Updates from the FDA’s Center for Drug Evaluation and Research: Drugs in Development, LABA Safety, and More

hree speakers from the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research discussed the latest updates in asthma-related drugs during a session at the 2018 AAAAI Annual Meeting.

Badrul A. Chowdhury, MD, PhD, FAAAAI, noted the role of precision medicine and its emergence as an effective treatment approach that accounts for individual gene variability, environment, and lifestyle of each patient. “Asthma is a complex disease and phenotypes vary based on age,” he said.

Dr. Chowdhury then discussed the four biologic agents approved for asthma:

• Omalizumab: Approved for patients ≥6 years with moderate to severe persistent asthma whose disease is inadequately controlled by inhaled corticosteroids
• Mepolizumab: Approved for patients ≥12 years with severe eosinophilic asthma as maintenance therapy
• Reslizumab: Approved for patients ≥18 years with severe eosinophilic asthma as maintenance therapy
• Benralizumab: Approved for patients ≥12 years with severe eosinophilic asthma as maintenance therapy

There are other biologic agents that may be approved for asthma in the future, including:

• Dupilumab: An anti-IL-4 receptor alpha
• Tezepelumab: An anti-epithelial-cell-derived cytokine thymic stromal lymphopoietin
• Lebrikizumab: An anti-IL-13 agent

Sofia Chaudhry, MD, then discussed different clinical trial approaches to comparing safety and efficacy of asthma agents.

A control trial involves comparing an investigation agent with some form of control—placebo, a lower dose of an investigation drug, or another agent. Benefits of a placebo trial include the ability to fully measure the investigational drug’s effect, but ethical and practical issues arise because patients in the placebo cohort are not receiving an optimal standard of care (SOC). This leads to the idea of an add-on control study, in which the trial assesses SOC plus placebo or the investigational treatment. The use of SOC in both cohorts has a less ethical concern than placebo-containing trials; however, these studies can be difficult to demonstrate superiority, as SOC can sometimes include other FDA-approved drugs, perhaps in the same drug pathway as the agent under review.

Alternative trial approaches from the literature include:

• Shorter control period: Determine ethically acceptable controlled treatment period.
• Early escape to rescue treatment rather than fixed treatment duration: Limits risk of prolonged use of substandard treatment, but can lead to relatively short duration to assess efficacy.
• Randomized withdrawal: Entire trial population uses active treatment and then is randomized to continue to active treatment or placebo. This allows a longer treatment period and shows how long a treatment should be used, but has the potential for an exaggerated treatment effect.

An active controlled trial is another option that minimizes bias by allowing for randomization and blinding and has a comparator for safety assessments; however, this design makes it difficult to establish superiority of the investigational agent. The same pathway would need to be compared for a fair comparison, said Dr. Chaudhry. A noninferiority trial design compares the investigational treatment with an active treatment and allows for a longer treatment duration. However, assay sensitivity must be considered, and researchers need to establish the clinically-meaningful non-inferiority margin.

Future developments in clinical trials should include broadened patient populations, consideration of treatment effects on other atopic conditions, and use of real-world evidence, she suggested.

Robert Lim, MD gave a safety update on long-acting beta-adrenoceptor agonists (LABAs). There is a long history of concern with LABAs due to reported hospitalizations, intubation, and death, dating back to the 1990s. The Serevent Nationwide Surveillance and Salmeterol Multicenter Asthma Research Trial initially raised these safety concerns, leading the FDA to conduct a meta-analysis. From the findings, boxed warnings were required for all LABA-containing products, and the FDA also required post-marketing studies to further understand these safety concerns.

Four studies were conducted in the adult population, as well as one in pediatric patients, and these showed that LABA plus inhaled corticosteroid (ICS) combinations were associated with less serious asthma-related events than ICS alone (TABLE). Following the updated findings, the FDA removed the boxed warnings from the labeling of ICS/LABA combination products, and changed the medication guide to a patient information leaflet. The warning was revised to emphasize the continued risk of LABA monotherapy.

Presentation 4710: Update from the US Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER)