Office of Clinical Pharmacology

Silver Spring, MD, United States

Office of Clinical Pharmacology

Silver Spring, MD, United States
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Strasinger C.,U.S. Food and Drug Administration | Raney S.G.,Office of Research and Standards | Tran D.C.,Office of Clinical Pharmacology | Ghosh P.,Office of Research and Standards | And 4 more authors.
Journal of Controlled Release | Year: 2016

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al., 2004 Prausnitz et al. (2004) [1]; Hadgraft and Lane, 2006 Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.


Liu J.,Office of Clinical Pharmacology | Florian J.,Office of Clinical Pharmacology | Birnkrant D.,U.S. Food and Drug Administration | Murray J.,U.S. Food and Drug Administration | Jadhav P.R.,Office of Clinical Pharmacology
Clinical Infectious Diseases | Year: 2012

Background.The purpose of this research was to compare interferon (IFN) responsiveness in treatment-naive and pegylated interferon -ribavirin (P/R)-experienced subjects and to understand the implications of comparability in IFN responsiveness across treatment courses on drug development and clinical decision making.Methods.Data from 3750 subjects treated with P/R in 8 trials were reviewed. The change in hepatitis C virus (HCV) RNA at week 4 in response to P/R was compared according to end-of-study (EOS) status (responder, relapser, partial and null responder) for treatment-naive subjects and the previous P/R response status (known as prior relapsers, prior partial responders, and prior null responders at the baseline) for P/R-experienced subjects.Results.In subjects receiving a first course of P/R treatment (treatment-naive subjects), HCV RNA change after 4 weeks of P/R was correlated with EOS status on a P/R regimen. Importantly, for the first time, we have quantitatively demonstrated that IFN responsiveness in P/R-experienced subjects administered a second course of P/R treatment was similar to the IFN responsiveness in the treatment-naive subjects with corresponding EOS status.Conclusions.We contend that P/R-experienced subjects are represented within treatment-naive subjects. There are 2 important implications of this finding: (1) from a drug development perspective, a successful direct antiviral plus P/R therapy (IFN-based triple therapy) trial in P/R-experienced subjects may serve as supportive evidence in treatment-naive subjects; and (2) from a clinical decision perspective, previous P/R exposure should not alter new treatment decisions involving IFN-based triple therapy, as the IFN responsiveness to a second course of IFN is comparable.


Kluetz P.G.,U.S. Food and Drug Administration | Pierce W.,U.S. Food and Drug Administration | Maher V.E.,U.S. Food and Drug Administration | Zhang H.,Office of Biostatistics | And 13 more authors.
Clinical Cancer Research | Year: 2014

OnMay 15, 2013, the U.S. Food and Drug Administration (FDA) approved radium Ra-223 dichloride (Ra-223; Xofigo injection; Bayer HealthCare Pharmaceuticals Inc.) for the treatment of patients with castrationresistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. The FDA review was based on clinical trial BC1-06, which randomly allocated patients (2:1) to either Ra-223 plus best standard of care (BSoC) or placebo plus BSoC. The primary endpoint was overall survival (OS) with a key secondary endpoint of time to first symptomatic skeletal event (SSE). A statistically significant improvement in OS was demonstrated [HR, 0.70; 95% confidence interval, 0.55-0.88, P = 0.0019]. At the prespecified interim analysis, the median OS durations were 14.0 and 11.2 months in the Ra-223 and placebo arms, respectively. The improvement in OS was supported by a delay in time to first SSE favoring the Ra-223 arm. The most common (>10%) adverse reactions in patients receiving Ra-223 were nausea, diarrhea, vomiting, and peripheral edema. The most common (>10%) hematologic laboratory abnormalities were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Ra-223 is the first a-emitting radiotherapeutic and the first radiopharmaceutical to demonstrate anOSadvantage in metastatic prostate cancer. Clin Cancer Res; 20(1); 9-14. © 2013 AACR.


PubMed | U.S. Food and Drug Administration, Office of Research and Standards and Office of Clinical Pharmacology
Type: | Journal: Journal of controlled release : official journal of the Controlled Release Society | Year: 2016

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industrys conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industrys best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form.


Liu J.,Office of Clinical Pharmacology | Jadhav P.,Office of Clinical Pharmacology | Wang Y.,Office of Clinical Pharmacology | Gobburu J.,Office of Clinical Pharmacology
AAPS Journal | Year: 2013

Dose-response analysis is one of the accepted efficacy endpoints to establish effectiveness. The purpose of this research was to inform selection of an appropriate pre-specified primary dose-response analysis to demonstrate drug efficacy in a registration trial. The power and the type I error rate of the placebo-corrected (i.e., simply adjusting the observed treatment value by subtracting the placebo mean) and the placebo-anchored (i.e., including the placebo data as dose 0 in the regression) slope analyses were assessed based on regulatory submission data for two antihypertensive drugs and simulated data from hypothetical clinical trials. In the simulated hypothetical trials, the impact of different dosing strategies (i.e., the fixed dose versus the weight-based per kilogram dose), sample size, and scenarios governing the drug exposure-response relationship (e.g., E max, ED 50, and SD) was also evaluated. For each scenario, a total 300 replications were simulated. The placebo-anchored slope analysis is always more powerful to demonstrate effectiveness in all plausible scenarios. The difference between the placebo-anchored and the placebo-corrected analyses was maximum when the studied doses were too high. However, the dose-response analysis is not sensitive to the dosing strategies. Furthermore, the type I error rate of these two methods was also found to be comparable. The design of dose-response studies should carefully consider these results to justify the inclusion of placebo and the analysis method. The pharmaceutical industry and the regulatory agencies are equally responsible for using the appropriate methods of primary analysis and providing justification in the protocol. © 2013 American Association of Pharmaceutical Scientists.


Zhu H.,Office of Clinical Pharmacology | Wang Y.,Office of Clinical Pharmacology
Journal of Pharmacokinetics and Pharmacodynamics | Year: 2011

We explored the type I error rate (false positive rate) associated with exposure-response (ER) analyses for two compounds in a fixed-dose combination product through simulations. In the simulations, at least one compound was assumed to be inactive, whereas the active compound followed Emax model at different concentration ranges. The simulated data were independently evaluated by pre-specified univariate or multivariate linear, log-linear models, and mixed linear log-linear models. The type I error rate was evaluated by comparing the total number of falsely identified significant slope estimates with the total number of models with successful convergence. We demonstrated that ER analyses results based on data from fixed-dose combination products at various dose levels should be interpreted with caution. A univariate analysis, even though is appropriate to guide dose selection, is inadequate to identify the active compound. Multivariate analyses can be applied to determine the active compound only when the underlying ER relationship for each compound (especially for the active compound) has been adequately defined or approximated. The false positive rate in determining a significant ER relationship is elevated, when the underlying ER relationship (especially for the active compound) is erroneously or inadequately defined. Without the assurance of the correct structural models, the identified significant ER relationship does not necessarily indicate that the compound associated with the significant slope estimate is pharmacologically active. © Springer Science+Business Media, LLC (outside the USA) 2011.


McCance-Katz E.F.,University of California at San Francisco | McCance-Katz E.F.,San Francisco General Hospital | Sullivan L.E.,Yale University | Nallani S.,Office of Clinical Pharmacology
American Journal on Addictions | Year: 2010

Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.© American Academy of Addiction Psychiatry.


Jiang X.-L.,University of Florida | Zhao P.,Office of Clinical Pharmacology | Barrett J.S.,Children's Hospital of Philadelphia | Lesko L.J.,University of Florida | Schmidt S.,University of Florida
CPT: Pharmacometrics and Systems Pharmacology | Year: 2013

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that undergoes extensive phase I and II metabolism. To better understand the kinetics of this process and to characterize the dynamic changes in metabolism and pharmacokinetics (PK) between children and adults, we developed a physiologically based PK (PBPK) model for APAP integrating in silico, in vitro, and in vivo PK data into a single model. The model was developed and qualified for adults and subsequently expanded for application in children by accounting for maturational changes from birth. Once developed and qualified, it was able to predict clinical PK data in neonates (0-28 days), infants (29 days to 2 years), children (2 to 12 years), and adolescents (12-17 years) following intravenous and orally administered APAP. This approach represents a general strategy for projecting drug exposure in children, in the absence of pediatric PK information, using previous drug-and system-specific information of adults and children through PBPK modeling. © 2013 ASCPT.


Wang Y.,Office of Clinical Pharmacology | Lee J.Y.,Office of Clinical Pharmacology | Michele T.,Center for Drug Evaluation and Research | Chowdhury B.A.,Center for Drug Evaluation and Research | Gobburu J.V.,Office of Clinical Pharmacology
International Journal of Clinical Pharmacology and Therapeutics | Year: 2012

Objective: Indacaterol is a long-acting β-agonist (LABA) approved by FDA in 2011 at a dose of 75 μg once daily for the treatment of chronic obstructive pulmonary disease (COPD). During the review process for indacaterol approval, data were reanalyzed by FDA to evaluate the validity of the model-based conclusions regarding dose selection. Methods: The same dose-response model applied by the sponsor was used to analyze a subset of the original data. Model predictions were compared with observed data to evaluate the model. Subgroups were created to visualize the relationship between key model parameters and covariates. The Emax model structure was evaluated for a meta-analysis. Results: Patient-level analyses showed that the model-based claim of additional benefit of 150 μg over 75 μg for more severe patients is not supported by the data. Mis-specified covariate model structures for key parameters contributed to this inconsistency. The assumed Emax model structure is not supported by the study-level data and the study-level analysis overestimates the incremental difference between two adjacent doses. Conclusions: Even though model-based drug development is highly desirable, thorough model evaluation and justification is necessary to ensure the validity of related decisions.


Li Z.,Office of Clinical Pharmacology | Zhou H.,Office of Clinical Pharmacology | Lu Y.,Office of Clinical Pharmacology | Colatsky T.,Office of Clinical Pharmacology
CPT: Pharmacometrics and Systems Pharmacology | Year: 2014

Influenza virus infections represent a serious public health problem worldwide, due to the rapid emergence of drug resistance. One strategy to improve treatment efficacy is to combine drugs that act synergistically. Potentially useful drug combinations are typically identified through empirical testing using in vitro and animal models, but the complexity of the clinical situation warrants the use of more careful analysis and sophisticated approaches. To explore new approaches, we constructed a mechanistic model representing the interaction of antiviral drugs with the viral replication pathway and human immune responses. Simulation of combination therapy using oseltamivir and amantadine predicted significant therapeutic synergy only when immune response was included, in agreement with previous in vitro and in vivo studies using amantadine-resistant strains. Our model can be used to predict the optimal doses for combination therapy, and also raises questions about current drug evaluation methods that do not account for immune system interactions. © 2014 ASCPT All rights reserved.

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