Characterizing and Communicating Uncertainty in the Assessment of Benefits and Risks of Pharmaceutical Products Workshop Summary (2014) / Chapter Skim
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Appendix B: FDA Case Studies
Appendix B: FDA Case Studies
Pages 91-104
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From page 91... ...
At the time, there was considerable uncertainty about the magnitude of the risk of PML to patients exposed to Tysabri and whether there were any identifiable risk factors that could be reliably used to identify patients at greater risk. In making its decision on whether to allow re-marketing of the drug, FDA considered whether the risk of PML (and uncertainty about the risk)
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From page 92... ...
In September 2005, after conducting an extensive safety assessment, the sponsor submitted additional efficacy and safety evidence and requested reauthorization to market the drug. FDA's re-marketing decision hinged in large part on its conclusions about the risk of PML associated with Tysabri.
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From page 93... ...
FDA determined that the design, implementation, and analysis of the safety assessment were adequate. The assessment confirmed the two previously-identified PML cases but did not identify any other cases, out of 1869 MS patients treated for a median duration of 120 weeks.
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From page 94... ...
meeting to gather expert input into the Agency's decision. At the meeting, patients, family, and health care providers testified to the difference that Tysabri had made in the lives of MS patients, as well as the willingness of patients to continue treatment despite the risk of PML.
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From page 95... ...
requiring prescribing and administration only by certified health care providers, use only in patients enrolled in the program and who met necessary conditions, documented patient counselling, and patient evaluation at 3 and 6 months after initial treatment and every 6 months thereafter.
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From page 96... ...
Both cases occurred in MS patients in Europe, and both patients were receiving Tysabri as monotherapy. However, FDA concluded in an August 2008 advisory11 that it "still believes that Tysabri monotherapy may confer a lower risk of PML than when Tysabri is used together with other immunomodulatory medications." Today, the risk of PML associated with Tysabri is much better understood.
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From page 97... ...
. 17 See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ ucm108662.htm (accessed August 23, 2014)
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From page 98... ...
The low numbers of major adverse cardiac events (MACE) observed in the Anoro Ellipta premarket clinical trials made it difficult to draw definitive conclusions about CV risk for this specific product.
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From page 99... ...
observed in the Anoro Ellipta pre-market clinical trials made it difficult to draw definitive conclusions about CV risk of this product. Therefore, an important question in FDA's approval decision for Anoro Ellipta was whether to require a post-market study to further assess potential CV risk.
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From page 100... ...
. FDA's assessment and conclusion on the CV risk of Spiriva HandiHaler is explained in a New England Journal of Medicine (NEJM)
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From page 101... ...
was approved in 2012. The pre-market evidence included a safety database limited in size, which hindered FDA's ability to draw definitive conclusions.29 Because of this, and given the lingering uncertainty of possible disparate safety profiles of tiotropium delivered by different devices (the TIOSPIR trial was not yet published)
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From page 102... ...
However, the question remained whether additional postmarket studies would be required to further assess CV safety for this drug. The drug sponsor had proposed conducting observational studies to explore any possible CV risks.
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From page 103... ...
Such publication commonly leads to urgent calls to take immediate regulatory action, without acknowledgment of potential pitfalls in the interpretation of data from meta-analyses and pooled analyses, such as those encountered in the tiotropium evaluation. We must use measured restraint during our evaluations to ensure that safe drugs remain on the market and that their use is not restricted in a way that unnecessarily denies beneficial interventions to patients who need them.
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From page 104... ...
FDA updated this communication in October, 2008, announcing the publication of the Singh 2008 meta-analysis and the completion of the clinical trial UPLIFT. In 2010, in addition to its NEJM article, FDA posted on its website another update38 explaining its conclusions that the available data do not support an association between Spiriva HandiHaler and CV risk.
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