In the pharmaceutical industry, all analytical methods must be shown to deliver unbiased and precise results. In an assay qualification or validation study, the trueness, accuracy and intermediate precision are usually assessed by comparing the measured concentrations to their nominal levels. Trueness is assessed by using Confidence Intervals of mean measured concentration, accuracy by Prediction Intervals

Self and Mauritsen developed a sample size determination procedure for score tests in generalized linear models under contiguous alternatives. Its performance may deteriorate when the effect size is large. We propose a modification of the Self–Mauritsen method by taking into account of the variance of the score statistic under both the null and alternative hypotheses, and extend the method to noninferiority

While administration of a vaccine may be associated with a particular adverse event (AE), a vaccine interaction adverse event (VIAE) occurs when the relationship between administration of one vaccine and an AE is influenced by the administration of an additional vaccine or vaccines in a nonadditive manner. In clinical trials, it is often challenging to detect AEs from vaccine or drug interactions due

Simultaneous global drug development with multiregional studies is becoming a common strategy for increasing efficiency of the development process. In particular, multiregional dose-finding studies can be informative to identify inter-ethnic difference in dose-response relationships early in development. An application of MCP-Mod to multiregional studies is discussed in this article. We consider sample

The objective of this paper is to provide a list of considerations when selecting a statistical method for demonstrating comparability. Two approaches are proposed and evaluated against these considerations. One approach applies a quality range and the second approach is based on the concept of “acceptability”.

For clinical trials in patients with asthma, chronic obstructive pulmonary disease, and relapsing-remitting multiple sclerosis, regulatory guidelines state that a non-inferiority clinical trial is an option. Aiming at establishing assay sensitivity, a three-arm non-inferiority trial, including an experimental treatment, a reference treatment, and a placebo, the so-called gold-standard non-inferiority

Abstract–Accelerated failure time (AFT) models give an intuitive estimator for survival data analysis, but there is a risk of model misspecification. As a serious problem of model misspecification, the test size is likely to be far from the nominal level. Many researchers provided asymptotic corrections of various test statistics under model misspecification. However, their corrected statistics do

Abstract–Platform trials are increasingly popular in clinical research since these trials can evaluate multiple treatments in targeted subgroups of patients within a single trial infrastructure. In this article, we describe the development and implementation of a new clinical trial design OPTIM-ARTS (Open Platform Trial Investigating Multiple Compounds—Adaptive Randomized Design with Treatment Selection)—with

Some clinical trials in ophthalmology or dermatology randomize patients into two or more treatment groups, and observations are made for one or more anatomical regions (or sites) for each patient. In this case, patients are primary sampling units, and their responses for multiple anatomical sites are usually correlated. Useful randomization-based extensions of the Cochran–Mantel–Haenszel method are

The aim of this work is to present an adaptive two-stage seamless design for a phase II/III clinical trial in chronic obstructive pulmonary disease (COPD). This approach implies sample size re-estimation based on the primary outcome efficacy variable, namely the annual acute exacerbation (AE) rate. Patient recruitment in COPD trials can be slow; the proposed statistical approach may allow for a faster

It is common for clinical trials to include strata of patients with different risks of disease. In cancer trial settings, patients with different prior treatment history, tumor stages, metastatic sites may be included in a single trial. This is especially so for early phase studies that are exploratory in nature. In many cases, patient responses from these strata may be ordered. For example earlier

As a national public health surveillance resource, Vaccine Adverse Event Reporting System (VAERS) is a key component in ensuring the safety of vaccines. Numerous methods have been used to conduct safety studies with the VAERS database. These efforts focus on the downstream statistical analysis of the vaccine and adverse event associations. In this paper, we primarily focus on processing the raw data

In potency assays, the relative potency (RP) is the measure of the biological activity of a test product relative to a reference standard. It is calculated as the horizontal difference between the log(concentration)-response curves of each product. Parallelism (or similarity) between those curves is required for the RP to be meaningful. The literature proposes equivalence tests for similarity, based

Meta-analysis can be especially useful for evaluation of vaccine safety, since individual studies often have limited power to detect an increase in safety risk. In order to gain a perspective on the current state of utilization of the technique of meta-analysis for evaluation of vaccine safety and to assess the methodological characteristics of these meta-analyses, we conducted a systematic review

In many clinical studies, the time to event of interest may involve several causes of failure. Furthermore, when the failure times are not completely observed, and instead are only known to lie somewhere between two observation times, interval censored competing risk data occur. For estimating regression coefficient with right censored competing risk data, Fine and Gray introduced the concept of censoring

Abstract–In Clinical Trials, not all randomized patients follow the course of treatment they are allocated to. The potential impact of such deviations is increasingly recognized, and it has been one of the reasons for a redefinition of the targets of estimation (“Estimands”) in the ICH E9 draft Addendum. Among others, the effect of treatment assignment, regardless of the adherence, appears an Estimand

(2020). Guest Editors’ Note. Statistics in Biopharmaceutical Research: Vol. 12, Evolution of Statistical Science: Translating Data to Innovative Health Care, pp. 129-129.

Abstract–To evaluate a novel vaccine, randomized clinical trials are often conducted to assess how much the infection or disease rate is reduced in the vaccinated group as compared to the unvaccinated group. Because of low incidence rate for the clinical endpoint, the sample size based on exact conditional binomial test is often very large for vaccine efficacy trials, which poses big challenge for

Randomized clinical trials designed to establish noninferiority of an experimental therapy as compared to a standard (active-control) therapy as measured by binomial proportions are being widely used. Randomization is often stratified by prognostic factors. We propose a Mantel–Haenszel (MH) type test to demonstrate noninferiority in terms of the differences in success proportions and when the noninferiority

In this article, we provide guidance on how statisticians can use interactive visual analytics to assist medical personnel through the entire clinical safety review process. For the general assessment of safety data (e.g., adverse events, laboratory measurements), we recommend a review flow with the first step using a display that leverages statistical methods to identify events with stronger evidence

In recent years there has been a lot of interest to test for similarity between biological drug products, commonly known as biologics. Biologics are large and complex molecule drugs that are produced by living cells and hence these are sensitive to the environmental changes. In addition, biologics usually induce antibodies which raise the safety and efficacy issues. The manufacturing process is also

Multiplicity is a common issue in clinical drug development and there exists many proposals for the handling of multiple testing in clinical trials. However, the literature on testing procedures for claiming success on at least k out of m tests and the operating characteristics of these procedures is still sparse. Such testing is very relevant in biosimilar drug development, for example, where products

The two-arm parallel design that is commonly used to assess biosimilarity has the drawback that it does not take into account the inherent variability within the reference products. The three-arm parallel design was proposed to solve this problem. The purpose of this article was to extend the previous results to the time-to-event endpoints in the exponential model, the Cox proportional hazard model

In medical and clinical studies, videos, images, or other form of information carriers may be centrally read to provide scores or measurements for medically or clinically meaningful endpoints. Since the simple one central reading process may lead to biased final reported scores, different central reading processes that aim to reduce the potential bias are used including the double central reading with

In drug development programs, phase II studies may be carried out as multi-arm trials aiming to identify treatment(s) with the optimal benefit-to-risk profile(s). Succeeding confirmatory phase III trials then attempt to demonstrate efficacy and safety of the designated treatment(s). While upmost important to consider multi-arm phase II/III study(ies) holistically to optimize drug development, sample

Abstract The log-rank test is most powerful under proportional hazards (PH). In practice, non-PH patterns are often observed in clinical trials, such as in immuno-oncology; therefore, alternative methods are needed to restore the efficiency of statistical testing. Three categories of testing methods were evaluated, including weighted log-rank tests, Kaplan–Meier curve-based tests (including weighted

Tang derived the exact power formulas for t tests and analysis of covariance (ANCOVA) in superiority, noninferiority (NI), and equivalence trials. The power calculation in equivalence trials can be simplified by using Owen’s Q function, which is available in standard statistical software. We extend the exact power determination method for ANCOVA to unstratified and stratified multi-arm randomized trials

Abstract Pharmacokinetic (PK) studies are conducted to learn about the absorption, distribution, metabolism, and excretion processes of an externally administered compound by measuring its concentration in bodily tissue at a number of time points after administration. Two methods are available for this analysis: modeling and non-compartmental. When concentrations of the compound are low, they may be

The Simes test is designed to test a single null hypothesis formed by taking the intersection of multiple null hypotheses using their p-values. In this short note, we explore a novel application of the Simes test for testing a single null hypothesis in a group sequential setting based on the p-values from sequential looks. We refer to this test as the group sequential Simes test (GSST). It turns out

Benefit-risk analysis using prioritized multiple outcomes has been proposed for use in randomized controlled trials with two treatment groups. This research extends the two-group comparison to testing for a trend over multiple treatment groups, for example, multiple doses, in terms of a composite outcome that is derived from pairwise comparisons of subjects between groups or by ranking subjects of

The Cox proportional hazard (PH) model is widely used to determine the effects of risk factors and treatments (covariates) on survival time of subjects that might be right censored. The selection of covariates depends crucially on the specific form of the conditional hazard model, which is often assumed to be PH, accelerated failure time (AFT), or proportional odds (PO). However, we show that none

In this article, we propose several Bayesian model selection procedures, based on the spike and slab priors, to select significant variables while accounting for some restrictions on them. We concentrate on the following methods: Kuo and Mallick, stochastic search variable selection (SSVS), Ishwaran and Rao (NMIG). Bayesian computation is straightforward via simple Gibbs sampling algorithm. The methods

Draft ICH E9(R1) Addendum on “Estimands and Sensitivity Analysis in Clinical Trials” provides different strategies for addressing intercurrent events in defining an estimand and describing the treatment effect that is targeted. The set of considered intercurrent events will depend on the specific therapeutic setting and trial objectives. This article considers a case study of a long-term prevention

The use of adaptive population selection designs has become widespread in response to the emergence of numerous targeted therapies. Such designs provide an opportunity to stop the recruitment of patients in a population in midcourse when this population does not benefit from the treatment being tested. Several types of designs have been developed in different settings; however, the procedures for setting

Clinical safety and immunogenicity data in vaccines are commonly dichotomized into responder and nonresponder binary data. This article expands upon Fagerland, Lyndersen, and Laake to further study Newcombe’s hybrid score and Fisher’s conditional exact test using imbalanced randomization in vaccine clinical studies. The intent of this article is to study a potential statistical issue in clinical study

Assessment of agreement between measurement methods is an important problem in medical practice and research. Several two one-sided tests (TOST) procedures have been proposed to evaluate whether two methods have sufficient agreement. These TOST techniques of limits of agreement or normal percentiles are natural generalizations of the favorable TOST procedure of mean differences. But their fundamental

Noninferiority clinical trials aim to show an experimental treatment is therapeutically no worse than standard of care, particularly if the new treatment is preferred for reasons such as cost, convenience, safety, and so on. Noninferiority trials are by nature less conservative than superiority studies: protocol violations may increase bias toward the alternative hypothesis of noninferiority. Our objective

Recent evidence has shown that structural magnetic resonance imaging (MRI) is an effective tool for Alzheimer’s disease (AD) prediction. While traditional MRI-based prediction uses images acquired at a single time point, a longitudinal study is more sensitive and accurate in detecting early pathological changes of the AD. Two main statistical difficulties arise in the longitudinal MRI-based analysis:

Batch effects are the sources of variation in drug substances and drug products in terms of potency. Although the implication of batch effects has been widely recognized in statistical literature, the batch variability information is usually not considered in designing and analyzing clinical studies. In this article, the impact of batch variability is systematically explored for both the design and

We discuss using prediction as a flexible and practical approach for monitoring futility in clinical trials with two co-primary endpoints (CPE). This approach is appealing in that it provides quantitative evaluation of potential effect sizes and associated precision, and can be combined with flexible error-spending strategies. We extend prediction of effect size estimates and the construction of predicted

In this paper we consider three-arm non-inferiority (NI) trial that includes an experimental, a reference, and a placebo arm. While for binary outcomes the risk difference (RD) is the most common and well explored functional form for testing efficacy (or effectiveness), recent FDA guideline suggested other measures such as relative risk (RR) and odds ratio (OR) on the basis of which NI of an experimental

Some clinical trialists, especially those working in rare or pediatric disease, have suggested borrowing information from similar but already-completed clinical trials. This paper begins with a case study in which relying solely on historical control information would have erroneously resulted in concluding a significant treatment effect. We then attempt to catalog situations where borrowing historical

Neoadjuvant (preoperative) approach to breast cancer treatment has become widely accepted. Traditionally the primary objective of neoadjuvant treatment is to improve subsequent surgical intervention and the effectiveness are often evaluated by its ability achieving complete pathological response (pCR), the eradication of the malignant disease in the breast and axillary lymph nodes. More recently, neoadjuvant

Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As

To test the anticancer effect of combining two drugs targeting different biological pathways, the popular way to show synergistic effect of drug combination is a heat map or surface plot based on the percent excess the Bliss prediction using the average response measures at each combination dose. Such graphs, however, are inefficient in the drug screening process and it doesn't give a statistical inference

For randomized group sequential survival trial designs with unbalanced treatment allocation, the widely used Schoenfeld formula is inaccurate, and the commonly used information time as the ratio of number of events at interim look to the number of events at the end of trial can be biased. In this paper, a sample size formula for the two-sample log-rank test under the proportional hazards model is proposed

For designing single-arm phase II trials with time-to-event endpoints, a sample size formula is derived for the modified one-sample log-rank test under the proportional hazards model. The derived formula enables new methods for designing trials that allow a flexible choice of the underlying survival distribution. Simulation results showed that the proposed formula provides an accurate estimation of

Many modern serial dilution assays are based on fluorescence intensity (FI) readouts. We study optimal transformation model choice for fitting five parameter logistic curves (5PL) to FI-based serial dilution assay data. We first develop a generalized least squares-pseudolikelihood type algorithm for fitting heteroscedastic logistic models. Next we show that the 5PL and log 5PL functions can approximate

A rapidly increasing number of Phase I dose-finding studies, and in particular those based on the standard 3+3 design, are being prolonged with the inclusion of dose expansion cohorts (DEC) in order to better characterize the toxicity profiles of experimental agents and to study disease-specific cohorts. These trials consist of two phases: the usual dose escalation phase that aims to establish the

Docosahexaenoic acid (DHA) is a good source of fat that can be taken up through food, such as fish, or taken as a supplement. Evidence is building that DHA provides a high yield, low risk strategy to reduce preterm birth and/or low birth weight. These births are great costs to society. A recently completed phase III trial revealed that higher birth weight and gestational age were associated with DHA

In designing a clinical trial for comparing two or more treatments with respect to overall survival (OS), a proportional hazards assumption is commonly made. However, in many cancer clinical trials, patients pass through various disease states prior to death and because of this may receive treatments other than originally assigned. For example, patients may crossover from the control treatment to the

Meta-analysis has been widely applied to rare adverse event data because it is very difficult to reliably detect the effect of a treatment on such events in an individual clinical study. However, it is known that standard meta-analysis methods are often biased, especially when the background incidence rate is very low. A recent work by Bhaumik et al. (2012) proposed new moment-based approaches under

In the future, clinical trials will have an increased emphasis on pragmatism, providing a practical description of the effects of new treatments in realistic clinical settings. Accomplishing pragmatism requires better summaries of the totality of the evidence in ways that clinical trials consumers---patients, physicians, insurers---find transparent and allow for informed benefit:risk decision-making

In March 2011, a Final Rule for expedited reporting of serious adverse events took effect in the United States for studies conducted under an Investigational New Drug (IND) application. In December 2012, the U.S. Food and Drug Administration (FDA) promulgated a final Guidance describing the operationalization of this Final Rule. The Rule and Guidance clarified that a clinical trial sponsor should have

In pharmaceutical research, making multiple statistical inferences is standard practice. Unless adjustments are made for multiple testing, the probability of making erroneous determinations of significance increases with the number of inferences. Closed testing is a flexible and easily explained approach to controlling the overall error rate that has seen wide use in pharmaceutical research, particularly

The effects of interventions are multi-dimensional. Use of more than one primary endpoint offers an attractive design feature in clinical trials as they capture more complete characterization of the effects of an intervention and provide more informative intervention comparisons. For these reasons, multiple primary endpoints have become a common design feature in many disease areas such as oncology

In non-inferiority trials, acceptable efficacy of an experimental treatment is established by ruling out some defined level of reduced effect relative to an effective active control standard. Serial use of non-inferiority trials may lead to newly approved therapies that provide meaningfully reduced levels of benefit; this phenomenon is called bio-creep. Simulations were designed to facilitate understanding

We discuss the decision-making frameworks for clinical trials with multiple co-primary endpoints in a group-sequential setting. The decision-making frameworks can account for flexibilities such as a varying number of analyses, equally or unequally spaced increments of information and fixed or adaptive Type I error allocation among endpoints. The frameworks can provide efficiency, i.e., potentially

We congratulate the authors on their comments on innovative approaches to drug development that fall out of the traditional mold and may result in more quickly bringing safe and effective treatments to patients. Changes in the overall clinical develop approach are most relevant to "breakthrough" therapies, which have generally yielded exceptional efficacy data in early clinical studies, motivating