Marisa Papaluca - Academia.edu (original) (raw)
Papers by Marisa Papaluca
Clinical pharmacology and therapeutics, Jan 4, 2015
High throughput molecular and functional profiling of patients is a key driver of precision medic... more High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice. This article is protected by copyright. All rights reserved.
Clinical Cases in Mineral and Bone Metabolism
The identification of new risk factors for specific diseases is an enduring theme in medical rese... more The identification of new risk factors for specific diseases is an enduring theme in medical research. Advances in molecular biology, genetics, and computational biology are accelerating the pace of this work. The research seeks to increase our understanding of the causes of diseases, but there is also hope that the recognition of new risk factors will lead to improved methods for identifying persons who are in the early stages of, or at high risk for, the diseases of concern. Research has shown, however, that a genomic biomarker must have a much stronger association with the disease outcome than we ordinarily see in etiologic research if it is to provide a basis for early diagnosis or prediction in individual patients. However, even if the literature contains ~150,000 reports of disease-associated molecular markers, there are still very few validated biomarkers of proven and robust clinical utility. At present there is no established, standardized means for validating the association between a marker (or set of markers) and clinical outcomes. The Regulatory Authorities have undertaken a number of initiatives in order to enhance the use of biomarkers in drug development, to promote a more informed drug development and maximise the benefit of innovative medicines to the patients.
Expert review of clinical pharmacology, Jan 23, 2015
Unmet medical needs are a priority for organizations such as the WHO and major public-private ini... more Unmet medical needs are a priority for organizations such as the WHO and major public-private initiatives, such as Innovative Medicines Initiative, were established to speed up the development of better and safer medicines for patients. To assist such projects, the EMA in its 'Road Map to 2015' considered the mapping of unmet medical needs as a priority. This study has identified medical conditions for which the EMA could not identify developments in the pharmaceutical pipelines, that is, 'white spots'. Our analysis was made using external data sources as well as mining data of the EMA. The main areas for white spots were oncology, infectious diseases and certain psychiatric conditions. According to our data and a review of literature, in a number of these white spots, diagnostic tools may even be missing. The identification of those conditions will benefit stakeholders, including regulators, research funding bodies and patients' organizations.
Expert opinion on pharmacotherapy, 2015
The quantity and quality of data for determining the dose and treatment schedule of medicinal pro... more The quantity and quality of data for determining the dose and treatment schedule of medicinal products is directly related to how safe and efficacious these medicines are and how successful they can be used to treat patients. This review provides an analysis of dose-related label modifications of recently approved drugs. It shows which areas could benefit from a better dose-exposure-response understanding, both during initial assessment and after marketing authorisation. This analysis highlights regulators' considerations in dosage evaluations and provides reflections for drug developers on how to ensure best possible dose selection in the interest of the patients. Using modelling and simulation, pharmacogenomics, population pharmacokinetics, physiologically based pharmacokinetic models and drug-drug interaction studies in conjunction with well-designed clinical trials will improve the understanding of the pharmacology of medicines, of the physiology of the disease and of the do...
International Journal of Immunopharmacology, 1980
Principles and Practice of Pharmaceutical Medicine, 2007
ABSTRACT
. In addition, an algorithm has been developed to aid appropriate clinical categorization of pati... more . In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.
Clinical Pharmacology & Therapeutics, 2013
Drug regulatory agencies are mandated to protect public health but also to promote it by ensuring... more Drug regulatory agencies are mandated to protect public health but also to promote it by ensuring patients' access to safe and effective drugs. Despite recent successful innovative drug approvals by the European Medicines Agency (EMA) 1,2 and the US Food and Drug Administration (FDA), 3 there has been a decline in innovative medicines that are developed and potentially able to enter the market in the next 5 years. 4 Investment in research and development decreased in the past 2 years for the first time in two decades. 5 Pharmaceutical research and development resulted in considerable successes in treating infectious diseases in the past century, and the general focus then shifted to oncology and recently to chronic debilitating diseases in an aging population. The success of biological drugs, dominated in the recent years by monoclonal antibodies, could be seen as a herald of how targeted therapies could further augment modern medicine, whereas more recent fields of pharmaceutical science such as gene therapy and personalized medicine have yet to meet expectations. Regulators are often perceived as focusing on risks and safety issues and how to avoid them. 7 A recent perspective criticized a safety-centered regulatory attitude as one resulting in a situation in which the "cheapest and safest medicine, as the cliché goes, is always the one never approved" 8 and advocated innovation in regulatory science. Certainly, safety of patients is of utmost importance, but we consider that the primary regulator's task is not "risk assessment" in isolation but "benefit-risk assessment, " linked with openness to progress in the field, so that benefits to patients of innovative drugs-drugs that move the field forward, e.g., by employing a new mechanism of action or by a new drug format-are neither overlooked nor compromised by regulatory requirements.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, 2011
The classification procedure, introduced by the European Regulation on advanced therapy medicinal... more The classification procedure, introduced by the European Regulation on advanced therapy medicinal products (ATMPs), has received a tremendous interest from companies, academic and public sponsors developing ATMPs. This procedure gives companies the opportunity to verify whether or not the product they are developing can be considered an ATMP and can therefore benefit from the new regulatory pathway introduced in the European Union for these types of medicinal products. This procedure is optional, free of charge and may take place at any stage of the development of an ATMP in advance of applying for a marketing authorisation. In case of doubt, briefing meetings organised by the European Medicines Agency Innovation Task Force may help preparing for an ATMP classification and are a starting point for the interactions between the Agency and the developers of ATMPs. This article reviews the advantages of the classification procedure for both the developers of ATMPs and the European regulatory network. Since the introduction of this procedure and up to 10 November 2010, the Committee for Advanced Therapies (CAT) has finalised 38 applications for classification.
Trials, 2014
Since the first methodological publications on adaptive study design approaches in the 1990s, the... more Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures. We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the ...
Public Health Genomics, 2010
Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently d... more Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently defined by the regulatory authorities at an international level as 'the investigation of variations of DNA and RNA characteristics as related to drug response' (PGx), and the study of 'the influence of variations in DNA sequence on drug efficacy and toxicity' (PGt). In recent years a number of studies have in fact produced growing evidence that, besides the effects of age, sex, diseases, and different drugs interactions, genetic factors play a role in the inter-individual variability of drugs response. The increasing genomic knowledge has also raised the profile and role of the so called 'genomic biomarkers' (GBs) in drug development, approval, and clinical use. The aims of this review are to (a) revisit the general understanding of the role of genomics and genetics in drug response, (b) provide an update on the definition and classification criteria of GBs as recently defined at a global level by regulatory agencies such as the European Medicines Agency and the Food and Drug Administration, and (c) illustrate with some examples current and potential applications of biomarkers in clinical practice and in drug development.
Nature Reviews Drug Discovery, 2014
Nature Reviews Drug Discovery, 2013
Pharmacogenetics, one of the cornerstones of personalized medicine, has the potential to change t... more Pharmacogenetics, one of the cornerstones of personalized medicine, has the potential to change the way in which health care is offered by stratifying patients into various pretreatment categories, such as likely responders, likely non-responders or likely to experience adverse drug reactions. In order to advance drug development and regulatory science, regulatory agencies globally have promulgated guidelines on pharmacogenetics for nearly a decade. The aim of this article is to provide an overview of new guidelines for the implementation of pharmacogenetics in drug development from a multiregional regulatory perspective - encompassing Europe, the United States and Japan - with an emphasis on clinical pharmacokinetics.
Nature Biotechnology, 2010
By streamlining the qualification process for biomarkers, coordinated protocols recently implemen... more By streamlining the qualification process for biomarkers, coordinated protocols recently implemented at the different regulatory agencies can facilitate progress and provide impetus to novel biomarker discovery and validation.
Nature Biotechnology, 2010
The first formal qualification of safety biomarkers for regulatory decision making marks a milest... more The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.
Nature Biotechnology, 2009
Journal of Biomedicine and Biotechnology, 2003
The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines E... more The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products.
Critical Reviews in Oncology/Hematology, 2002
Pharmacology and Toxicology, 2000
The safety of biotechnological products used for medicinal products is addressed by EU council di... more The safety of biotechnological products used for medicinal products is addressed by EU council directives. The general principles and the regulatory framework for the handling of new drug applications within this areas are described both with respect to benefit/risk evaluation, quality assessment, preclinical safety and efficacy testing.
Clinical pharmacology and therapeutics, Jan 4, 2015
High throughput molecular and functional profiling of patients is a key driver of precision medic... more High throughput molecular and functional profiling of patients is a key driver of precision medicine. DNA and RNA characterization has been enabled at unprecedented cost and scale through rapid, disruptive progress in sequencing technology, but challenges persist in data management and interpretation. We analyze the state-of-the-art of large-scale unbiased sequencing in drug discovery and development, including technology, application, ethical, regulatory, policy and commercial considerations, and discuss issues of LUS implementation in clinical and regulatory practice. This article is protected by copyright. All rights reserved.
Clinical Cases in Mineral and Bone Metabolism
The identification of new risk factors for specific diseases is an enduring theme in medical rese... more The identification of new risk factors for specific diseases is an enduring theme in medical research. Advances in molecular biology, genetics, and computational biology are accelerating the pace of this work. The research seeks to increase our understanding of the causes of diseases, but there is also hope that the recognition of new risk factors will lead to improved methods for identifying persons who are in the early stages of, or at high risk for, the diseases of concern. Research has shown, however, that a genomic biomarker must have a much stronger association with the disease outcome than we ordinarily see in etiologic research if it is to provide a basis for early diagnosis or prediction in individual patients. However, even if the literature contains ~150,000 reports of disease-associated molecular markers, there are still very few validated biomarkers of proven and robust clinical utility. At present there is no established, standardized means for validating the association between a marker (or set of markers) and clinical outcomes. The Regulatory Authorities have undertaken a number of initiatives in order to enhance the use of biomarkers in drug development, to promote a more informed drug development and maximise the benefit of innovative medicines to the patients.
Expert review of clinical pharmacology, Jan 23, 2015
Unmet medical needs are a priority for organizations such as the WHO and major public-private ini... more Unmet medical needs are a priority for organizations such as the WHO and major public-private initiatives, such as Innovative Medicines Initiative, were established to speed up the development of better and safer medicines for patients. To assist such projects, the EMA in its 'Road Map to 2015' considered the mapping of unmet medical needs as a priority. This study has identified medical conditions for which the EMA could not identify developments in the pharmaceutical pipelines, that is, 'white spots'. Our analysis was made using external data sources as well as mining data of the EMA. The main areas for white spots were oncology, infectious diseases and certain psychiatric conditions. According to our data and a review of literature, in a number of these white spots, diagnostic tools may even be missing. The identification of those conditions will benefit stakeholders, including regulators, research funding bodies and patients' organizations.
Expert opinion on pharmacotherapy, 2015
The quantity and quality of data for determining the dose and treatment schedule of medicinal pro... more The quantity and quality of data for determining the dose and treatment schedule of medicinal products is directly related to how safe and efficacious these medicines are and how successful they can be used to treat patients. This review provides an analysis of dose-related label modifications of recently approved drugs. It shows which areas could benefit from a better dose-exposure-response understanding, both during initial assessment and after marketing authorisation. This analysis highlights regulators' considerations in dosage evaluations and provides reflections for drug developers on how to ensure best possible dose selection in the interest of the patients. Using modelling and simulation, pharmacogenomics, population pharmacokinetics, physiologically based pharmacokinetic models and drug-drug interaction studies in conjunction with well-designed clinical trials will improve the understanding of the pharmacology of medicines, of the physiology of the disease and of the do...
International Journal of Immunopharmacology, 1980
Principles and Practice of Pharmaceutical Medicine, 2007
ABSTRACT
. In addition, an algorithm has been developed to aid appropriate clinical categorization of pati... more . In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.
Clinical Pharmacology & Therapeutics, 2013
Drug regulatory agencies are mandated to protect public health but also to promote it by ensuring... more Drug regulatory agencies are mandated to protect public health but also to promote it by ensuring patients' access to safe and effective drugs. Despite recent successful innovative drug approvals by the European Medicines Agency (EMA) 1,2 and the US Food and Drug Administration (FDA), 3 there has been a decline in innovative medicines that are developed and potentially able to enter the market in the next 5 years. 4 Investment in research and development decreased in the past 2 years for the first time in two decades. 5 Pharmaceutical research and development resulted in considerable successes in treating infectious diseases in the past century, and the general focus then shifted to oncology and recently to chronic debilitating diseases in an aging population. The success of biological drugs, dominated in the recent years by monoclonal antibodies, could be seen as a herald of how targeted therapies could further augment modern medicine, whereas more recent fields of pharmaceutical science such as gene therapy and personalized medicine have yet to meet expectations. Regulators are often perceived as focusing on risks and safety issues and how to avoid them. 7 A recent perspective criticized a safety-centered regulatory attitude as one resulting in a situation in which the "cheapest and safest medicine, as the cliché goes, is always the one never approved" 8 and advocated innovation in regulatory science. Certainly, safety of patients is of utmost importance, but we consider that the primary regulator's task is not "risk assessment" in isolation but "benefit-risk assessment, " linked with openness to progress in the field, so that benefits to patients of innovative drugs-drugs that move the field forward, e.g., by employing a new mechanism of action or by a new drug format-are neither overlooked nor compromised by regulatory requirements.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, 2011
The classification procedure, introduced by the European Regulation on advanced therapy medicinal... more The classification procedure, introduced by the European Regulation on advanced therapy medicinal products (ATMPs), has received a tremendous interest from companies, academic and public sponsors developing ATMPs. This procedure gives companies the opportunity to verify whether or not the product they are developing can be considered an ATMP and can therefore benefit from the new regulatory pathway introduced in the European Union for these types of medicinal products. This procedure is optional, free of charge and may take place at any stage of the development of an ATMP in advance of applying for a marketing authorisation. In case of doubt, briefing meetings organised by the European Medicines Agency Innovation Task Force may help preparing for an ATMP classification and are a starting point for the interactions between the Agency and the developers of ATMPs. This article reviews the advantages of the classification procedure for both the developers of ATMPs and the European regulatory network. Since the introduction of this procedure and up to 10 November 2010, the Committee for Advanced Therapies (CAT) has finalised 38 applications for classification.
Trials, 2014
Since the first methodological publications on adaptive study design approaches in the 1990s, the... more Since the first methodological publications on adaptive study design approaches in the 1990s, the application of these approaches in drug development has raised increasing interest among academia, industry and regulators. The European Medicines Agency (EMA) as well as the Food and Drug Administration (FDA) have published guidance documents addressing the potentials and limitations of adaptive designs in the regulatory context. Since there is limited experience in the implementation and interpretation of adaptive clinical trials, early interaction with regulators is recommended. The EMA offers such interactions through scientific advice and protocol assistance procedures. We performed a text search of scientific advice letters issued between 1 January 2007 and 8 May 2012 that contained relevant key terms. Letters containing questions related to adaptive clinical trials in phases II or III were selected for further analysis. From the selected letters, important characteristics of the ...
Public Health Genomics, 2010
Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently d... more Pharmacogenomics (PGx) and pharmacogenetics (PGt) are emerging interdisciplinary areas recently defined by the regulatory authorities at an international level as 'the investigation of variations of DNA and RNA characteristics as related to drug response' (PGx), and the study of 'the influence of variations in DNA sequence on drug efficacy and toxicity' (PGt). In recent years a number of studies have in fact produced growing evidence that, besides the effects of age, sex, diseases, and different drugs interactions, genetic factors play a role in the inter-individual variability of drugs response. The increasing genomic knowledge has also raised the profile and role of the so called 'genomic biomarkers' (GBs) in drug development, approval, and clinical use. The aims of this review are to (a) revisit the general understanding of the role of genomics and genetics in drug response, (b) provide an update on the definition and classification criteria of GBs as recently defined at a global level by regulatory agencies such as the European Medicines Agency and the Food and Drug Administration, and (c) illustrate with some examples current and potential applications of biomarkers in clinical practice and in drug development.
Nature Reviews Drug Discovery, 2014
Nature Reviews Drug Discovery, 2013
Pharmacogenetics, one of the cornerstones of personalized medicine, has the potential to change t... more Pharmacogenetics, one of the cornerstones of personalized medicine, has the potential to change the way in which health care is offered by stratifying patients into various pretreatment categories, such as likely responders, likely non-responders or likely to experience adverse drug reactions. In order to advance drug development and regulatory science, regulatory agencies globally have promulgated guidelines on pharmacogenetics for nearly a decade. The aim of this article is to provide an overview of new guidelines for the implementation of pharmacogenetics in drug development from a multiregional regulatory perspective - encompassing Europe, the United States and Japan - with an emphasis on clinical pharmacokinetics.
Nature Biotechnology, 2010
By streamlining the qualification process for biomarkers, coordinated protocols recently implemen... more By streamlining the qualification process for biomarkers, coordinated protocols recently implemented at the different regulatory agencies can facilitate progress and provide impetus to novel biomarker discovery and validation.
Nature Biotechnology, 2010
The first formal qualification of safety biomarkers for regulatory decision making marks a milest... more The first formal qualification of safety biomarkers for regulatory decision making marks a milestone in the application of biomarkers to drug development. Following submission of drug toxicity studies and analyses of biomarker performance to the Food and Drug Administration (FDA) and European Medicines Agency (EMEA) by the Predictive Safety Testing Consortium's (PSTC) Nephrotoxicity Working Group, seven renal safety biomarkers have been qualified for limited use in nonclinical and clinical drug development to help guide safety assessments. This was a pilot process, and the experience gained will both facilitate better understanding of how the qualification process will probably evolve and clarify the minimal requirements necessary to evaluate the performance of biomarkers of organ injury within specific contexts.
Nature Biotechnology, 2009
Journal of Biomedicine and Biotechnology, 2003
The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines E... more The evaluation of quality, safety, and efficacy of medicinal products by the European Medicines Evaluation Agency (EMEA) via the centralized procedure is the only available regulatory procedure for obtaining marketing authorization for gene therapy (GT) medicinal products in the European Union. The responsibility for the authorization of clinical trials remains with the national competent authorities (NCA) acting in a harmonized framework from the scientific viewpoint. With the entry into force of a new directive on good clinical practice implementation in clinical trials as of 1 May 2004, procedural aspects will also be harmonized at EU level. Scientifically sound development of medicinal products is the key for the successful registration of dossiers and for contributing to the promotion and protection of public health. The objective of this paper is to introduce the EMEA regulatory processes and scientific activities relevant to GT medicinal products.
Critical Reviews in Oncology/Hematology, 2002
Pharmacology and Toxicology, 2000
The safety of biotechnological products used for medicinal products is addressed by EU council di... more The safety of biotechnological products used for medicinal products is addressed by EU council directives. The general principles and the regulatory framework for the handling of new drug applications within this areas are described both with respect to benefit/risk evaluation, quality assessment, preclinical safety and efficacy testing.