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Analytical and statistical comparability of generic enoxaparins from the US market with the originator product

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 2015年 115卷 431-442页

作者： Mourier, Pierre A. J. Agut, Christophe Souaifi-Amara, Hajer Herman, Frederic Viskov, Christian Sanofi F-94403 Vitry Sur Seine France Sanofi R&D F-34184 Montpellier France Experis IT Life Sci F-92723 Nanterre France Sanofi CMC Biostat & Programming Ctr Rech Vitry Sur Seine F-94403 Vitry Sur Seine France

Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by Sanofi is one of the most widely prescribed LMWHs and has been used since 1993 in the USA. In 2010, US Food and Drug Administration approval for supplying generic enoxaparin was granted to Sandoz and subsequently to Amphastar. Little is known, however, of the differences in composition of these preparations. In this study, samples from several batches of generic enoxaparins were purchased on the US market and analyzed with state of the art methodologies, including disaccharide building blocks quantification, nuclear magnetic resonance (NMR), and a combination of orthogonal separation techniques. Direct high-performance liquid chromatography analysis of the different enoxaparin batches revealed distinct process fingerprints associated with each manufacturer. Disaccharide building block analysis showed differences in the degree of sulfation, the presence of glycoserine derivatives, as well as in proportions of disaccharides. Results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a clear distinction to be made between the enoxaparin batches according to their manufacturer. These results were further confirmed by orthogonal analytical techniques, including NMR, which revealed compositional differences of oligosaccharides both in low- and high-affinity antithrombin fractions of enoxaparin. (C) 2015 The Authors. Published by Elsevier B.V.

关键词： Analytical comparability Disaccharide quantification Enoxaparin Generic Chemometrics Nuclear magnetic resonance

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A confirmatory basket design considering non-inferiority and superiority testing

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JOURNAL OF BIOPHARMACEUTICAL STATISTICS 2024年第2期34卷 205-221页

作者： Zhang, Yaohua Chu, Chenghao Beckman, Robert A. Gao, Lei Laird, Glen Yi, Bingming Vertex Pharmaceut Inc Dept Biometr Boston MA 02210 USA Georgetown Univ Lombardi Comprehens Canc Ctr Dept Oncol Med Ctr Washington DC USA Georgetown Univ Lombardi Comprehens Canc Ctr Dept Biostat Bioinformat & Biomath Med Ctr Washington DC USA Georgetown Univ Innovat Ctr Biomed Informat Med Ctr Washington DC USA Moderna Dept Biostat & Programming Cambridge MA USA

For multiple rare diseases as defined by a common biomarker signature, or a disease with multiple disease subtypes of low frequency, it is often possible to provide confirmatory evidence for these disease or subtypes (baskets) as a combined group. A novel drug, as a second generation, may have marginal improvement in efficacy overall but superior efficacy in some baskets. In this situation, it is appealing to test hypotheses of both non-inferiority overall and superiority on certain baskets. The challenge is designing a confirmatory study efficient to address multiple questions in one trial. A two-stage adaptive design is proposed to test the non-inferiority hypothesis at the interim stage, followed by pruning and pooling before testing a superiority hypothesis at the final stage. Such a design enables an efficient and novel registration pathway, including an early claim of non-inferiority followed by a potential label extension with superiority on certain baskets and an improved benefit-risk profile demonstrated by longer term efficacy and safety data. Operating characteristics of this design are examined by simulation studies, and its appealing features make it ready for use in a confirmatory setting, especially in emerging markets, where both the need and the possibility for efficient use of resources may be the greatest.

关键词： Basket design non-inferiority two-stage design

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Bleeding Risk in Patients With Atrial Fibrillation The AMADEUS Study

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CHEST 2011年第1期140卷 146-155页

作者： Lane, Deirdre A. Kamphuisen, Pieter W. Minini, Pascal Buller, Harry R. Lip, Gregory Y. H. Univ Birmingham City Hosp Ctr Cardiovasc Sci Birmingham B18 7QH W Midlands England Univ Amsterdam Acad Med Ctr Dept Vasc Med NL-1105 AZ Amsterdam Netherlands Sanofi Aventis Res & Dev Biostat & Programming Chilly Mazarin France

Objective: This study aimed to assess the impact of combination antithrombotic therapy on stroke and bleeding risk compared with anticoagulation therapy only in patients with atrial fibrillation (AF). Methods: Post hoc analysis of 4,576 patients with AF (mean +/- SD age, 70.1 +/- 9.1 years;men, 66.5%) enrolled in the Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation (AMADEUS) trial were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) (n = 2,283) or dose-adjusted vitamin K antagonists (VKAs) (international normalized ratio, 2.0-3.0) (n = 2,293). Of these patients, 848 (18.5%) received antiplatelet therapy (aspirin, clopidogrel, ticlopidine, etc) in addition to anticoagulation treatment (combination antithrombotic therapy). Results: A total of 572 (15.3% per year) clinically relevant bleeding and 103 (2.6% per year) major bleeding events occurred. Patients receiving combination antithrombotic therapy had a 2.3- to 2.5-fold increased risk of clinically relevant bleeding events and major bleeding events, respectively, compared with those receiving anticoagulation therapy only. Multivariate analyses (hazard ratio, 95% CI) revealed that the risk of clinically relevant bleeding was significantly increased by age 65 to 74 years (1.44, 1.14-1.82) and >= 75 years (1.59, 1.24-2.04, P = .001) and by combination antithrombotic therapy (2.47, 2.07-2.96, P < .0001). The same held true for major bleeding events, with analogous figures for age 65 to 74 years (2.26, 1.08-4.71) and >= 75 years (4.19, 1.98-8.87, P = .0004) and for combination antithrombotic therapy (2.23, 1.49-3.34, P < .0001). Combination antithrombotic therapy was not associated with a decrease in ischemic stroke risk compared with anticoagulation therapy only (11 [1.4% per year] vs 22 [0.7% per year];adjusted hazard ratio, 2.01;95% CI, 0.94-4.30;P = .07). Conclusions: Combination antithrombotic therapy increases the risk of clinically relev

关键词： Aged Anticoagulants/adverse effects Anticoagulants/therapeutic use Atrial Fibrillation/complications Dose-Response Relationship, Drug Drug Therapy, Combination England/epidemiology England/epidemiology Female Hemorrhage/chemically induced Hemorrhage/epidemiology Humans Incidence Injections, Subcutaneous Male Oligosaccharides/administration & dosage Oligosaccharides/adverse effects Platelet Aggregation Inhibitors/administration & dosage Platelet Aggregation Inhibitors/adverse effects Prognosis Risk Assessment/methods Risk Factors Stroke/etiology Stroke/prevention & control Warfarin/adverse effects Warfarin/therapeutic use

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Comments on "A taxonomy of estimands for regulatory clinical trials with discontinuations"

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STATISTICS IN MEDICINE 2017年第27期36卷 4414-4416页

作者： Doi, Masaaki Watanabe, Daisuke Takenouchi, Kazumasa Tsuchikawa, Masaru Japan Pharmaceut Mfg Assoc Causal Inference Working Grp Data Sci Expert Comm Drug Evaluat Comm Tokyo Japan Toray Industries Ltd Clin Data Sci & Qual Management Dept Tokyo Japan Sanofi KK Biostat Biostat & Programming Res & Dev Clin Sci & Operat Tokyo Japan Astellas Pharma Inc Biostat Grp Data Sci Tokyo Japan Zeria Pharmaceut Co Ltd Clin Adm Tokyo Japan

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Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials

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DRUG INFORMATION JOURNAL 2010年第5期44卷 617-632页

作者： Quan, Hui Li, Mingyu Chen, Joshua Gallo, Paul Binkowitz, Bruce Ibia, Ekopimo Tanaka, Yoko Ouyang, Soo Peter Luo, Xiaolong Li, Gang Menjoge, Shailendra Talerico, Steven Ikeda, Kimitoshi Sanofi Aventis Biostat & Programming Bridgewater NJ 08807 USA Boehringer Ingelheim GmbH & Co KG Ingelheim Germany

Multiregional clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and fully realize the opportunities, a PhRMA MRCT Cross-Functional Key Issue Team (KIT) was formed in 2008. One of the work streams within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for superiority trials with continuous endpoints, then extend briefly to noninferiority trials, random effect models, binary endpoints, and survival endpoints. Computations and simulations are used to study the properties of the proposed definitions, particularly the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerations for trial design as well as for data analysis. The consistency assessment relies heavily on the definition of regions and the number of regions. We recommend working with health authorities to define region in a manner that is sensible from a practical interpretation standpoint and also makes region consistency assessment a feasible undertaking.

关键词： Ethnic effect Sample size Power Noninferiority Interaction Random effect model

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Estimation of Stratified Mark-Specific Proportional Hazards Models Under Two-Phase Sampling with Application to HIV Vaccine Efficacy Trials

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STATISTICS IN BIOSCIENCES 2017年第1期9卷 259-283页

作者： Yang, Guangren Sun, Yanqing Qi, Li Gilbert, Peter B. Jinan Univ Sch Econ Guangzhou 510632 Guangdong Peoples R China Univ North Carolina Charlotte Dept Math & Stat Charlotte NC 28223 USA Sanofi Biostat & Programming Bridgewater NJ 08807 USA Univ Washington Dept Biostat Seattle WA 98109 USA Fred Hutchinson Canc Ctr Seattle WA 98109 USA

An objective of preventive HIV vaccine efficacy trials is to understand how vaccine-induced immune responses to specific protein sequences of HIV-1 associate with subsequent infection with specific sequences of HIV, where the immune response biomarkers are measured in vaccine recipients via a two-phase sampling design. Motivated by this objective, we investigate the stratified mark-specific proportional hazards model under two-phase biomarker sampling, where the mark is the genetic distance of an infecting HIV-1 sequence to an HIV-1 sequence represented inside the vaccine. Estimation and inference procedures based on inverse probability weighting of complete-cases and on augmented inverse probability weighting of complete-cases are developed. Asymptotic properties of the estimators are derived and their finite-sample performances are examined in simulation studies. The methods are shown to have satisfactory performance and are applied to the RV144 vaccine trial to assess whether immune response correlates of HIV-1 infection are stronger for HIV-1 infecting sequences similar to the vaccine than for sequences distant from the vaccine.

关键词： Augmented inverse probability weighting Auxiliary variables Case-cohort design Censored failure time HIV vaccine efficacy trial Inverse probability-weighted complete-case

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Complications of biceps tenodesis based on location, fixation, and indication: a review of 1526 shoulders

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JOURNAL OF SHOULDER AND ELBOW SURGERY 2019年第3期28卷 461-469页

作者： McCrum, Christopher L. Alluri, R. Kiran Batech, Michael Mirzayan, Raffy Univ Texas Southwestern Med Ctr Dallas Dept Orthopaed Surg Dallas TX 75390 USA Univ Southern Calif Keck Sch Med Dept Orthopaed Surg Los Angeles CA USA Kaiser Permanente Dept Biostat Programming Serv Pasadena CA USA Kaiser Permanente Dept Biostat Res Database Serv Pasadena CA USA Kaiser Permanente Southern Calif Dept Orthopaed Surg Baldwin Pk CA USA

Background: Long head of the biceps tendon (LHBT) tenodesis is predominantly performed for 2 reasons: anterior shoulder pain (ASP) or structural reasons (partial tear, dislocation). Methods: Between 2006 and 2014, all cases of primary LHBT tenodesis performed at an integrated health care system were retrospectively reviewed. Complications were analyzed by tenodesis location (below or out of the groove [OOG] vs leaving tendon in the groove [ITG]), fixation method (soft tissue vs implant), and indication (preoperative ASP vs structural). Results: Among 1526 shoulders, persistent ASP did not differ by fixation method (11.0% for implant vs 12.8% for soft tissue, P =.550) or location (10.8% for OOG vs 12.9% for ITG, P =.472). Soft-tissue tenodesis cases had more frequent new-onset ASP (11.9% vs 2.6%, P <.001) and subjective weakness (8.50% vs 3.92%, P <.001) but less frequent revisions (0% vs 1.19%, P =.03) than implant tenodesis cases. No difference was found between ITG and OOG for persistent ASP (12.9% vs 10.8%, P =.550), new-onset ASP (6.5% vs 2.8%, P =.339), cramping (1.70% vs 2.31%, P =.737), deformity (4.72% vs 4.62%, P =.532), or subjective weakness (6.23% vs 4.32%, P =.334), but ITG cases had more revisions (1.51% vs 0.60%, P =.001). Among implant tenodesis cases, 1 shoulder (0.085%) sustained a fracture. Conclusion: The overall complication rate of LHBT tenodesis was low. Of the shoulders, 10.8% to 12.9% continued to have ASP, regardless of whether the LHBT was left ITG. Soft-tissue tenodesis cases had higher rates of new-onset ASP and subjective weakness. No significant difference for tenodesis ITG or OOG was found in biceps-related complications. (C) 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

关键词： Shoulder long head of biceps tendon tenodesis subpectoral suprapectoral complications anterior shoulder pain

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An Efficient Procedure for Calculating Sample Size Through Statistical Simulations

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STATISTICS IN BIOPHARMACEUTICAL RESEARCH 2018年第1期10卷 1-8页

作者： Maruo, Kazushi Tada, Keisuke Ishii, Ryota Gosho, Masahiko Natl Ctr Neurol & Psychiat Translat Med Ctr Dept Clin Epidemiol Tokyo 1878551 Japan Sanofi KK Biostat & Programming Tokyo Japan Kowa Co Ltd Clin Data Sci Dept Tokyo Japan Univ Tsukuba Dept Clin Trial & Clin Epidemiol Fac Med Tsukuba Ibaraki Japan

While planning clinical trials, when simple formulas are unavailable to calculate sample size, statistical simulations are used instead. However, one has to spend much computation time obtaining adequately precise and accurate simulated sample size estimates, especially when there are many scenarios for the planning and/or the specified statistical method is complicated. In this article, we summarize the theoretical aspect of statistical simulation-based sample size calculation. Then, we propose a new simulation procedure for sample size calculation by fitting the probit model to simulation result data. From the theoretical and simulation-based evaluations, it is suggested that the proposed simulation procedure provide more efficient and accurate sample size estimates than ordinary algorithm-based simulation procedure especially when estimated sample sizes are moderate to large, therefore it would help to dramatically reduce the computational time required to conduct clinical trial simulations.

关键词： Clinical trial design Finite sample bias Probit model

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Estimating long-term trends in the incidence and prevalence of opiate use/injecting drug use and the number of former users: Back-calculation methods and opiate overdose deaths

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AMERICAN JOURNAL OF EPIDEMIOLOGY 2004年第10期160卷 994-1004页

作者： De Angelis, D Hickman, M Yang, SY Univ London Imperial Coll Sci Technol & Med CRDHB London SW6 1RQ England Hlth Protect Agcy Stat Unit London England MRC Biostat Unit Cambridge CB2 2BW England GlaxoSmithKline BDS Stat & Programming London England

The authors explored an age-specific back-calculation approach to estimating long-term trends in the incidence and prevalence of opiate use/injecting drug use (IDU) in England for 1968-2000. The incidence of opiate use/ IDU was estimated by combining information on the observed opiate overdose deaths of persons aged 15-44 years with knowledge on the distribution of the time between starting opiate use/IDU and death by overdose (incubation time distribution). The resulting incidence, together with the incubation time distribution, other drug-related mortality, and the general age-specific mortality rate, was then used to estimate the prevalence of current and former users. Provisional estimates suggested two major increases in incidence in the late 1970s and early 1990s, with models including information on age at death suggesting a recent decline since 1997 and that prevalence of opiate use/IDU increased substantially in the 1990s. Results were crucially dependent on assumptions about key parameters of the back-calculation framework. In theory, the approach is a valuable addition to the portfolio of indirect methods for estimating incidence and prevalence of dependent opiate use/IDU. In practice, its full potential will be realized only once better information on the process of stopping opiate use/ IDU becomes available and more precise estimates of current and historical overdose mortality are obtained.

关键词： epidemiologic methods incidence overdose prevalence substance abuse, intravenous

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Minimizing Patient Burden Through the Use of Historical Subject-Level Data in Innovative Confirmatory Clinical Trials: Review of Methods and Opportunities

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THERAPEUTIC INNOVATION & REGULATORY SCIENCE 2018年第5期52卷 546-559页

作者： Lim, Jessica Walley, Rosalind Yuan, Jiacheng Liu, Jeen Dabral, Abhishek Best, Nicky Grieve, Andrew Hampson, Lisa Wolfram, Josephine Woodward, Phil Yong, Florence Zhang, Xiang Bowen, Ed GlaxoSmithKline Clin Stat Collegeville PA USA UCB Ctr Excellence Stat Innovat Slough Berks England Allergan Stat Sci & Programming Irvine CA USA GlaxoSmithKline Adv Biostat & Data Analyt Ctr Excellence Uxbridge Middx England Novartis Pharma AG Stat Methodol & Consulting Basel Switzerland Astellas Data Sci Biostat Leiden Netherlands Pfizer Biostat Worldwide Res & Dev Cambridge MA USA Eli Lilly & Co Global Stat Sci Indianapolis IN 46285 USA GlaxoSmithKline R&D Data Ctr Excellence Collegeville PA USA

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials. General principles to consider when incorporating historical control data in a new trial are presented. Bayesian and frequentist approaches are outlined including how the operating characteristics for such a trial can be obtained. Finally, examples of approved new treatments that incorporated historical controls in their confirmatory trials are presented.

关键词： TransCelerate historical controls propensity score Bayesian informative prior

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