Regulation and Risk


warning changes in labelling) were obtained and a list was produced of the key content, organisation and formatting characteristics.


DDLs informing physicians of warning changes were issued in 25.8% of cases. DDLs were most likely to be sent when the warning change involved information about patients who should not receive the drug or would be at increased risk or when the change involved a black box warning. Ratings of these letters by 10 primary care physicians showed the most significant deficiency to be that the most relevant information was not easily apparent.


This study indicates that the presentation of critical prescribing or safety information may influence how a physician responds. Greater attention to presentation in DDLs may increase the likelihood that physicians will read, remember and act on presented information.


Dosing and Monitoring Guidelines


Labelling included left ventricular ejection fraction (LVEF) testing before the initial mitoxantrone infusions and all infusions of cumulative doses ≥100mg/m2. Product labelling was revised in 2005 to recommend LVEF testing prior to each infusion. This monitoring/labelling change was described in DHCPLs issued to providers who also received additional educational programmes and materials. Complete blood counts (CBCs), liver function tests (LFTs) and urine pregnancy tests were also recommended for mitoxantrone patients prior to each dose.


A retrospective study was conducted (using both claims and chart data) on doctors’ adherence to dosing and monitoring guidelines for mitoxantrone, which was approved for treatment of multiple sclerosis in 2000.6


In this study, 548 patients were included in claims data used and 261 patients in the medical records data used. Results showed LVEF testing was performed for only 18.2 and 10.6% of infusions according to claims data and chart data, respectively. CBCs were performed for 78.2 and 83.0% of infusions according to claims data and chart data, respectively. LFTs were performed approximately half of the time. Pregnancy tests were only performed for 10.0 and 7.7% of infusions according to claims data and chart data, respectively.


Overall, there were clear indications that the clinicians followed monitoring guidelines for CBC and cumulative dosing guidelines for mitoxantrone. However, adherence to the other laboratory monitoring recommendations was low, with the lowest being pregnancy testing. There was an increase in LVEF testing, but the increase was only modest. The authors recommended both automated and manual data be used to improve qualitative and quantitative assessments of adherence to dosing and monitoring guidelines. Of interest, there was concern expressed by the author about the source of funding to allow monitoring of adherence to guidelines for ‘older’ drugs, such as mitoxantrone, which is now off-patent.6


Do Risk Evaluation and Mitigation Strategy Communication Tools Work?


Review of the effectiveness of MedGuides as a REMS tool presents valid concerns, particularly since most of the existing REMS today require only a MedGuide. Published studies cited in this review do not provide supportive evidence that suggest MedGuides have been effective risk mitigation tools in the past.11,23


Consumers receive so


much paper information they can no longer differentiate which is the truly important product safety information. When they do read a MedGuide, they often find it lengthy and difficult to understand.


24


While the examples cited in this article suggest that relevant safety information must be obviously stated in HCP communications, with emphasis focused on the most important message of the letter(s), DDLs do not appear to substantially change co-prescriptions of contraindicated drugs. They do not profoundly affect laboratory testing or patient monitoring in any durable manner either. Thus, printed materials and practice guidelines have not been shown to change prescribing behaviour24


and do not appear to be an effective risk communication tool when used as the sole risk intervention.


In a recent RPM Report, the FDA stated that the best way to communicate drug safety messages was to use the existing tools developed over decades by the drug industry.25


However, DDLs and


Drug safety surveillance requires effective communication of findings to prescribers and the general public, but it is not yet clear that methods for such communication can be implemented on a national scale.20


Evidence has shown that drug utilisation letters sent to both pharmacists and physicians have more impact in changing prescribing behaviour than letters sent only to the physicians.28


Alternative Risk Evaluation and Mitigation Strategy Tools for the Future One recommendation for changing prescribing behaviour is to strengthen the role of the pharmacist as a risk manager to disseminate information to patients about new drug interactions or other product risks.26


Interventions that


focus on another person in the drug-use process, in addition to the physician, may therefore have greater effect on a change in prescribing a targeted drug than letters to physicians alone.28


Strengthening the role of the pharmacist may go hand-in-hand with the need for the employment of programming techniques and methods to change physician behaviour.27


A variety of techniques and methods of


training have been used to get the attention of physicians and change prescribing behaviour, although didactic continuing medical education (CME) lectures and clinical guidelines have been found to have minimal impact.24,27


Methods that have been effective include endorsement of national professional guidelines by local opinion leaders, interactive/ hands-on workshops, performance reporting, peer/patient feedback and periodic reminders.27


A combination of these strategies is likely to be most effective in the mitigation of product risks.27


There has been sizeable debate and widespread scepticism about the effect of CME on the performance of physicians,29


and thus there is a


question about the actual impact of CME in risk mitigation. Some evidence has shown that traditional CME lectures and approaches to educating physicians and/or other health professionals do not produce changes in learner behaviour.24


Evidence indicates that this form of education may be effective and make a small change in physician prescribing behaviour, especially in settings that permit the use of targeted, multiple exposures and sequenced activities.24,29


Davis et al. performed a review of 105 studies that evaluated the impact of CME on short- and long-term physician practice performance.29


DRUG DEVELOPMENT


DHCPLs have been shown to have limited durable effects in positively changing prescribing behaviours to mitigate product risks in patients. While regulators hope to favourably alter prescribing patterns through DDLs, it has been noted that the marketing efforts of manufacturers and the media also play a role in the outcome of the warning.20


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