Rank Regression in Stability Analysis

Stability data are often collected to determine the shelf-life of certain characteristics of a pharmaceutical product, for example, a drug\u27s potency over time. Statistical approaches such as the linear regression models are considered as appropriate to analyze the stability data. However, most of these regression models in both theory and practice rely heavily on their underlying parametric assumptions, such as normality of the continuous characteristics or their transformations. In this article, we propose and study some rank-based regression procedures for the stability data when the linear regression models are semiparametric with unspecified error structure. Numerical studies including Monte Carlo simulations and practical examples are demonstrated with the proposed procedures as well

Can initial vaginal bleeding patterns in etonogestrel implant users predict subsequent bleeding in the first 2 years of use?

ObjectivesTo evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use.Study designWe reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as "favorable" (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or "unfavorable' (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively.ResultsWe evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75-85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%-50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001).ConclusionImplant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant

Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials

Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system (RAAS) inhibitors and mineralocorticoid receptor antagonists (MRAs), which improve clinical outcomes in people with chronic kidney disease (CKD) and/or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with CKD. However, their effect on hyperkalemia has not been systematically evaluated. / Methods: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk and/or with CKD, in which serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory determine serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios (HR) and corresponding 95% CI pooled using random effects models to obtain summary treatment effects, overall and across key subgroups. / Results: Results from six trials were included comprising 49,875 participants assessing four SGLT2 inhibitors. 1,754 participants developed serious hyperkalemia and an additional 1,119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (HR 0.84, 95% CI 0.76-0.93), an effect consistent across studies (P-heterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (HR 0.80, 95% CI 0.68-0.93; P-heterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups including baseline kidney function, history of heart failure, RAAS inhibitor, diuretic and MRA use. SGLT2 inhibitors did not increase the risk of hypokalemia (HR 1.04, 95% CI 0.94-1.15; P-heterogeneity=0.42). / Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, without increasing the risk of hypokalemia

Gradient of Risk and Associations With Cardiovascular Efficacy of Ertugliflozin by Measures of Kidney Function Observations From VERTIS CV

Ukraine: Olga Godlevska, Ivan Chopey, Zinaida Teliatnikova, Petro Kuskalo, Orest Abrahamovych, Borys Mankovskyi, Ivan Fushtey, Galyna Myshanych, Susanna Tykhonova, Vira Tseluyko, Olena Koval, Oleksandr Parkhomenko, Oleksandr Prokhorov, Myroslava Vayda, Larysa Martymianova, Viktoriia Zharinova, Lyudmyla Prystupa, Larysa Pererva, Oleksandr Kovalov, Lyubov Sokolova, Volodymyr Botsyurko, Vitaliy Maslyanko, Maryna Vlasenko, Tetyana Khomazyuk, Anna Kulyk, Volodymyr Synenko, Oleksandr Karpenko, Yuriy Mostovoy, Olga Gyrina, Maryna Dolzhenko, Oleksandra Donets, Inna Sorokina, Yaroslav Malynovsky, Olena Lysunets, Roman Petrovskyy, Svitlana Panina

Ertugliflozin and Slope of Chronic eGFR: Prespecified Analyses from the Randomized VERTIS CV Trial

Background and objectives A reduction in the rate of eGFR decline, with preservation of $0.75 ml/min per 1.73 m2 per year, has been proposed as a surrogate for kidney disease progression. We report results from prespecified analyses assessing effects of ertugliflozin versus placebo on eGFR slope from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Design, setting, participants, & measurements Patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease were randomized to placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg (1:1:1). The analyses compared the effect of ertugliflozin (pooled doses, n55499) versus placebo (n52747) on eGFR slope per week and per year by random coefficient models. Study periods (weeks 0–6 and weeks 6–52) and total and chronic slopes (week 0 or week 6 to weeks 104, 156, 208, and 260) were modeled separately and by baseline kidney status. Results In the overall population, for weeks 0–6, the least squares mean eGFR slopes (ml/min per 1.73 m2 per week [95% confidence interval (95% CI)]) were 20.07 (20.16 to 0.03) and 20.54 (20.61 to 20.48) for the placebo and ertugliflozin groups, respectively; the difference was 20.47 (20.59 to 20.36). During weeks 6–52, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were 20.12 (20.70 to 0.46) and 1.62 (1.21 to 2.02) for the placebo and ertugliflozin groups, respectively; the difference was 1.74 (1.03 to 2.45). For weeks 6–156, least squares mean eGFR slopes (ml/min per 1.73 m2 per year [95% CI]) were 21.51 (21.70 to 21.32) and 20.32 (20.45 to 20.19) for the placebo and ertugliflozin groups, respectively; the difference was 1.19 (0.95 to 1.42). During weeks 0–156, the placebo-adjusted difference in least squares mean slope was 1.06 (0.85 to 1.27). These findings were consistent by baseline kidney status. Conclusions Ertugliflozin has a favorable placebo-adjusted eGFR slope .0.75 ml/min per 1.73 m2 per year, documenting the kidney function preservation underlying the clinical benefits of ertugliflozin on kidney disease progression in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Clinical Trial registry name and registration number: US National Library of Medicine, ClinicalTrials.gov NCT01986881. Date of trial registration: November 13, 2013

Novel Design and Analysis for Rare Disease Drug Development

For rare disease drug development, the United States (US) Food and Drug Administration (FDA) has indicated that the same standards as those for drug products for common conditions will be applied. To assist the sponsors in rare disease drug development, the FDA has initiated several incentive programs to encourage the sponsors in rare disease drug development. In practice, these incentive programs may not help in achieving the study objectives due to the limited small patient population. To overcome this problem, some out-of-the-box innovative thinking and/or approaches, without jeopardizing the integrity, quality, and scientific validity of rare disease drug development, are necessarily considered. These innovative thinking and/or approaches include but are not limited to (i) sample size justification based on probability statements rather than conventional power analysis; (ii) demonstrating not-ineffectiveness and not-unsafeness rather than demonstrating effectiveness and safety with the small patient population (i.e., limited sample size) available; (iii) the use of complex innovative designs such as a two-stage seamless adaptive trial design and/or an n-of-1 trial design for flexibility and the efficient assessment of the test treatment under study; (iv) using real-world data (RWD) and real-world evidence (RWE) to support regulatory submission; and (v) conducting an individual benefit–risk assessment for a complete picture of the clinical performance of the test treatment under investigation. In this article, we provide a comprehensive summarization of this innovative thinking and these approaches for an efficient, accurate and reliable assessment of a test treatment used for treating patients with rare diseases under study. Statistical considerations including challenges and justifications are provided whenever possible. In addition, an innovative approach that combines innovative thinking and these approaches is proposed for regulatory consideration in rare disease drug development