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Raritan, NJ, United States

Patel N.,Cytel, Inc | Bolognese J.,Cytel, Inc | Chuang-Stein C.,Pfizer | Hewitt D.,Merck And Co. | And 2 more authors.
Drug Information Journal | Year: 2012

Traditionally, sample size considerations for phase 2 trials are based on the desired properties of the design and response information from the trials. In this article, we propose to design phase 2 trials based on program-level optimization. We present a framework to evaluate the impact that several phase 2 design features have on the probability of phase 3 success and the expected net present value of the product. These factors include the phase 2 sample size, decision rules to select a dose for phase 3 trials, and the sample size for phase 3 trials. Using neuropathic pain as an example, we use simulations to illustrate the framework and show the benefit of including these factors in the overall decision process. © The Author(s) 2012.

Chapuy C.I.,Brigham and Womens Hospital | Nicholson R.T.,Brigham and Womens Hospital | Aguad M.D.,Brigham and Womens Hospital | Chapuy B.,Dana-Farber Cancer Institute | And 4 more authors.
Transfusion | Year: 2015

BACKGROUND Daratumumab (DARA), a promising novel therapy for multiple myeloma, is an IgG1κ monoclonal antibody that recognizes CD38 on myeloma cells. During routine compatibility testing, we observed that the plasma of five of five DARA-treated patients demonstrated a positive antibody screen and panreactivity on red blood cell (RBC) panel testing. We hypothesized that the observed panreactivity reflected DARA binding to CD38 on reagent RBCs, and we investigated methods to prevent this binding. STUDY DESIGN AND METHODS DARA binding to CD38+ or CD38- HL60 cells was assessed by flow cytometry. To remove cell surface CD38, cells were incubated with dithiothreitol (DTT) or trypsin. Soluble CD38 or anti-DARA was used to neutralize DARA in solution. Routine blood bank serologic methods were used to test samples from DARA-treated patients and normal plasma samples spiked with DARA and/or alloantibodies. RESULTS Normal plasma samples spiked with DARA (0.1-10 μg/mL) and incubated with reagent RBCs recapitulated the interference observed with samples from DARA-treated patients. Flow cytometry experiments confirmed DARA binding to CD38+ HL60 cells, but not to CD38- controls. DTT treatment of CD38+ HL60 cells reduced DARA binding by 92% by denaturing cell surface CD38. Treating DARA-containing plasma with soluble CD38 or anti-DARA idiotype also inhibited DARA binding. CONCLUSION DARA causes panreactivity in vitro by binding to CD38 on reagent RBCs. Treating reagent RBCs with DTT is a robust method to negate the DARA interference, enabling the safe provision of blood to DARA-treated patients. Because DTT denatures Kell antigens, K- units are provided to these patients. © 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.

Stuyver L.J.,Janssen Diagnostics Inc. | Verbeke T.,Open Web Analytics | Van Loy T.,Janssen Diagnostics Inc. | Van Gulck E.,Janssen Infectious Disease CREATe | Tritsmans L.,Janssen RandD
Virology Journal | Year: 2013

Background: Human polyomaviruses (HPyV) infections cause mostly unapparent or mild primary infections, followed by lifelong nonpathogenic persistence. HPyV, and specifically JCPyV, are known to co-diverge with their host, implying a slow rate of viral evolution and a large timescale of virus/host co-existence. Recent bio-informatic reports showed a large level of peptide homology between JCPyV and the human proteome. In this study, the antibody response to PyV peptides is evaluated. Methods. The in-silico analysis of the HPyV proteome was followed by peptide microarray serology. A HPyV-peptide microarray containing 4,284 peptides was designed and covered 10 polyomavirus proteomes. Plasma samples from 49 healthy subjects were tested against these peptides. Results: In-silico analysis of all possible HPyV 5-mer amino acid sequences were compared to the human proteome, and 1,609 unique motifs are presented. Assuming a linear epitope being as small as a pentapeptide, on average 9.3% of the polyomavirus proteome is unique and could be recognized by the host as non-self. Small t Ag (stAg) contains a significantly higher percentage of unique pentapeptides. Experimental evidence for the presence of antibodies against HPyV 15-mer peptides in healthy subjects resulted in the following observations: i) antibody responses against stAg were significantly elevated, and against viral protein 2 (VP2) significantly reduced; and ii) there was a significant correlation between the increasing number of embedded unique HPyV penta-peptides and the increase in microarray fluorescent signal. Conclusion: The anti-peptide HPyV-antibodies in healthy subjects are preferably directed against the penta-peptide derived unique fraction of the viral proteome. © 2013 Stuyver et al.; licensee BioMed Central Ltd.

Higton D.,Astrazeneca | Young G.,Glaxosmithkline | Timmerman P.,Janssen RandD | Abbott R.,Shire Pharmaceuticals | And 2 more authors.
Bioanalysis | Year: 2012

Accelerator mass spectrometry (AMS) is being used more widely to provide PK data for early decision making or to generate absolute bioavailability data in later phases of development. Presently, there is no clear consensus on the level of the scientific validation required for these assays. The European Bioanalysis Forum (EBF) has conducted two surveys with its members and presented the results at its 4th Open Symposium. With AMS being used for discrete scientific assessment, method establishment of AMS assays should focus on science rather than trying to fit the assay parameters into validation criteria used for Regulated Bioanalysis guidance, and an amount of freedom of execution and interpretation is needed. Hence, the EBF focuses their recommendation on introducing terminology around scientific qualification or validation to be used in relation to AMS. Guidance is given on which parameters should be investigated when a qualified method is required. The recommendations of the EBF for scientific validation are described herein. The scientific validation of AMS assays will be different to that applied for LC-MS/MS assays, and an example is that accuracy and precision limits, as used for ligand-binding assays, would be more appropriate. © 2012 Future Science Ltd.

Van De Merbel N.C.,Bioanalytical Laboratory | Van De Merbel N.C.,University of Groningen | De Vries R.,Janssen RandD
Bioanalysis | Year: 2013

Apart from the well-known matrix effects that can occur in ESI LC-MS, biological matrices may have other effects influencing the quantitative reliability of bioanalytical methods. In this paper, six case studies are presented that show the effect that aging, that is the change in properties and composition of biological matrices over time, can have on the performance of bioanalytical methods. It is shown that selectivity can be affected due to the formation or disappearance of endogenous compounds. Stability can be influenced because of the decrease (or increase) of enzyme activities and recovery can be impacted if the extractability from binding sites in the matrix is enhanced or decreased. A general discussion on the importance of these matrix effects is provided as well as a perspective on how to properly address them in the method-development and validation stages of regulated bioanalysis. © 2013 Future Science Ltd.

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