Raritan, NJ, United States
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Uryniak T.,Astrazeneca | Chan I.S.F.,Merck And Co. | Fedorov V.V.,Glaxosmithkline | Jiang Q.,Amgen | And 4 more authors.
Statistics in Biopharmaceutical Research | Year: 2011

Ideally, a clinical trial should be able to demonstrate not only a statistically significant improvement in the primary efficacy endpoint, but also that the magnitude of the effect is clinically relevant. One approach to address this question, often proposed by clinical societies and regulatory guidance, is a responder analysis, in which a continuous primary efficacy measure is dichotomized into "responders" and "nonresponders." This article represents a Pharmaceutical Research and Manufacturers of America (PhRMA) position on responder analyses. With respect to demonstration of the existence of a treatment effect, we find that the well-known loss of statistical power associated with a responder analysis outweighs any real or perceived benefits of this approach. However, between-group comparisons of the percentages of "responders" can play a role in the assessment and reporting of the clinical meaningfulness of the treatment effect. © American Statistical Association Statistics in Biopharmaceutical Research.


Ellens H.,Glaxosmithkline | Deng S.,Drug Metabolism and Pharmacokinetics | Coleman J.,Statistical science | Bentz J.,Eli Lilly and Company | And 32 more authors.
Drug Metabolism and Disposition | Year: 2013

In the 2012 Food and Drug Administration (FDA) draft guidance on drug-drug interactions (DDIs), a new molecular entity that inhibits Pglycoprotein (P-gp) may need a clinical DDI study with a P-gp substrate such as digoxin when themaximumconcentration of inhibitor at steady state divided by IC50 ([I1]/IC50) is0.1 or concentration of inhibitor based on highest approved dose dissolved in 250 ml divide by IC50 ([I2]/IC 50) is10. In this article, refined criteria are presented, determined by receiver operating characteristic analysis, using IC50 values generated by 23 laboratories. P-gp probe substrates were digoxin for polarized cell-lines and N-methyl quinidine or vinblastine for P-gp overexpressed vesicles. Inhibition of probe substrate transport was evaluated using 15 known P-gp inhibitors. Importantly, the criteria derived in this article take into account variability in IC50 values. Moreover, they are statistically derived based on the highest degree of accuracy in predicting true positive and true negative digoxin DDI results. The refined criteria of [I1]/IC50 0.03 and [I2]/IC50 45 and FDA criteria were applied to a test set of 101 in vitro-in vivo digoxin DDI pairs collated from the literature. The number of false negatives (none predicted but DDI observed) were similar, 10 and 12%, whereas the number of false positives (DDI predicted but not observed) substantially decreased from 51 to 40%, relative to the FDA criteria. On the basis of estimated overall variability in IC50 values, a theoretical 95%confidence interval calculation was developed for single laboratory IC 50 values, translating into a range of [I1]/IC50 and [I2]/IC50 values. The extent by which this range falls above the criteria is a measure of risk associated with the decision, attributable to variability in IC50 values. © 2013 by The American Society for Pharmacology.


Marshall J.D.,Vaccine Platform Group | Heeke D.S.,Translational Biology Group | Rao E.,Translational Biology Group | Maynard S.K.,Vaccine Platform Group | And 10 more authors.
PLoS ONE | Year: 2016

The best-characterized Toll-like receptor 4 (TLR4) ligands are lipopolysaccharide (LPS) and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL). Although both molecules are active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants. © 2016 Marshall et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | Vaccine Platform Group, University of Washington, MedImmune, Statistical science and 3 more.
Type: Journal Article | Journal: PloS one | Year: 2016

The best-characterized Toll-like receptor 4 (TLR4) ligands are lipopolysaccharide (LPS) and its chemically modified and detoxified variant, monophosphoryl lipid A (MPL). Although both molecules are active for human TLR4, they demonstrate a potency preference for mouse TLR4 based on data from transfected cell lines and primary cells of both species. After a high throughput screening process of small molecule libraries, we have discovered a new class of TLR4 agonist with a species preference profile differing from MPL. Products of the 4-component Ugi synthesis reaction were demonstrated to potently trigger human TLR4-transfected HEK cells but not mouse TLR4, although inclusion of the human MD2 with mTLR4 was able to partially recover activity. Co-expression of CD14 was not required for optimal activity of Ugi compounds on transfected cells, as it is for LPS. The species preference profile for the panel of Ugi compounds was found to be strongly active for human and cynomolgus monkey primary cells, with reduced but still substantial activity for most Ugi compounds on guinea pig cells. Mouse, rat, rabbit, ferret, and cotton rat cells displayed little or no activity when exposed to Ugi compounds. However, engineering the human versions of TLR4 and MD2 to be expressed in mTLR4/MD2 deficient mice allowed for robust activity by Ugi compounds both in vitro and in vivo. These findings extend the range of compounds available for development as agonists of TLR4 and identify novel molecules which reverse the TLR4 triggering preference of MPL for mouse TLR4 over human TLR4. Such compounds may be amenable to formulation as more potent human-specific TLR4L-based adjuvants than typical MPL-based adjuvants.


Borman P.,Analytical science Chemical Development | Chatfield M.,Statistical science | Jackson P.,Analytical Chemist in Analytical science chemical Development | Laures A.,Analytical Chemist in Analytical science chemical Development | Okafo G.,Glaxosmithkline
Pharmaceutical Technology | Year: 2010

This paper describes a novel approach for assessing method robustness that uses risk-based assessment tools to identify, score, prioritize, and group method parameters. The authors evaluated these parameters using reduced fractional factorial designs (i.e., reduced-method robustness) to evaluate the suitability of analytical methods before full validation. The authors' approach helped to identify high-risk method parameters earlier in the development process, thereby offering potential resource savings.


Faiola B.,Rti International | Faiola B.,Glaxosmithkline | Peterson R.A.,Glaxosmithkline | Kimbrough C.L.,Statistical science | And 2 more authors.
Toxicologic Pathology | Year: 2010

The innate immune response is known to modify hepatocellular injury induced by toxicants. To assess the role of IL-10, a component of the innate immune response, in toxicant-induced injury of biliary epithelium, wild-type (WT) and IL-10 knockout mice (KO) were given a single toxic dose (50 mg/kg) of ±-napthylisothiocyanate (ANIT) and assessed at twenty-four-hour intervals for four days following treatment. Clinical signs of toxicity were greater in WT mice. Unexpectedly, over the course of the study, there was a consistent tendency for ANIT-treated IL-10 KO mice to have less hepatocellular injury than WT mice. However, changes in the biliary epithelium differed in that there was more histologic evidence of inflammation and necrosis on days 2 and 3, respectively, in ANIT-treated IL-10 KO mice compared with WT mice. Proliferation of biliary epithelium and hepatocytes was greater and/or occurred earlier in the ANIT-treated IL-10 KO mice compared with the ANIT-treated WT mice, suggesting a greater reparative response was needed for recovery after toxicant injury in the IL-10 KO mice. Overall, our data suggest that IL-10 KO mice have less hepatocellular injury than WT mice following a toxic dose of ANIT and that biliary epithelial injury is accentuated in the KO mice. Copyright © 2010 by The Author(s).


PubMed | Statistical Science
Type: | Journal: Pharmaceutical statistics | Year: 2016

We study the properties of treatment effect estimate in terms of odds ratio at the study end point from logistic regression model adjusting for the baseline value when the underlying continuous repeated measurements follow a multivariate normal distribution. Compared with the analysis that does not adjust for the baseline value, the adjusted analysis produces a larger treatment effect as well as a larger standard error. However, the increase in standard error is more than offset by the increase in treatment effect so that the adjusted analysis is more powerful than the unadjusted analysis for detecting the treatment effect. On the other hand, the true adjusted odds ratio implied by the normal distribution of the underlying continuous variable is a function of the baseline value and hence is unlikely to be able to be adequately represented by a single value of adjusted odds ratio from the logistic regression model. In contrast, the risk difference function derived from the logistic regression model provides a reasonable approximation to the true risk difference function implied by the normal distribution of the underlying continuous variable over the range of the baseline distribution. We show that different metrics of treatment effect have similar statistical power when evaluated at the baseline mean. Copyright 2016 John Wiley & Sons, Ltd.

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