One of the important roles of a drug regulatory agency is to provide timely and accurate information on the safety and efficacy of medicines. While pre-approval clinical trials characterize the common adverse reactions associated with a new medicine and some of the less common serious adverse reactions, the full safety profile of the medicine continues to be refined after approval based on information from marketing experience. For that reason, post-approval drug safety surveillance systems are in place to detect previously unrecognized adverse drug reactions and to characterize better both new and previously known adverse drug reactions.
While pre-approval clinical trials are conducted by a limited number of research physicians, post-approval safety monitoring is, in many ways, the responsibility of the entire drug use system. The Agenzia italiana del farmaco (AIFA) describes pharmacovigilance as a multi-participant activity:
“La Farmacovigilanza coinvolge a diversi livelli tutta la comunità: pazienti, prescrittori, operatori sanitari, aziende farmaceutiche, istituzioni ed accademia e la segnalazione può essere effettuata non solo dall’operatore sanitario ma anche dai cittadini.”
Because a successful pharmacovigilance system depends on careful clinical observations made at the point of care, prescribers who monitor patients for suspected adverse drug reactions and who report those suspected adverse drug reactions to pharmacovigilance centers, regulatory authorities and to drug manufacturers, provide critical inputs to the pharmacovigilance system. However, a successful pharmacovigilance system requires more than inputs and analysis of drug safety data. It also generates an output. The essential output of a pharmacovigilance is, as noted above, timely and accurate information on the safety of medicines, which the entire drug system – and especially prescribers and patients – can use to make informed decisions about pharmacotherapy. This information is typically conveyed to the prescriber as an update to the medicine’s approved label or as another form of warning.
While much has been written about the role of prescribers and other practitioners in reporting suspected adverse drug reactions, there is less guidance on how prescribers should use the output of pharmacovigilance systems, and there are little data on how prescribing decisions have been affected by updated labeling and drug safety warnings from regulatory agencies. A recent publication by Dusetzina colleagues systematically reviewed forty-nine studies published between January 1990 and November 2010 that examined the impact of warnings from the US Food and Drug Administration on drug utilization and health behaviors. Some warnings had a measurable impact; when they did, it was usually a decrease in drug use. In some cases, drug use decreased in subpopulations of patients who were not the subject of the warning. An analysis of substitution of treatment found that the extent of substitution was variable across therapeutic indications. When warnings recommended specific monitoring, the analysis found that there was often a decline in drug use and that changes in monitoring were often transient.
The analysis by Dusetzina and colleagues raises many important issues, one of which is an understanding of how prescribers should use the warning and what the impact of a drug safety warning should be. Because the goal of updated labels and of drug safety warnings is to improve informed decision making, it is important that prescribers understand that drug labels are periodically updated to incorporate new safety information and that they should use this new information in choosing the best treatment for their patients. Thus, it is critical that prescribers become aware of new safety information. Contemporary physicians are bombarded with information about many things from many sources. It is thus important that updated safety information be made available via means that are readily identifiable as important information that the physician should read. Information could come directly from regulatory agencies or pharmaceutical manufacturers, or indirectly from, for example, professional societies, clinical facilities, or educational organizations. In addition to traditional paper based media, a variety of electronic media can be used, including e-mails and various forms of web postings.
As in all forms of communications, it is not sufficient for physicians simply to receive the communication – they must read it and incorporate the messages into their decision making. It is important to note that there is no pre-defined action that applies to all label changes that a physician should take. While many studies in the analysis by Dusetzina and colleagues noted a decline in prescribing after a warning, it is not necessarily the case that the most appropriate response to new safety information is to stop prescribing the medicine. While stopping a medicine in response to new safety information may be the best clinical decision in some cases, in other cases, alternative therapies may be less appropriate for the patients. Similarly, no therapy at all may put the patient at risk for poorer health outcomes. The physician should carefully consider how the new information alters the benefit-risk profile of the medicine, and compare that to other treatment options. If the medicine is continued, additional monitoring for adverse drug reactions may be needed.
In summary, the physician has two important roles in the pharmacovigilance system, one at each end of the process. The first is to provide careful clinical observations of suspected adverse drug reactions to the pharmacovigilance system. The second is to use the information provided by the pharmacovigilance system to optimize decision making regarding pharmacotherapy.
- Med Care 2012;50:466-78. CDI NS
- Med Care 2012;50:463-5. CDI NS