Attendees packed the annual update presented by representatives from the U.S. Food and Drug Administration at the ATS International Conference.

At their annual update at the ATS International Conference, U.S. Food and Drug Administration officials outlined changes and new research regarding the safety of a number of drug therapies for pulmonary disease.

Because of safety concerns, in February the FDA announced recommendations for changes in labeling for long-acting beta-agonist (LABA) drugs for the treatment of asthma. The FDA’s Badrul A. Chowdhury, M.D., Ph.D., opened the agency’s annual ATS update by describing research findings that led to concern about LABAs and the goals of the labeling changes.

Dr. Chowdhury, who is director of the FDA’s Division of Pulmonary, Allergy and Rheumatology (DPARP) products in the Center for Drug Evaluation and Research, said the FDA called for the changes following an analysis of research showing increased risks of severe exacerbations of asthma symptoms leading to patient hospitalizations and some asthma-related deaths. The recommendations only apply to the treatment of asthma using LABAs, and not for exercise-induced bronchospasm or COPD.

The FDA has determined that the benefits of LABAs in the treatment of asthma outweigh the potential risks when the drugs are used according to the recommended changes in labeling, Dr. Chowdhury said.

The FDA provided new recommendations for the use of LABAs for the treatment of asthma including:

• Contraindicate use of LABAs in asthma for all ages without concomitant use of a long-term control medication, such as inhaled corticosteroids (ICSs);
• Stop LABA, if possible, once asthma control is achieved and maintained, and continue the use of a long-term control medication, such as ICSs;
• Recommend against LABA use in patients whose asthma is adequately controlled on low- or medium-dose ICSs; and
• Recommend fixed-dose combination products containing LABA and ICSs in pediatric and adolescent patients who require addition of an LABA to ICSs.

Dr. Chowdhury said the most important goal of the changes is to assure that LABAs are used with a long-term control medication, such as ICSs. Additionally, the FDA is requiring the creation of a risk evaluation and mitigation strategy, including a revised patient medication guide and an education plan for healthcare providers.

Addressing the use of long-acting anticholinergic inhalers to relieve COPD symptoms, the FDA’s Theresa M. Michele, M.D., outlined the agency’s evaluation of data reporting adverse cardiovascular events in patients using Spiriva HandiHaler and Spiriva Respimat.

The HandiHaler, using the active ingredient tiotropium bromide, is approved for use in the U.S. as a maintenance treatment for bronchospasm caused by COPD, and to reduce disease exacerbations. Spiriva Respimat, which is approved for use only in Europe, also uses tiotropium bromide.

Dr. Michele, a DPARP medical team leader, described data from a pooled analysis and a meta-analysis in the literature indicating an increased risk of heart attacks, stroke and death among patients using tiotropium. The FDA issued an early communication in 2008 warning of these risks and launched a safety review.

In 2009 the FDA analyzed results from the Understanding the Potential Long-Term Impacts on Function with Tiotropium(UPLIFT) study, a four-year clinical trial testing the safety of the Spiriva HandiHaler compared to placebo in 5,992 COPD patients.

Dr. Michele said the FDA analysis of the large trial found no significant increased risk of heart attack, stroke or death in patients using HandiHaler versus placebo. As a result, the agency’s Pulmonary-Allergy Drugs Advisory Committee voted to end the FDA safety review, citing the UPLIFT data’s resolution of HandiHaler safety concerns.

Banu A. Karimi-Shah, M.D., a DPARP medical officer, updated ATS attendees about emerging therapies for idiopathic pulmonary fibrosis (IPF), primarily data from InterMune’s new drug application for pirfenidone. Many patients diagnosed with the fatal disease, and their families, had hoped the drug would gain FDA approval, but it did not.

Dr. Karimi-Shah opened the discussion with background information, reminding the audience that there are no FDA-approved therapies for the treatment of IPF, and even what had been considered the “standard of care” has not been conclusively shown to alter underlying fibrosis or disease progression. She then focused her discussion on regulatory issues that were raised by the pirfenidone application.

The pirfenidone registration program consisted of two phase III, randomized, double-blind, placebo-controlled clinical trials that used lung function, absolute change from baseline in forced vital capacity (FVC), as the primary endpoint. All-cause mortality was a pre-specified exploratory endpoint that was also looked at closely, given the fatal prognosis of the disease, she said.

The company achieved the primary endpoint in only one of the two pivotal trials.  The two studies analyzed together and separately did not demonstrate a statistically significant benefit for pirfenidone in all-cause mortality. Dr. Karimi-Shah also outlined some of the issues with using lung function as an endpoint in IPF clinical trials.

“Minimally important differences in lung function parameters in patients with IPF have not been formally established,” she said, emphasizing that surrogate endpoints for mortality have not been prospectively validated in IPF, and given the fatal prognosis of IPF within three to five years, “mortality is the ideal and most compelling primary endpoint.”

“The FDA ruled this spring that the pirfenidone clinical trials did not meet the agency’s definition of “substantial evidence” for efficacy and asked the drug’s maker, InterMune, to conduct another clinical trial, Dr. Karimi-Shah said.

Dr. Karimi-Shah concluded her presentation by noting that the FDA recognizes that IPF is a devastating disease with no approved therapy.

“The agency understands the desperation of patients, however, as regulators, we must always be vigilant that we do not allow desperation to be substituted for evidence of efficacy,” she said.