Journal of biopharmaceutical statistics
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Applications of personalized medicine are becoming increasingly prominent. A well-characterized market-ready companion diagnostic assay (CDx) is often desired for patient enrollment in device-drug pivotal clinical trial(s) so that Food and Drug Administration can ensure that appropriate clinical and analytical validation studies are planned and carried out for CDx. However, such a requirement may be difficult or impractical to accomplish. ⋯ A concordance study (or bridging study) will be required to assess the agreement between CDx and CTA in order to bridge the clinical data (e.g. overall survival) from CTA to CDx and to evaluate the drug efficacy in CDx intended use population. In this article, we will discuss statistical challenges in study design and data analysis for bridging study. Particularly, we aimed to provide statistical methods on how to estimate the drug efficacy in CDx intended use population using results from bridging study and CTA-drug pivotal clinical trial.
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In dose-finding trials of chemotherapeutic agents, the goal of identifying the maximum tolerated dose is usually determined by considering information on toxicity only, with the assumption that the highest safe dose also provides the most promising outlook for efficacy. Trials of molecularly targeted agents challenge accepted dose-finding methods because minimal toxicity may arise over all doses under consideration and higher doses may not result in greater response. In this article, we propose a new early-phase method for trials investigating targeted agents. We provide simulation results illustrating the operating characteristics of our design.
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The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. ⋯ The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.
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Since the adoption of the ICH Q8 document concerning the development of pharmaceutical processes following a quality by design (QbD) approach, there have been many discussions on the opportunity for analytical procedure developments to follow a similar approach. While development and optimization of analytical procedure following QbD principles have been largely discussed and described, the place of analytical procedure validation in this framework has not been clarified. ⋯ Adequate statistical methodologies have also their role to play: such as design of experiments, statistical modeling, and probabilistic statements. The outcome of analytical procedure validation is also an analytical procedure design space, and from it, control strategy can be set.
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The concept of quality by design (QbD) as published in ICH-Q8 is currently one of the most recurrent topics in the pharmaceutical literature. This guideline recommends the use of information and prior knowledge gathered during pharmaceutical development studies to provide a scientific rationale for the manufacturing process of a product and provide guarantee of future quality. This poses several challenges from a statistical standpoint and requires a shift in paradigm from traditional statistical practices. ⋯ In many cases, these criteria are complicated longitudinal data with successive acceptance criteria over a defined period of time. A common example is a dissolution profile for a modified or extended-release solid dosage form that must fall within acceptance limits at several time points. A Bayesian approach for longitudinal data obtained in various conditions of a design of experiment is provided to elegantly address the ICH-Q8 recommendation to provide assurance of quality and derive a scientifically sound design space.