Evaluating the safety of prescription drugs prior to approval and monitoring their safety once they have been marketed should be a major priority in any drug regulatory system.
Over the past two decades, about 3-to-4% of the drugs approved by the Therapeutic Products Directorate (TPD), the arm of Health Canada charged with approving new prescription drugs, have subsequently had to be withdrawn from the market due to safety reasons.
Although the percentage of withdrawals has remained relatively stable, aggressive marketing of new drugs means that an increasing number of people are exposed to these drugs before they are removed from the market. In the two-to-four years that bromfenac, dexfenfluramine and mibefradil were on the U.S. market in the mid- to late 1990s, 6.4 million people were exposed to them. Two of the five most heavily promoted drugs in Canada in 2000 (Baycol and Vioxx) were subsequently withdrawn because of safety issues.
Furthermore, vigilance about drug safety needs to be continuously maintained even for older medications. The accompanying Table shows that even drugs that have been on the market for a considerable length of time cannot be regarded as safe.
With Health Canada’s Expert Advisory Committee on the Vigilance of Health Products recently embarking on a consultation about its tools for communicating risk, it is timely to examine Health Canada’s activities with respect to drug safety.
Over the past decade, financing for the TPD has shifted from coming entirely from government appropriations to the current situation where about one-third of the revenue comes from pharmaceutical companies in the form of user fees. This shift in financing has raised concerns about whether Health Canada’s primary commitment is still to public health or to the pharmaceutical industry.
One way of evaluating where Health Canada’s priorities lie is to look at how it allocates its resources. In the fiscal year ending March 31, 2004, the TPD had 423 employees and revenue of $38 million, compared to 90 employees and a budget of $8 million for the Marketed Health Products Directorate (MHPD), the branch of Health Canada responsible for drug safety. Two years later, the ratios had only marginally improved: although the MHPD now had 120 staff and a budget of $13 million, the comparable figures for the TPD were 525 employees and $42 million.
Faster drug approvals
The TPD has committed to approve non-priority drugs within 300 days, and priority drugs within 180 days. Whether or not the speed at which drugs are approved results in a greater percentage of unsafe drugs reaching the market is the subject of an ongoing debate.
A study from the United States suggests that the true effect of faster approvals on safety is not the overall rate of withdrawals, but what happens to those drugs approved on the cusp of the approval deadline clock. (The American Food and Drug Administration [FDA] has a statutory requirement to approve 90% of new drug applications within specific periods, depending on whether it is a standard or priority review. If it fails to meet that obligation, then renewal of the Prescription Drug User Fees Act, authorizing the collection of user fees from pharmaceutical companies, may be endangered.)
The conclusion is that, when drugs are approved in the immediate pre-deadline period, there is a substantially higher rate of withdrawals and/or safety labelling changes compared to drugs approved after the deadline. In other words, it appears that, if the deadline is imminent the FDA does a less thorough job of reviewing drugs in order to avoid crossing the deadline.
Revenue to the TPD will also suffer if service standards (approval of new drugs within the targeted time) are not met. If the actual performance in a given fiscal year is more than 110% of the target for that fee category, penalties apply for the amount in excess. Fees are then to be reduced for the next reporting year by a percentage equivalent to the performance not achieved, up to a maximum of 50%. Faced with the prospect of penalties, it is possible that the TPD might follow the pattern set by the FDA and quickly approve new drugs to avoid incurring a financial loss in the next year.
Lack of measurable standards
Although Health Canada, through its cost recovery initiative, has committed itself to achieving measurable standards with regard to drug approval times, it has no standards for safety issues. For example, there is no standard for the length of time that it will take between the receipt of an adverse drug reaction (ADR) report and when that report has been analyzed and posted on Health Canada’s Medeffect Adverse Reaction Database.
The United Kingdom commits to three-to-seven days to process ADR reports, and Australia targets initial professional review of adverse drug reaction reports within three days. Health Canada has explicitly rejected developing standards, claiming that “development of quantitative service standards for post-market surveillance activities or compliance and enforcement activities is difficult, given the unpredictability and volatility of the activities involved.”
When important safety problems are identified with drugs, the company manufacturing the product sends out a notice of the safety issue on behalf of Health Canada to health care providers, and Health Canada posts a notice for the public on its web-site. Single letters or web-site announcements about safety problems have been shown to have little or no impact on the prescribing of drugs. Health Canada does not make any effort to monitor the impact of the safety information it provides or authorizes, and a paper published in September 2008 in the Canadian Medical Association Journal confirms that these warning letters make no difference to how Canadian doctors prescribe anti-psychotic medications.
Bill C-51, which was introduced into Parliament last spring, incorporates the principle of progressive licensing: moving from an “all-or-none situation”–either license the drug or don’t–to a position where drugs are followed throughout their entire life-cycle. The promise of this new system is that ongoing re-evaluation of the risks and benefits of medications will pick up serious safety issues earlier and help to better target drug therapy.
Under Bill C-51 Health Canada, acting through the Minister of Health, will be given the additional authority to issue the market authorization for a drug, subject to additional terms and conditions, and suspend the authorization if the company does not follow through on its obligations.
In practice, these new powers will likely mean that Health Canada will be able to require companies to carry out post-marketing studies to look at new or unresolved drug safety problems. While in theory this additional information should be valuable in assessing new products, there are worries about relying on industry-funded studies. A systematic review has shown that commercially sponsored research is much more likely to result in positive outcomes than research funded from any other source.
The safety of prescription drugs is an ongoing issue, but Health Canada continues to put the bulk of its resources into the drug approval system rather than on the evaluation and monitoring of the safety of medications. The lack of measureable standards for drug safety is one indication of the emphasis that Health Canada puts on safety matters. Prioritizing new drug approvals may be a reflection of the change in the source of revenue for the organization, and preserving the amount of money coming from drug companies could further jeopardize drug safety through hasty approvals.
The shift to progressive licensing through Bill C-51 offers some hope of re-focusing Health Canada’s priorities, but only if it is willing to take post-marketing safety studies out of the hands of the pharmaceutical companies.
(Joel Lexchin—[email protected]--is a Professor in the School of Health Policy and Management at York University, where he teaches health policy in general and pharmaceutical policy in particular. He also works in the Emergency Department at the University Health Network and is an Associate Professor in the Department of Family and Community Medicine at the University of Toronto.)