A comparative study of confidence intervals to assess biosimilarity from analytical data

Assessment of analytical similarity of tier 1 quality attributes is based on a set of hypotheses that tests the mean difference of reference and test products against a margin adjusted for standard deviation of the reference product. Thus, proper assessment of the biosimilarity hypothesis requires statistical tests that account for the uncertainty associated with the estimations of the mean differences and the standard deviation of the reference product. Recently, a linear reformulation of the biosimilarity hypothesis has been proposed, which facilitates development and implementation of statistical tests. These statistical tests account for the uncertainty in the estimation process of all the unknown parameters. In this paper, we survey methods for constructing confidence intervals for testing the linearized reformulation of the biosimilarity hypothesis and also compare the performance of the methods. We discuss test procedures using confidence intervals to make possible comparison among recently developed methods as well as other previously developed methods that have not been applied for demonstrating analytical similarity. A computer simulation study was conducted to compare the performance of the methods based on the ability to maintain the test size and power, as well as computational complexity. We demonstrate the methods using two example applications. At the end, we make recommendations concerning the use of the methods.     

Principal stratum strategy: Potential role in drug development

A randomized trial allows estimation of the causal effect of an intervention compared to a control in the overall population and in subpopulations defined by baseline characteristics. Often, however, clinical questions also arise regarding the treatment effect in subpopulations of patients, which would experience clinical or disease related events post-randomization. Events that occur after treatment initiation and potentially affect the interpretation or the existence of the measurements are called intercurrent events in the ICH E9(R1) guideline. If the intercurrent event is a consequence of treatment, randomization alone is no longer sufficient to meaningfully estimate the treatment effect. Analyses comparing the subgroups of patients without the intercurrent events for intervention and control will not estimate a causal effect. This is well known, but post-hoc analyses of this kind are commonly performed in drug development. An alternative approach is the principal stratum strategy, which classifies subjects according to their potential occurrence of an intercurrent event on both study arms. We illustrate with examples that questions formulated through principal strata occur naturally in drug development and argue that approaching these questions with the ICH E9(R1) estimand framework has the potential to lead to more transparent assumptions as well as more adequate analyses and conclusions. In addition, we provide an overview of assumptions required for estimation of effects in principal strata. Most of these assumptions are unverifiable and should hence be based on solid scientific understanding. Sensitivity analyses are needed to assess robustness of conclusions.     

Statistical considerations for assessing precision of heterogeneous duplicate measurements: An application to pharmaceutical bioanalysis

Duplicate analysis is a strategy commonly used to assess precision of bioanalytical methods. In some cases, duplicate analysis may rely on pooling data generated across organizations. Despite being generated under comparable conditions, organizations may produce duplicate measurements with different precision. Thus, these pooled data consist of a heterogeneous collection of duplicate measurements. Precision estimates are often expressed as relative difference indexes (RDI), such as relative percentage difference (RPD). Empirical evidence indicates that the frequency distribution of RDI values from heterogeneous data exhibits sharper peaks and heavier tails than normal distributions. Therefore, traditional normal-based models may yield faulty or unreliable estimates of precision from heterogeneous duplicate data. In this paper, we survey application of the mixture models that satisfactorily represent the distribution of RDI values from heterogeneous duplicate data. A simulation study was conducted to compare the performance of the different models in providing reliable estimates and inferences of percentile calculated from RDI values. These models are readily accessible to practitioners for study implementation through the use of modern statistical software. The utility of mixture models are explained in detail using a numerical example.     

Estimands in hematologic oncology trials

The estimand framework included in the addendum to the ICH E9 guideline facilitates discussions to ensure alignment between the key question of interest, the analysis, and interpretation. Therapeutic knowledge and drug mechanism play a crucial role in determining the strategy and defining the estimand for clinical trial designs. Clinical trials in patients with hematological malignancies often present unique challenges for trial design due to complexity of treatment options and existence of potential curative but highly risky procedures, for example, stem cell transplant or treatment sequence across different phases (induction, consolidation, maintenance). Here, we illustrate how to apply the estimand framework in hematological clinical trials and how the estimand framework can address potential difficulties in trial result interpretation. This paper is a result of a cross-industry collaboration to connect the International Conference on Harmonisation (ICH) E9 addendum concepts to applications. Three randomized phase 3 trials will be used to consider common challenges including intercurrent events in hematologic oncology trials to illustrate different scientific questions and the consequences of the estimand choice for trial design, data collection, analysis, and interpretation. Template language for describing estimand in both study protocols and statistical analysis plans is suggested for statisticians' reference.     

Statistical analysis of data from dilution assays with censored correlated counts

Frequently, count data obtained from dilution assays are subject to an upper detection limit, and as such, data obtained from these assays are usually censored. Also, counts from the same subject at different dilution levels are correlated. Ignoring the censoring and the correlation may provide unreliable and misleading results. Therefore, any meaningful data modeling requires that the censoring and the correlation be simultaneously addressed. Such comprehensive approaches of modeling censoring and correlation are not widely used in the analysis of dilution assays data. Traditionally, these data are analyzed using a general linear model on a logarithmic-transformed average count per subject. However, this traditional approach ignores the between-subject variability and risks, providing inconsistent results and unreliable conclusions. In this paper, we propose the use of a censored negative binomial model with normal random effects to analyze such data. This model addresses, in addition to the censoring and the correlation, any overdispersion that may be present in count data. The model is shown to be widely accessible through the use of several modern statistical software.     

Robust exchangeability designs for early phase clinical trials with multiple strata

Clinical trials with multiple strata are increasingly used in drug development. They may sometimes be the only option to study a new treatment, for example in small populations and rare diseases. In early phase trials, where data are often sparse, good statistical inference and subsequent decision‐making can be challenging. Inferences from simple pooling or stratification are known to be inferior to hierarchical modeling methods, which build on exchangeable strata parameters and allow borrowing information across strata. However, the standard exchangeability (EX) assumption bears the risk of too much shrinkage and excessive borrowing for extreme strata. We propose the exchangeability–nonexchangeability (EXNEX) approach as a robust mixture extension of the standard EX approach. It allows each stratum‐specific parameter to be exchangeable with other similar strata parameters or nonexchangeable with any of them. While EXNEX computations can be performed easily with standard Bayesian software, model specifications and prior distributions are more demanding and require a good understanding of the context. Two case studies from phases I and II (with three and four strata) show promising results for EXNEX. Data scenarios reveal tempered degrees of borrowing for extreme strata, and frequentist operating characteristics perform well for estimation (bias, mean‐squared error) and testing (less type‐I error inflation). Copyright © 2015 John Wiley & Sons, Ltd.     

Modeling immunogenecity data to establish screening bioassays cut point

The response of immunogenecity anti-drug antibody (ADA) generally includes biological and analytical variability. The nature of biological and analytical variations may lead to a variety of symmetric and asymmetric ADA data. As a result, current statistical methods may yield unreliable results because these methods assume special types of symmetric or asymmetric ADA data. In this paper, we survey and compare parametric models that are useful for analyzing a variety of asymmetric data that have rarely been used to calculate assay cut points. These models include symmetric distributions as limiting case; therefore, they are useful in the analysis of a variety of symmetric data. We also investigate two nonparametric approaches that have received little attention in screening cut point calculations. A simulation study was conducted to compare the performance of the methods. We evaluate the methods using four published different types of data, and make recommendations concerning the use of the methods.