a ‘dear health professional’ letter was sent to physicians on April 10, 2003. The primary focus of both media attention and the advisories was the increased risk of venous thromboembolism (VTE) with Diane-35. In the ten months from January to October 2003, the rate of voluntary adverse drug reaction reports increased more than ten-fold, from an average of 0.4 to 4.6 reports per month. The additional 46 reports over this time period were almost all serious according to the World Health Organization definition and included 33 reports of VTE and 5 additional deaths. It is unlikely that the rate of death and serious adverse events rose dramatically following press and regulatory attention; a much more likely explanation of this difference is that physicians and patients became more aware of Diane-35’s potential risks, and were more likely to suspect the drug as a possible cause and to report the events that occurred.”7

It is noteworthy that CBC’s interest in Diane-35 was sparked by a Women and Health Protection awareness campaign that focused on direct-to-consumer advertising of Diane-35 and associated problems.

One important way to increase reporting by individuals of harm caused by therapeutic drugs is education and awareness-raising about the potential for harm associated with any particular drug or class of drugs. Consumer groups, formed to provide and exchange information, are in a good position to carry out these activities effectively. Two such examples follow.

DES
The drug diethylstilbestrol (DES), a synthetic estrogen, was prescribed to pregnant women between 1941 and 1971 to prevent miscarriage. Extrapolating from the incidence of a rare form of vaginal cancer found in young women and attributed solely to DES,8 it is estimated that DES was prescribed to up to 400,000 women in Canada, especially those who had a history of miscarriage, slight bleeding or diabetes. Beginning in 1952, studies showed that DES did not, in fact, prevent miscarriage, and even appeared to increase its risk.9 Despite the proof of its ineffectiveness and the mounting evidence that DES was linked to significant risks, it was not banned for use in pregnancy until 1971, 30 years after it was introduced. Links to vaginal and testicular cancers in the children of “DES mothers” were found in the early 1970s and women who were taking DES were later found to have an increased risk of breast cancer.

In 1982, Harriet Simand decided to contact the media to see if she could find out more about other women who had been exposed to DES, either directly or in utero. The New York branch of a US group called DES Action put her in touch with the CBC producers of “Take 30” and, in March 1982, Harriet appeared on “Take 30” and asked women to get in touch if they or their mothers had taken DES. Within weeks over 100 letters arrived in the mail.

The response prompted Shirley and Harriet Simand to expand the work they were doing to raise awareness about DES to other parts of Canada, creating DES Action chapters in several cities. The groups identified doctors to screen women for problems that might be DES-related. Through the media, DES Action members raised DES’ profile and alerted both women and men to the problems associated with the drug.10

Depo-Provera
Depo-Provera is a long-acting, injectable contraceptive hormone drug. In the 1980s, Depo-Provera was approved for use in Canada as a treatment for endometriosis and selected cancers. In 1988, Upjohn Canada’s application for the approval of Depo-Provera as a contraceptive provoked considerable protest from Canadian women’s health groups and the formation of the Canadian Coalition on Depo-Provera. Following presentations by many disability advocates, women’s health advocates and representatives from the Aboriginal community about harms caused by this form of contraception, Health Canada rejected the application. The manufacturer resubmitted the

Opposition to Depo-Provera by consumer groups continued as evidence of both short-term and long-term harms caused by the drug continued to accumulate. Studies from New Zealand and elsewhere demonstrated an increased breast cancer risk among Depo users, as well as decreases in bone density leading to osteoporosis. Nevertheless, it continued to be prescribed and was a popular form of birth control, particularly among young women. It was not until November, 2004 that the pharmaceutical giant, Pfizer, acknowledged what research had shown many years earlier, and what women’s health groups had pointed out repeatedly: use of Depo-Provera can cause a significant loss of bone mineral density, the loss increases with duration of use, and the loss may not be completely reversible. The Canadian Coalition on Depo-Provera had pointed out these harmful effects in a letter to the Canadian Minister of Health and Welfare more than ten years earlier.

The case for greater consumer involvement
Women, as the primary recipients of therapeutic drugs, have a strong interest in creating collective, consumer-based awareness of harm caused by both new and established treatments. The above examples demonstrate what organized groups of consumers have been able to do in situations where serious harm was occurring as a result of widespread use of approved therapeutic drugs. The accumulation of data indicating serious harm was significantly assisted through the efforts of consumers, mainly women, who worked together at the community level to inform and educate, enabling others to identify their experiences as harm caused by a drug, and encouraging them to come forward and tell their stories. Consumer health groups, if adequately resourced, clearly have the potential to improve reporting by assisting individuals in identifying harm caused by therapeutic drugs and helping them to file reports. They can also bring problems to the attention of regulators sooner and more effectively than individuals. Furthermore, their greater personal interest in the outcome may well make them more effective than both the pharmaceutical companies and the health professionals in this task.

Conclusions

Health Canada operates under both political and economic constraints. Political directives, based on the government’s Throne Speech, have committed Health Canada to implementing faster approvals for new drugs; to date, there has been no equivalent political commitment to improve post-market surveillance of therapeutic drugs. In addition, resource allocation decisions make it difficult for Health Canada to implement existing regulations and systems to effectively monitor post-market harm caused by drugs. Persistent lobbying from the pharmaceutical industry to promote speedy approvals of new drugs compounds the problem. Women’s and consumer groups have an essential role to play in educating consumers, pooling information about harms caused by drugs and bringing this information to the government’s attention. The goal of such groups is to connect consumers with consumers, to help people identify when they are experiencing harm caused by a drug, and to educate them about the need to report harm. Consumers’ groups can also facilitate the gathering and reporting of larger numbers of adverse events, thereby mitigating the tendency of regulators to downplay individual case reports.

For post-market drug surveillance to work effectively, there must, as a starting point, be a sharp increase in consumer reporting directly to government. This can be achieved by launching an information campaign directed to consumers that encourages consumers to report harm directly to Health Canada. To achieve this, consumers’ and women’s health groups that have demonstrated expertise in this area must be supported to do the job they do well.

Women and Health Protection is financially supported by the Women’s Health Contribution Program of Health Canada. The views expressed herein do not necessarily represent the views of Health Canada.

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Notes

1 A more accurate term would be “post-approval”, or “post-licensing”. The term “post-market” has been used throughout this paper as it is the commonly used terminology.

2 Efficacy refers to data obtained under ideal conditions, as in a clinical trial when variables are held under control and subjects are selected. Effectiveness, on the other hand, refers to a real world situation, where a variety of uncontrolled factors may intervene, for example: people simultaneously taking other medications or having other medical conditions, people not always following dosage instructions correctly or forgetting to take all of their pills, etc.

3 Health Canada effectively recognizes this “experimental” status in that it considers an “unusual failure in efficacy” of a drug as an adverse reaction and requires manufacturers to report all of these cases as long as a drug is considered “new”, which for the purposes of this requirement is a minimum of seven years after it has first been marketed in Canada.

4 In 2003, the Canadian government committed $190 million to be spent over a 5-year period to improve drug regulatory systems. Of the $40 million earmarked for year one, only $2.5 million was allocated to the Marketed Health Products Directorate, the branch responsible for post-market surveillance. [Joel Lexchin in CMAJ, August 3, 2004; 171(3).]

5 Guidelines for Reporting Adverse Reactions to Marketed Drugs. Guidelines for the Canadian Pharmaceutical Industry on Reporting Adverse Reactions to Marketed Drugs (Vaccines Excluded). Published in 1996, Revised July 2001. Health Product Safety Information Division, Bureau of Licensed Product Assessment, Therapeutic Products Directorate, Health Canada. www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/industry_guidelines_e.html

6 Fuller, C, Women & Adverse Drug Reactions: Reporting in the Canadian Context. Women & Health Protection, Toronto. October 2002 (available on the WHP website at www.whp-apsf.ca).

7 Mintzes, B, Drug regulatory failure in Canada: The case of Diane-35. Women and Health Protection, Toronto. October 2004 (available on the WHP website at www.whp-apsf.ca).

8 Clear cell carcinoma has been found in non-DES related cases, but only in post-menopausal women.

9 Dieckmann WJ, Davis ME, Rynkiewicz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol 1953; 66(5):1062-81.

10 DES Action Canada provides information about diethylstilbestrol on its website, an excellent example of advocacy on the Internet. Its website address is www.web.ca/~desact/anglais/anglais.html.

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