July 02, 2018
Recent research published in the New England Journal of Medicine found that the FDA’s decision to remove a boxed warning on inhaled corticosteroids for the risk of serious asthma-related events associated with combination therapy was clinically appropriate.
A team of FDA researchers led by Sally M Seymour, MD, of the Office of New Drugs at the FDA, explained in a recent perspective that while removal of boxed warnings is rare, currently available clinical data supported it in this case.
“For years, the risks associated with the use of long-acting beta-agonists (LABAs) in patients with asthma have been uncertain, and some health care professionals have recommended conducting large clinical trials to gather important safety information on these products,” they wrote. “In December 2017, FDA removed the boxed warning on combination products containing an inhaled corticosteroid and a LABA on the basis of results from recently completed large safety trials that the agency required manufacturers to conduct. Removal of a boxed warning isn’t common, but we at the FDA believe that the data generated from the mandated trials support this regulatory action.”
They said that in 2003, the boxed warning was required due to clinical findings that showed an increased risk of asthma-related hospitalization, intubation, and death associated with use of LABAs. However, these data were collected before patients were taking inhaled corticosteroids in combination with LABAs as the standard of care. While it was hypothesized that the inhaled corticosteroids would offset the asthma risk associated with LABAs there was no research to support this claims and the FDA was forced to apply the LABA boxed warning to combination products.
In order for the FDA to approve new combination products, they required manufacturers to conduct broader safety studies that evaluated the safety of combination products compared with inhaled corticosteroids alone. The present research team combined data from the three completed adult and adolescent clinical trials to determine if safety risks differed between combination products and inhaled corticosteroids without LABAs.
The researchers found that there was no significant increase in the risks for severe asthma-related outcomes associated with the use of combination products, compared with inhaled corticosteroids alone.
However, they noted that results from these clinical trials cannot answer all of the safety concerns surrounding LABAs.
“Some uncertainties remain, and we cannot conclude that there is no increase in risk associated with combination products containing an inhaled corticosteroid and a LABA as compared with inhaled corticosteroids alone,” they wrote. “Although the trials found that combination therapy reduces the rate of exacerbations that require the administration of systemic corticosteroids, none of them showed a decrease in asthma-related hospitalizations.”
The researchers concluded by emphasizing the quality of their decision to remove the boxed warning from combination products.
“The FDA’s decision to remove the boxed warning from combination products was based on our assessment of data from FDA-required trials,” Dr Seymour and colleagues concluded. “Any FDA mandate for large safety trials should be predicated on science and patient welfare and established for the purpose of answering important safety questions to improve health care providers’ knowledge and patient care. The removal of a boxed warning from a product label is not a common occurrence, but the evidence in this instance was decisive.”
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