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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We propose a method for determining the criticality of residual host cell DNA, which is characterized through two attributes, namely the size and amount of residual DNA in biopharmaceutical product. By applying a mechanistic modeling approach to the problem, we establish the linkage between residual DNA and product safety measured in terms of immunogenicity, oncogenicity, and infectivity. Such a link makes it possible to establish acceptable ranges of residual DNA size and amount. Application of the method is illustrated through two real-life examples related to a vaccine manufactured in Madin Darby Canine Kidney cell line and a monoclonal antibody using Chinese hamster ovary (CHO) cell line as host cells.
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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 In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a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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In quality control of drug products, tolerance intervals are commonly used methods to assure a certain proportion of the products covered within a pre-specified acceptance interval. Depending on the nature of the quality attributes, the corresponding acceptance interval could be one-sided or two-sided. ⋯ To better utilize tolerance intervals for quality assurance, we reviewed the computation method and studied their statistical properties in terms of batch acceptance probability in this article. We also illustrate the application of one-sided and two-sided tolerance, as well as two one-sided tests through the examples of dose content uniformity test, delivered dose uniformity test, and dissolution test.
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According to ICH Q6A (1999), a specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. For drug products, specifications usually consist of test methods and acceptance criteria for assay, impurities, pH, dissolution, moisture, and microbial limits, depending on the dosage forms. They are usually proposed by the manufacturers and subject to the regulatory approval for use. ⋯ In this article, we describe and discuss the statistical issues of commonly used approaches in setting or revising specifications (usually tighten the limits), including reference interval, (Min, Max) method, tolerance interval, and confidence limit of percentiles. We also compare their performance in terms of the interval width and the intended coverage. Based on our study results and review experiences, we make some recommendations on how to select the appropriate statistical methods in setting product specifications to better ensure the product quality.