Demonstrating that Real World Evidence Is Fit-For-Purpose to Support Labeling: Parallels to Patient Reported Outcomes in the Pursuit of Labeling Claims.

INTRODUCTION: In December 2021, U.S. Food & Drug Administration (FDA) will issue guidance on the use of real-world evidence (RWE) to support new indications or expanded product labeling. While difficult to foresee what FDA will require, learnings can be gleaned from previous paradigm shifts at FDA, such as for patient reported outcomes (PROs) in 2006-2009. METHODS: We contrast published requirements for justifying PROs as fit-for-purpose for a specific labeling claim with a potential approach to justify RWE as fit-for-purpose to support expanded labeling or a new indication. RESULTS: PRO labeling claims require a PRO Evidence Dossier that includes: specific wording of claim, clinical trial hypothesis structure and endpoint model, and justification that the PRO is relevant and meaningful to patients in the target population (content validity) with adequate psychometric properties. FDA's 2018 RWE Framework outlined critical considerations for using RWE to support regulatory decisions, including data quality, relevancy, provenance, and transparency. Strong parallels exist between the evidence required to justify that PROs are fit-for-purpose to support specific labeling claims and evidence to justify RWE as fit-for-purpose for specific research questions and labeling. Early discussion with FDA is encouraged. CONCLUSION: Drawing on parallels with use of PROs in labeling, RWE for regulatory purposes should be evaluated within the context of specific labeling or indication, specific study design and analysis plans, and the data attributes of data source. Sponsors seeking a new indication or labeling expansion based on RWE should justify that a specific data source and specific study design are fit-for-purpose.

Carbon footprint of self-selected US diets: nutritional, demographic, and behavioral correlates.

BACKGROUND: A substantial portion of greenhouse gas emissions (GHGE) has been attributed to the food sector, but little is known about the association between the carbon footprint of individual self-selected diets in the United States and nutritional quality. OBJECTIVES: The aims of this study were to assess the GHGE from individual self-selected diets in the United States and examine their association with nutritional quality of the diets, demographic patterns, and food-related behaviors. METHODS: The dietary GHGE from US adults (>18 y, N = 16,800) in the 2005-2010 National Health and Nutrition Examination Survey (NHANES) were calculated by linking all foods consumed in their 24-h recall diets to our new database of food environmental impacts. Diets were ranked by GHGE/1000 kcal. Those in the top and bottom quintiles were compared on the US Healthy Eating Index (HEI) and on the amounts of specific nutrients known to be under- or overconsumed in the US population. Demographic and behavioral variables from the NHANES were also correlated to these dietary carbon footprints. RESULTS: Diets in the bottom quintile accounted for one-fifth the total emissions (GHGE/1000 kcal) of those in the top quintile, yet had significantly higher (P < 0.001) HEI scores by 2.3 ± 0.7 points on a 100-point scale. These low-GHGE diets contained higher amounts of fiber and vitamin E and lower amounts of sodium and saturated fats, whereas high-GHGE diets contained higher amounts of vitamins A and D, choline, calcium, iron, and potassium. Low-GHGE diets had less meat, dairy, and solid fats, and more poultry, plant protein foods, oils, whole and refined grains, and added sugars. CONCLUSIONS: Food patterns responsible for lower GHGE had a better overall diet quality and were more nutritious on several key dimensions, although not all. These results can inform dietary guidance and other policies that seek to address the goals of improved dietary intakes and reduced food-related emissions.

Drug Development for Asthma and COPD: A Regulatory Perspective.

This review addresses drug development intended to support United States clearance for asthma and COPD by explaining basic regulatory terms and broadly discussing the regulatory pathways to clearance. Some of the key clinical regulatory challenges that are faced by drugs for asthma and COPD are explained and clarified, both overall and by class of drug, citing relevant examples that emphasize key lessons. Generic drug development of inhaled drugs is also addressed. The purpose of this review is to provide the reader with a greater understanding and appreciation of asthma and COPD drug development from the regulatory perspective.

Precision Medicine, Diabetes, and the U.S. Food and Drug Administration.

The U.S. Food and Drug Administration (FDA) has long sought to achieve the broader use of personalized medicine, which is better targeting of FDA-approved therapies through incorporating precise knowledge of a patient's underlying condition to therapies optimally chosen to match those needs. While some strides have been made in precision medicine-particularly in oncology and rare genetic diseases-most of the standard general medicine indications have yet to realize the benefits of precision-guided therapies. This includes those for diabetes mellitus (DM), both type 1 and type 2. Although the scientific and regulatory considerations needed to move to a more "precise" future of DM prevention and treatment differ between the two disease subsets, scientific advances in both must occur before the FDA can incorporate precision medicine into its oversight of DM drug development and approval. This article provides an overview of the regulatory expectations and challenges in realizing a future where the therapeutics for DM are informed by precise knowledge of a patient's genetics and specific phenotype.

Pulmonary oil micro-embolism (POME) syndrome: a review and summary of a large case series.

The use of steroid compounds formulated in oil for depot injection can be associated with acute pulmonary reactions characterized primarily by cough, but sometimes with other associated symptoms. The pathophysiology of these reactions remains unclear, although they are reported in the literature as 'POMEs' or pulmonary oil micro-embolism events. We report on a large case series and propose a case definition for these events. These events can raise significant concern even though they are often self-limited. It is hoped that clinicians will recognize these events more readily and be able to inform patients better, and that future reports and assessments can benefit from our proposed case definition.

Analyzing risk response dynamics on the web: the case of Hurricane Katrina.

Using a unique data set that documented the hourly web-surfing behavior of over 140,000 Internet users in five southeastern states in August 2005, we explore the dynamics of information gathering as Hurricane Katrina developed and then hit South Florida and the Northern Gulf Coast. Using both elementary statistical methods and advanced techniques from functional data analysis,((1)) we examine both how storm events (such as the posting of warnings) affected traffic to weather-related websites, and how this traffic varied across locations and by characteristics of the web user. A general finding is that spatial-temporal variation in weather-site web traffic generally tracked the timing and scale of the storm threat experienced by a given area. There was, however, considerable variation in this responsiveness. Residents in Florida counties that had been most directly affected by Hurricane Dennis just a month earlier, for example, displayed more active visitation rates than those who had been less affected. We also find evidence of a gender effect where male users displayed a disproportionately larger rate of visitation to weather sites given the onset of storm warnings than females. The implications of this work for the broader study of behavioral risk response dynamics during hazards are explored.

U.S. regulatory perspective on the minimal clinically important difference in chronic obstructive pulmonary disease.

This paper outlines the regulatory issues surrounding the determination and use of minimally clinically important differences (MCID) in assessing measures of outcomes from treatments of chronic obstructive pulmonary disease (COPD). To place this discussion in context, it is important to understand the current state of approved therapies for COPD, as well as newer directions in therapy. This paper discusses the currently available, approved drug therapies for COPD in the United States and how they were approved. This is followed by an overview on the use of MCID for assessing outcomes in therapies for COPD, as well the more general experience with MCID from the U.S. regulatory perspective.

Inhaled fluticasone propionate by diskus in the treatment of asthma: a comparison of the efficacy of the same nominal dose given either once or twice a day.

STUDY OBJECTIVE: In September 2000, the US Food and Drug Administration (FDA) approved the use of Flovent Diskus (FD) [fluticasone propionate; GlaxoSmithKline; Research Triangle Park, NC], which is an orally inhaled, dry-powder corticosteroid, for the maintenance treatment of asthma at dosages of 50 to 1,000 microg administered twice-daily. Once-daily dosage regimens did not receive approval. This article will detail six clinical trials, five of which incorporated comparative once-daily and twice-daily treatment arms of the same nominal dose of FD. DESIGN: Six 12-week, randomized, double-blind, placebo-controlled studies in patients with mild-to-moderate asthma, including two pediatric asthma trials (patient age, 4 to 11 years) of total daily doses of fluticasone propionate (FP) of 100 or 200 microg, and four adult and adolescent studies of total daily doses of FP of 100, 200, or 500 microg. RESULTS: Twice-daily dosing was numerically superior to once-daily dosing at the same nominal dose in all comparative studies for the primary end point, change in predose FEV(1). In five trials, the results of the once-daily dosage of FP were statistically indistinguishable from those with placebo. One trial demonstrated the superiority of FP, 500 microg once-daily, over placebo; however, the effect size was half that observed with twice-daily dosing. Once-daily FP dosing showed no advantage in safety or in patient adherence to medication. CONCLUSIONS: In the FDA review of once-daily dosing of the FD regimen, 100 or 200 microg once-daily dosing was not shown to be significantly better than placebo. FP 500 microg once-daily was found to be superior to placebo, but at about one half the effect size as the same nominal dose given bid. No advantage in patient safety or adherence was demonstrated for once-daily administration over twice-daily administration, and once-daily administration is not currently recommended.

Serious asthma exacerbations in asthmatics treated with high-dose formoterol.

OBJECTIVE: To review three prospective, randomized, placebo-controlled, double-blind clinical studies of formoterol (Foradil Aerolizer; Novartis Pharmaceuticals; Basel, Switzerland) at dosages of 12 microg and 24 microg bid for the treatment of patients with asthma. DATA SOURCES: Clinical studies submitted to the US Food and Drug Administration in support of the approval of Foradil Aerolizer for marketing in the United States. RESULTS: More patients treated regularly with formoterol, 24 micro g bid, had a serious asthma exacerbation than did patients who had been treated with placebo. In the first study, 4 of 135 adult patients (3%) who had been treated with formoterol, 24 microg bid, had a serious asthma exacerbation compared to none of 136 placebo-treated patients. In the second study, 5 of 136 patients (3.7%) treated with formoterol, 24 microg bid, had a serious asthma exacerbation compared to 2 of 141 placebo-treated patients (1.4%). In the third study, 11 of 171 pediatric patients (6.4%) treated with formoterol, 24 microg bid, had a serious asthma exacerbation compared to none of 176 placebo-treated patients. CONCLUSION: Regular use of high-dose inhaled formoterol (24 microg bid) may be associated with more frequent serious asthma exacerbations.

Bringing new nebulizer technologies to market: regulatory issues.

This review outlines regulatory issues involved in bringing new nebulizer technologies to market and describes the regulatory roles of the Center for Devices and Radiologic Health and the Center for Drug Evaluation and Research. The responsible agency is determined by whether a new device involves a new drug formulation.