Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

A Boxed Warning for Montelukast: The FDA Perspective.

The U.S. Food and Drug Administration (FDA) became aware of postmarketing reports of neuropsychiatric adverse events with Singulair (montelukast) use in 2007. Over the years, the FDA has conducted reviews of the clinical trial safety data, focused analyses of postmarketing reports, and reviews of the published literature. These activities have resulted in successive labeling updates and public communications. However, there has been continued concern among stakeholders about the risk of neuropsychiatric events and the lack of awareness among prescribers and patients/caregivers. On the basis of these concerns, the FDA embarked on another comprehensive review and also conducted a new observational study using claims data in the Sentinel Distributed Database. In September 2019, the FDA held a public Advisory Committee meeting to discuss its review and solicit recommendations from the panel regarding labeling and communication strategies. After careful consideration of the available data and feedback received during the FDA Advisory Committee meeting, the FDA required a boxed warning and a revision specifically for the allergic rhinitis indication to reserve use of montelukast to patients who have an inadequate response or intolerance to alternative therapies. Based on benefit-risk considerations, the asthma indication was not changed. To provide insight into the process and rationale for the required labeling changes, we provide an overview of the decision-making framework we used.

Drug Interaction Between Febuxostat and Thiopurine Antimetabolites: A Review of the FDA Adverse Event Reporting System and Medical Literature.

BACKGROUND: There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout. OBJECTIVE: To determine the clinical impact of the febuxostat-thiopurine DI. DESIGN AND SETTING: Case series derived from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature. PATIENTS: Nineteen patients who received concomitant febuxostat and either AZA or 6-MP. MEASUREMENTS: Laboratory and clinical data. RESULTS: Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only. LIMITATIONS: Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostat-thiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting. CONCLUSION: Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.

A Novel Pharmacokinetic Bridging Strategy to Support a Change in the Route of Administration for Biologics.

Determination of appropriate pharmacokinetic end point to bridge different dosing regimens is often a challenge when developing a new route of administration. Trough concentrations (Ctrough) are often considered the most relevant PK end point to predict efficacy (ACR20/DAS28) in the treatment of rheumatoid arthritis for biologics. However, no systematic research has been conducted to evaluate this approach. We developed a novel strategy to predict the most relevant PK variables that may be used to support a change in the route of administration for biological products. Our analysis indicated that matching only Ctrough when switching from intravenous dosing to subcutaneous dosing with decreasing dosing interval may result in a lower treatment response. If only average concentration (Cave) is considered as the relevant variable, our analysis showed that treatment response may be worsened when switching from subcutaneous dosing to intravenous dosing with increasing dosing interval. The study results demonstrated that matching a single pharmacokinetic end point (Ctrough or Cave) may not be sufficient to ensure efficacy when switching between intravenous dosing and subcutaneous dosing. A practical novel pharmacokinetic bridging approach is provided to support a change in the route of administration for biological products.

The Effect of FDA Drug Safety Communications on Patterns of Tiotropium Dispensing: A U.S. Health Plan Claims Database Study.

BACKGROUND: The FDA issued 2 main drug safety communications (DSCs) on the cardiovascular safety of tiotropium in March 2008 (warning of a potential increased stroke risk) and January 2010 (informing of an absence of a significant increased stroke risk or cardiovascular events based on findings from a large trial). OBJECTIVE: To describe the effect of the FDA DSCs on medication dispensing of tiotropium in a large U.S. claims database. METHODS: Initiation of tiotropium products among patients with chronic obstructive pulmonary disease (COPD) aged 40 years and older was determined monthly from 2006-2012 using medication dispensing from the IMS Lifelink Health Plan Claims Database. Similarly, monthly initiation of products containing long-acting beta-agonists (LABAs) was calculated to explore product switching. The effect of the 2008 and 2010 FDA DSCs was measured using interrupted time-series analysis. Subgroups of patients with greater cardiovascular risk were also examined. RESULTS: A decreasing trend in initiation of tiotropium-containing products was present before the initial 2008 DSC. The decline in tiotropium initiation continued until January 2010, accompanied by an increased initiation of LABA-containing products in patients with COPD. In the presence of the existing decreasing trend, the initial DSC was followed by an immediate 2.8% (P = 0.02) further reduction in tiotropium initiation. Tiotropium initiation increased 2.5% (P = 0.03) immediately after the 2010 DSC, reducing the overall decline in rate and stabilizing (flattening) the trend. No significant changes in dispensing level or trend were observed among COPD patients with cardiovascular comorbidity. CONCLUSIONS: Cardiovascular safety concerns may have affected tiotropium initiation as indicated by the decrease in tiotropium dispensing shown immediately following the initial DSC. The effect was alleviated as concerns lessened following the most recent DSC. DISCLOSURES: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors are employed by the FDA and have no conflict of interest relevant to the content of this study. The views expressed herein do not necessarily represent the views of the FDA.

The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005-2011.

OBJECTIVE: Evidence of safety issues associated with long-acting beta2-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. METHODS: A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single-ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. RESULTS: LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. CONCLUSION: The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities.

The US Food and Drug Administration's drug safety recommendations and long-acting beta2-agonist dispensing pattern changes in adult asthma patients: 2003-2012.

BACKGROUND: Emerging safety issues associated with long-acting beta2-agonist (LABA) have led to multiple regulatory activities by the US Food and Drug Administration (FDA) since 2003, including Drug Safety Communications (DSCs) in 2010. These DSCs had three specific recommendations for the safe use of LABA products in adult asthma treatment. METHODS: We examined the initiation of LABA-containing products for adult asthma treatment using an intermittent time series approach in a claims database from 2003 to 2012. We assessed the alignment of dispensing patterns with the following 2010 FDA recommendations: 1) contraindicated use of single-ingredient (SI)-LABA without an asthma controller medication (ACM); 2) a LABA should only be used when asthma is not adequately controlled on inhaled corticosteroids (ICSs) or ACM; and 3) step-down asthma therapy (e.g., discontinue LABA) when asthma control is achieved. RESULTS: There were 477,922 adults (18-64 years old) dispensed a new LABA during 2003-2012. Among LABA initiators, patients who initiated an SI-LABA and who did "not" have an ACM dispensed on the same date decreased from >9% in 2003 (the initial labeling change) to <2% post 2010 DSCs (p-value <0.0001 in the segmented regression model). The proportion of asthma patients dispensed an ICS in 6 months prior to initiating LABA treatment did not increase. The proportion of patients with longer than 4 months of continuous treatment did not decrease over the study period. CONCLUSION: Although the decrease in SI-LABA initiation is consistent with FDA's recommendations, low ICS dispensing before initiating a LABA and LABA continuation practices require further efforts to move toward the recommended safe practices.

Changing patterns of asthma medication use related to US Food and Drug Administration long-acting ß2-agonist regulation from 2005-2011.

BACKGROUND: Safety concerns associated with long-acting ß2-agonists (LABAs) have led to many US Food and Drug Administration (FDA) regulatory activities for this class of drugs. Little is known about the effect of these regulatory activities on use of LABA-containing agents or other asthma medications. METHODS: We created rolling cohorts of pediatric and adult asthmatic patients in the Mini-Sentinel Distributed Database between January 2005 and June 2011. The proportions of asthmatic patients using LABA-containing products, inhaled corticosteroids (ICSs), leukotriene modifiers, short-acting ß2-agonists, oral corticosteroids, other bronchodilators, and no medications were measured on a monthly basis, and the changes were evaluated by using interrupted time series with segmented regression analysis. RESULTS: When the 2005 regulatory activity was announced, there were statistically significant decreases in the use of fixed-dose ICS-LABA agents in children (-0.98 percentage points) and adults (-1.24 percentage points). Increased use of ICSs and leukotriene modifiers was observed just after the regulatory activities were announced in both children and adults. Although of smaller magnitude, continued favorable changes in the use of LABA agents were observed after the 2010 FDA regulatory activity. CONCLUSION: The 2005 and 2010 FDA regulatory activities might have contributed to reduced use of LABA agents, as intended; however, their effect, independent of other factors, cannot be determined. Use of other classes of asthma medications was similarly affected.

International Guidelines for Bioequivalence of Locally Acting Orally Inhaled Drug Products: Similarities and Differences.

International regulatory agencies have developed recommendations and guidances for bioequivalence approaches of orally inhaled drug products (OIDPs) for local action. The objective of this article is to discuss the similarities and differences among these approaches used by international regulatory authorities when applications of generic and/or subsequent entry locally acting OIDPs are evaluated. We focused on four jurisdictions that currently have published related guidances for generic and/or subsequent entry OIDPs. They are Therapeutic Goods Administration (TGA) in Australia, Health Canada (HC) in Canada, European Medicines Association (EMA) of European Union (EU), and the Food and Drug Administration (FDA) in the United States of America (USA). The comparisons of these bioequivalence (BE) recommendations are based on selection of reference products, formulation and inhaler device comparisons, and in vitro tests and in vivo studies, including pharmacokinetic (PK), pharmacodynamics (PD), and clinical studies. For the in vivo studies, the study design, choices of dose, subject inclusion/ exclusion criteria, study period, study endpoint, and equivalence criteria are elaborated in details. The bioequivalence on multiple-strength products and waiver options are also discussed.

Long-acting beta2-adrenergic agonist in pediatric and adolescent asthma patients, 2003-2011.

OBJECTIVES: To evaluate changes in the dispensing patterns of long-acting beta2-adrenergic agonist (LABA) in pediatric and adolescent asthma patients in relation to multiple Food and Drug Administration (FDA) regulatory activities from 2003 to 2011. METHODS: We estimated LABA dispensing to pediatric asthma patients across three periods: 2003-2004 (after the first labeling change), 2005-2009 (after regulatory activities in 2005 and before 2010 LABA labeling change) and 2010-2011 (after 2010 LABA labeling change), using the IMS Health Plan Claims database. We estimated dispensing patterns over time for single-ingredient (SI) LABA and fixed-dose combination (FDC) of inhaled corticosteroid (ICS) and LABA (FDC-ICS/LABA). We also evaluated prior use of non-LABA asthma-control medication (ACM) before LABA initiation. RESULTS: Of the 147 862 pediatric and adolescent asthma patients who initiated a LABA during the entire study period, the majority (96%) were FDC-ICS/LABA initiators. The proportion of SI-LABA among any LABA initiators was small and declined (9%, 4% and 2%, trend test p < 0.001) for the three periods. Among the patients who initiated, the proportions with prior use of an ACM (1-90 days prior) were 35%, 36% and 39% for the three periods. CONCLUSIONS: The significant decline in the proportion of SI-LABA initiation over these years is consistent with FDA's recommendations. However, the favorable trend cannot be solely attributed to FDA activities as changes to clinical practice guidelines, and media publicity may have played a role. Investigating the reasons for the low ACM use before LABA initiation may inform approaches to further improve appropriate use of LABA in young asthma patients.