Asthma Warnings Not Working Well, FDA Fears As GSK Seeks Expanded LABA Approval
This article was originally published in The Pink Sheet Daily
Executive Summary
LABA prescribing patterns haven’t changed despite FDA’s labeling instructions on asthma safety concerns, agency concludes.
An FDA analysis of epidemiologic and drug utilization data for a class of respiratory drugs highlights the limits of the agency’s risk management strategies when it comes to changing prescribing practices of potentially dangerous treatments.
These data on the use of long-acting beta agonists (LABAs) were also supported by the results of a Mini-Sentinel study that looked at the prescribing practices of the drug class (Also see "Mini-Sentinel Project Will Evaluate Impact Of LABA Label Change" - Pink Sheet, 26 Sep, 2011.).
The agency’s Office of Surveillance and Epidemiology reviewed utilization patterns of long-acting beta agonist as part of its March 17 briefing package for the March 19 advisory panel review of GlaxoSmithKline PLC’s supplemental NDA for Breo Ellipta (fluticasone furoate/vilanterol), an inhaled corticosteroid/LABA combo seeking an expanded indication to treat asthma in patients 12 years of age and older (see related story, (Also see "Breo Ellipta’s Adolescent Data Could Be Highest Hurdle For Asthma Claim" - Pink Sheet, 17 Mar, 2015.)).
Evidence of the extent of appropriate use of LABAs “is germane to consideration of whether the fluticasone-vilanterol combination product is likely to be used appropriately in asthmatic patients, FDA’s briefing documentssay.
Since 2003 the FDA has communicated to healthcare professionals and the public information on the risk associated with the use of LABA products and recommendations for their safe use. LABAs have been associated with an increased risk of severe exacerbation of asthma symptoms leading to hospitalizations as well as death in some asthma patients taking LABAs.
In 2010, the agency implemented a class-wide risk evaluation and mitigation strategy (REMS), and employed its Safe Use Initiative to help mitigate these risks further after it found some of its initial steps taken to change LABA practices didn’t seem to be working (Also see "FDA Calls For Class-Wide REMS For LABA Asthma Drugs" - Pink Sheet, 22 Feb, 2010.).
And it followed up these changes by asking LABA sponsors to conduct post-marketing studies comparing the addition of LABAs to inhaled corticosteroids versus inhaled corticosteroids alone to evaluate safety in more than 50,000 patients. These trials should complete in 2017.
But the recent OSE review, supported by Mini-Sentinel data, indicates FDA’s risk mitigation work is still falling short.
If Breo Ellipta is approve for asthma treatment, continued periodic post-marketing surveillance for evidence of off-label and other inappropriate uses should be conducted, OSE said.
If Breo Ellipta is approve for asthma treatment, continued periodic post-marketing surveillance for evidence of off-label and other inappropriate uses should be conducted, OSE said.
The OSE review suggests some favorable and some unfavorable degrees of adherence to most of FDA’s recommendations on the safe use of LABA products. Similar results were found in a Mini-Sentinel database review, the briefing documents add.
OSE evaluated four FDA recommendations on LABAs:
- LABA products should not be used alone for the treatment of asthma
- A LABA product should be used as additional therapy only in patients who are not adequately controlled on an asthma-controller medication, such as an inhaled corticosteroids (ICS)
- Patients should commence step down therapy of a LABA once asthma control is achieved and maintained
- Specifically for pediatric and adolescent asthma patients who require the addition of a LABA to an ICS, they should use a fixed-dose combination ICS/LABA to ensure adherence with both medications.
On the first recommendation, FDA’s review of IMS health care claims data found that the proportion of patients starting single-ingredient LABAs as a share of all LABA initiators declined significantly over the 2003-2012 study period for both adults and pediatrics.
This was consistent with the Mini Sentinel study which looked at 1.4 million child and adult patients with a diagnostic claim for asthma who started a LABA during Jan. 200 through June 2011. In Mini-Sentinel data, single ingredient LABA use in patients under 65 declined from 14% in Jan. 2005 to 4% in June 2011.
Similarly regarding recommendation four, FDA found that the majority of LABA products in children where fixed dose ICS/LABA combos. Nearly 468,000 pediatric patients received a prescription for an ICS/LABA combo compared to only 3,500 patients who received a prescription for a single-ingredient LABA in 2014.
Did Marketing Counteract FDA’s Warnings?
However, “the evidence on adherence to recommendation II (LABA only as add-on therapy) is not quite as encouraging,” FDA said. FDA found that while there was some increase in the use of ICS or other asthma controller medication in children before initiating the LABA treatment, the overall proportions were not high (less than 51%) and there was no increase in adults age 18-64 years over the 2003-2012 period.
The data actually show a decrease in prior ICS dispending before LABA initiation in adults patients with a diagnostic claim for asthma.
The Mini-Sentinel study found that less than 50% of asthma patients had any evidence of receipt of an asthma-controller medication within 90 days of the LABA index data and no increase in trend was observed from 2005 to 2011.
Advertising and the broad availability of samples of ICS/LABA combos may be to blame for the low prevalence of asthma controller medication use prior to the initiation of a LABA, FDA said.
FDA described the marketing of ICS/LABA combos as “aggressive” and added that studies have shown that physicians are more likely to prescribe medications for which they have samples in their office.
One unknown is the extent of adherence to FDA’s recommendation to discontinue LABA use or “step down” once asthma control has been achieved. More granular clinical data is needed to understand this current prescribing practice, FDA said.
The review found that for children and adults, the proportion with longer than two months of continuous LABA dispensing after first treatment episode increased over the 2003-2012 period, but added that they cannot say why or if these data reflect appropriate continuation of LABA therapy. The duration of LABA dispending over time is a surrogate measure, they note.
The Mini-Sentinel study found over 55% of patients discontinued a LABA at 30 days and this first treatment episode of continuous LABA dispensing also increased after 2010. OSE said these measures are also too broad to discern appropriate step down therapy.
The LABA data marks the second time in the past few weeks FDA’s risk mitigation ability has come into question. A recent Public Citizen petition to FDA also said FDA’s label warnings failed to change prescribing practices of an antifungal that can cause liver injury (Also see "FDA Safety Updates Fail Antifungal Patients, Public Citizen Argues" - Pink Sheet, 24 Feb, 2015.).