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In this issue of JAMA Internal Medicine, Perry and colleagues1 review the concordance of medicines safety advisories among drug regulatory authorities in Australia, Canada, the United Kingdom, and the United States during a 10-year period. Across 680 individual safety issues, the authors report significant differences in the frequency with which individual regulatory authorities issued safety advisories for drugs approved in their respective jurisdictions, ranging from 29.6% (Australia) to 52.4% (United Kingdom). The frequency with which only 1 of the 4 regulatory authorities issued a safety advisory for an individual issue ranged from 11.1% (Australia) to 20.7% (United Kingdom).
Perry et al1 raise important issues for discussion in addressing the concordance of safety advisories among regulators. However, it should perhaps not be surprising that safety advisories differ across regulatory authorities, in part because some authorities may have more than one type of advisory. 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. Other issues may also contribute to the differences across the regulatory authorities, such as the extent of use of a particular medicine in a country, the specific policies and operating procedures of different health care systems, and a regulatory authority’s determination of the severity of the new risk being described and the public health importance of the new risk in its jurisdiction. Moreover, it is not clear if the safety advisories examined in this analysis included product labeling changes not associated with any additional communication by the regulatory authority. Despite these limitations, discordances observed by the authors warrant discussion of how regulators communicate the safety of medicines to the public and the anticipated outcome of these communications.
First, the principal way of communicating new information about medicine safety is through an update to the medicine’s approved labeling. Although labeling updates may occur frequently throughout a product’s life cycle,2 their association with the safe use of medicines is not consistent. For example, Dusetzina and colleagues3 systematically reviewed 49 publications (January 1990-November 2010) that assessed the outcome of US Food and Drug Administration (FDA) warnings—primarily, changes to product labels (commonly referred to as package inserts)—on medication use and prescribing practices. Measures of the outcomes (eg, dispensed prescriptions and adherence to clinical monitoring recommendations) varied among the 49 studies, but the most common finding was a decrease, sometimes transient, in drug use immediately after a warning was issued. Dusetzina et al3(p466) concluded that “[a]lthough some FDA drug risk communications had immediate and strong impacts, many had either delayed or had no impact on health care utilization or health behaviors.”
Second, regulatory authorities may issue additional safety advisories either to notify the public of product label updates or to announce that a new safety issue, not yet described in the product label, has been identified for further investigation. Each authority has its own criteria for issuing these advisories. In the United States, the use of these advisories is relatively new. In 2007, the FDA initiated a program to communicate potential drug risks early in the assessment of the available data, which it has since updated. The outcome of these advisories is less well studied than that of warnings.
Finally, even when multiple regulatory authorities decide that a safety advisory is warranted in response to a given safety issue, the advisories issued may differ in terms of recommendations, sometimes markedly so. Although regulatory agencies share information with each other about product-specific safety issues, the goal of such sharing is generally to exchange information and provide transparency with regard to rationale, so that each regulatory body can understand the bases for differing decisions and recommendations4; transparency, rather than harmonized outcome, is the primary goal. Discordances can occur for many reasons, but they are most likely to occur either when there are differing conclusions about whether a risk exists or when there is agreement on the risk assessment but a difference in the benefit-risk analysis or risk management options. With the increasing global reach of communications, such discordance can create confusion if the basis for the differing conclusions is not made clear.
The findings by Perry and colleagues1 add another dimension to the questions that must be answered as we attempt to optimize the extent and manner of communicating drug safety information, as well as their outcome to ensure safe prescribing of medicines to patients. 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. Regulators have an important role to play in providing such evidence.
Drug safety assessments and benefit-risk analyses are complicated undertakings and do not always lend themselves to clear-cut, universally accepted interpretations. When faced with new drug safety information, and especially when there are discordant interpretations of that 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. Finally, regulatory authorities need to continue efforts 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.
Corresponding Author: Gerald J. Dal Pan, MD, MHS, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Bldg 22, Room 4304, Silver Spring, MD 20993 (email@example.com).
Published Online: April 29, 2019. doi:10.1001/jamainternmed.2019.0266
Conflict of Interest Disclosures: None reported.
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Dal Pan GJ. Gauging the Effectiveness of Medicines Safety Communications From Global Regulatory Agencies. JAMA Intern Med. Published online April 29, 2019179(7):984–985. doi:10.1001/jamainternmed.2019.0266
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