Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient

Data reported directly by patients about how they feel and function are rarely included in oncology drug labeling in the United States, in contrast to Europe and to nononcology labeling in the United States, where this practice is more common. Multiple barriers exist, including challenges unique to oncology trials, and industry's concerns regarding cost, logistical complexities, and the Food and Drug Administration's (FDA's) rigorous application of its 2009 guidance on the use of patient-reported outcome (PRO) measures. A panel consisting of representatives of industry, FDA, the PRO Consortium, clinicians, and patients was assembled at a 2014 workshop cosponsored by FDA to identify practical recommendations for overcoming these barriers. Key recommendations included increasing proactive encouragement by FDA to clinical trial sponsors for including PROs in drug development programs; provision of comprehensive PRO plans by sponsors to FDA early in drug development; promotion of an oncology-specific PRO research agenda; development of an approach to existing ("legacy") PRO measures, when appropriate (focused initially on symptoms and functional status); and increased FDA and industry training in PRO methodology. FDA has begun implementing several of these recommendations

Developmental effects on sleep–wake patterns in infants receiving a cow’s milk-based infant formula with an added prebiotic blend: A Randomized Controlled Trial

Background Few studies have evaluated nutritive effects of prebiotics on infant behavior state, physiology, or metabolic status. Methods In this double-blind randomized study, infants (n = 161) received cow’s milk-based infant formula (Control) or similar formula with an added prebiotic blend (polydextrose and galactooligosaccharides [PDX/GOS]) from 14–35 to 112 days of age. Infant wake behavior (crying/fussing, awake/content) and 24-h sleep–wake actograms were analyzed (Baseline, Days 70 and 112). Salivary cortisol was immunoassayed (Days 70 and 112). In a subset, exploratory stool 16S ribosomal RNA-sequencing was analyzed (Baseline, Day 112). Results One hundred and thirty-one infants completed the study. Average duration of crying/fussing episodes was similar at Baseline, significantly shorter for PDX/GOS vs. Control at Day 70, and the trajectory continued at Day 112. Latency to first and second nap was significantly longer for PDX/GOS vs. Control at Day 112. Cortisol awakening response was demonstrated at Days 70 and 112. Significant stool microbiome beta-diversity and individual taxa abundance differences were observed in the PDX/GOS group. Conclusions Results indicate faster consolidation of daytime waking state in infants receiving prebiotics and support home-based actigraphy to assess early sleep–wake patterns. A prebiotic effect on wake organization is consistent with influence on the gut–brain axis and warrants further investigation. Impact Few studies have evaluated nutritive effects of prebiotics on infant behavior state, cortisol awakening response, sleep–wake entrainment, and gut microbiome. Faster consolidation of daytime waking state was demonstrated in infants receiving a prebiotic blend in infant formula through ~4 months of age. Shorter episodes of crying were demonstrated at ~2 months of age (time point corresponding to age/developmental range associated with peak crying) in infants receiving formula with added prebiotics. Results support home-based actigraphy as a suitable method to assess early sleep–wake patterns. Prebiotic effect on wake organization is consistent with influence on the gut–brain axis and warrants further investigation

Biogeography rather than substrate type determines bacterial colonization dynamics of marine plastics

Since the middle of the 20th century, plastics have been incorporated into our everyday lives at an exponential rate. In recent years, the negative impacts of plastics, especially as environmental pollutants, have become evident. Marine plastic debris represents a relatively new and increasingly abundant substrate for colonization by microbial organisms, although the full functional potential of these organisms is yet to be uncovered. In the present study, we investigated plastic type and incubation location as drivers of marine bacterial community structure development on plastics, i.e., the Plastisphere, via 16S rRNA amplicon analysis. Four distinct plastic types: high-density polyethylene (HDPE), linear low-density polyethylene (LDPE), polyamide (PA), polymethyl methacrylate (PMMA), and glass-slide controls were incubated for five weeks in the coastal waters of four different biogeographic locations (Cape Verde, Chile, Japan, South Africa) during July and August of 2019. The primary driver of the coastal Plastisphere composition was identified as incubation location, i.e., biogeography, while substrate type did not have a significant effect on bacterial community composition. The bacterial communities were consistently dominated by the classes Alphaproteobacteria, Gammaproteobacteria, and Bacteroidia, irrespective of sampling location or substrate type, however a core bacterial Plastisphere community was not observable at lower taxonomic levels. Overall, this study sheds light on the question of whether bacterial communities on plastic debris are shaped by the physicochemical properties of the substrate they grow on or by the marine environment in which the plastics are immersed. This study enhances the current understanding of biogeographic variability in the Plastisphere by including biofilms from plastics incubated in the previously uncharted Southern Hemisphere

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

Background and aimsTreprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.MethodsPatients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.ResultsA total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.ConclusionGenetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.The reviews of this paper are available via the supplemental material section

A pilot study of oral treprostinil pharmacogenomics and treatment persistence in patients with pulmonary arterial hypertension.

Background and aimsTreprostinil is a prostacyclin analog used to treat pulmonary arterial hypertension. Dosing is empiric and based on tolerability. Adverse effects are common and can affect treatment persistence. Pharmacogenomic variants that may affect treprostinil metabolism and transport have not been well-characterized. We aimed to investigate the pharmacogenomic sources of variability in treatment persistence and dosing.MethodsPatients were prospectively recruited from an IRB approved biobank registry at a single pulmonary hypertension center. A cohort of patients who received oral treprostinil were screened for participation. Pharmacogenomic analysis was for variants in CYP2C8, CYP2C9, and ABCC4. A retrospective review was conducted for demographics, clinical status, dosing, and response. Fisher's exact test was used for categorical data and Kruskal-Wallis test or Wilcoxon rank sum were used for continuous data.ResultsA total of 15 patients received oral treprostinil and were consented. Their median age was 53 years, 73% were female, and 93% were White. The median total daily dose was 22.5 mg (13.5, 41) at last clinical observation. 40% of patients discontinued treatment with a majority due to adverse effects. Approximately 27% of patients had a loss-of-function variant in CYP2C8 (*1/*3 or *1/*4), whereas 47% of patients had a loss-of-function variant in CYP2C9 (*1/*2, *1/*3, or *2/*2). Minor allele frequencies for ABCC4 (rs1751034 and rs3742106) were 0.17 and 0.43, respectively. Survival analysis showed that increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation [hazard ratio (HR): 0.13; 95% confidence interval (CI): 0.02, 0.91; p = 0.04]. Genetic variants were not significantly associated with dosing.ConclusionGenetic variants responsible for the metabolism and transport of oral treprostinil were common. Increased CYP2C9 activity score was associated with decreased risk for treatment discontinuation. However, dosing was not associated with genetic variants in metabolizing enzymes for treprostinil. Our findings suggest significant variability in treatment persistence to oral treprostinil, with pharmacogenomics being a potentially important contributor.The reviews of this paper are available via the supplemental material section

sj-docx-2-aop-10.1177_10600280221129348 – Supplemental material for Direct Oral Anticoagulants Versus Warfarin for Venous Thromboembolism Prophylaxis in Patients With Nephrotic Syndrome: A Retrospective Cohort Study

Supplemental material, sj-docx-2-aop-10.1177_10600280221129348 for Direct Oral Anticoagulants Versus Warfarin for Venous Thromboembolism Prophylaxis in Patients With Nephrotic Syndrome: A Retrospective Cohort Study by Aminat Tijani, Eric M. Coons, Britta Mizuki, Miranda Dermady, Katerina Stanilova, Ashley L. Casey, Muhannad Alqudsi, Mariella Gastanaduy, Ardem Elmayan, Adi Bamnolker and Juan Carlos Q. Velez in Annals of Pharmacotherapy</p