Regulatory advisories are a common method of disseminating emerging safety risks from prescription drugs, and the role of the FDA in communicating will grow with the Sentinel Initiative and other regulatory efforts to improve safe prescription use (59
). Most studies we examined were empiric analyses of drug and non-drug utilization; many fewer examined patient-provider communication and decision-making or risk perception. Since the communications had highly variable effects, the small number of contexts investigated relative to the number of settings where advisories have been issued is noteworthy.
The communications examined differed in several ways, such as whether they focused on a single drug, targeted a specific subpopulation, or addressed an idiosyncratic risk. Although the nature of the studies precludes quantitative comparisons, several suggestive conclusions can be drawn. First, advisories recommending greater monitoring do not appear to have led to large and sustained changes. For example, increases in laboratory monitoring for troglitazone, pemoline or antipsychotics and clinical monitoring for antidepressants were generally incomplete and/or temporary and often led to decreases in medication use. Second, in settings where incident and prevalent use was examined, such as in the case of cisapride, terfenadine, and antidepressants, warning information appears to have been adopted more quickly for new rather than continuing medication users. Despite this, it is not clear from these reports whether continuing users or their providers were well informed regarding the specific risks addressed. Third, principles of risk communication suggest that warnings will be most effective in cases where they are specific, where acceptable alternatives are available and where the messaging is reinforced over time (5
). The case of cisapride provides one example, where the first and less specific messaging did not lead to large changes in co-prescribing with contraindicated therapies, compared with subsequent more specific communications (21
). Interestingly, the magnitude of substitution within a class where an advisory was issued for a single agent varied across settings, from little evidence of substitution of pioglitazone for rosiglitazone, to modest increases in clarithromycin for telithromycin, to larger increases in antidepressants other than paroxetine, albeit with additional advisories regarding other specific anti-depressants. Finally, based on the selected primary data collected from surveys and focus groups, most physicians appeared aware of general safety concerns, though many provider respondents disagreed with advisory content. The single study examining parental attitudes and beliefs suggest they had limited understanding or awareness of the OTC cough medicine communication.
As with other public policies, FDA communications have the potential for unintended consequences. Antipsychotic and antidepressant advisories were associated with decreased use in non-targeted populations, and there is evidence of increases in suicides among children following the antidepressant advisories (44
). Decreases in telithromycin use also appeared to occur non-selectively; the advisory did not appear to affect the proportion of all uses that were for off-label indications (32
). These studies are not the first to suggest the potential for unintended consequences from regulatory warnings regarding prescription drugs (61
), and their potential demonstrates the challenge that policy-makers face to design risk messages that are maximally effective, specific, and that don’t become risks themselves.
Our study has a number of limitations. First, the number of different therapeutic areas, communications, outcomes, and study designs used precluded anything more than a qualitative analysis of findings from the studies that we gathered (63
). The heterogeneity of studies does not permit for an “average effect” of FDA communications to be estimated, nor an estimate of the relative potency or impact of one form of communication compared with another. Second, regulatory advisories exist within a sea of information that may influence health care utilization and behaviors (64
), and thus the complexity of the phenomenon studied, and multitude of potential influences that may shape behavior, also limit conclusions drawn from this type of review. Third, our study was limited to the peer-reviewed literature regarding FDA drug risk communications. Finally, although the behavioral responses that most studies examined are relevant to stakeholders, they provide incomplete information on the efficacy of a communication; the absence of a strong response may indicate a previously informed population, or a population where the new information was insufficient to prompt different decision-making, whereas the presence of a strong response may indicate over compensation on the part of patients and providers (8
Our review also raises several questions. None of the studies examined included rigorous assessment of how the effect of advisories may vary across groups of physicians, practices, or other communities. Given the complex determinants of health care utilization and health behavior, there is likely substantial variation in responsiveness to FDA communications among different subsets of providers and patients (66
). In addition, although one-fifth of the studies examined were based on surveys or qualitative investigations, little is known regarding how these risk communications affected patients’ communication with health care providers or their risk perceptions. Also, few studies(43
) examined medication switching among individual patients. Thus, although some studies provide insights regarding how a regulatory communication may lead to changes in market share within a therapeutic class, almost none provide a window for understanding how individual patients’ pharmacotherapies change as a result of an advisory or label warning. Finally, few studies examined health outcomes associated with medication changes that may have ensued following an FDA communication. Since the goals of risk communication are to minimize potential harms, understanding the impact of an FDA communication’s intended (and unintended) consequences on patient health outcomes should be a priority.