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Regulators Uneven on Safety Warnings on New Drugs

Diana Swift
April 30, 2019

A 10-year review of national regulatory agencies of four English-speaking countries has found that health regulators do not always notify physicians and the public about postapproval emergent harms associated with newer drugs.

The findings suggest that clinicians need to be vigilant when prescribing new medicines.

The review, published online April 29 in JAMA Internal Medicine, shows that there is considerable variation in pharmacovigilance and communication patterns between regulators in the United States, Canada, the United Kingdom, and Australia. The United States comes in third after the United Kingdom and Canada in terms of the frequency of distributing drug safety advisories.

Using data from the regulators' current and archived websites, Lucy T. Perry, MPharMed, of the Charles Perkins Center and School of Pharmacy in the Faculty of Medicine and Health at the University of Sydney, New South Wales, Australia, identified 1441 safety advisories across the four jurisdictions that covered 680 drug-related risks from 2007 through 2016. The authors defined safety advisories as notifications to prescribers or the public about a potential or confirmed drug risk, aside from problems related to production quality, shortages, or overdoses.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued the highest proportion of advisories, covering 344 of 657 drug-risk problems (52.4%) related to medicines approved in the United Kingdom. It was followed by Health Canada (HC), which released advisories for 317 of 635 drug-risk problems (49.9%).

In the United States, the US Food and Drug Administration (FDA) sent out notifications on 265 of 647 safety problems (41.0%). Australia's Therapeutic Goods Administration (TGA) released advisories for 183 of 619 (29.6%.)

Among countries, the overall frequency of safety advisories differed significantly (P < .001).

"In each country, drug regulators were not sending out safety warnings about all of the risks of drugs," study coauthor Barbara Mintzes, PhD, an associate professor of pharmacy at the University of Sydney, told Medscape Medical News. "Doctors need to be careful when prescribing new drugs, especially for patients who were not studied in the premarketing phase."

She advised physicians to use new drugs cautiously, especially when treating high-risk patients, such as children, pregnant and lactating women, the elderly, immunocompromised individuals, and those taking more than five drugs.

On the measure of being the only regulator of the four to release an advisory, the FDA distributed warnings on 89 of 647 (13.8%) drug safety problems. The MHRA was the most frequent sole issuer, with 136 of 657 (20.7%). HC released notifications on 122 of 635 (19.2%), and the TGA was sole distributor for 69 of 619 notifications (11.1%), making it the least likely to send out safety advisories (P < .001; Bonferroni adjusted significance P = .006).

For just 70 of the 680 identified drug-risk problems (10.3%), regulators issued advisories in every country where the drug was marketed. For 40 of 573 drug-risk problems, all four countries had approved the drug and also issued advisories.

Medscape Medical News previously reported that almost a third of drugs newly approved by the FDA turn out to have safety problems unknown at the time of approval.

Perry and colleagues note that similar inconsistencies in safety advisories were seen in a 2014 comparative analysis of direct health professional communications issued by four European countries.

Although the current study did not address other ways by which regulators may have communicated risk, a sensitivity analysis that included safety letters sent out by the US Risk Evaluation and Mitigation Strategies showed little impact on results, finding a 57% vs 59% FDA discordance rate.

"Further study into the regulators' decision making and action thresholds (based on seriousness of harm or strength of evidence) and the follow-on effects of these decisions and actions is required to fully elucidate the public health implications of these policies," the authors write.

Currently, there is no information on how these communication gaps affected adverse drug events in the four countries. "It isn't possible to compare the numbers of reports in adverse drug reaction databases, as reporting is voluntary and we know that there is underreporting," Mintzes said. Her group is conducting follow-up research to see whether differences between regulators in the decision to warn makes a difference with respect to prescribing and patient health.

In a commentary published alongside the new report, Gerald J. Dal Pan, MD, MHS, of the Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research at the FDA in Silver Spring, Maryland, notes that a prior review found that whereas some FDA safety warnings had a rapid, strong effect, many had little effect on healthcare behavior or use.

Dal Pan comments that the new four-country comparison expands the questions that must be answered in order to determine the ideal extent and manner of communicating drug safety information.

"Many aspects of optimal drug safety communication — such as the most effective dissemination outlets, the appropriate timing and frequency, and the minimization of unanticipated adverse consequences — still require evidence that is based on robust communication science," he writes.

He notes that safety advisories will inevitably differ across jurisdictions, with some authorities using several different types advisories. "Because the authors do not specify the details of the methods they used to identify safety advisories, the comparability in the safety advisories across the 4 regulatory authorities is difficult to assess," he writes.

The picture may be clouded further by differences in the use of particular medicines in different countries, by differences in the operating procedures in different healthcare systems, and by differences in regulatory authorities' evaluations of risk severity. Furthermore, it is not clear whether the advisories in the current review include product labeling changes — the most common method of updating drug safety information — that were not associated with additional notifications.

Dal Pan points out that assessment of drug safety and analysis of benefit vs risk are complex processes the results of which are not always easy to interpret. When given new drug safety information, "practitioners should examine the totality of the evidence and the uncertainties around that evidence to determine how best to incorporate the new information into practice, as should all professional societies and organizations that develop practice guidelines," he writes.

In addition, he notes that regulatory authorities need to be as transparent as possible in their safety advisories so that practitioners have the information necessary to make informed decisions about how they will use a medicine.

The research was funded by grants from the National Health and Medical Research Council of Australia and the Canadian Institutes of Health Research, which had no role in any aspect of the study. Perry has reported employment with George Clinical Pty Ltd outside the submitted work. The other authors and Dal Pan have reported no relevant financial relationships.

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Reviewed on 4/30/2019

SOURCE: Medscape, April 30, 2019. JAMA Intern Med. Published online April 29.

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