Publications by authors named "Yow-Ming Wang"

38 Publications

2020 White Paper on Recent Issues in Bioanalysis: BAV Guidance, CLSI H62, Biotherapeutics Stability, Parallelism Testing, CyTOF and Regulatory Feedback ( - Recommendations on Biotherapeutics Stability, PK LBA Regulated Bioanalysis, Biomarkers Assays, Cytometry Validation & Innovation - Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine).

Bioanalysis 2021 Mar 29;13(5):295-361. Epub 2021 Jan 29.

Health Canada, Ottawa, ON, Canada.

The 14 edition of the Workshop on Recent Issues in Bioanalysis (14 WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 2A) BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation and (Part 2B) Regulatory Input. Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 4, and 6 (2021), respectively.
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http://dx.doi.org/10.4155/bio-2021-0005DOI Listing
March 2021

Communicating Immunogenicity-Associated Risk in Current U.S. FDA Prescription Drug Labeling: A Systematic Evaluation.

Ther Innov Regul Sci 2020 11 16;54(6):1363-1371. Epub 2020 May 16.

Office of Clinical Pharmacology, Office of Translational Sciences, US Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.

Background: Communicating the clinical impact of immunogenicity in labeling is important for safe and effective use of certain prescription products. Current U.S. Food and Drug Administration (FDA) guidance does not provide comprehensive recommendations on the communication of clinical impact of immunogenicity in labeling. To understand current labeling practice, we evaluated the immunogenicity data and clinical impact information in labeling of selected prescription products.

Methods: We created a database of 71 therapeutic biologics and drug products that had an immunogenicity assessment initially approved by FDA's Center for Drug Evaluation and Research between 2014 and 2018. We analyzed the content and format of immunogenicity information (e.g., anti-drug antibody incidence and/or immunogenicity impact on pharmacokinetics (PK), safety, and/or effectiveness) in the most recent approved labeling.

Results: Immunogenicity information was in the ADVERSE REACTIONS section in 98% of the reviewed labeling. Immunogenicity impact on PK was reported in 52% of the labeling, typically within the ADVERSE REACTIONS section, but supportive PK data were often not included in the CLINICAL PHARMACOLOGY section. Additionally, the immunogenicity impact on safety and/or effectiveness was communicated in 70% of the labeling, with 23% clearly communicating the effect as clinically meaningful, and 10% providing actionable recommendations.

Conclusions: Most of the reviewed labeling includes immunogenicity information within the ADVERSE REACTIONS section. However, there is inconsistency in providing supportive PK data and high variability in reporting immunogenicity impact on safety and effectiveness in labeling. Development of a communication framework that allows for consistent inclusion of immunogenicity impact statements in labeling could improve how immunogenicity risk is conveyed in prescription drug labeling.
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http://dx.doi.org/10.1007/s43441-020-00161-zDOI Listing
November 2020

Elucidating the Impact of Immunogenicity Assessment Postapproval: A Targeted Analysis of Immunogenicity Postmarketing Requirements and Commitments.

Clin Pharmacol Ther 2021 Mar 28;109(3):697-704. Epub 2020 Sep 28.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

Insufficient availability of data to evaluate immunogenicity incidence or clinical impact during regulatory review could require further evaluation postapproval. Through a keyword search of all postmarketing requirements and commitments (PMRs/PMCs) associated with products with their original US Food and Drug Administration (FDA) approvals between 2009 and 2018, we identified products that had PMRs/PMCs established to address concerns or uncertainty related to immunogenicity. Of the 113 relevant products, 50% had an immunogenicity-related PMR/PMC; of these, 68% were related to developing immunogenicity assays and 48% requested an assessment of clinical impact. Fifty-five percent of the products with a fulfilled PMR/PMC had a change in the immunogenicity information in their labeling immediately following fulfillment. This work highlights that there are often unknowns associated with immunogenicity incidence and/or impact at the time of approval. Earlier regulatory discussions on immunogenicity assessments in premarket development could improve the understanding and communication of the risk/benefit profile and reduce the need for some immunogenicity PMRs/PMCs.
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http://dx.doi.org/10.1002/cpt.2038DOI Listing
March 2021

Systematic Review of Device Parameters and Design of Studies Bridging Biologic-Device Combination Products Using Prefilled Syringes and Autoinjectors.

AAPS J 2020 02 27;22(2):52. Epub 2020 Feb 27.

Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (OCP/CDER/FDA), 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. A systematic review on the device parameters and the PK comparability studies bridging the two presentations was conducted. Subsequently, whether device parameters or the PK study design may have influenced the PK comparability study results was evaluated. The reported device parameters for AI and PFS are generally consistent across BLAs, whereas the approach to assess PK comparability varied, including the study design. Most PK comparability studies met bioequivalence (BE) criteria. Upon inspection of the studies that did not meet BE criteria, injection depth of AI and the injection site for either AI or PFS were identified as potential influencing factors to the outcome of PK comparability study. This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination product development strategy, specifically design considerations for device and PK comparability studies.
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http://dx.doi.org/10.1208/s12248-020-0433-8DOI Listing
February 2020

2019 White Paper On Recent Issues in Bioanalysis: FDA BMV Guidance, ICH M10 BMV Guideline and Regulatory Inputs ( - Recommendations on 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and Regulatory Agencies' Input on Bioanalysis, Biomarkers and Immunogenicity).

Bioanalysis 2019 Dec 9;11(23):2099-2132. Epub 2019 Dec 9.

US FDA, Silver Spring, MD, USA.

The 2019 13 Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of , issues 22 and 24 (2019), respectively.
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http://dx.doi.org/10.4155/bio-2019-0270DOI Listing
December 2019

2019 White Paper on Recent Issues in Bioanalysis: FDA Immunogenicity Guidance, Gene Therapy, Critical Reagents, Biomarkers and Flow Cytometry Validation (Part 3 - Recommendations on 2019 FDA Immunogenicity Guidance, Gene Therapy Bioanalytical Challenges, Strategies for Critical Reagent Management, Biomarker Assay Validation, Flow Cytometry Validation & CLSI H62).

Bioanalysis 2019 Dec 10;11(24):2207-2244. Epub 2019 Dec 10.

Janssen R&D, Spring House, PA, USA.

The 2019 13 Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA, USA on April 1-5, 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers New Insights in Biomarker Assay Validation, Current & Effective Strategies for Critical Reagent Management, Flow Cytometry Validation in Drug Discovery & Development & CLSI H62, Interpretation of the 2019 FDA Immunogenicity Guidance and Gene Therapy Bioanalytical Challenges. Part 1 (Innovation in Small Molecules and Oligonucleotides & Mass Spectrometry Method Development Strategies for Large Molecule Bioanalysis) and Part 2 (Recommendations on the 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy) are published in volume 11 of , issues 22 and 23 (2019), respectively.
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http://dx.doi.org/10.4155/bio-2019-0271DOI Listing
December 2019

Use of pharmacodynamic/response biomarkers for therapeutic biologics regulatory submissions.

Biomark Med 2019 07 18;13(10):805-809. Epub 2019 Jun 18.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation & Research, Food & Drug Administration, Silver Spring, MD 20993, USA.

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http://dx.doi.org/10.2217/bmm-2019-0197DOI Listing
July 2019

Effect of Body Weight on Risk-Benefit and Dosing Regimen Recommendation of Secukinumab for the Treatment of Moderate to Severe Plaque Psoriasis.

Clin Pharmacol Ther 2019 07 12;106(1):78-80. Epub 2019 Jun 12.

Office of New Drugs, US Food and Drug Administration, Silver Spring, Maryland, USA.

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http://dx.doi.org/10.1002/cpt.1478DOI Listing
July 2019

Monoclonal Antibodies and Fc-Fusion Proteins for Pediatric Use: Dosing, Immunogenicity, and Modeling and Simulation in Data Submitted to the US Food and Drug Administration.

J Clin Pharmacol 2019 08 13;59(8):1130-1143. Epub 2019 Mar 13.

Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.

The experience with the use of monoclonal antibodies and Fc-fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight-based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.
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http://dx.doi.org/10.1002/jcph.1406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617747PMC
August 2019

Considerations for Biologic Product Drug-Drug Interactions: A Regulatory Perspective.

Clin Pharmacol Ther 2019 06 7;105(6):1332-1334. Epub 2019 Mar 7.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

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http://dx.doi.org/10.1002/cpt.1366DOI Listing
June 2019

2018 White Paper on Recent Issues in Bioanalysis: focus on immunogenicity assays by hybrid LBA/LCMS and regulatory feedback (Part 2 - PK, PD & ADA assays by hybrid LBA/LCMS & regulatory agencies' inputs on bioanalysis, biomarkers and immunogenicity).

Bioanalysis 2018 Dec 29;10(23):1897-1917. Epub 2018 Nov 29.

F Hoffmann-La Roche, Basel, Switzerland.

The 2018 12 Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for PK, PD and ADA assays by hybrid LBA/LCMS and regulatory agencies' input. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 3 (LBA/cell-based assays: immunogenicity, biomarkers and PK assays) are published in volume 10 of , issues 22 and 24 (2018), respectively.
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http://dx.doi.org/10.4155/bio-2018-0285DOI Listing
December 2018

2018 White Paper on Recent Issues in Bioanalysis: focus on flow cytometry, gene therapy, cut points and key clarifications on BAV (Part 3 - LBA/cell-based assays: immunogenicity, biomarkers and PK assays).

Bioanalysis 2018 Dec 29;10(24):1973-2001. Epub 2018 Nov 29.

Amador Bioscience, Pleasanton, CA, USA (formerly of OncoMed, Redwood City, CA, USA).

The 2018 12 Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day full immersion in bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations for large molecule bioanalysis, biomarkers and immunogenicity using LBA and cell-based assays. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 2 (hybrid LBA/LCMS for biotherapeutics and regulatory agencies' inputs) are published in volume 10 of , issues 22 and 23 (2018), respectively.
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http://dx.doi.org/10.4155/bio-2018-0287DOI Listing
December 2018

Role of Modeling and Simulation in the Development of Novel and Biosimilar Therapeutic Proteins.

J Pharm Sci 2019 Jan 3;108(1):73-77. Epub 2018 Nov 3.

Therapeutic Biologics and Biosimilar Staff, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.

Modeling and simulation (M&S) is an important enabler of knowledge integration in novel biological product development programs. Given the volume of data generated from clinical trials and the complexity of pharmacokinetic (PK) and pharmacodynamic (PD) properties for reference products, extending the use of M&S to biosimilar development is logical. Assessing PK and PD similarity is normally a critical part of demonstrating biosimilarity to a reference product. Thoughtful considerations are necessary in study design to minimize the PK and PD variability, thereby increasing the sensitivity for detecting potential differences between products. In addition, the sensitivity of PD biomarkers depends partly on their relevance to the mechanism(s) of action and the dynamic range of PD response(s), including the impact of certain structural differences on PD in the relevant population. As such, opportunities exist for leveraging the available M&S knowledgebase to maximize the efficiency in the design and interpretation of PK and PD similarity studies. This article describes M&S applications which have contributed to and can continue to enhance biosimilar development programs.
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http://dx.doi.org/10.1016/j.xphs.2018.10.053DOI Listing
January 2019

Individualized Dosing of Therapeutic Monoclonal Antibodies-a Changing Treatment Paradigm?

AAPS J 2018 09 5;20(6):99. Epub 2018 Sep 5.

Projections Research Inc., 535 Springview Lane, Phoenixville, Pennsylvania, 19460, USA.

The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Although there are factors associated with poor treatment outcomes in IBD, one cause for treatment failure may be low mAb exposure. Consequently, gastroenterologists have begun using therapeutic drug monitoring (TDM) to guide dose adjustment. However, while beneficial, TDM does not provide sufficient information to effectively adjust doses. The pharmacokinetics (PK) and pharmacodynamics (PD) of mAbs are complex, with numerous factors impacting on mAb PK and PD. The concept of dashboard-guided dosing based on Bayesian PK models allows physicians to combine TDM with factors influencing mAb PK to individualize therapy more effectively. One issue with TDM has been the slow turnaround of assay results, either necessitating an additional clinic visit for a sample or reacting to TDM results at a subsequent, rather than the current, dose. New point-of-care (POC) assays for mAbs are being developed that would potentially allow physicians to determine drug concentration quickly. However, work remains to understand how to determine what target exposure is needed for an individual patient, and whether the combination of POC assays and dashboards presents a safe approach with substantial outcome benefit over the current standard of care.
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http://dx.doi.org/10.1208/s12248-018-0257-yDOI Listing
September 2018

Evaluating and Reporting the Immunogenicity Impacts for Biological Products--a Clinical Pharmacology Perspective.

AAPS J 2016 Mar 31;18(2):395-403. Epub 2015 Dec 31.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA's clinical pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (n = 108) reported the incidence of immunogenicity and 49% (n = 59) reported immunogenicity impact on efficacy. However, only 26% (n = 31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before vs. after ADA formation) is a useful alternative to between-subject (ADA+ vs. ADA-) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time.
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http://dx.doi.org/10.1208/s12248-015-9857-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779104PMC
March 2016

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction.

Mol Genet Metab 2016 Feb 10;117(2):66-83. Epub 2015 Nov 10.

OTS, CDER, FDA, Silver Spring, MD 20993-0002, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ymgme.2015.11.001DOI Listing
February 2016

Population pharmacokinetic-pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure.

J Clin Pharmacol 2015 Nov 14;55(11):1236-47. Epub 2015 Jul 14.

Clinical Pharmacology, M&S, Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA.

Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration. Oral absorption half-life was 0.62 hours, and absolute bioavailability was estimated as 90%; elimination half-life was approximately 18.5 hours. Variability in pharmacokinetic parameters was not explained by patient baseline characteristics. Omecamtiv mecarbil plasma concentration was directly correlated with increases in SET and LVOTSV between healthy volunteers and patients with HF. The maximum increase from baseline in SET (delta SET) estimated by an Emax model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6 mL per 100 ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5 mg dosed every 8, 12, and 24 hours) showed that a pharmacodynamic effect (delta SET ≥20 milliseconds) could be maintained in the absence of excessive omecamtiv mecarbil plasma concentrations.
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http://dx.doi.org/10.1002/jcph.538DOI Listing
November 2015

Biological products for the treatment of psoriasis: therapeutic targets, pharmacodynamics and disease-drug-drug interaction implications.

AAPS J 2014 Sep 4;16(5):938-47. Epub 2014 Jul 4.

Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.
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http://dx.doi.org/10.1208/s12248-014-9637-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147058PMC
September 2014

Pediatric news.

J Pediatr Pharmacol Ther 2014 Jan;19(1):64-5

Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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http://dx.doi.org/10.5863/1551-6776-19.1.64DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998972PMC
January 2014

Bioanalytical method validation: concepts, expectations and challenges in small molecule and macromolecule--a report of PITTCON 2013 symposium.

AAPS J 2014 May 4;16(3):586-91. Epub 2014 Apr 4.

Office of Clinical Pharmacology, Center for Drug Evaluations and Research, United States Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

The concepts, importance, and implications of bioanalytical method validation has been discussed and debated for a long time. The recent high profile issues related to bioanalytical method validation at both Cetero Houston and former MDS Canada has brought this topic back in the limelight. Hence, a symposium on bioanalytical method validation with the aim of revisiting the building blocks as well as discussing the challenges and implications on the bioanalysis of both small molecules and macromolecules was featured at the PITTCON 2013 Conference and Expo. This symposium was cosponsored by the American Chemical Society (ACS)-Division of Analytical Chemistry and Analysis and Pharmaceutical Quality (APQ) Section of the American Association of Pharmaceutical Scientists (AAPS) and featured leading speakers from the Food & Drug Administration (FDA), academia, and industry. In this symposium, the speakers shared several unique examples, and this session also provided a platform to discuss the need for continuous vigilance of the bioanalytical methods during drug discovery and development. The purpose of this article is to provide a concise report on the materials that were presented.
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http://dx.doi.org/10.1208/s12248-014-9597-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012041PMC
May 2014

Immunogenicity and PK/PD evaluation in biotherapeutic drug development: scientific considerations for bioanalytical methods and data analysis.

Bioanalysis 2014 Jan;6(1):79-87

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation & Research, US FDA, MD 20993, USA.

With the advent of novel technologies, considerable advances have been made in the evaluation of the relationship between PK and PD. Ligand-binding assays have been the primary assay format supporting PK and immunogenicity assessments. Critical and in-depth characterizations of the ligand-binding assay of interest can provide valuable understanding of the limitations, for interpreting PK/PD and immunogenicity results. This review illustrates key challenges with regard to understanding the relationship between anti-drug antibody and PK/PD, including confounding factors associated with the development and validation of ligand-binding assays, mechanisms by which anti-drug antibody impacts PK/PD, factors to consider during data analyses and interpretation, and a perspective on integrating immunogenicity data into the well-established quantitative modeling approach. Through recognizing these challenges, we propose some opportunities for improvements in the development and validation of fit-for-purpose bioanalytical methods.
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http://dx.doi.org/10.4155/bio.13.302DOI Listing
January 2014

Pharmacokinetic and pharmacodynamic modeling of romiplostim in animals.

Pharm Res 2013 Mar 19;30(3):655-69. Epub 2012 Dec 19.

Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.

Purpose: Romiplostim is a novel thrombopoiesis-stimulating peptibody that targets the thrombopoietin c-Mpl receptor, resulting in increased platelet production. The pharmacodynamic-mediated disposition (PDMDD) and its stimulatory effect on platelet production in Sprague-Dawley rats, rhesus monkeys, and cynomolgus monkeys following IV bolus and SC administration at various dose levels were determined.

Methods: The pharmacokinetic (PK) profile was described by a PDMDD model that accounts for romiplostim binding to the c-Mpl receptor. The PD model contained a series of aging compartments for precursor cells in bone marrow and platelets. The stimulatory function was described by an on-and-off function operating on the fractional receptor occupancy (RO). The threshold effect, RO(thr), and K(D) parameters were determinants of drug potency, whereas S(max) reflected drug efficacy.

Results: The model implicated that receptor-mediated clearance was negligible. RO(thr) estimated occupancies were 0.288, 0.385, 0.771 for rats, rhesus, and cynomolgus monkeys, respectively. The analogous estimated values of K(D) were 4.05, 2320, and 429 ng/mL, implying that romiplostim was much more potent in rats, which was confirmed by a dose-response (ratio of peak platelet count to baseline) relationship.

Conclusions: The model adequately described romiplostim serum concentrations and platelet counts in rats, rhesus monkeys, and cynomolgus monkeys, and quantified linear clearance, PDMDD, and potency of romiplostim.
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http://dx.doi.org/10.1007/s11095-012-0894-2DOI Listing
March 2013

Romiplostim dose-response in patients with myelodysplastic syndromes.

Br J Clin Pharmacol 2013 Jun;75(6):1445-54

Amgen SA, Barcelona, Spain.

Aim: To characterize the romiplostim dose-response in subjects with low or intermediate-1 risk myelodysplastic syndromes (MDS) receiving subcutaneous romiplostim.

Methods: Data from 44 MDS subjects receiving subcutaneous romiplostim (dose range 300-1500 μg week(-1) ) were used to develop a pharmacodynamic model consisting of a romiplostim-sensitive progenitor cell compartment linked to the peripheral blood compartment through four transit compartments representing the maturation in the bone marrow from megakaryocytes to platelets. A kinetics of drug effect model was used to quantify the stimulatory effect of romiplostim on the proliferation of sensitive progenitor cells and pharmacodynamics-mediated disposition was modelled by assuming the kinetics of drug effect constant (kDE ) to be proportional to the change in platelet count relative to baseline.

Results: The estimated values (between subject variability) for baseline platelet count, mean transit time, and kDE were 24 × 10(9) l(-1) (47%), 9.6 days (44%) and 0.28 days(-1) , respectively. MDS subjects had a shorter platelet lifespan (42 h) than healthy subjects (257 h). Romiplostim effect was described for responders (78%) and non-responders (22%). The average weekly stimulatory effect of romiplostim on the production rate of sensitive progenitor cells at baseline was 269% per 100 μg week(-1) for responders. Body weight, age, gender and race were not statistically related to romiplostim pharmacodynamic parameters. Visual predictive checks confirmed the model adequacy.

Conclusion: The time course of platelet counts in MDS subjects receiving subcutaneous administration of escalating doses of romiplostim was characterized and showed a linear dose-response for romiplostim responders to increase the platelet counts.
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http://dx.doi.org/10.1111/bcp.12041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690103PMC
June 2013

A survey of applications of biological products for drug interference of immunogenicity assays.

Pharm Res 2012 Dec 18;29(12):3384-92. Epub 2012 Aug 18.

Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA.

Purpose: Biological drugs in circulation can interfere with anti-drug antibody (ADA) assays and cause false ADA negatives. We surveyed the applications of biological products approved by FDA during 2005-2011 for prevalence of drug interferences and proposed approaches to address this issue scientifically.

Methods: The immunogenicity assay drug tolerance, steady-state drug concentrations, and immunogenicity rates were reviewed for 26 BLA/NDA and 2 sBLA.

Results: Many FDA approved biologics had higher steady-state drug concentrations than the drug tolerance of ADA assays, by 1.2- to 800-fold. Reported immunogenicity rates may be negatively impacted. Some sponsors triaged immunogenicity samples according to the drug tolerance, leaving some samples un-assayed or reporting them as inconclusive ADA; but these samples were interpreted as ADA- for calculating immunogenicity rates.

Conclusions: Implementation of ADA assays that can tolerate therapeutic drug concentrations is imperative. Given drug interferences, we propose in this paper the following practices: (i) to measure drug concentrations in ADA samples, (ii) to explicitly list all ADA status, including inconclusive ADA and un-assayed samples, (iii) to calculate population immunogenicity rates based on only subjects with confirmed ADA+ and ADA-, and (iv) to make available ADA assay specifics relevant to the use of ADA data in disease management.
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http://dx.doi.org/10.1007/s11095-012-0833-2DOI Listing
December 2012

The Discovery of VX-745: A Novel and Selective p38α Kinase Inhibitor.

ACS Med Chem Lett 2011 Oct 28;2(10):758-63. Epub 2011 Jul 28.

Vertex Pharmaceuticals , 130 Waverly Street, Cambridge, Massachusetts 02139-4242, United States.

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme-ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b]pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation.
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http://dx.doi.org/10.1021/ml2001455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018046PMC
October 2011

A randomized, double-blind study of romiplostim to determine its safety and efficacy in children with immune thrombocytopenia.

Blood 2011 Jul 18;118(1):28-36. Epub 2011 Apr 18.

Department of Pediatrics, Division of Hematology, Weill Medical College of Cornell University, New York, NY, USA.

Romiplostim, a thrombopoietin-mimetic peptibody, increases and maintains platelet counts in adults with immune thrombocytopenia (ITP). In this first study of a thrombopoietic agent in children, patients with ITP of ≥ 6 months' duration were stratified by age 1:2:2 (12 months-< 3 years; 3-< 12 years; 12-< 18 years). Children received subcutaneous injections of romiplostim (n = 17) or placebo (n = 5) weekly for 12 weeks, with dose adjustments to maintain platelet counts between 50 × 10(9)/L and 250 × 10(9)/L. A platelet count ≥ 50 × 10(9)/L for 2 consecutive weeks was achieved by 15/17 (88%) patients in the romiplostim group and no patients in the placebo group (P = .0008). Platelet counts ≥ 50 × 10(9)/L were maintained for a median of 7 (range, 0-11) weeks in romiplostim patients and 0 (0-0) weeks in placebo patients (P = .0019). The median weekly dose of romiplostim at 12 weeks was 5 μg/kg. Fourteen responders received romiplostim for 4 additional weeks for assessment of pharmacokinetics. No patients discontinued the study. There were no treatment-related, serious adverse events. The most commonly reported adverse events in children, as in adults, were headache and epistaxis. In this short-term study, romiplostim increased platelet counts in 88% of children with ITP and was well-tolerated and apparently safe. The trial was registered with http://www.clinicaltrials.gov as NCT00515203.
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http://dx.doi.org/10.1182/blood-2010-10-313908DOI Listing
July 2011

Investigation of the pharmacokinetics of romiplostim in rodents with a focus on the clearance mechanism.

Pharm Res 2011 Aug 8;28(8):1931-8. Epub 2011 Apr 8.

Pharmacokinetics and Drug Metabolism Department, Amgen Inc., One Amgen Center Drive, 28-3-B, Thousand Oaks, California 91320, USA.

Purpose: Romiplostim, a treatment for adults with immune thrombocytopenia (ITP), is a novel thrombopoietin mimetic agent with a similar mechanism of action as thrombopoietin with no sequence homology. Structurally, it is a peptibody containing thrombopoietin mimetic peptides and the Fc portion of human IgG(1). We investigated romiplostim pharmacokinetics in rodents with a focus on the clearance mechanism.

Methods: Studies with appropriate controls were conducted in four models: FcRn knockout mice, thrombocytopenic mice, splenectomized rats, and bilateral nephrectomized rats. Catabolic breakdown of romiplostim was investigated in normal rats. The primary analytical method determines the intact/active romiplostim concentration, and the secondary method determines the sum of romiplostim and its catabolic degradants.

Results: FcRn interaction results in prolonged exposure. Platelets are involved in the target-mediated elimination, a saturable process and more prominent at low dose. Splenectomy does not affect the romiplostim pharmacokinetics in rats, an observation not unexpected. Nephrectomy in rats results in a greater increase of romiplostim exposure at a higher romiplostim dose, a nonlinearity likely due to saturation of competing pathway. Catabolism plays a major role in romiplostim elimination.

Conclusion: Romiplostim clearance involves multiple mechanisms, including a nonlinear pathway. Consequently, the relative contribution of different mechanisms appears to be dose dependent.
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http://dx.doi.org/10.1007/s11095-011-0420-yDOI Listing
August 2011

Bioanalytical considerations in the comparability assessment of biotherapeutics.

Bioanalysis 2011 Mar;3(6):613-22

PKDM Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

Comparison of biotherapeutic products before and after manufacturing changes is required to show that the products are highly similar. Besides in vitro assessment on the critical quality attributes and potency, biocomparability studies are sometimes required to demonstrate similarities in pharmacokinetic and pharmacodynamic characteristics. The complex and diverse nature of biotherapeutics requires multifaceted considerations in the biocomparability study design, bioanalytical measurements of drug concentrations and/or pharmacodynamic responses, immunogenicity analysis, data interpretation and decision making. A major perspective is to understand the structure and biological functions of the biotherapeutics in relation to the indication. Issues of a common standard and the importance of the use of ligand-binding assays that are sensitive to structural changes are discussed. It would not be possible to use the same process and one-size-fit-all criteria for biocomparability studies of all biologics. Previous examples from industry and our experience of the bioanalytical considerations for fit-for-purpose pharmacokinetic support and immunogenicity assessments are presented.
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http://dx.doi.org/10.4155/bio.11.25DOI Listing
March 2011