... Striving for an integrated drug-development process for neurodegeneration: the coalition agai... more ... Striving for an integrated drug-development process for neurodegeneration: the coalition against major diseases. Klaus Romero??? ??? 1 , Brian Corrigan??? 2 , Jon Neville??? 1 , Steve Kopko??? 3 & Marc Cantillon??? 1 ??? Author for correspondence. Sections: ... Steve Kopko. Marc Cantillon. ...
Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifyin... more Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contr...
The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/ph... more The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/pharmacodynamics (PK/PD) experiments, and hence the design of optimal doses and dose schedules for the treatment of tuberculosis. To determine if this model is useful for deriving PK/PD data relevant to clinical outcomes, we compared its quantitative output to that from clinical trials. We performed a PubMed search to identify clinical studies performed with antituberculosis therapy in which PK/PD data and/or parameters were documented or a dose-scheduling study design was employed. The search period was from January 1943 to December 2012. All clinical studies were published prior to HFS-TB experiments. Bias minimization was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical publications were scored for quality of evidence, with 1 as the highest score (randomized controlled trials or meta-analyses of such studies), and 4 as the lowest score. We identified 17 studies that examined the same parameters as in 8 HFS-TB studies. Fifteen of 17 studies had a quality-of-evidence score of 1. The sterilizing and bactericidal effect rates for isoniazid, rifampin, pyrazinamide, and ethambutol were the same in the HFS-TB as in patients. Time to emergence of resistance for monotherapy was the same as in patients. The PK/PD indices associated with efficacy were the same in HFS-TB as in patients for all drugs examined. The HFS-TB model is highly accurate at identifying optimal drug exposures, doses, and dosing schedules for use in the clinic.
The in vitro hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo exper... more The in vitro hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo experiments, was introduced more than a decade ago. Since then, it has been used to perform a large number of tuberculosis pharmacokinetics/pharmacodynamics (PK/PD) studies that have not been subjected to systematic analysis. We performed a literature search to identify all HFS-TB experiments published between 1 January 2000 and 31 December 2012. There was no exclusion of articles by language. Bias minimization was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Steps for reporting systematic reviews were followed. There were 22 HFS-TB studies published, of which 12 were combination therapy studies and 10 were monotherapy studies. There were 4 stand-alone Monte Carlo experiments that utilized quantitative output from the HFS-TB. All experiments reported drug pharmacokinetics, which recapitulated those encountered in humans. HFS-TB studies included log-phase growth studies under ambient air, semidormant bacteria at pH 5.8, and nonreplicating persisters at low oxygen tension of ≤ 10 parts per billion. The studies identified antibiotic exposures associated with optimal kill of Mycobacterium tuberculosis and suppression of acquired drug resistance (ADR) and informed predictions about optimal clinical doses, expected performance of standard doses and regimens in patients, and expected rates of ADR, as well as a proposal of new susceptibility breakpoints. The HFS-TB model offers the ability to perform PK/PD studies including humanlike drug exposures, to identify bactericidal and sterilizing effect rates, and to identify exposures associated with suppression of drug resistance. Because of the ability to perform repetitive sampling from the same unit over time, the HFS-TB vastly improves statistical power and facilitates the execution of time-to-event analyses and repeated event analyses, as well as dynamic system pharmacology mathematical models.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regime... more The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in anima...
Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug develo... more Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug development over several decades. The role of the DDTs used for evaluating the efficacy of antituberculosis drug combinations and the gaps in the evidence base for which new tools or approaches are needed are as yet undefined. We performed a landscape analysis based on a comprehensive literature review to create evidence based guidelines. There are 3 important questions that a DDT should answer with regard to antituberculosis drugs: What combination(s) of drugs will be most effective? What dose(s) and schedule(s) of each drug should be administered? and What duration(s) of treatment will be efficacious? Four DDTs were identified as having a track record to answer these questions: in vitro susceptibility tests, the hollow fiber system model of tuberculosis, mice, and guinea pigs. No single nonclinical in vitro or animal model recapitulates all aspects of human tuberculosis. Therefore, a combination of models is recommended for drug development. Gaps identified include the need for standardization of nonclinical model experiments, evaluation of animal models with pathology more similar to that in humans, and identification of experimental quantitative output in the DDTs that correlates with sterilizing effect in humans. There is a need for formal quantitative analyses of how well DDTs forecast clinical outcomes.
Failures in trials for Alzheimer's Disease (AD) may be attributable to inadequate dosing, pop... more Failures in trials for Alzheimer's Disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's Disease[1]. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the FDA and EMA. This article is protected by copyright. All rights reserved.
The placebo response and the underlying disease progression is difficult to differentiate in long... more The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer's disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug...
Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific... more Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific information at the point of care, particularly when treating patients with complex cardiovascular conditions. The formidable task for the prescriber is to synthesize information about all therapeutic options and match the best treatment with the characteristics of the individual patient. Computerized decision support systems have been developed with the goal of integrating such information and presenting the acceptable therapeutic options on the basis of their effectiveness, often with limited consideration of their safety for a specific patient. Assessing the safety of therapies relative to each patient is difficult, and sometimes impossible, because the evidence required to make such an assessment is either imperfect or does not exist. In addition, many of the alerts sent to prescribers by decision-support systems are not perceived as credible, and 'alert fatigue' causes warni...
Interactions of warfarin with other drugs or substances can pose a serious problem. We assessed t... more Interactions of warfarin with other drugs or substances can pose a serious problem. We assessed three drug information compendia-Clinical Pharmacology, ePocrates, and Micromedex-and the warfarin sodium (Coumadin) product label (August 2007) approved by the US Food and Drug Administration for listings of interactions between warfarin and drugs, biologics, foods, and dietary supplements. The drug information compendia and warfarin label differed greatly as to the total number of substances that interact with warfarin. Of a total of 648 entries from the four sources, only 50 were common to all the sources. The types of substances listed as interacting with warfarin were entire classes of drugs, individual drugs, and combinations; biologics; dietary supplements; foods; alcohol; and tobacco. These sources were then examined for classification by severity of interaction and the underlying evidence base. This study provides evidence that there is little concordance among commonly used drug...
As of 2012, approximately 4.3 million Americans experience some form of cardiac arrhythmia (CA). ... more As of 2012, approximately 4.3 million Americans experience some form of cardiac arrhythmia (CA). Assessment of economic burden and healthcare resource use on the overall CA population is limited. To assess healthcare expenditure and disparities in healthcare resource use in patients with all forms of CA in the US. Data from the Medical Expenditure Panel Survey were analyzed between 2004 and 2009. Patients aged≥18 years with any form of CA (identified via International Classification of Disorders Ninth Revision, Clinical Modification [ICD-9-CM] codes) were included. Primary independent variables included age, gender, race/ethnicity, and pharmacotherapy use. Outcomes of interest included total annual healthcare and prescription expenditures (inflation adjusted to 2011), use of anti-arrhythmic agents associated with CA, and inpatient, outpatient, or emergency room visits. Generalized linear models were used to assess the disparities across patient subgroups related to the outcomes. Annually, 5,750,440 individuals experienced CA in the US. Total direct annual healthcare cost of CA summed up to $US67.4 billion. Non-Hispanic whites and older adult patients had higher expenditures and use of healthcare resources (p<0.05). Female patients had significantly higher prescribed medication expenditures and a lower proportion of inpatient and emergency room visits related to arrhythmia (p<0.05). Patients taking anti-arrhythmic agents had significantly higher expenditure and a lower proportion of emergency department visits related to arrhythmia (p<0.05). CA represents a substantial economic burden in the US, especially for the older adult population. Patients other than non-Hispanic whites may not have adequate access to healthcare treatment for arrhythmia.
Journal of Pharmacokinetics and Pharmacodynamics, 2014
Medical-product development has become increasingly challenging and resource-intensive. In 2004, ... more Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical-product development (MIMPD), the Critical Path Institute (C-Path) [www.c-path.org], FDA, and International Society of Pharmacometrics [www.go-isop.org] co-sponsored a workshop in Washington, D.C. on September 26, 2013, to examine integrated approaches to developing and applying model- MIMPD. The workshop brought together an international group of scientists from industry, academia, FDA, and the European Medicines Agency to discuss MIMPD strategies and their applications. A commentary on the proceedings of that workshop is presented here.
Given a history of atrocities and violations of ethical principles, several documents and regulat... more Given a history of atrocities and violations of ethical principles, several documents and regulations have been issued by a wide variety of organizations. They aim at ensuring that health care and clinical research adhere to defined ethical principles. A fundamental component was devised to ensure that the individual has been provided the necessary information to make an informed decision regarding health care or participation in clinical research. This article summarizes the history and regulations for informed consent and discusses suggested components for adequate consent forms for daily clinical practice in surgery as well as clinical research.
Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA)... more Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA). Data from the Medical Panel Expenditure Survey were analyzed from 2004 to 2009. Patients aged ≥18 with any form of CA (identified via ICD-9-CM codes) were included. Primary outcomes included the physical and mental component scores (PCS and MCS) of the Short-Form 12 version 2 (SF-12) and EuroQoL-5D (EQ-5D) utility scores (US version). Patient demographics included insurance status, urban status, geographical region, federal poverty level, education, comorbidities, and disease-related risk factors of CA. Approximately 5,750,440 individuals had CA. Non-Hispanic Whites had the highest SF-12 MCS (mean 50.9; p < 0.001 across racial groups) and utility scores (mean 0.76; p < 0.001 across racial groups). Patients with both private and public insurance had significantly higher PCS (p = 0.001) and MCS (p < 0.001) in comparison with patients only covered by public insurance. Patients on antiarrhythmic agents had higher SF-12 MCS (51.4 vs. 48.4; p < 0.001) compared to individuals not on antiarrhythmic agents. Significantly lower QOL existed in specific subpopulations (e.g., patients with only public health insurance, racial/ethnic minorities, and those not exposed to antiarrhythmic agents) within the CA population.
... Striving for an integrated drug-development process for neurodegeneration: the coalition agai... more ... Striving for an integrated drug-development process for neurodegeneration: the coalition against major diseases. Klaus Romero??? ??? 1 , Brian Corrigan??? 2 , Jon Neville??? 1 , Steve Kopko??? 3 & Marc Cantillon??? 1 ??? Author for correspondence. Sections: ... Steve Kopko. Marc Cantillon. ...
Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifyin... more Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contr...
The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/ph... more The hollow fiber system model of tuberculosis (HFS-TB) is designed to perform pharmacokinetics/pharmacodynamics (PK/PD) experiments, and hence the design of optimal doses and dose schedules for the treatment of tuberculosis. To determine if this model is useful for deriving PK/PD data relevant to clinical outcomes, we compared its quantitative output to that from clinical trials. We performed a PubMed search to identify clinical studies performed with antituberculosis therapy in which PK/PD data and/or parameters were documented or a dose-scheduling study design was employed. The search period was from January 1943 to December 2012. All clinical studies were published prior to HFS-TB experiments. Bias minimization was done according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical publications were scored for quality of evidence, with 1 as the highest score (randomized controlled trials or meta-analyses of such studies), and 4 as the lowest score. We identified 17 studies that examined the same parameters as in 8 HFS-TB studies. Fifteen of 17 studies had a quality-of-evidence score of 1. The sterilizing and bactericidal effect rates for isoniazid, rifampin, pyrazinamide, and ethambutol were the same in the HFS-TB as in patients. Time to emergence of resistance for monotherapy was the same as in patients. The PK/PD indices associated with efficacy were the same in HFS-TB as in patients for all drugs examined. The HFS-TB model is highly accurate at identifying optimal drug exposures, doses, and dosing schedules for use in the clinic.
The in vitro hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo exper... more The in vitro hollow fiber system model of tuberculosis (HFS-TB), in tandem with Monte Carlo experiments, was introduced more than a decade ago. Since then, it has been used to perform a large number of tuberculosis pharmacokinetics/pharmacodynamics (PK/PD) studies that have not been subjected to systematic analysis. We performed a literature search to identify all HFS-TB experiments published between 1 January 2000 and 31 December 2012. There was no exclusion of articles by language. Bias minimization was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Steps for reporting systematic reviews were followed. There were 22 HFS-TB studies published, of which 12 were combination therapy studies and 10 were monotherapy studies. There were 4 stand-alone Monte Carlo experiments that utilized quantitative output from the HFS-TB. All experiments reported drug pharmacokinetics, which recapitulated those encountered in humans. HFS-TB studies included log-phase growth studies under ambient air, semidormant bacteria at pH 5.8, and nonreplicating persisters at low oxygen tension of ≤ 10 parts per billion. The studies identified antibiotic exposures associated with optimal kill of Mycobacterium tuberculosis and suppression of acquired drug resistance (ADR) and informed predictions about optimal clinical doses, expected performance of standard doses and regimens in patients, and expected rates of ADR, as well as a proposal of new susceptibility breakpoints. The HFS-TB model offers the ability to perform PK/PD studies including humanlike drug exposures, to identify bactericidal and sterilizing effect rates, and to identify exposures associated with suppression of drug resistance. Because of the ability to perform repetitive sampling from the same unit over time, the HFS-TB vastly improves statistical power and facilitates the execution of time-to-event analyses and repeated event analyses, as well as dynamic system pharmacology mathematical models.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2015
The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regime... more The first nonclinical drug development tool (DDT) advanced by the Critical Path to TB Drug Regimens (CPTR) Initiative through a regulatory review process has been endorsed by leading global regulatory authorities. DDTs with demonstrated predictive accuracy for clinical and microbiological outcomes are needed to support decision making. Regulatory endorsement of these DDTs is critical for drug developers, as it promotes confidence in their use in Investigational New Drug and New Drug Application filings. The in vitro hollow fiber system model of tuberculosis (HFS-TB) is able to recapitulate concentration-time profiles (exposure) observed in patients for single drugs and combinations, by evaluating exposure measures for the ability to kill tuberculosis in different physiologic conditions. Monte Carlo simulations make this quantitative output useful to inform susceptibility breakpoints, dosage, and optimal combination regimens in patients, and to design nonclinical experiments in anima...
Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug develo... more Several nonclinical drug-development tools (DDTs) have been used for antituberculosis drug development over several decades. The role of the DDTs used for evaluating the efficacy of antituberculosis drug combinations and the gaps in the evidence base for which new tools or approaches are needed are as yet undefined. We performed a landscape analysis based on a comprehensive literature review to create evidence based guidelines. There are 3 important questions that a DDT should answer with regard to antituberculosis drugs: What combination(s) of drugs will be most effective? What dose(s) and schedule(s) of each drug should be administered? and What duration(s) of treatment will be efficacious? Four DDTs were identified as having a track record to answer these questions: in vitro susceptibility tests, the hollow fiber system model of tuberculosis, mice, and guinea pigs. No single nonclinical in vitro or animal model recapitulates all aspects of human tuberculosis. Therefore, a combination of models is recommended for drug development. Gaps identified include the need for standardization of nonclinical model experiments, evaluation of animal models with pathology more similar to that in humans, and identification of experimental quantitative output in the DDTs that correlates with sterilizing effect in humans. There is a need for formal quantitative analyses of how well DDTs forecast clinical outcomes.
Failures in trials for Alzheimer's Disease (AD) may be attributable to inadequate dosing, pop... more Failures in trials for Alzheimer's Disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's Disease[1]. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the FDA and EMA. This article is protected by copyright. All rights reserved.
The placebo response and the underlying disease progression is difficult to differentiate in long... more The placebo response and the underlying disease progression is difficult to differentiate in longitudinal Alzheimer's disease (AD) studies, yet it is crucial to understand for designing clinical trials and interpreting results. The placebo response in ADAS-cog11 from various studies was evaluated against model predictions derived from historical placebo data to demonstrate potential interpretation of study results using a prior understanding of expected disease progression. The placebo response component from a previously published disease progression model was used to estimate the longitudinal placebo response, and the disease progression in the placebo group in various case studies were evaluated. In addition, placebo data from the Coalition Against Major Diseases (CAMD) database in mild to moderate AD patients is described. The case studies demonstrated potential different results in disease progression in a placebo group, and the impact on understanding the magnitude of drug...
Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific... more Optimal therapeutic decision-making requires integration of patient-specific and therapy-specific information at the point of care, particularly when treating patients with complex cardiovascular conditions. The formidable task for the prescriber is to synthesize information about all therapeutic options and match the best treatment with the characteristics of the individual patient. Computerized decision support systems have been developed with the goal of integrating such information and presenting the acceptable therapeutic options on the basis of their effectiveness, often with limited consideration of their safety for a specific patient. Assessing the safety of therapies relative to each patient is difficult, and sometimes impossible, because the evidence required to make such an assessment is either imperfect or does not exist. In addition, many of the alerts sent to prescribers by decision-support systems are not perceived as credible, and 'alert fatigue' causes warni...
Interactions of warfarin with other drugs or substances can pose a serious problem. We assessed t... more Interactions of warfarin with other drugs or substances can pose a serious problem. We assessed three drug information compendia-Clinical Pharmacology, ePocrates, and Micromedex-and the warfarin sodium (Coumadin) product label (August 2007) approved by the US Food and Drug Administration for listings of interactions between warfarin and drugs, biologics, foods, and dietary supplements. The drug information compendia and warfarin label differed greatly as to the total number of substances that interact with warfarin. Of a total of 648 entries from the four sources, only 50 were common to all the sources. The types of substances listed as interacting with warfarin were entire classes of drugs, individual drugs, and combinations; biologics; dietary supplements; foods; alcohol; and tobacco. These sources were then examined for classification by severity of interaction and the underlying evidence base. This study provides evidence that there is little concordance among commonly used drug...
As of 2012, approximately 4.3 million Americans experience some form of cardiac arrhythmia (CA). ... more As of 2012, approximately 4.3 million Americans experience some form of cardiac arrhythmia (CA). Assessment of economic burden and healthcare resource use on the overall CA population is limited. To assess healthcare expenditure and disparities in healthcare resource use in patients with all forms of CA in the US. Data from the Medical Expenditure Panel Survey were analyzed between 2004 and 2009. Patients aged≥18 years with any form of CA (identified via International Classification of Disorders Ninth Revision, Clinical Modification [ICD-9-CM] codes) were included. Primary independent variables included age, gender, race/ethnicity, and pharmacotherapy use. Outcomes of interest included total annual healthcare and prescription expenditures (inflation adjusted to 2011), use of anti-arrhythmic agents associated with CA, and inpatient, outpatient, or emergency room visits. Generalized linear models were used to assess the disparities across patient subgroups related to the outcomes. Annually, 5,750,440 individuals experienced CA in the US. Total direct annual healthcare cost of CA summed up to $US67.4 billion. Non-Hispanic whites and older adult patients had higher expenditures and use of healthcare resources (p<0.05). Female patients had significantly higher prescribed medication expenditures and a lower proportion of inpatient and emergency room visits related to arrhythmia (p<0.05). Patients taking anti-arrhythmic agents had significantly higher expenditure and a lower proportion of emergency department visits related to arrhythmia (p<0.05). CA represents a substantial economic burden in the US, especially for the older adult population. Patients other than non-Hispanic whites may not have adequate access to healthcare treatment for arrhythmia.
Journal of Pharmacokinetics and Pharmacodynamics, 2014
Medical-product development has become increasingly challenging and resource-intensive. In 2004, ... more Medical-product development has become increasingly challenging and resource-intensive. In 2004, the Food and Drug Administration (FDA) described critical challenges facing medical-product development by establishing the critical path initiative [1]. Priorities identified included the need for improved modeling and simulation tools, further emphasized in FDA's 2011 Strategic Plan for Regulatory Science [Appendix]. In an effort to support and advance model-informed medical-product development (MIMPD), the Critical Path Institute (C-Path) [www.c-path.org], FDA, and International Society of Pharmacometrics [www.go-isop.org] co-sponsored a workshop in Washington, D.C. on September 26, 2013, to examine integrated approaches to developing and applying model- MIMPD. The workshop brought together an international group of scientists from industry, academia, FDA, and the European Medicines Agency to discuss MIMPD strategies and their applications. A commentary on the proceedings of that workshop is presented here.
Given a history of atrocities and violations of ethical principles, several documents and regulat... more Given a history of atrocities and violations of ethical principles, several documents and regulations have been issued by a wide variety of organizations. They aim at ensuring that health care and clinical research adhere to defined ethical principles. A fundamental component was devised to ensure that the individual has been provided the necessary information to make an informed decision regarding health care or participation in clinical research. This article summarizes the history and regulations for informed consent and discusses suggested components for adequate consent forms for daily clinical practice in surgery as well as clinical research.
Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA)... more Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA). Data from the Medical Panel Expenditure Survey were analyzed from 2004 to 2009. Patients aged ≥18 with any form of CA (identified via ICD-9-CM codes) were included. Primary outcomes included the physical and mental component scores (PCS and MCS) of the Short-Form 12 version 2 (SF-12) and EuroQoL-5D (EQ-5D) utility scores (US version). Patient demographics included insurance status, urban status, geographical region, federal poverty level, education, comorbidities, and disease-related risk factors of CA. Approximately 5,750,440 individuals had CA. Non-Hispanic Whites had the highest SF-12 MCS (mean 50.9; p < 0.001 across racial groups) and utility scores (mean 0.76; p < 0.001 across racial groups). Patients with both private and public insurance had significantly higher PCS (p = 0.001) and MCS (p < 0.001) in comparison with patients only covered by public insurance. Patients on antiarrhythmic agents had higher SF-12 MCS (51.4 vs. 48.4; p < 0.001) compared to individuals not on antiarrhythmic agents. Significantly lower QOL existed in specific subpopulations (e.g., patients with only public health insurance, racial/ethnic minorities, and those not exposed to antiarrhythmic agents) within the CA population.
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Papers by Klaus Romero