Pharmaceutical Statistics最新文献_第10页

To Dilute or Not to Dilute: Nominal Titer Dosing for Genetic Medicines. 稀释还是不稀释：基因药物的名义滴度剂量。

IF 1.3 4区医学

Pharmaceutical Statistics Pub Date : 2024-11-01 Epub Date: 2024-06-25 DOI: 10.1002/pst.2406

Paul Faya, Tianhui Zhang

{"title":"To Dilute or Not to Dilute: Nominal Titer Dosing for Genetic Medicines.","authors":"Paul Faya, Tianhui Zhang","doi":"10.1002/pst.2406","DOIUrl":"10.1002/pst.2406","url":null,"abstract":"Recombinant adeno-associated virus (AAV) has become a popular platform for many gene therapy applications. The strength of AAV-based products is a critical quality attribute that affects the efficacy of the drug and is measured as the concentration of vector genomes, or physical titer. Because the dosing of patients is based on the titer measurement, it is critical for manufacturers to ensure that the measured titer of the drug product is close to the actual concentration of the batch. Historically, dosing calculations have been performed using the measured titer, which is reported on the drug product label. However, due to recent regulatory guidance, sponsors are now expected to label the drug product with nominal or \"target\" titer. This new expectation for gene therapy products can pose a challenge in the presence of process and analytical variability. In particular, the manufacturer must decide if a dilution of the drug substance is warranted at the drug product stage to bring the strength in line with the nominal value. In this paper, we present two straightforward statistical methods to aid the manufacturer in the dilution decision. These approaches use the understanding of process and analytical variability to compute probabilities of achieving the desired drug product titer. We also provide an approach for determining an optimal assay replication strategy for achieving the desired probability of meeting drug product release specifications.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"939-944"},"PeriodicalIF":1.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

T3 + 3: 3 + 3 Design With Delayed Outcomes. T3 + 3：延迟结果的 3 + 3 设计。

IF 1.3 4区医学

Pharmaceutical Statistics Pub Date : 2024-11-01 Epub Date: 2024-06-25 DOI: 10.1002/pst.2414

Jiaying Guo, Mengyi Lu, Isabella Wan, Yumin Wang, Leng Han, Yong Zang

{"title":"T3 + 3: 3 + 3 Design With Delayed Outcomes.","authors":"Jiaying Guo, Mengyi Lu, Isabella Wan, Yumin Wang, Leng Han, Yong Zang","doi":"10.1002/pst.2414","DOIUrl":"10.1002/pst.2414","url":null,"abstract":"Delayed outcome is common in phase I oncology clinical trials. It causes logistic difficulty, wastes resources, and prolongs the trial duration. This article investigates this issue and proposes the time-to-event 3 + 3 (T3 + 3) design, which utilizes the actual follow-up time for at-risk patients with pending toxicity outcomes. The T3 + 3 design allows continuous accrual without unnecessary trial suspension and is costless and implementable with pretabulated dose decision rules. Besides, the T3 + 3 design uses the isotonic regression to estimate the toxicity rates across dose levels and therefore can accommodate for any targeted toxicity rate for maximum tolerated dose (MTD). It dramatically facilitates the trial preparation and conduct without intensive computation and statistical consultation. The extension to other algorithm-based phase I dose-finding designs (e.g., i3 + 3 design) is also studied. Comprehensive computer simulation studies are conducted to investigate the performance of the T3 + 3 design under various dose-toxicity scenarios. The results confirm that the T3 + 3 design substantially shortens the trial duration compared with the conventional 3 + 3 design and yields much higher accuracy in MTD identification than the rolling six design. In summary, the T3 + 3 design addresses the delayed outcome issue while keeping the desirable features of the 3 + 3 design, such as simplicity, transparency, and costless implementation. It has great potential to accelerate early-phase drug development.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"959-970"},"PeriodicalIF":1.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141458677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Personalized Dose-Finding Algorithm Based on Adaptive Gaussian Process Regression. 基于自适应高斯过程回归的个性化剂量确定算法

IF 1.3 4区医学

Pharmaceutical Statistics Pub Date : 2024-11-01 Epub Date: 2024-08-09 DOI: 10.1002/pst.2417

Yeonhee Park, Won Chang

{"title":"A Personalized Dose-Finding Algorithm Based on Adaptive Gaussian Process Regression.","authors":"Yeonhee Park, Won Chang","doi":"10.1002/pst.2417","DOIUrl":"10.1002/pst.2417","url":null,"abstract":"Dose-finding studies play a crucial role in drug development by identifying the optimal dose(s) for later studies while considering tolerability. This not only saves time and effort in proceeding with Phase III trials but also improves efficacy. In an era of precision medicine, it is not ideal to assume patient homogeneity in dose-finding studies as patients may respond differently to the drug. To address this, we propose a personalized dose-finding algorithm that assigns patients to individualized optimal biological doses. Our design follows a two-stage approach. Initially, patients are enrolled under broad eligibility criteria. Based on the Stage 1 data, we fit a regression model of toxicity and efficacy outcomes on dose and biomarkers to characterize treatment-sensitive patients. In the second stage, we restrict the trial population to sensitive patients, apply a personalized dose allocation algorithm, and choose the recommended dose at the end of the trial. Simulation study shows that the proposed design reliably enriches the trial population, minimizes the number of failures, and yields superior operating characteristics compared to several existing dose-finding designs in terms of both the percentage of correct selection and the number of patients treated at target dose(s).","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"1181-1205"},"PeriodicalIF":1.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141907379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Applying the Estimand Framework to Non‐Inferiority Trials. 将 Estimand 框架应用于非劣效性试验。

IF 1.3 4区医学

Pharmaceutical Statistics Pub Date : 2024-11-01 Epub Date: 2024-08-08 DOI: 10.1002/pst.2433

Helle Lynggaard, Oliver N Keene, Tobias Mütze, Sunita Rehal

{"title":"Applying the Estimand Framework to Non‐Inferiority Trials.","authors":"Helle Lynggaard, Oliver N Keene, Tobias Mütze, Sunita Rehal","doi":"10.1002/pst.2433","DOIUrl":"10.1002/pst.2433","url":null,"abstract":"Most published applications of the estimand framework have focused on superiority trials. However, non-inferiority trials present specific challenges compared to superiority trials. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use notes in their addendum on estimands and sensitivity analysis in clinical trials that there may be special considerations to the implementation of estimands in clinical trials with a non-inferiority objective yet provides little guidance. This paper discusses considerations that trial teams should make when defining estimands for a clinical trial with a non-inferiority objective. We discuss how the pre-addendum way of establishing non-inferiority can be embraced by the estimand framework including a discussion of the role of the Per Protocol analysis set. We examine what clinical questions of interest can be formulated in the context of non-inferiority trials and outline why we do not think it is sensible to describe an estimand as 'conservative'. The impact of the estimand framework on key considerations in non-inferiority trials such as whether trials should have more than one primary estimand, the choice of non-inferiority margin, assay sensitivity, switching from non-inferiority to superiority and estimation are discussed. We conclude by providing a list of recommendations, and important considerations for defining estimands for trials with a non-inferiority objective.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"1156-1165"},"PeriodicalIF":1.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141902593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

On Some Modeling Issues in Estimating Vaccine Efficacy 关于估算疫苗疗效的一些模型问题

IF 1.5 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-10 DOI: 10.1002/pst.2440

Mauro Gasparini

引用次数: 0

A propensity score-integrated approach for leveraging external data in a randomized controlled trial with time-to-event endpoints. 在随机对照试验中利用外部数据的倾向得分整合方法，以时间为终点。

IF 16.4 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-01 Epub Date: 2024-03-05 DOI: 10.1002/pst.2377

Wei-Chen Chen, Nelson Lu, Chenguang Wang, Heng Li, Changhong Song, Ram Tiwari, Yunling Xu, Lilly Q Yue

引用次数: 0

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance. 根据估算指导，肿瘤学中的时间-事件估算值和随访损失。

IF 16.4 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-01 Epub Date: 2024-03-29 DOI: 10.1002/pst.2386

Jonathan M Siegel, Hans-Jochen Weber, Stefan Englert, Feng Liu, Michelle Casey

{"title":"Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.","authors":"Jonathan M Siegel, Hans-Jochen Weber, Stefan Englert, Feng Liu, Michelle Casey","doi":"10.1002/pst.2386","DOIUrl":"10.1002/pst.2386","url":null,"abstract":"Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and \"affect either the interpretation or the existence of the measurements associated with the clinical question of interest.\" We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest. Loss to follow-up in the presence of intercurrent events can affect the meaning and interpretation of the study results. We provide recommendations for trial design, stressing the need for close alignment of the clinical question of interest and study design, impact on data collection, and other practical implications. When patients cannot be systematically followed, compromise may be necessary to select the best available estimand that can be feasibly estimated under the circumstances. We discuss the use of sensitivity and supplementary analyses to examine assumptions of interest.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"709-727"},"PeriodicalIF":16.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Estimation of the odds ratio from multi-stage randomized trials. 从多阶段随机试验中估算几率比。

IF 16.4 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-01 Epub Date: 2024-03-10 DOI: 10.1002/pst.2378

Shiwei Cao, Sin-Ho Jung

引用次数: 0

Effects of sceptical priors on the performance of adaptive clinical trials with binary outcomes. 怀疑先验对二元结果适应性临床试验绩效的影响。

IF 1.3 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-01 Epub Date: 2024-03-29 DOI: 10.1002/pst.2387

Anders Granholm, Theis Lange, Michael O Harhay, Anders Perner, Morten Hylander Møller, Benjamin Skov Kaas-Hansen

{"title":"Effects of sceptical priors on the performance of adaptive clinical trials with binary outcomes.","authors":"Anders Granholm, Theis Lange, Michael O Harhay, Anders Perner, Morten Hylander Møller, Benjamin Skov Kaas-Hansen","doi":"10.1002/pst.2387","DOIUrl":"10.1002/pst.2387","url":null,"abstract":"It is unclear how sceptical priors impact adaptive trials. We assessed the influence of priors expressing a spectrum of scepticism on the performance of several Bayesian, multi-stage, adaptive clinical trial designs using binary outcomes under different clinical scenarios. Simulations were conducted using fixed stopping rules and stopping rules calibrated to keep type 1 error rates at approximately 5%. We assessed total sample sizes, event rates, event counts, probabilities of conclusiveness and selecting the best arm, root mean squared errors (RMSEs) of the estimated treatment effect in the selected arms, and ideal design percentages (IDPs; which combines arm selection probabilities, power, and consequences of selecting inferior arms), with RMSEs and IDPs estimated in conclusive trials only and after selecting the control arm in inconclusive trials. Using fixed stopping rules, increasingly sceptical priors led to larger sample sizes, more events, higher IDPs in simulations ending in superiority, and lower RMSEs, lower probabilities of conclusiveness/selecting the best arm, and lower IDPs when selecting controls in inconclusive simulations. With calibrated stopping rules, the effects of increased scepticism on sample sizes and event counts were attenuated, and increased scepticism increased the probabilities of conclusiveness/selecting the best arm and IDPs when selecting controls in inconclusive simulations without substantially increasing sample sizes. Results from trial designs with gentle adaptation and non-informative priors resembled those from designs with more aggressive adaptation using weakly-to-moderately sceptical priors. In conclusion, the use of somewhat sceptical priors in adaptive trial designs with binary outcomes seems reasonable when considering multiple performance metrics simultaneously.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"728-741"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Digital twins and Bayesian dynamic borrowing: Two recent approaches for incorporating historical control data. 数字双胞胎和贝叶斯动态借贷：纳入历史控制数据的两种最新方法。

IF 16.4 4区医学

Pharmaceutical Statistics Pub Date : 2024-09-01 Epub Date: 2024-03-04 DOI: 10.1002/pst.2376

Carl-Fredrik Burman, Erik Hermansson, David Bock, Stefan Franzén, David Svensson

{"title":"Digital twins and Bayesian dynamic borrowing: Two recent approaches for incorporating historical control data.","authors":"Carl-Fredrik Burman, Erik Hermansson, David Bock, Stefan Franzén, David Svensson","doi":"10.1002/pst.2376","DOIUrl":"10.1002/pst.2376","url":null,"abstract":"Recent years have seen an increasing interest in incorporating external control data for designing and evaluating randomized clinical trials (RCT). This may decrease costs and shorten inclusion times by reducing sample sizes. For small populations, with limited recruitment, this can be especially important. Bayesian dynamic borrowing (BDB) has been a popular choice as it claims to protect against potential prior data conflict. Digital twins (DT) has recently been proposed as another method to utilize historical data. DT, also known as PROCOVA™, is based on constructing a prognostic score from historical control data, typically using machine learning. This score is included in a pre-specified ANCOVA as the primary analysis of the RCT. The promise of this idea is power increase while guaranteeing strong type 1 error control. In this paper, we apply analytic derivations and simulations to analyze and discuss examples of these two approaches. We conclude that BDB and DT, although similar in scope, have fundamental differences which need be considered in the specific application. The inflation of the type 1 error is a serious issue for BDB, while more evidence is needed of a tangible value of DT for real RCTs.","PeriodicalId":19934,"journal":{"name":"Pharmaceutical Statistics","volume":" ","pages":"611-629"},"PeriodicalIF":16.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140028706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0