Silver Spring, MD, United States
Silver Spring, MD, United States

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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.


PubMed | National Cancer Institute, U.S. Food and Drug Administration, Office of New Drugs Quality Assurance, Office of Clinical Pharmacology and 2 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

On April 25, 2016, the U. S. Food and Drug Administration (FDA) approved cabozantinib (CABOMETYX{trade mark, serif}, Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior anti-angiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which RCC patients who had received prior anti-angiogenic therapy were treated with either cabozantinib 60 mg orally once daily (N=330) or everolimus 10 mg orally once daily (N=328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee (IRC) in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [HR 0.58 (95% CI: 0.45, 0.74); p<0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population also was demonstrated, with median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively [HR 0.66 (95% CI: 0.53, 0.83); p=0.0003]. The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation.


PubMed | University of Minnesota, OTS, Therapeutic Proteins, National MPS Society and 11 more.
Type: Journal Article | Journal: Molecular genetics and metabolism | Year: 2016

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.


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.


Couderc J.-P.,University of Rochester | Garnett C.,Office of Clinical Pharmacology | Garnett C.,Center for Drug Evaluation and Research | Li M.,Center for Drug Evaluation and Research | And 5 more authors.
Annals of Noninvasive Electrocardiology | Year: 2011

Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 ± 24 ms on drug and 9.8 ± 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 ± 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 ± 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods. ©2011, Wiley Periodicals, Inc.


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.

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