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Postmarketing Drug Safety Surveillance – Is Enough Being Done?
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Lately, there has been much in the news regarding new and ongoing safety concerns related to a variety of sometimes very commonly used drugs. For example, based on data from a meta-analysis, angiotensin receptor blockers (ARBs) have recently been associated with a modest increase in the risk for a new cancer diagnosis. Similarly, since its approval in 2009, additional information regarding prasugrel’s (Effient, Daiichi Sankyo/Eli Lilly and Company) association with new and worse malignancies has recently become available. During the last few years, there have been mounting concerns regarding rosiglitazone (Avandia, GlaxoSmithKline) and an association with increased risk for CV events, culminating with the FDA’s review of the safety issues associated with rosiglitazone in a joint meeting of the Endocrinological and Metabolic Drugs and the Drug Safety and Risk Management advisory committees on July 13 and 14. After a thorough review of the data available to the advisory committee members, there was a clear lack of consensus as to where to go from here with regard to the status of rosiglitazone. One third of members suggested the safety signal is too strong to allow rosiglitazone to stay on the market, while the other two third felt the drug should stay on the market with additional warnings.
During the last decade alone, there have been more than 20 drugs withdrawn from the market (either voluntarily or at the request of authorities) in the United States, Canada and Europe. These withdrawals are usually for issues related to serious adverse effects which were unexpected or more serious than expected based on data from phase-III clinical trials. In most cases, these serious adverse effects only became apparent from postmarketing surveillance data from the wider patient community. Postmarketing surveillance currently occurs in a variety of forms, including postmarketing clinical trials which generate new data; reanalysis of existing clinical trial data; and the FDA’s MedWatch program.
Based on the known limitations of clinical trials that include patients who have limited comorbid conditions and concomitant medications, the MedWatch program provides education about the importance of postmarketing surveillance, facilitates the reporting of adverse events and disseminates new, clinically useful safety information to providers and patients. However, because the MedWatch program is a passive system that relies on voluntary reporting of adverse events by physicians and other health care providers, these events are often underreported, making it impossible to calculate reliable estimates of adverse event rates. Additionally, reports often contain inadequate documentation and detail. Perhaps most pointedly, the MedWatch system relies primarily on drug manufacturers for the majority of collection, evaluation, and reporting of data from postmarketing studies of their own products.
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Recognizing that the MedWatch program alone was insufficient to systematically and rapidly identify potentially severe adverse events after a drug had been approved, the FDA implemented additional programs to help facilitate adverse event reporting and drug safety data assimilation. Created in 2005 and mandated by law in the FDA Amendments Act of 2007, the Drug Safety Oversight Board (DSB), advises the Center for Drug Evaluation and Research on the handling and communication of important and often emerging drug safety issues. Comprised of members from three FDA Centers and six other federal government agencies, one of the most important roles of the DSB is to help the FDA assess the impact of its safety decisions on the health care systems of its federal partners.
Another aspect of the FDA Amendments Act (this one implemented in 2008) gave the FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks. Dronedarone (Multaq, Sanofi Aventis) is an example of a drug approved in July 2009, which required a REMS. The goals of the dronedarone REMS is to prevent use in patients with NYHA Class IV, or unstable Class III HF, and to inform patients about the serious risks of dronedarone, including increased mortality in patients with severe unstable HF. Elements of the dronedarone REMS include medication and communication guides, as well as a formal assessment of the REMS performance to be provided to the FDA annually for the first 5 years after launch, with the first assessment due in August 2010.
Another REMS, this one associated with darbepoeitin (Aranesp, Amgen), includes a certification process whereby those who prescribe and dispense the product must be certified by completing a specific training program and attest to statements indicating that they understand the risks of the product. In addition, prescribers must agree to prescribe it only in accordance with approved indications and must agree to share the required and appropriate information with all patients for whom the medication is prescribed. The patient signs a form indicating acknowledgment and understanding of the information, and the prescriber signs indicating compliance with the required provision of information to the patient.
The newest aspect of the FDA’s drug safety assessment program is the Sentinel Initiative, a national electronic system that the FDA hopes will transform its ability to track the safety of drugs, biologics and medical devices. Launched in March 2008, the Sentinel Initiative aims to develop and implement a proactive system that will complement existing systems already in place to track reports of adverse events linked to use of an FDA-regulated product. Stemming from elements of the 2007 FDA Amendments Act, which required the development of methods to obtain access to disparate data sources and established a postmarket risk identification and analysis system to link and analyze health care data from multiple sources, the Sentinel Initiative will enable the FDA to actively query diverse automated health care data holders to evaluate possible medical product safety issues quickly and securely. Sources will include electronic health record systems, administrative databases, insurance claims databases and registries. The Sentinel Initiative will be developed and implemented in stages, and while it is a long way from being fully functional, the FDA has begun to develop the scientific operations needed for the Initiative, including plans for the creation of a coordinating center which will have continuous access to the automated health care data systems.
The REMS program is still a work in progress, and whether the implementation of REMS, which are now in place for more than 100 FDA-approved medications, will improve the long term safe use of medication in this country is unknown, especially since the responsibility for implementation and reporting continues to lie with the manufacturers. Perhaps coupled with the Sentinel Initiative, together these programs will improve the overall safe use of medications in the United States.
In the meantime, we continue to be faced with issues like whether or not rosiglitazone is associated with increased risk for CV events. Rosiglitazone has been on the market since 1999, and prior to the first broad reports in 2007 associating its use with increased risk of adverse outcomes, it ranked 28th amongst the top brand-name drugs prescribed, with over 11 million prescriptions in 2006. In 2009, it had fallen to 103rd with 2.3 million prescriptions. While use has dropped significantly, likely based on safety concerns, prescriptions written in 2009 exposed almost as many patients to a drug with a questionable risk-benefit profile. Until we have fully functioning programs and systems in place to consistently and uniformly assess medication safety after a drug is approved, we will continue to be faced with scenarios such as this.
Rhonda M. Cooper-DeHoff, PharmD, MS, is an associate professor at the University of Florida College of Pharmacy in Gainesville, Fla. and is the column editor for Cardiology Today’s Pharmacology Consult.