A disease progression model of longitudinal lung function decline in idiopathic pulmonary fibrosis patients.

Pirfenidone and nintedanib are the first two FDA-approved therapies for treatment of idiopathic pulmonary fibrosis (IPF). The clinical programs for pirfenidone and nintedanib included 1132 patients in the placebo arms and 1691 patients in the treatment arms across 6 trials. We developed a disease progression model to characterize the observed variability in lung function decline, measured as percent predicted forced vital capacity (%p-FVC), and its decrease in decline after treatment. The non-linear longitudinal change in %p-FVC was best described by a Weibull function. The median decreased decline in %p-FVC after treatment was estimated to be 1.50% (95% CI [1.12, 1.79]) and 1.96% (95% CI [1.47, 2.36]) at week 26 and week 52, respectively. Smoking status, weight, %p-FVC, %p-DLco and oxygen use at baseline were identified as significant covariates affecting decline in %p-FVC. The decreased decline in %p-FVC were observed among all subgroups of interest, of which the effects were larger at 1 year compared to 6 months. Based on the disease progression model smoking status and oxygen use at baseline may affect the treatment effect size. At week 52, the decreased decline in %p-FVC for current smokers and patients with oxygen use at baseline were 1.56 (90% CI [1.02, 1.99]) and 2.32 (90% CI [1.74, 2.86]), respectively. These prognostic factors may be used to enrich studies with patients who are more likely to respond to treatment, by demonstrating a lesser decline in lung function, and therefore provide the potential to allow for IPF studies with smaller study populations or shorter durations.

The U.S. Food and Drug Administration's Experience with Ivacaftor in Cystic Fibrosis. Establishing Efficacy Using In Vitro Data in Lieu of a Clinical Trial.

On May 17, 2017, the U.S. Food and Drug Administration expanded the patient population for use of ivacaftor to include patients with cystic fibrosis with relatively rare mutations in the cystic fibrosis transmembrane conductance regulator gene. The label expansion is unique in that clinical efficacy was not based on clinical data but on in vitro assay data demonstrating increased chloride ion transport across cells in response to ivacaftor. Such an approach provides a pathway for adding difficult-to-study mutation-based cystic fibrosis subpopulations to the indication as well as defining mutations unresponsive to ivacaftor and has important implications for cystic fibrosis drug development and other rare genetic diseases whose genetics and disease pathophysiology are well understood.

Exposure-Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 2: Continuous Model).

Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation-based power analysis. The developed population PK/PD models adequately described the relationship between serum concentrations and changes in ACR subcomponents. The trial simulation and subsequent power analysis showed that SJC and TJC appeared to be more sensitive than the other 5 ACR subcomponents to detect treatment effect over placebo/methotrexate. These 7 ACR subcomponents had similar power in detecting the treatment difference between different doses. In addition, the continuous measures of ACR subcomponents did not appear to be more sensitive than binary measures.

Acute Exacerbation and Decline in Forced Vital Capacity Are Associated with Increased Mortality in Idiopathic Pulmonary Fibrosis.

RATIONALE: Exploration of FVC as it relates to mortality in idiopathic pulmonary fibrosis (IPF), a chronic, progressive, and ultimately fatal parenchymal lung disease, is important both clinically and to the current drug development paradigm. We evaluated the association between FVC decline and mortality in what is to our knowledge the largest well-characterized placebo cohort to date. Additionally, we sought to explore the risk of death caused by acute exacerbations and to further validate previously identified baseline predictors of mortality. OBJECTIVES: To validate and further characterize FVC decline, acute exacerbations, and previously identified baseline predictors as they relate to risk of death. METHODS: A total of 1,132 placebo subjects from six studies used for the clinical development of nintedanib and pirfenidone for the treatment of IPF were included in the present analysis. Deaths were captured as all-cause mortality. A stratified Cox proportional hazards model was used to test the association between baseline predictors, decline in FVC % predicted from baseline, acute exacerbations, and death. Decline in FVC % predicted and exacerbations were treated as time-varying covariates. RESULTS: Subjects were followed for a mean of 60 weeks. At baseline, age, smoking status, lower FVC % predicted, and lower diffusing capacity of the lung for carbon monoxide % predicted were associated with an increased risk of death. The risk of death was also increased for subjects having one or more exacerbations with a hazard ratio (HR) of 10.3 (95% confidence interval [CI], 5.7-18.7). Compared with an FVC % predicted absolute decline from baseline at any time during the study of less than 5%, a decline greater than or equal to 10% to less than 15% was associated with an increased risk of death, with an HR of 2.2 (95% CI, 1.1-4.4), as was a decline greater than or equal to 15%, which was estimated with an HR of 6.1 (95% CI, 3.1-11.8). A decline ranging from greater than or equal to 5% to less than 10% was not associated with increased mortality. CONCLUSIONS: Our analyses validate the importance of baseline FVC, diffusing capacity of the lung for carbon monoxide, age, and smoking status as predictors of mortality and strengthen the association between decline in FVC and exacerbations with death, verifying a decline in FVC as an appropriate endpoint in IPF drug development. Clinical trial registered with www.clinicaltrials.gov (NCT00514683, NCT01335464, NCT01335477, NCT00287729, NCT00287716, and NCT01366209).

Tiotropium Respimat Is Effective for the Treatment of Asthma at a Dose Lower Than That for Chronic Obstructive Pulmonary Disease.

Anticholinergic drug products are not part of the current treatment paradigm for asthma, despite their widespread availability for chronic obstructive pulmonary disease (COPD) and interest in their use for asthma. Published study results, mostly of short duration and primarily with ipratropium and tiotropium, have revealed inconsistent efficacy results. Consequently, the role of inhaled anticholinergic drugs in the treatment of asthma has been unclear. This commentary discusses and comments on data from five clinical trials in adults that were submitted by Boehringer Ingelheim to the U.S. Food and Drug Administration to support approval of tiotropium delivered by the Respimat device (Spiriva Respimat) for the treatment of asthma. These trials provided substantial evidence that supported the approval of Spiriva Respimat at a recommended dose of 2.5 µg once daily for asthma. Notably, in trials that evaluated two doses of tiotropium, 2.5 µg and 5 µg (the dose approved for COPD), pulmonary function measures for Spiriva Respimat 2.5 µg once daily were better overall than those obtained for the 5-µg once-daily dose, thus justifying selection of the lower dose for asthma. Spiriva Respimat represents the first new class of drug approved by the U.S. Food and Drug Administration for the treatment of asthma in more than a decade. The availability of Spiriva Respimat for asthma along with other novel therapies currently under development has the potential to impact asthma treatment guidelines.

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.

Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience.

Cystic fibrosis (CF) is a life-shortening inherited disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR), which encodes for the CF transmembrane conductance regulator (CFTR) ion channel that regulates chloride and water transport across the surface of epithelial cells. Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR. Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent. The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

Dosing regimen determination for juvenile idiopathic arthritis: a review of studies during drug development.

Juvenile idiopathic arthritis (JIA) is the most common childhood arthritis. In the past 10-15 years, the medical treatment options of JIA have greatly evolved and expanded due to a better understanding of the disease and the application of biologic agents. Regulations pertinent to pediatric clinical research have also helped provide a legal basis for investigating the effects of drugs and biologics in pediatrics and facilitate the pediatric drug development. The evaluation of clinical pharmacology, efficacy, and safety has provided valuable labeling information for pediatric use, including comparing exposure between adult and pediatric patients, bridging different formulations and regimens, providing appropriate dose selection recommendation with the modeling and simulation approach, and assessing the risks and benefits. This review summarizes the drugs and biologics with JIA labeling implications and discusses the application of clinical pharmacology, safety, and efficacy assessment in determining pediatric dosing regimens.

Limitations of model based dose selection for indacaterol in patients with chronic obstructive pulmonary disease.

OBJECTIVE: Indacaterol is a long-acting ß-agonist (LABA) approved by FDA in 2011 at a dose of 75 µg once daily for the treatment of chronic obstructive pulmonary disease (COPD). During the review process for indacaterol approval, data were reanalyzed by FDA to evaluate the validity of the model based conclusions regarding dose selection. METHODS: The same dose response model applied by the sponsor was used to analyze a subset of the original data. Model predictions were compared with observed data to evaluate the model. Subgroups were created to visualize the relationship between key model parameters and covariates. The Emax model structure was evaluated for a meta-analysis. RESULTS: Patient-level analyses showed that the model based claim of additional benefit of 150 µg over 75 µg for more severe patients is not supported by the data. Mis-specified covariate model structures for key parameters contributed to this inconsistency. The assumed Emax model structure is not supported by the study-level data and the study-level analysis overestimates the incremental difference between two adjacent doses. CONCLUSIONS: Even though model based drug development is highly desirable, thorough model evaluation and justification is necessary to ensure the validity of related decisions.

Demonstrating Bioequivalence of Locally Acting Orally Inhaled Drug Products (OIPs): Workshop Summary Report.

This March 2009 Workshop Summary Report was sponsored by Product Quality Research Institute (PQRI) based on a proposal by the Inhalation and Nasal Technology Focus Group (INTFG) of the American Association of Pharmaceutical Scientists (AAPS). Participants from the pharmaceutical industry, academia and regulatory bodies from the United States, Europe, India, and Brazil attended the workshop with the objective of presenting, reviewing, and discussing recommendations for demonstrating bioequivalence (BE) that may be considered in the development of orally inhaled drug products and regulatory guidances for new drug applications (NDAs), abbreviated NDAs (ANDAs), and postapproval changes. The workshop addressed areas related to in vitro approaches to demonstrating BE, biomarker strategies, imaging techniques, in vivo approaches to establishing local delivery equivalence and device design similarity. The workshop presented material that provided a baseline for the current understanding of orally inhaled drug products (OIPs) and identified gaps in knowledge and consensus that, if answered, might allow the design of a robust, streamlined method for the BE assessment of locally acting inhalation drugs. These included the following: (1) cascade impactor (CI) studies are not a good 2 predictor of the pulmonary dose; more detailed studies on in vitro/in vivo correlations (e.g., suitability of CI studies for assessing differences in the regional deposition) are needed; (2) there is a lack of consensus on the appropriate statistical methods for assessing in vitro results; (3) fully validated and standardized imaging methods, while capable of providing information on pulmonary dose and regional deposition, might not be applicable to the BE of inhaled products mainly due to the problems of having access to radiolabeled innovator product; (4) if alternatives to current methods for establishing local delivery BE of OIPs cannot be established, biomarkers (pharmacodynamic or clinical endpoints) with a sufficiently steep dose-response need to be identified and validated for all relevant drug classes; and (5) the utility of pharmacokinetic studies for evaluating "local pulmonary delivery" equivalence deserves more attention. A summary of action items for seminars and working groups to address these topics in the future is also presented.

In vitro considerations to support bioequivalence of locally acting drugs in dry powder inhalers for lung diseases.

Dry powder inhalers (DPIs) are used to deliver locally acting drugs (e.g., bronchodilators and corticosteroids) for treatment of lung diseases such as asthma and chronic obstructive pulmonary disease (COPD). Demonstrating bioequivalence (BE) for DPI products is challenging, primarily due to an incomplete understanding of the relevance of drug concentrations in blood or plasma to equivalence in drug delivery to the local site(s) of action. Thus, BE of these drug/device combination products is established based on an aggregate weight of evidence, which utilizes in vitro studies to demonstrate equivalence of in vitro performance, pharmacokinetic or pharmacodynamic studies to demonstrate equivalence of systemic exposure, and pharmacodynamic and clinical endpoint studies to demonstrate equivalence in local action. This review discusses key aspects of in vitro studies in supporting the establishment of BE for generic locally acting DPI products. These aspects include comparability in device resistance and equivalence in in vitro testing for single inhalation (actuation) content and aerodynamic particle size distribution.

Delayed onset and protracted progression of anaphylaxis after omalizumab administration in patients with asthma.

BACKGROUND: Risk of anaphylaxis is included in the prescribing information for omalizumab, but the nature of these reactions merits further elaboration. OBJECTIVE: To describe cases of anaphylaxis associated with omalizumab administration in patients with asthma. METHODS: We reviewed spontaneous postmarketing adverse event reports submitted to the US Food and Drug Administration's Adverse Event Reporting System database and to the manufacturers of omalizumab and cases published in the literature through December 2006. Diagnostic criteria for anaphylaxis outlined by the National Institute of Allergy and Infectious Diseases and the Food Allergy and Anaphylaxis Network were used to screen cases. RESULTS: One-hundred twenty-four cases of anaphylaxis associated with omalizumab administration in patients with asthma were identified. Many cases had a delayed onset of symptoms beyond 2 hours after dose administration. Many cases were also characterized by a protracted progression, with individual signs and symptoms of anaphylaxis staggered over hours. Review of the case reports did not reveal any predictive risk factors for the delayed onset or protracted progression of anaphylaxis. CONCLUSION: Omalizumab-induced anaphylaxis may be characterized by a delayed onset and a protracted progression of symptoms. CLINICAL IMPLICATIONS: The unusual timing of anaphylaxis in these cases challenges our understanding of anaphylaxis. A delayed onset of symptoms and protracted progression of anaphylaxis should be taken into account when administering omalizumab.