Office Of Clinical Pharmacology Research Articles

A Modified Delphi Study to Establish Essential Clinical Pharmacology Competencies.

Competency-based education has been commonly used to enhance the healthcare workforce for some time. A translational discipline that is integral to drug development and impactful on healthcare and public health is clinical pharmacology. With such contribution, it is essential that the clinical pharmacology workforce is adequately equipped to address the demands of emerging trends of drug development. The primary objective of this study was to determine the most significant competencies needed for a clinical pharmacologist in the regulatory environment. A two round modified Delphi technique was administered to 29 clinical pharmacologists within the Office of Clinical Pharmacology (OCP) between November 2021-January 2022. A questionnaire consisting of core and technical competencies was administered electronically using SurveyMonkey ® to gain consensus about essential clinical pharmacology competencies. Participants used a Likert scale to rank importance of competencies from strongly agree (1), agree (2), neutral (3), disagree (4), strongly disagree (5). Participants also suggested topics to be included in the next round. Consensus was set at 60%. The competencies receiving the most consensus at 60% in round one and the new topics proceeded to the second round. In the second and final round, participants ranked the suggested competencies. Descriptive statistics and a McNemar change test were utilized to analyze data. Only data from the participants who completed both rounds was used in the study. In round one participants ranked all fifty-six core and technical competencies as essential with consensus of at least 60%. In round two, participants ranked sixty-two competencies as essential with consensus of at least 60%. A McNemar change test demonstrated stability of ranking between rounds. Essential core and technical competencies can build education programs to sustain the emerging clinical pharmacology workforce in the Office of Clinical Pharmacology. The Delphi technique is a suitable approach to determine essential competencies because it cultivates consensus and gains insight from experts in the forefront of drug development.

Addressing the Knowledge Gaps for Providing Optimal Drug Pharmacotherapy for the Obese.

The Journal of Clinical PharmacologyAccepted Articles Supplement Article Addressing the Knowledge Gaps for Providing Optimal Drug Pharmacotherapy for the Obese Gilbert J. Burckart Pharm.D., FCP, Corresponding Author Gilbert J. Burckart Pharm.D., FCP [email protected] orcid.org/0000-0003-2005-9301 Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD, USA Corresponding Author: Dr. Gilbert J. Burckart, Rm 3184, Bldg 51, 10903 New Hampshire Ave, Silver Spring, MD, USA. Email: [email protected]Search for more papers by this authorDavid J. Greenblatt M.D., FCP, David J. Greenblatt M.D., FCP Program in Pharmacology and Drug Development, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USASearch for more papers by this author Gilbert J. Burckart Pharm.D., FCP, Corresponding Author Gilbert J. Burckart Pharm.D., FCP [email protected] orcid.org/0000-0003-2005-9301 Office of Clinical Pharmacology, US Food and Drug Administration, Silver Spring, MD, USA Corresponding Author: Dr. Gilbert J. Burckart, Rm 3184, Bldg 51, 10903 New Hampshire Ave, Silver Spring, MD, USA. Email: [email protected]Search for more papers by this authorDavid J. Greenblatt M.D., FCP, David J. Greenblatt M.D., FCP Program in Pharmacology and Drug Development, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USASearch for more papers by this author First published: 02 May 2023 https://doi.org/10.1002/jcph.2264 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as https://doi.org/10.1002/jcph.2264 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

In Memoriam: Varsha Bhatt-Mehta, PharmD, MS, FCCP.

The Journal of Clinical PharmacologyAccepted Articles In Memoriam In Memoriam: Varsha Bhatt-Mehta, PharmD, MS, FCCP Gelareh Abulwerdi Ph.D. M.S, Corresponding Author Gelareh Abulwerdi Ph.D. M.S [email protected] Office of Clinical Pharmacology, U.S. FDA, Silver Spring, Maryland, USA Correspondence Gelareh Abulwerdi, Ph.D., M.S., Office of Clinical Pharmacology, U.S. FDA. Email: [email protected]Search for more papers by this authorGilbert J. Burckart Pharm.D, Gilbert J. Burckart Pharm.D orcid.org/0000-0003-2005-9301 Office of Clinical Pharmacology, U.S. FDA, Silver Spring, Maryland, USASearch for more papers by this authorMilap C. Nahata Pharm.D. M.S. FCCP FASHP FAPhA FPPA, Milap C. Nahata Pharm.D. M.S. FCCP FASHP FAPhA FPPA Colleges of Pharmacy and Medicine, Ohio State University, Columbus, Ohio, USASearch for more papers by this authorHanna Phan Pharm.D. FCCP FPPA, Hanna Phan Pharm.D. FCCP FPPA College of Pharmacy, University of Michigan, Ann Arbor, Maryland, USASearch for more papers by this author Gelareh Abulwerdi Ph.D. M.S, Corresponding Author Gelareh Abulwerdi Ph.D. M.S [email protected] Office of Clinical Pharmacology, U.S. FDA, Silver Spring, Maryland, USA Correspondence Gelareh Abulwerdi, Ph.D., M.S., Office of Clinical Pharmacology, U.S. FDA. Email: [email protected]Search for more papers by this authorGilbert J. Burckart Pharm.D, Gilbert J. Burckart Pharm.D orcid.org/0000-0003-2005-9301 Office of Clinical Pharmacology, U.S. FDA, Silver Spring, Maryland, USASearch for more papers by this authorMilap C. Nahata Pharm.D. M.S. FCCP FASHP FAPhA FPPA, Milap C. Nahata Pharm.D. M.S. FCCP FASHP FAPhA FPPA Colleges of Pharmacy and Medicine, Ohio State University, Columbus, Ohio, USASearch for more papers by this authorHanna Phan Pharm.D. FCCP FPPA, Hanna Phan Pharm.D. FCCP FPPA College of Pharmacy, University of Michigan, Ann Arbor, Maryland, USASearch for more papers by this author First published: 24 April 2023 https://doi.org/10.1002/jcph.2250 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as https://doi.org/10.1002/jcph.2250 AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Accepted ArticlesAccepted, unedited articles published online and citable. The final edited and typeset version of record will appear in the future. RelatedInformation

Relationship between beta‐amyloid (Ab) plaque reduction and clinical benefit: the rationale for aducanumab approval

AbstractBackgroundAducanumab was approved in 2021 by the US FDA under the accelerated approval pathway. However, the Office of Clinical Pharmacology at FDA recommended the regular approval based on three key findings.MethodExposure‐response analyses were conducted to quantify the relationship between aducanumab longitudinal exposure and responses (standardized uptake values ratios for beta amyloid and various clinical endpoints) in all clinical trials. To explain the difference between aducanumab and other compounds with negative results in the past, publicly available data were combined with the aducanumab data to demonstrate the relationship between amyloid reduction and clinical endpoint improvement across multiple compounds with similar mechanism of action. The probability to observe the overall positive findings in the aducanumab program was quantified under the assumption that aducanumab is ineffective.ResultsPositive exposure‐response (disease progression) relationship for multiple clinical endpoints from all clinical trials was identified. Positive exposure‐amyloid reduction relationship was established. Consistent amyloid reduction‐clinical endpoint improvement relationship across multiple compounds was observed. If aducanumab is assumed to be ineffective, it is extremely impossible to observe the overall positive findings in the aducanumab program. These results provided convincing evidence to support aducanumab’s effectiveness.ConclusionFDA made the right decision for millions of Alzheimer patients. The observed clinical benefit from aducanumab treatment is clinically meaningful.

Pediatric Ontogeny: Moving From Translational Science to Drug Development.

Pediatric Ontogeny: Moving From Translational Science to Drug Development.

Emerging Role of Organ-on-a-Chip Technologies in Quantitative Clinical Pharmacology Evaluation.

The recently enacted Prescription Drug User Fee Act (PDUFA) VI includes in its performance goals “enhancing regulatory science and expediting drug development.” The key elements in “enhancing regulatory decision tools to support drug development and review” include “advancing model‐informed drug development (MIDD).” This paper describes (i) the US Food and Drug Administration (FDA) Office of Clinical Pharmacology's continuing efforts in developing quantitative clinical pharmacology models (disease, drug, and clinical trial models) to advance MIDD, (ii) how emerging novel tools, such as organ‐on‐a‐chip technologies or microphysiological systems, can provide new insights into physiology and disease mechanisms, biomarker identification and evaluation, and elucidation of mechanisms of adverse drug reactions, and (iii) how the single organ or linked organ microphysiological systems can provide critical system parameters for improved physiologically‐based pharmacokinetic and pharmacodynamic evaluations. Continuous public‐private partnerships are critical to advance this field and in the application of these new technologies in drug development and regulatory review.

Physiologically Based Pharmacokinetic Modeling in Regulatory Science: An Update From the U.S. Food and Drug Administration’s Office of Clinical Pharmacology

This commentary provides an update on the status of physiologically based pharmacokinetic modeling and simulation at the U.S. Food and Drug Administration's Office of Clinical Pharmacology. Limitations and knowledge gaps in integration of physiologically based pharmacokinetic approach to inform regulatory decision making, as well as the importance of scientific engagement with drug developers who intend to use this approach, are highlighted.

In Memoriam: Darrell R. Abernethy 1949–2017

In Memoriam: Darrell R. Abernethy 1949–2017

In Memoriam: Darrell R. Abernethy, 1949–2017

In Memoriam: Darrell R. Abernethy, 1949–2017

Immunogenicity considerations for antibody-drug conjugates: a focus on neutralizing antibody assays.

Immunogenicity considerations for antibody-drug conjugates: a focus on neutralizing antibody assays.

The Utility of Modeling and Simulation in Drug Development and Regulatory Review

US Food and Drug Administration (FDA) has identified innovation in clinical evaluations as a major scientific priority area. This paper provides case studies and updates to describe the efforts by the FDA's Office of Clinical Pharmacology in its development and application of regulatory science, focusing on modeling and simulation. Key issues and challenges are identified that need to be addressed to promote the uptake of modeling and simulation approaches in drug regulation. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. 102:2912-2923, 2013.

Office of Clinical Pharmacology Science Day: A Forum to Stimulate Innovation in Clinical Pharmacology

The Office of Clinical Pharmacology (OCP) of the US Food and Drug Administration (FDA) has hosted an office-wide event called Science Day (SD) since 1999. SD 2012 included presentations on physiologically based pharmacokinetic models, exposure-response analyses, and other research projects. SD provides a forum for showcasing clinical pharmacology (CP) research within the OCP and provides an opportunity for professional development. This article discusses the evolution of Science Day and then focuses on SD 2012 as an example platform for promotion of regulatory research.

Regulatory Modeling and Simulation Moves Into the Next Gear in Europe

The increasing pace of investments across academia and industry in the areas of pharmacometrics and systems pharmacology has the potential to profoundly impact drug discovery and development efficiency. In addition, it is being recognized that model-based approaches have also increasingly become important in regulatory decision making.1,2,3 For example, an analysis of 198 new drug application and biological license application submissions, reviewed by the US Food and Drug Administration's Division of Pharmacometrics during the period 2000–2008, suggested an impact of the pharmacometrics analysis on drug approval and labeling decisions in ~65% of the cases. Although the potential for regulatory impact of modeling and simulation (M&S) appears to be shared by regulators across most international agencies, there are marked differences in the implementation of pharmacometric assessments during drug registration.1 For example, to date, the US Food and Drug Administration is the only regulatory agency that has a dedicated Pharmacometrics group, formed within the Office of Clinical Pharmacology in 2009,2 which not only reviews submissions but also conducts its own analyses. It now appears that regulatory M&S moves into the next gear in Europe as well, because in a recent press release, the European Medicines Agency (EMA) announced the creation of a new regulatory M&S working group being effective from the end of January 2013 (http://www.ema.europa.eu/ema/). This announcement builds on the output from a joint EMA and European Federation of Pharmaceutical Industries and Associations (EFPIA) workshop on M&S,4 held at the end of 2011, at which representatives from industry, academia, and regulatory agencies discussed the current and future role of M&S in the development and registration of medicinal products. Specifically, one of the actions from the workshop was that the “EMA will aim to increase the regulatory M&S competence in Europe by coordinating the expertise across Member States to provide a consistent approach in product-related and methodology-related discussions,”4 and the recent announcement demonstrates that the European regulators have started to deliver on this commitment. Consistent with the journal's mission to be a “publication platform for Pharmacometrics and Systems Pharmacology that will contribute to further growth of the disciplines and a broader application and better integration of the model-based approaches across the research and development spectrum,”5 the current issue of CPT: Pharmacometrics & Systems Pharmacology contains a full report of the plenary session4 and four breakout sessions6,7,8,9 of the EMA/EFPIA Workshop on M&S, coauthored by a range of discipline leaders from EMA, EFPIA, and European academic centers.

Don't Get Boxed In: Commentary on the Visual Inspection Practices to Assess Exposure-Response Relationships From Binary Clinical Variables

The Journal of Clinical PharmacologyVolume 52, Issue 12 p. 1912-1917 Don't Get Boxed In: Commentary on the Visual Inspection Practices to Assess Exposure-Response Relationships From Binary Clinical Variables Ms Shailly Mehrotra BPharm, Ms Shailly Mehrotra BPharm Ellicott City, MarylandSearch for more papers by this authorDr Jeffry Florian Jr PhD, Dr Jeffry Florian Jr PhD Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Jogarao Gobburu PhD, MBA, Corresponding Author Dr Jogarao Gobburu PhD, MBA Schools of Pharmacy and Medicine, University of Maryland, Baltimore, Maryland Address for correspondence: Jogarao Gobburu, 20 Penn Street HSF II, Baltimore, MD 21201; e-mail: [email protected].Search for more papers by this author Ms Shailly Mehrotra BPharm, Ms Shailly Mehrotra BPharm Ellicott City, MarylandSearch for more papers by this authorDr Jeffry Florian Jr PhD, Dr Jeffry Florian Jr PhD Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MarylandSearch for more papers by this authorDr Jogarao Gobburu PhD, MBA, Corresponding Author Dr Jogarao Gobburu PhD, MBA Schools of Pharmacy and Medicine, University of Maryland, Baltimore, Maryland Address for correspondence: Jogarao Gobburu, 20 Penn Street HSF II, Baltimore, MD 21201; e-mail: [email protected].Search for more papers by this author First published: 07 March 2013 https://doi.org/10.1177/0091270011429568Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume52, Issue12December 2012Pages 1912-1917 RelatedInformation

CYP2D6 Genotype Information to Guide Pimozide Treatment in Adult and Pediatric Patients

The occurrence of pimozide-induced arrhythmias is concentration dependent. Hence, it is important for prescribers to consider causes of increased pimozide exposure. This article summarizes the U.S. Food and Drug Administration's (FDA's) review of drug interaction and pharmacogenomic studies and discusses pharmacokinetic simulations we performed to develop new cytochrome P450 2D6 (CYP2D6) genotype-guided dosing recommendations for pimozide. Pharmacokinetic parameters by CYP2D6 genotype were derived from a published single-dose pharmacogenomic study of pimozide. We simulated what pimozide exposures would result from a multiple-dose scenario in different CYP2D6 genotype groups: extensive, intermediate, and poor metabolizers. The maximum dose for poor metabolizers was defined as the dose that would not exceed pimozide concentrations following 10 mg daily in extensive metabolizers and intermediate metabolizers (the current maximum dose in an unselected population). Dose-ranging analyses revealed that 4 mg daily in CYP2D6 poor metabolizers was the maximum dose that would not result in plasma concentrations in excess of those observed in extensive metabolizer and intermediate metabolizer patients receiving 10 mg daily. CYP2D6 genotyping is now consequently recommended in the pimozide product label before exceeding 4 mg of pimozide daily in adults or 0.05 mg/kg/d in children. Previously, dose adjustment was recommended every 3 days to achieve the desired clinical response for all patients. The label was modified to subsequently reflect that pimozide doses should not be increased earlier than 14 days in patients who are known CYP2D6 poor metabolizers. Given the risk of increased pimozide concentrations and longer time to steady state in CYP2D6 poor metabolizers, the FDA has revised the pimozide label to provide clinicians with clearer dosing, titration, and genotype testing recommendations. The new information is intended to enhance therapeutic individualization of pimozide in pediatric and adult patients.

Best Practice in the Use of Physiologically Based Pharmacokinetic Modeling and Simulation to Address Clinical Pharmacology Regulatory Questions

Physiologically based pharmacokinetic (PBPK) models are increasingly used by drug developers to evaluate the effect of patient factors on drug exposure. Between June 2008 and December 2011, the Office of Clinical Pharmacology at the US Food and Drug Administration (FDA) received 25 submissions containing PBPK analyses. This report summarizes the essential content of a PBPK analysis needed in a regulatory submission for the purpose of addressing clinical pharmacology questions.

Clinical Pharmacology Aspects of Sex-Related Drug Products

Clinical pharmacology plays an important role in drug development, including evaluation of a drug's pharmacokinetics (PK), interaction potential, exposure-response relationship, and pharmacogenomics (Table 1). Reviewers in the Office of Clinical Pharmacology at the US Food and Drug Administration (FDA) consider these issues to facilitate drug development and to ensure that drug products are safe and effective. This article highlights some of the important clinical pharmacology topics in the development of sex-related drug products.

Regulatory Focus: Bringing home the genome: the US FDA's role in realizing personalized medicine.

Regulatory Focus: Bringing home the genome: the US FDA's role in realizing personalized medicine.

Updated Announcement - AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years.

Updated Announcement—AAPS and FDA Agreement to Build Quantitative Alzheimer’s Disease Model

American Association of Pharmaceutical Scientists (AAPS) and Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration (FDA) have a Cooperative Research and Development Agreement (CRADA) to build a quantitative Alzheimer’s Disease Model. AAPS is seeking fellows who are interested in applying quantitative ‘learning’ approaches for solving drug development and regulatory challenges. Specifically, the incumbent will work with the FDA Pharmacometrics group (Silver Spring, MD) to develop and apply Alzheimer’s Disease Model to drug development. The fellowship is for 2 years.