(2020). Introduction to the 2020 Special Issue on Vaccines and Biologics. Statistics in Biopharmaceutical Research: Vol. 12, 2020 Special Issue on Vaccines and Biologics, pp. 253-253.

Abstract–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 (CIs) of mean measured concentration, accuracy

Abstract–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 rate. Patient recruitment in COPD trials can be slow; the proposed statistical approach may allow for a

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. 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 of published

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 article, we primarily focus on processing the raw data

In 2017, FDA circulated a draft guidance on analytical similarity assessment to assist the sponsors for providing totality-of-the-evidence in support of the demonstration of biosimilarity between a proposed biosimilar product and an innovative biological product. The guidance was subsequently withdrawn by the FDA due to some major criticisms received from general public. These major criticisms include

In Treatment of Physician Choice (TPC) trials, patients randomized to the control arm are treated with one of several drugs which are predetermined prior to the initiation of the trial. Statistical analysis in TPC trials typically hinge on a comparison of the experimental arm to the control arm, with the data from the control arm pooled across treatments. The robustness of the treatment effect for

Pharmaceutical and biotechnology industries manufacture their products in clean rooms, which are designed to minimize levels of particulates (like microorganisms recovered from the air or from the clean room surfaces). Alert and action limits are employed to monitor and control the state of the room, keeping the level of particulates at appropriate levels. Particulate monitoring systems could generate

An initial proposal was made to start 30 monkeys in the Run-In Period of a preclinical translational research study, to have 24 or more animals qualify for randomization in the subsequent Treatment Period. Based upon data from previous studies, Bayesian posterior prediction indicated that successful enrolment was highly unlikely. At least 67 animals were required to achieve an acceptable posterior

In addition to extensive pre-clinical testing, commercialization of medical devices in the United States (US) under some circumstances may be supported with clinical data derived from single arm studies where the clinical endpoint is compared with a performance goal (PG). Since the performance is expected to be different between two clinically-defined mutually-exclusive patient subpopulations, the

Abstract The Cape-Covid trial is an embedded clinical trial within the ongoing Cape-Cod trial. The Covid-19 pandemic appeared while we were conducting a randomized trial assessing the effectiveness of corticosteroids in severe community-acquired pneumonia. We took advantage of this ongoing trial to embed a sub-trial assessing hydrocortisone in SARS-CoV-2 infected patients. In this manuscript, we wish

Abstract Very recently the new pathogen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified and the coronavirus disease 2019 (COVID-19) declared a pandemic by the World Health Organization. The pandemic has a number of consequences for ongoing clinical trials in non-COVID-19 conditions. Motivated by four current clinical trials in a variety of disease areas we illustrate the

In confirmatory clinical trials, it has been proposed to use a simple iterative graphical approach to construct and perform intersection hypotheses tests with a weighted Bonferroni-type procedure to control type I errors in the strong sense. Given Phase II study results or other prior knowledge, it is usually of main interest to find the optimal graph that maximizes a certain objective function in

In oncology trials, non-inferiority concepts (e.g., shortening duration of chemotherapy) have sometimes been evaluated without preliminary knowledge of an experimental treatment being non-inferior to the standard treatment, and thus, a prompt consideration for futility stop is vital. Because such concepts are usually examined in a patient population with a good prognosis, it is often the case that

The world is in the midst of a pandemic. We still know little about the disease COVID-19 or about the virus (SARS-CoV-2) that causes it. We do not have a vaccine or a treatment (aside from managing symptoms). We do not know if recovery from COVID-19 produces immunity, and if so for how long, hence we do not know if “herd immunity” will eventually reduce the risk or if a successful vaccine can be developed

Abstract The COVID-19 outbreak is impacting clinical trials in many ways, such as patient recruitment, data collection and data analysis. To proceed in this difficult time, the adoption of new technologies and new approaches for conducting clinical trials needs to be accelerated. Simultaneously, regulatory agencies such as the US FDA and EMA have issued guidance to help the pharmaceutical industry

Reference-based controlled imputations have become a popular tool to assess the sensitivity of primary analysis inference to different post-dropout assumptions and to yield an alternative effectiveness estimand of treatment effect. As the imputation and analysis models are uncongenial in this setting, Rubin’s variance estimator overestimates the repeated sampling variability of the multiple imputation

The use of non-inferiority clinical trials continues to increase. At the same time, this study design remains complex with numerous issues related to the planning, implementation, and analysis of such trials. In this systematic review, we expand previous reviews, and evaluate reporting of the statistical methods used for design and analysis of non-inferiority trials with binomial proportions. We assessed

The concepts and implementation of standardized mean differences and minimum effect tests have been emphasized in ANOVA. The corresponding processes and implications are, however, not yet well explicated in the context of ANCOVA. To enhance the usefulness of ANCOVA, this article describes the minimum effect tests of standardized contrast as a valuable alternative to the hypothesis testing of no effect

Abstract The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity. An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19. The results from this research need to be obtained as rapidly as possible. This presents a number of challenges associated with considerable uncertainty over

Abstract The COVID-19 pandemic has impacted ongoing clinical trials. We consider particular impacts on non-inferiority clinical trials, which aim to show that an investigational treatment is not markedly worse than an existing active control with known benefit. Because interpretation of non-inferiority trials requires cross-trial validation involving untestable assumptions, it is vital that they be

The COVID-19 pandemic has a global impact on the conduct of clinical trials of medical products. This paper discusses implications of the COVID-19 pandemic on clinical research methodology aspects and provides points to consider in order to assess and mitigate the risk of seriously compromising the integrity and interpretability of clinical trials. The information in this paper will support discussions

Under a black cloud glimpsing a silver lining: Comment on Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 Pandemic. Statistics in Biopharmaceutical Research. Accepted 8 June 2020.

COVID-19 outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining

(2020). The Hazards of Period Specific and Weighted Hazard Ratios. Statistics in Biopharmaceutical Research. Ahead of Print.

Abstract p-Values are viewed by many as the root cause of the so-called replication crisis, which is characterized by the prevalence of positive scientific findings that are contradicted in subsequent studies. The spectrum of proposed solutions includes redefining statistical significance, abandoning the concept of statistical significance, or eliminating the use of p-values altogether. The unintended

Repeated data are increasingly collected in studies to investigate the trajectory of change in measurements over time. Determining a link between one repeated measurement with another that is considered as the biomarker for disease progression, may provide a new target for drug development. When a third variable is associated with one of the two measurements, partial correlation after eliminating the

The use of multiple imputation to address missing data has improved the quality of clinical trial reporting but has also introduced the nuisance of results that are subject to sampling variability introduced by using a finite number of imputations. There is a tradeoff between ensuring that enough imputations are used to obtain accurate results for decision making while at the same time keeping the

With the recent advancement in immuno-oncology, next-stage early oncology development is focusing on identifying the best combinations of established immunotherapies with new agents to either overcome drug resistance or achieve synergic effects. Although the combination is the focus, safety profile of the new agent alone must be explored. Therefore, many trials have both monotherapy and add-on combination

ABSTRACT The COVID-19 pandemic has had and continues to have major impacts on planned and ongoing clinical trials. Its effects on trial data create multiple potential statistical issues. The scale of impact is unprecedented, but when viewed individually, many of the issues are well defined and feasible to address. A number of strategies and recommendations are put forward to assess and address issues

Comment on: Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID‐19 Pandemic. Statistics in Biopharmaceutical Research. Accepted 1 June 2020.

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

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

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

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

(2020). Bayesian Model Selection in Order-Restricted Two-Way ANOVA Mixed Models. Statistics in Biopharmaceutical Research: Vol. 12, 2020 Special Issue on Vaccines and Biologics, pp. 369-379.

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