Drug safety issues that are more frequently occurring, more serious and for which action is recommended are considered more important by HCPs to be informed about, and are more often preferred to be received immediately (i.e. through a DHPC). Similarly, when drug safety issues are more frequently occurring or when action is recommended, HCPs preferred to receive information on this safety issue at the moment of prescribing this drug to a patient (e.g. through a CPOE system). Discussing the safety issue with colleagues was the most common stated action. Most of the stated actions were affected by the frequency and seriousness of the safety issue. HCPs were more likely to stop prescribing the drug to new patients and to discontinue or reconsider the drug in patients already taking the drug in case of safety issues that occurred in at least 1 out of 1000 patients and/or for issues that could be irreversible and potentially life threatening. The type of evidence for the safety issue (i.e. whether it was based on clinical research or on epidemiological research and spontaneous reporting) had no impact on the preferences and responses towards the drug safety communications. Our study showed a surprisingly low familiarity with DHPCs among medical specialists, especially among those in training, who had a higher preference for receiving such information through other information channels.

Our results provide a deeper understanding on the influence of the content of safety messages on whether and when HCPs prefer to be informed about drug safety issues. Their perceived importance of being informed and being informed immediately depended evidently on three elements of the safety issue, that is, the frequency, the seriousness and the need for action. Although this may seem apparent, it underscores the value of providing direct communications for these types of safety issues. HCPs use multiple sources to obtain drug safety information, which differ in being distributed directly to them, such as DHPCs or bulletins, or are accessible on demand [12]. The majority of hospital-based HCPs in our study indicated they prefer to be informed about important drug safety issues immediately (i.e. through a DHPC), whereas less important safety issues could be communicated through periodic information sources, such as newsletters. This wish to be informed rapidly has been expressed before [12]. The optimal way of disseminating this information is still unclear, since information overload is a previously identified problem [4, 12]. In our study, HCPs preferred communication about more frequently occurring safety issues and safety issues with the recommendation of additional monitoring at the moment of prescribing, such as through a CPOE system. Other studies showed that pop-up warnings in the CPOE can be effective [20], although again it is advised to use such warnings in moderation in order to prevent ‘alert fatigue’ [21, 22].

Furthermore, our study illustrates that DHPCs concerning more frequently occurring and more serious drug safety issues are more likely to impact drug utilization, whereas the impact for less frequent or serious issues is likely to be limited. Regarding the seriousness, this is in line with earlier studies showing a larger decrease in drug use for more serious safety issues [6]. Where other studies showed that HCPs want to be informed about the frequency of safety issues [9, 12], our study adds that the likelihood to take action will differ depending on the content of such information. DHPCs have been criticized for a lack of clinical relevance and clear recommendations [9,10,11,12]. Our study showed that DHPCs with a clear recommendation to conduct additional testing were considered more important and were more likely to result in actions compared with DHPCs asking to be alert. This confirms findings from an earlier study, where a clear recommendation showed more impact than a more complicated warning [23]. A review conducted in the UK observed that communications with a restriction or change in indication had a larger impact than communications without a recommendation for action [13]. Another study, however, did not find a significant difference between communications with or without an explicit prescribing advice [3]. This discrepancy could be explained by differences in the content of the recommendations included, of which the clarity and quality should also be taken into account [10]. When a DHPC is lengthy, some HCPs may just quickly screen it and not read the part including the relevant recommendation [4]. One of the most common stated actions following the DHPC was to discuss the safety issue with colleagues. A previous study already indicated that the opinions of other clinicians were considered important to assess the clinical utility of the safety information received [9]. Uncertainties or debate about the clinical utility of a safety issue may result in a lack of action, and, therefore, may limit the impact of the DHPC in practice. According to our study, actions following a DHPC were only minimally impacted by the life span of the drug, confirming the results from a previous study [6].

Only half of the participating medical specialists and nearly all participating hospital pharmacists indicated that they were familiar with DHPCs, as opposed to a previous study among Dutch HCPs which showed higher familiarity of 72% among general practitioners, 85% among specialists, but similar rates of 95% among hospital pharmacists [8]. A more recent study showed a familiarity of 92% among pharmacists, specialists and GPs without significant differences between the professions, except for Italy where pharmacists were more familiar with the DHPC than GPs (99% vs 90%) [24]. The low familiarity among medical specialists in our study may be explained in part by the proportion of specialists in training in our study. More generally, HCPs may find it challenging to keep up to date on drug safety issues and some disregard DHPCs because these are mistaken for biased information coming from a pharmaceutical company [4, 12]. Furthermore, HCPs expect that important messages will be repeated through various channels [9, 12]. The medical specialists in our study clearly preferred and used multiple other channels to obtain or receive drug safety information.

Currently, for all drug safety issues for which a DHPC is deemed necessary, the same strategy is used by urgently distributing the information through direct mailings. This risk communication strategy cannot easily be altered considering legal obligations of pharmaceutical companies and regulators. Several studies have already provided recommendations to improve the process, such as using multiple channels and more trustworthy senders [5, 7, 8] and providing clear recommendations [9, 10, 12, 25]. Besides the confirmation that multiple channels are preferred, our findings support the need to adapt the current communication strategy and tailor it to the content of the message. For many hospital-based HCPs, the preferred moment of communication depends on this content. They prefer that less urgent safety issues are communicated only periodically. Thus, drug safety issues that are rare or very rare, not irreversible nor life threatening and without immediate action needed may be combined in periodical newsletters. These would typically include DHPCs that are distributed to raise awareness of the safety issue and safety issues that require ‘watchful waiting’. In such cases, this strategy would generate time to assess the clinical implications of the safety issue and formulate clearer recommendations, which could improve the uptake and impact of the information [13, 25]. Furthermore, the hospital-based HCPs prefer that multiple channels are used, and many prefer that safety information currently distributed in DHPCs is automatically incorporated into clinical guidelines and the information sources they commonly use when actively searching for drug information. This is in line with previous findings of HCPs who were concerned they might miss one-off communications [9, 12]. An additional channel for receiving important safety information, preferred particularly by medical specialists, is the CPOE. This would be an appropriate channel to provide alerts when additional monitoring is needed, but also other clinically relevant recommendations; for example, restrictions of indications or new contra-indications could be incorporated in CPOE systems. This is likely to increase the uptake and impact of such recommendations. Finally, our study showed that the perceived importance of being informed and preferences for the timing of the communication did not depend on the source of the safety issue, that is, evidence from epidemiological studies or spontaneous reports or clinical trials.

Our exploratory study was a first to examine the impact of the content elements of drug safety information on the preferences and responses of hospital-based HCPs towards such communications. Given the explorative nature of this study, we did not correct for multiple testing. By creating hypothetical DHPCs, several content elements were systematically varied whereas other factors were kept constant. This experimental design gives insight into the impact of these elements without the influence of factors that can be difficult to control, such as personal experiences. On the other hand, elimination of such factors can also be considered a limitation, since they can play a role when validating safety information [9]. Furthermore, using hypothetical DHPCs inhibits any assessment of actual behaviour, and we were only able to evaluate the impact of the content elements on stated actions. Also, our survey design does not allow for assessing any long-term impact. All respondents were hospital-based HCPs in the Netherlands, and our findings may not be generalizable to other countries as it has been found that preferences for how to receive drug safety information may vary depending on clinical and cultural contexts [25]. In addition, our results may not be generalizable to other HCPs in the Netherlands. Our respondents were recruited indirectly and therefore a real response rate could not be calculated. However, the estimated medical specialist population of interest, including those in training, was 9780 in 2019, resulting in a response rate of 1.1% [26]. The estimated hospital pharmacist population including those in training was 675 in 2019, resulting in a response rate of 10.9% [27]. We did include a diverse group of hospital-based HCPs when looking at their disciplines, age and working experience. Of note, this information was missing for 28% of our respondents, due to HCPs not completing the full questionnaire.