Matilde Sanchez-Kam

Early weight loss while on lorcaserin, diet and exercise as a predictor of week 52 weight-loss outcomes.

To identify an early treatment milestone that optimizes sensitivity and specificity for predicting ≥5% weight loss at Week (W) 52 in patients with and without type 2 diabetes on lorcaserin or placebo.

Lorcaserin for Smoking Cessation and Associated Weight Gain A Randomized 12-Week Clinical Trial

Introduction Lorcaserin is a selective serotonin 2C receptor agonist approved by the Food and Drug Administration for chronic weight management. Preclinical data suggest that it may also be effective in smoking cessation through modulation of the dopaminergic reward system. Methods This was a 12-week, randomized, double-blind, placebo-controlled trial conducted in 30 centers in the United States. Six hundred three adult smokers with a Body Mass Index of 18.5-35 kg/m2, averaging at least 10 cigarettes/day with no period of abstinence >3 months for the past year were randomized to lorcaserin 10 mg once daily (QD), 10 mg twice daily (BID) or placebo; all received standardized smoking cessation counseling weekly. The target quit date was day 15. The primary endpoint was the exhaled carbon monoxide confirmed Continuous Abstinence Rate for weeks 9-12 (month 3). Results Continuous Abstinence Rates for month 3 were 5.6%, 8.7%, and 15.3% for the placebo, QD and BID groups, respectively (BID vs. placebo odds ratio 3.02, 95% confidence interval 1.47, 6.22, p = .0027. Change in weight at week 12 (randomized population) was -0.01, -0.35 and -0.98 kg, respectively (p = .0004, BID vs. placebo), and +0.73, +0.76, and -0.41 kg in participants achieving month 3 continuous abstinence. The most frequent adverse events were headache, nausea, constipation, and fatigue. Conclusions Lorcaserin with counseling was associated with dose-related increases in smoking cessation and prevention of associated weight gain over a 3-month period. Further investigation of lorcaserin in smoking cessation is warranted. Trial Registration: ClinicalTrials.gov. Identifier: NCT02044874. Implications This randomized, controlled trial demonstrated that lorcaserin used in conjunction with standard cessation counseling was associated with dose-related increases in smoking cessation and prevention of associated weight gain. To our knowledge, this is the first demonstration in humans of a potential role of 5-HT2C agonism in the modulation of central neurological circuits involved with reward.

Sample Size Re-estimation Designs In Confirmatory Clinical Trials—Current State, Statistical Considerations, and Practical Guidance

A sample size re-estimation (SSR) design is a flexible, adaptive design with the primary purpose of allowing sample size of a study to be reassessed in the mid-course of the study to ensure adequate power. In real world drug product, biologic, and device development, there may be large uncertainty in key factors that drive the sample size estimation for a confirmatory clinical trial. For example, early phase studies may have encouraging results but could be of shorter duration, or use a different endpoint than what is required for confirmatory phase clinical trials. The negative impact of high uncertainty at design stage for a confirmatory trial can be mitigated by an SSR design. Recent surveys have reported an encouraging upward trend in the use of SSR designs in clinical trials since the release of the draft guidance for adaptive design clinical trials for drugs and biologics by the U.S. Food and Drug Administration in 2010 (U.S. Food and Drug Administration (FDA) (February, 2010), Draft Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics). To support broad understanding and acceptance of SSR designs in confirmatory settings, especially unblinded SSR designs, we summarize statistical methods pertaining to SSR designs, including recent development in this field, and discuss design alternatives among blinded SSR, unblinded SSR, and conventional group sequential designs. To support appropriate implementation of SSR designs, we make recommendations on operational logistics for trial conduct based on accumulated experience in recent years, and provide points to consider for final data analysis and reporting for studies where the sample size has been increased following either a blinded or an unblinded SSR algorithm.

A Practical Guide to Data Monitoring Committees in Adaptive Trials

Adaptive clinical trials require access to interim data to carry out trial modification as allowed by a prespecified adaptation plan. A data monitoring committee (DMC) is a group of experts that is charged with monitoring accruing trial data to ensure the safety of trial participants and that in adaptive trials may also play a role in implementing a preplanned adaptation. In this paper, we summarize current practices and viewpoints and provide guidance on evolving issues related to the use of DMCs in adaptive trials. We describe the common types of adaptive designs and point out some DMC-related issues that are unique to this class of designs. We include 3 examples of DMCs in late-stage adaptive trials that have been implemented in practice. We advocate training opportunities for researchers who may be interested in serving on a DMC for an adaptive trial since qualified DMC members are fundamental to the successful execution of DMC responsibilities.

Evaluation and Review of Strategies to Assess Cardiovascular Risk in Clinical Trials in Patients with Type 2 Diabetes Mellitus

This article is a result of the efforts of the American Statistical Association Biopharmaceutical Section Working Group on Safety. With representatives from different institutions, this group reviewed the drugs approved by the United States Food and Drug Administration (FDA) to treat Type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. The main objective of this article is to understand the impact of FDA guidance of 2008 on assessment of CV risk in antidiabetes development programs, which are summarized and displayed in chronological order. Compared to New Drug Applications (NDAs) submitted prior to the FDA 2008 guidance, the number of patient-years significantly increased for NDAs approved in the post-guidance era. To meet guidance requirements on CV risk assessment, meta-analyses and large cardiovascular outcome trials (CVOTs) have been conducted. These CVOTs provide an opportunity to assess safety signals beyond CV risk and assess the benefit/risk ratio better in diabetic patients with a high risk for CV events, but they also present challenges. The advantages and disadvantages of different CV assessment strategies are summarized in this manuscript. Finally, we raise some emerging questions and discuss future opportunities for CV risk assessment research. Supplementary materials for this article are available online.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials

Background: There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. Methods: In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. Results: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. Conclusions: Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

Sources of Safety Data and Statistical Strategies for Design and Analysis: Postmarket Surveillance

Background: Safety data are continuously evaluated throughout the life cycle of a medical product to accurately assess and characterize the risks associated with the product. The knowledge about a medical product’s safety profile continually evolves as safety data accumulate. Methods: This paper discusses data sources and analysis considerations for safety signal detection after a medical product is approved for marketing. This manuscript is the second in a series of papers from the American Statistical Association Biopharmaceutical Section Safety Working Group. Results: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from passive postmarketing surveillance systems compared to other sources. Conclusions: Signal detection has traditionally relied on spontaneous reporting databases that have been available worldwide for decades. However, current regulatory guidelines and ease of reporting have increased the size of these databases exponentially over the last few years. With such large databases, data-mining tools using disproportionality analysis and helpful graphics are often used to detect potential signals. Although the data sources have many limitations, analyses of these data have been successful at identifying safety signals postmarketing. Experience analyzing these dynamic data is useful in understanding the potential and limitations of analyses with new data sources such as social media, claims, or electronic medical records data.

On quantitative methods for clinical safety monitoring in drug development

ABSTRACT Safety monitoring and reporting has achieved a greater level of attention in the past 15 years. Statisticians play an important role in learning about a drugs safety profile. An ASA safety monitoring working group was established with a goal to empower the biostatistics community to play a proactive role and better enable quantification in safety monitoring. As part of its effort, this article presents a systematic review and unique perspective on the existing methodology developments, which include Bayesian and frequentist, blinded versus unblinded safety monitoring, individual versus aggregate data meta-analyses, pre-, and post-marketing methods, static versus dynamic safety reviews, and methods of visualization. These perspectives may serve as a background for future statistical work, both in methodology development and its application.

Statistical Considerations for Cardiovascular Outcome Trials in Patients with Type 2 Diabetes Mellitus

ABSTRACT This is the second article written by the American Statistical Association Biopharmaceutical Section Safety Working Group. In the first article, we reviewed the drugs approved by the United States Food and Drug Administration to treat type 2 diabetes mellitus during 2002–2014 with a focus on the cardiovascular (CV) risk assessment. We discussed different strategies to address premarketing and post-marketing CV risk requirements and raised some questions that required further research. The main objective of this article is to outline statistical challenges encountered at the design and analysis stages of cardiovascular outcome trials (CVOTs). We discuss statistical challenges and strategies for testing multiple endpoints, populations, and doses; choosing an event window; addressing premarketing and post-marketing requirements for CV events with group-sequential and adaptive designs; designing a CVOT for noninferiority and superiority testing; assessing effects in subgroups; and evaluating patients retention and missing data challenges.

P-179 Safety, Pharmacokinetics and Pharmacodynamics of Etrasimod (APD334), an Oral Selective S1P Receptor Modulator, After Dose-Escalation, in Healthy Volunteers

Background: APD334 is an oral, selective, next-generation S1P receptor modulator with the potential for optimised targeting of S1P receptors related to inflammatory bowel disease. Methods: The objective of this first clinical study was to evaluate the safety, tolerability, pharmacokinetic (PK) properties and pharmacodynamic response (lymphopenia) of ascending doses of APD334 when administered as a single oral dose to healthy adult subjects. The study was a randomised, double-blind, dose-escalation design. For each dose a separate cohort of up to 8 subjects were randomised, 6 to APD334 and 2 to placebo. Dosing started at 0.1 mg and was planned to escalate to 0.35, 1, 3, 5, 10, 20, and 40 mg. Subjects were healthy adult men and women, 18 to 45 years, non-smokers, no prescription medications with a body weight of 50 to 100 kg. Following a screening period of up to 21 days a single dose was administered on day 1 with prior and subsequent inpatient observations and procedures undertaken until at least day 7/Exit. Results: Forty subjects were enrolled and completed the study; 30 subjects were included in the PK analyses. APD334 doses of 0.1, 0.35, 1, 3, and 5 mg were assessed. APD334 was well tolerated at the 0.1, 0.35, 1, and 3 mg dose levels. In the 5 mg APD334 cohort, 1 subject experienced first degree Atrioventricular (AV) block and second degree AV block with bradycardia, and 2 subjects experienced first degree AV block, 1 of which was associated with bradycardia. These events, although asymptomatic, led to discontinuation of further dose escalation. Dose-related declines in blood pressure and heart rate from baseline compared to placebo were noted. Only the decline in heart rate at the 3.0 and 5.0 mg doses was statistically significant (P < 0.05). These declines resolved during follow-up, without intervention. PK parameters for 0.1, 0.35, 1, 3, and 5 mg doses were Cmax (&mgr;g/mL), mean (SD); 0.00173 (0.00061), 0.00628 (0.00036), 0.0172 (0.0055), 0.0605 (0.0117), 0.102 (0.019); AUC0-inf (&mgr;g·h/mL) 0.0798 (0.0213), 0.268 (0.031), 0.793 (0.168), 2.60 (0.84), 4.39 (0.61) and demonstrate dose-proportionality. Tmax (h), median (range) was; 6 (4.00–12.00), 7 (1.50–24.0), 6 (2.00–8.00), 3.5 (1.50–8.00), 4 (3.00–6.00). The mean terminal half-life of APD334 was consistent between dose groups, ranging from 30.7 to 37.4 hours. APD334 at 0.1, 0.35, and 1 mg had little effect on total T, B, and Natural Killer (NK) cell counts when compared to baseline or placebo at each dose, as was observed for total lymphocyte counts. Dose-related decreases in total lymphocyte and T cell counts were observed at 3 and 5 mg. There were no other clinically significant safety issues with respect to; vital signs, electrocardiograms, pulmonary function, ophthalmoscopy, or clinical laboratory tests. Conclusions: The study demonstrates that APD334 was well tolerated when orally administered to healthy volunteers at dose levels 0.1 mg up to 3 mg and supports evaluation of APD334 in further clinical studies across this dose range.