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The regulatory standards of the United States Food and Drug Administration (FDA) require substantial evidence of effectiveness from adequate and well-controlled trials, for drugs developed in both adults and children. However, when scientifically justified, relying on extrapolation may be acceptable. Historically, the FDA's extrapolation approach was based on draft guidance published in 2014, which introduced the categories of full, partial, and no extrapolation. The European Medicines Agency (EMA) took a different view on pediatric extrapolation. To better understand the use of extrapolation to support pediatric drug development and approval, we reviewed the pediatric labeling changes published by the FDA, focusing on the labeling updates between 1/1/2015 and 7/31/2021, the period where the extrapolation approach is in transition to harmonize with the EMA. Within this time window, among the 265 drugs and biological products with pediatric labeling changes, 169 (63.8%) were identified where extrapolation was used. This includes 64 (24.2%) labeling changes, where full extrapolation was used, and 105 (39.6%) labeling changes, where partial extrapolation was used. The major disease areas that extrapolation was used include neuroscience (40/53, 75.5%) and infectious disease (20/28, 71.4%). The extrapolation approach was identified in terms of source population beyond the use of adult as well as extrapolation from clinical trials conducted in the same drug class. The use of extrapolation increased the rates of new and expanded pediatric indication in the period. This review gives the most recent landscape of pediatric labeling changes using extrapolation. With the released ICH (International Council for Harmonization) E11A guidance in April 2022, the paper also provides insights for future pediatric drug development programs. [ABSTRACT FROM AUTHOR]

The paper applies a functional approach to the analysis of an emerging technology within an innovation system (IS) in a developing country. By doing so, the paper identifies the advantages and drawbacks of the approach through a dynamic analysis and highlights the life cycle of an IS within which a new technology is emerging. This is done empirically by analysing the emergence of biosimilars within the infant Turkish biotechnology system mainly from the perspective of firms. Our analysis of the Turkish case illustrates how the tool of functional approach could be valuable in understanding the dynamics of a technology in a developing country context. Policy suggestions and implications of the study are presented as concluding remarks. [ABSTRACT FROM PUBLISHER]

Predictive toxicology plays an integral role in determining the toxicological profiles of chemicals for safety assessment. Vitamin D is an essential vitamin for the regulation of calcium absorption and homeostasis, as well as the treatment and prevention of several diseases such as rickets and osteomalacia. According to European Medicines Agency (EMA) Guideline on setting health-based exposure limits for use in risk identification in the manufacturing of different medicinal products in shared facilities, permitted daily exposure (PDE) calculation for active pharmaceutical ingredients (APIs) should be done by the medicinal product producers. PDE calculation is mainly based on critical toxicological endpoints such as repeated dose toxicity, genotoxicity, carcinogenicity, developmental and reproductive toxicity, and hypersensitivity potential. During this procedure, critical toxicological endpoints data of an API can be used to predict the PDE of another API that has a similar chemical structure. In the present paper, human toxicological endpoints of vitamin D2, D3, and their metabolites were evaluated and afterwards the data gaps in the toxicological endpoints were filled by forming a category. The read-across was justified by the structural and metabolic similarities. Molecular similarity and mechanistic relevance were found to be substantial, resulting in low uncertainty. The untested vitamin D analogs within the category can be read across with confidence to complete the data gaps related to the human health endpoints. [ABSTRACT FROM AUTHOR]

The starting point of the MindTheRisk project has been to raise socio-political questions about whether lay public’s understanding is satisfied about the genetic information they receive, and to what extent regulators do take this aspect on board when they decide to allow or restrict genetic testing or to develop communications about genetic testing. This article draws on the concepts that have emerged among the risk research community to tackle “risk tolerance’’. It explores the application of those concepts to the sharing and regulating of genetic risk information. We start with a conceptualisation of risk acceptability/tolerability in the genetic context, before turning to concrete hurdles that need to be overcome and questions that need to be answered. Finally, we suggest some direction for policy. The paper is based on an in-depth review supplemented by pilot interviews conducted with the European Medicines Agency, National regulatory agencies, academic and members of a patient organisation, all directly involved in policy. [ABSTRACT FROM PUBLISHER]

Targeting IL-17A using Secukinumab, a humanized monoclonal immunoglobulin G1 (IgG1)/κ against IL-17A is a therapeutic option for immune-mediated disorders such as psoriasis and ankylosing spondylitis. The US Food and Drug Administration and the European Medicines Agency have approved it for the treatment of moderate to severe plaque psoriasis, active psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondylarthritis. Recently it has also been approved for use in children with severe plaque psoriasis, active psoriatic arthritis, and enthesitis-related arthritis. This review focuses on the role of Secukinumab in the management of children and adolescents with enthesitis-related arthritis and psoriatic arthritis. We discuss the salient findings of pivotal RCTs and other studies supporting the use of Secukinumab in adults and children, in particular, focusing on its safety and efficacy. Secukinumab is a therapeutic target for psoriasis, psoriatic arthritis, and spondyloarthropathies in both adults and children. No major safety signals are observed with its use in short-term follow-up. Thus far, Secukinumab has not been found to significantly increase the risk of tuberculosis (TB). [ABSTRACT FROM AUTHOR]

Over the past 10 years, European pharmaceutical regulators (especially the European Medicines Agency [EMA]) have enacted a wave of transparency policies. Since 2010, the overwhelming majority have focused on releasing more scientific medicines information online and providing open access to regulatory data. Amongst other benefits, EMA expects its policies to build public trust and provide outsiders with a better understanding of regulatory decision-making. Yet, few studies have empirically examined the EMA’s transparency policies, especially on the end users of ‘transparent’ information (e.g. medical doctors or patients). This paper presents standout findings from a November 2014 survey conducted in Spain, Germany, France and the United Kingdom with a sample of 1005 general practitioners and medical specialists treating either multiple sclerosis, rheumatoid arthritis, osteoporosis, idiopathic pulmonary fibrosis or HIV/AIDS. The study found that 76% of respondents think it is a bad idea to release information into the public domain before possible safety issues have been investigated by the regulators and (relevant) pharmaceutical company. The results also suggested that medical doctors in Europe have a poor understanding of pharmaceutical regulatory activities. In particular, the majority were largely unaware of the current activities of the EMA, did not have good knowledge of how the regulators assess the safety of medicines (e.g. only 17% said they had good knowledge of how EMA assess the safety of medicines) and were unfamiliar with regulatory documents frequently used by regulators and industry to discuss the safety of medicines (e.g. in approving a medicine). [ABSTRACT FROM PUBLISHER]

The concept of transparency has gained widespread appeal in the European pharmaceutical domain, not least at the European Medicines Agency (EMA). Agency policies have two main objectives: (1) to enable the reuse of data (e.g. clinical study reports) and (2) to empower patients to directly and indirectly make more informed decisions on medicines. Past research has almost exclusively focused on the perspectives of external researchers intending to reanalyse data made publically available. Few studies, however, have explored what can be learnt from the perspectives of other actors (e.g. health care professionals, patients, the regulators themselves, industry and others). This empirical study explores the EMA’s transparency policies from the perspectives of patients. After presenting the results of a survey (N = 1010) with a sample of individuals diagnosed with five specific medical conditions (HIV/AIDS, multiple sclerosis, rheumatoid arthritis, osteoporosis and idiopathic pulmonary fibrosis) from four EU countries (Germany, Spain, France and the UK), the authors argue that EMA’s transparency policies do not adequately address the real-world complexities of communicating with patients. In turn, the paper concludes that the perspective of patients provides an essential contribution to understanding the full net effects (positive, negative and/or limited) of EMA’s transparency policies. [ABSTRACT FROM PUBLISHER]

Regulatory guidelines are necessary to standardize the evaluation procedure in bioequivalence. Revisions in the guidelines occur in order to resolve any previously unclear issues and to address new needs. In this paper, the authors discuss the major regulatory requirements for bioequivalence assessment before and after the EMA guidelines of 2010 and unveil their differences. The authors compiled this review following the critical exploration of literature articles and regulatory guidance documents. This was achieved through searching MEDLINE, Scopus, and the official EMA site. The authors found, in the post-2010 era, that the major differences in the regulatory framework refer to: the choice of clinical designs, the assessment of highly variable drugs, biowaivers, the pharmacokinetics parameters used, and the explicit definition for the use of metabolite data, enantiomers, and endogenous substances. Also, product-specific guidelines have started to be issued, while recommendations are now provided for some special formulations like orodispersible tablets. Other issues were elucidated like studies in the fasting or fed state and the dissolution assessment. The EMA regulatory framework on bioequivalence changed significantly in the post-2010 era. Many issues are now defined more explicitly, while others are newly introduced. However, some issues remain unresolved. [ABSTRACT FROM AUTHOR]

Recently approved by the FDA and European Medicines Agency, CAR-T cell therapy is a new treatment option for B-cell malignancies. Currently, CAR-T cells are manufactured in centralized facilities and face bottlenecks like complex scaling up, high costs, and logistic operations. These difficulties are mainly related to the use of viral vectors and the requirement to expand CAR-T cells to reach the therapeutic dose. In this paper, by using Sleeping Beauty-mediated genetic modification delivered by electroporation, we show that CAR-T cells can be generated and used without the need for ex vivo activation and expansion, consistent with a point-of-care (POC) approach. Our results show that minimally manipulated CAR-T cells are effective in vivo against RS4;11 leukemia cells engrafted in NSG mice even when inoculated after only 4 h of gene transfer. In an effort to better characterize the infused CAR-T cells, we show that 19BBz T lymphocytes infused after 24 h of electroporation (where CAR expression is already detectable) can improve the overall survival and reduce tumor burden in organs of mice engrafted with RS4;11 or Nalm-6 B cell leukemia. A side-by-side comparison of POC approach with a conventional 8-day expansion protocol using Transact beads demonstrated that both approaches have equivalent antitumor activity in vivo. Our data suggest that POC approach is a viable alternative for the generation and use of CAR-T cells, overcoming the limitations of current manufacturing protocols. Its use has the potential to expand CAR immunotherapy to a higher number of patients, especially in the context of low-income countries. [ABSTRACT FROM AUTHOR]

In recent decades, a series of regulatory agencies has been created at the European Union (EU) level. The existing literature on EU agencies focuses either on autonomy as a reason for the creation of such agencies or on the autonomy that they are granted by design. As a result, we do not know much about how EU agencies' actual autonomy comes about. This article therefore probes into the early development of two specific agencies. On the basis of document analysis and interviews with agency staff members, national experts, EU officials, external stakeholders, and clients, it explores why, in practice, the European Medicines Agency (EMA) seems to have developed a higher level of autonomy than the European Food Safety Authority (EFSA), even though on paper EMA appears to be as autonomous as, or if anything, less autonomous than EFSA. The article demonstrates the importance of investigating the managerial strategies of EU regulatory agencies to understand the actual practice of their autonomy and points to legitimacy as a key condition affecting the early development of such agencies. [ABSTRACT FROM PUBLISHER]

The article focuses on the classification of recent developments in regulations related to biomedical technology in Europe. Several innovations by the European Medicines Agency (EMA) led to the formation of the new Advanced Therapy Medicinal Products (ATMP) Regulation, which is related to the field of regenerative medicine. Regenerative medicine is used for the treatment of major medical conditions such as heart disease, diabetes, and cancer. Classification of biomedical technology involves commensuration, which draws the attention of distinct cognitive or practical domains.

The European Medicines Agency (EMEA) leads in providing regulatory guidelines to this emerging industry. While biosimilars are not yet available in the United States, as the legal and regulatory pathway is being developed there, biosimilars and other such products are marketed in other regions of the world. We reviewed the European assessment reports of biosimilars to gain insights into the current practices pertaining to the pharmacokinetic (PK) and pharmacodynamic (PD) similarity evaluations because we believe that they might help to shape the future global regulatory landscape. This paper illustrates the molecular complexity of therapeutic proteins, challenges associated with PK and PD evaluations, limitations of similarity assessment using PK and PD endpoints, and design considerations for PK and PD studies. The scope of biotechnology-derived products will be limited to therapeutic protein products, including recombinant human proteins, fusion proteins, and monoclonal antibodies. The challenges to demonstrate similarity are complex and appear to be unique to each therapeutic agent; therefore, the requirements for regulatory approval will most likely continue to be handled at a product-specific level as stipulated in current EMEA guidelines. [ABSTRACT FROM AUTHOR]

This study seeks to investigate the impact of strengthened requirements for clinical evaluation for medical device manufacturers in Europe due to the new Medical Device Regulations. Qualitative interviews were conducted with eight clinical evaluation consultants from eight different European countries who review and approve clinical evaluation reports for manufacturers prior to their submission to notified bodies. The study describes the sources of device clinical evaluation evidence and describes the consultants' recommendations and challenges encountered when reviewing Clinical Evaluation Reports. The findings from the study demonstrate that understanding what constitutes sufficient clinical evidence poses the biggest challenge to the generation of an MDR-compliant Clinical Evaluation Report. Additionally, the study identified a knowledge and skills gap in the generation and assessment of acceptable regulatory and clinical data. Further, there is heterogeneity in the reviews of Clinical Evaluation Reports received by consultants and inadequate guidance to enable compliance by manufacturers. This study found that some manufacturers of certain CE-marked medical devices are planning to remove them from the EU market upon expiration of their certificate, and in the case of new innovative devices, some manufacturers may launch in other non-EU markets. [ABSTRACT FROM AUTHOR]

Networks of national authorities are often mandated to help enforce EU policies, but receive less scholarly attention than EU agencies. This article examines two networks in the policy areas of medical devices and aviation incident investigation. These are puzzling cases, as two EU agencies already existed in similar policy areas: the European Medicines Agency (EMA) and the European Aviation Safety Authority (EASA). Why did EU legislators mandate new networks of national authorities, and not existing EU agencies? The article argues that national authorities' experts held a central position in the decision-making process and have considerably influenced the decision not to mandate the EMA and the EASA. The article also refines a common assumption about the Commission, and argues that it seems less keen to establish new EU agencies if these already exist in largely similar policy areas. The article's case studies rely on 24 interviews and an analysis of primary and secondary documentation. [ABSTRACT FROM AUTHOR]

Probiotics may be registered as food supplements or drugs. This article summarizes differences in European regulations of probiotics registered as food supplements and drugs, as well as issues related to the quality of probiotic products. For registration as a drug, the European Medicines Agency demands extensive and detailed quality, efficacy and safety evidence; whereas compulsory analyses requested for food supplements consist only in a nutritional analysis. As a result, the quality of those probiotics registered as drugs, compared to food supplements, is in general controlled with higher standards. Despite these differences and whatever the status of the probiotic product, its efficacy and safety has to be documented in well conducted randomized controlled trials (RCTs). Furthermore, this paper reviews recent evidence on the use of probiotics for gastrointestinal diseases, evaluating all the existing information up to January 2014. In all eligible published studies in which use of probiotics for gastrointestinal diseases were investigated and reported, no language limitations were applied. Special focus is placed on RCTs (or their meta-analyses) showing positive results, so that the findings may be applicable to everyday clinical practice. Currently, the best documented clinical areas appear to be probiotics efficacy for the treatment of acute gastroenteritis in children and for the prevention of antibiotic-associated diarrhea both in children and in adults. In other gastrointestinal conditions, some promising observations are emerging, but no definitive conclusions can be reached at present. [ABSTRACT FROM AUTHOR]

Current interventions for irritable bowel syndrome with constipation tend to target single symptoms of the disorder, with multiple symptom relief only achieved through the use of combinations of therapies. Hence, there remains an unmet need for well-tolerated and effective treatments for irritable bowel syndrome with constipation that target abdominal symptoms, including abdominal pain and bowel symptoms. [ABSTRACT FROM AUTHOR]

The article focuses on the draft guidance released by the U.S. Food and Drug Administration (FDA) for adaptive designs. According to the draft guidance, adaptive designs refer to research that contains a planned opportunity for modification of specified aspects of the field. The European Medicines Agency (EMEA) defines adaptive design as adaptive if statistical methodology permits the design element modification. It adds that the guidance provides useful framework for the types of adaptations.

Background: Several biotechnology-derived drugs are reaching the end of their patent lives. As a result, so-called biosimilar products are in development, and a few have already gained approval in Europe and other countries such as the USA. Biosimilars, unlike generic versions of conventional drugs, are not identical to their reference product, and their production is complex and sensitive to even slight changes in the manufacturing and storage process. Therefore, the registration of these products requires more stringent evaluation than that for conventional generics.Methods and scope: A consensus group of experts from the Near and Middle East discussed the currently available guidelines for registration of biosimilars – including those produced by the European Medicines Agency (EMEA) – and their application in this region. To inform this report, a literature search was also conducted on PubMed in January 2008, using the search terms ''biosimilar'' and ''follow-on biologic''. This paper provides an overview of the issues in the development and registration of biosimilars, a description of the EMEA guidelines and the recommendations of the consensus group for the registration of biosimilars in the Middle East.Findings: Because of the complex nature of biosimilars and their potential immunogenicity, these products cannot undergo the abbreviated approval process used for generic agents. Instead demonstration of their quality, safety and efficacy, in comparison with their reference biological product, is required.Conclusions: The consensus group recommended the implementation of the EMEA guidelines as the basis of Regional guidelines for the registration of biosimilars in the Near and Middle East. Registration would, therefore, require demonstration of the robustness of the manufacturing process and quality-control methods, the comparability of pharmacokinetics, pharmacodynamics, efficacy and safety between the biosimilar and reference product and plans for post-marketing surveillance of the long-term risks and immunogenicity of new biosimilars. [ABSTRACT FROM AUTHOR]

Few studies have empirically examined the relationship between trust and its consequences in the pharmaceutical context (e.g. the consequences of trust in medicines advice for patient behaviour). This study empirically examined the European public's perceived trustworthiness of medical, societal, and industry sources of medicines advice, and its consequences for their behavioural intentions including their medicine-taking and information-seeking behaviour. A representative survey (N = 6,001) was conducted with adults from six European countries: Great Britain, France, Germany, Denmark, Italy, and Poland. As expected, respondents consistently rated advice from medical sources (GPs, pharmacists, local hospitals, emergency services) as significantly more trustworthy than advice from societal sources (the Internet, friends/relatives, and the mass media) and, especially, industry (pharmaceutical companies and brand specific websites). A structural equation model then revealed strong associations between the public's perceived trustworthiness of these medical, societal, and industry sources and their medicine-taking and information seeking intentions. Important national variations were found including in the public's opinions on when authorities should convey new safety information. Implications for communicating benefit-risk information in a more transparent regulatory environment are discussed, including the importance of maintaining and strengthening trust in medical actors and committing more resources to supporting national risk communication. [ABSTRACT FROM AUTHOR]

Growing concerns over the related problems of speedily bringing innovative pharmaceuticals (especially so-called precision medicines) to market, and addressing areas of unmet medical need, have engendered critical scrutiny of the existing process for the licensing of pharmaceutical products. The objective is to enable these products to receive approval sooner, but on the basis of the provision of less complete evidence, than was previously the case. This article examines the attempts made to tackle this issue at European Union level, through a pilot programme exploring 'adaptive' approaches to licensing operated by the European Medicines Agency. Responses to this initiative indicate significant difficulty in securing regulatory legitimacy in this context. This suggests that innovative pharmaceutical technologies are disruptive of existing regulatory frameworks, such that future attempts to accommodate them within these may be susceptible to failure. [ABSTRACT FROM AUTHOR]

On 23 September 2010, the US FDA and the EMA issued statements announcing their response to data implicating the use of the antidiabetes drug rosiglitazone (Avandia®, GlaxoSmithKline plc, London, UK) with an increased risk of cardiovascular events, including acute myocardial infarction and stroke. The EMA has implemented an immediate suspension of the drug, meaning that it will no longer be available in Europe. The FDA stopped short of a total suspension, but has stated that use of the drug should be restricted to patients with Type 2 diabetes who cannot control their diabetes with other medications. In this article, Bernard Cheung of the Expert Review of Clinical Pharmacology Editorial Advisory Board gives his insight into the matter. Cheung graduated from the University of Cambridge (UK) and received a PhD in Clinical Pharmacology in 1995. He then joined the University of Hong Kong as the Lecturer in Clinical Pharmacology and later became Professor. He held the Chair in Clinical Pharmacology and Therapeutics at the University of Birmingham (UK) in 2007--2009. Cheung's main research interest is in cardiovascular diseases and risk factors, including hypertension and the metabolic syndrome. He works on vasoactive peptides, such as adrenomedullin and urotensin II. He is also interested in clinical trials, meta-analyses, drug utilization and medication safety and is the Chief Editor of the Open Diabetes Journal, and an Executive Editor of the British Journal of Clinical Pharmacology. [ABSTRACT FROM AUTHOR]

Dupilumab is a treatment option newly licensed for adolescents with moderate to severe atopic dermatitis (AD). It reduces type 2 inflammation by blocking the shared receptor subunit for IL-4/-13. Dupilumab affects three disease mechanisms in atopic dermatitis: the skin barrier, the Th2-cell differentiation and the class switch to IgE. This report is based on a systematic literature search of the PubMed Database. Dupilumab showed promising results in improving AD signs, symptoms and quality of life in adolescents with moderate to severe AD. The safety profile of dupilumab in adolescents with moderate to severe AD closely resembled the known safety profile of dupilumab in adults with moderate to severe AD. Injection-site reactions and conjunctivitis were the relevant side-effects. Skin infections were less frequently observed compared to placebo. Dupilumab was approved by the Food and Drug Administration in March 2019 and by the European Medicines Agency in August 2019 for the treatment of adolescents with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical therapies or when those therapies are not advisable. Since it is the first licensed drug it will likely become the reference drug for adolescents with moderate to severe AD. [ABSTRACT FROM AUTHOR]

Introduction: There have been significant clinical advances in the understanding of the diagnosis and benefits of long-term recombinant human growth hormone (rhGH) replacement in adults with GH deficiency (GHD) since its approval in 1996 by the United States Food and Drug Administration. Areas covered: We searched PubMed, Medline, CINAHL, EMBASE and PsychInfo databases between January 2000 and June 2019 for published studies evaluating adults with GHD. We reviewed the data of the oral macimorelin test compared to the GHRH plus arginine and the insulin tolerance tests that led to its approval by the United States FDA and European Medicines Agency for adult diagnostic testing. We summarize the clinical advances of long-term benefits of rhGH therapy and the potential effects of GH receptor polymorphisms on individual treatment responsiveness. We identify that non-adherence and discontinuation rates are high and recommend strategies to support patients to improve adherence. We also provide an overview of several long-acting GH (LAGH) preparations currently under development and their potential role in improving treatment adherence. Expert opinion: This article summarizes recent clinical advances in rhGH replacement therapy, the biological and molecular aspects that may influence rhGH action, and offers practical strategies to enhance adherence in adults with GHD. [ABSTRACT FROM AUTHOR]

The article reports on restrictions in systemic piroxicam use recommended by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency in July 2008. It notes that the restriction emanated from a review of nonsteroidal antiinflammatory drug (NSAIDs), including piroxicam, which CHMO completed on the efficacy and safety NSAIDs in 2005 and 2006. The drug was recommended by the CHMP to be used only for pain and inflammatory joints in patients with rheumatoid arthritis, osteoarthritis, and Bechteew's disease.

Ruxolitinib is a JAK 1/2 inhibitor approved in 2011 by the Food and Drug Administration (FDA) for the treatment of patients with myelofibrosis. Currently, side effects related to the use of ruxolitinib are routinely managed through therapeutic dose adjustment and blood count monitoring. However, the evaluation of plasma concentration of this compound and other tyrosine kinase inhibitors is becoming of increasing importance, since the therapeutic efficacy of this class of drugs is characterized by a marked variability caused by the presence of genetic polymorphisms, drug–drug interactions, and potential poor patient adherence. Therapeutic drug monitoring of these compounds is thus required to ensure both an optimal response and the reduction of potential adverse effects. In this manuscript, we describe the development and validation of a reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantification of ruxolitinib in plasma, using a liquid chromatographic system equipped with a fluorometric detector (FL) and a mobile phase at pH 4.8 composed of 67:33 water:acetonitrile. The excitation and emission wavelengths were set to 320 nm and 386 nm, respectively. The lower limit of quantification in plasma was 0.1 ng/mL, and the response was linear across the concentration range from 0.2 to 500 ng/mL. The developed methodology, based on a simple extraction procedure and on a rapid chromatographic analysis involving a 5 minutes total analysis time, was validated according to the European Medicines Agency (EMA) guidelines, and may be considered as alternative and complementary to other previously proposed approaches. [ABSTRACT FROM AUTHOR]

The increasing nanomedicine usage has raised concerns about their possible impact on human health. Present evaluation strategies for nanomaterials rely on a case-by-case hazard assessment. They take into account material properties, biological interactions, and toxicological responses. Authorities have also emphasized that exposure route and intended use should be considered in the safety assessment of nanotherapeutics. In contrast to an individual assessment of nanomaterial hazards, we propose in the present work a novel and unique evaluation strategy designed to uncover potential adverse effects of such materials. We specifically focus on spherical engineered nanoparticles used as parenterally administered nanomedicines. Standardized assay protocols from the US Nanotechnology Characterization Laboratory as well as the EU Nanomedicine Characterisation Laboratory can be used for experimental data generation. We focus on both cellular uptake and intracellular persistence as main indicators for nanoparticle hazard potentials. Based on existing regulatory specifications defined by authorities such as the European Medicines Agency and the United States Food and Drug Administration, we provide a robust framework for application-oriented classification paired with intuitive decision making. The Hazard Evaluation Strategy (HES) for injectable nanoparticles is a three-tiered concept covering physicochemical characterization, nanoparticle (bio)interactions, and hazard assessment. It is cost-effective and can assist in the design and optimization of nanoparticles intended for therapeutic use. Furthermore, this concept is designed to be adaptable for alternative exposure and application scenarios. To the knowledge of the authors, the HES is unique in its methodology based on exclusion criteria. It is the first hazard evaluation strategy designed for nanotherapeutics. [ABSTRACT FROM AUTHOR]

A traditional principle of the randomized controlled trial is that the p-value comparing treatment groups should be computed from the simple crude data. This assumes that the size of the study is sufficiently large for an accurate and precise estimation of the difference between groups. There are situations where the accuracy and precision of the study can be improved by statistical adjustment for baseline covariates, including when the outcome is continuous and available at baseline. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) recommend covariate adjustment in trials as a tool to improve the efficiency of the analysis and to avoid conditional bias from chance covariate imbalance. The recent DYNAGITO randomized controlled trial compared the effectiveness of the single inhaler tiotropium-olodaterol combination for the treatment of COPD with tiotropium alone in reducing the rate of exacerbations over 52 weeks. The pre-specified crude analysis produced a rate ratio of 0.93 (p-value > 0.01, not significant) comparing the tiotropium-olodaterol combination with tiotropium alone. However, a sensitivity analysis adjusted for the baseline rate of exacerbations and other factors produced a rate ratio of 0.89 (p-value 0.001, significant). The DYNAGITO trial is an example where statistical adjustment was justified but not used. Future trials of COPD therapy could be designed more efficiently, be made less costly, while improving the accuracy and precision of their data and the resulting conclusions. [ABSTRACT FROM AUTHOR]

Introduction: Bioequivalence testing for locally acting gastrointestinal drugs is a challenging issue for both regulatory authorities and pharmaceutical industries. The international regulatory framework has been characterized by the lack of specific bioequivalence tests that has generated a negative impact on the market competition and drug use in clinical practice. Areas covered: This review article provides an overview of the European Union and United States regulatory frameworks on bioequivalence criteria for locally acting gastrointestinal drugs, also discussing the most prominent scientific issues and advances that has been made in this field. A focus on oral modified release mesalamine formulations will be also provided, with practical examples of the regulatory pathways followed by pharmaceutical companies to determine bioequivalence. Expert commentary: The development of a scientific rationale to demonstrate bioequivalence in this field has been complex and often associated with uncertainties related to scientific and regulatory aspects. Only in recent years, thanks to advanced knowledge in this field, the criteria for bioequivalence assessment are undergoing substantial changes. This new scenario will likely result in a significant impact on pharmaceutical companies, promoting more competition through a clearer regulatory approach, conceived for streamlining the demonstration of therapeutic equivalence for locally acting gastrointestinal drugs. [ABSTRACT FROM AUTHOR]

Introduction: The first biosimilar infliximab, CT-P13 infliximab-dyyb was approved in 2013 by the European Medicines Agency (EMA) and in 2016 by the United States Food and Drug Administration (FDA) and has been used for the treatment of rheumatoid arthritis (RA) for 4 years. Areas covered: CT-P13 with the three brand names on the market has highly similar efficacy and safety profiles but lower price than originator infliximab and are approved in more than 80 countries. One of the most important determinants of the implementation of CT-P13 in the treatment of RA is scientific evidence from clinical studies and real-world pharmacovigilance data. Here, we review all available clinical data supporting the similarity of CT-P13 to originator infliximab in its clinical efficacy and safety for the treatment of RA and related arthritis. In addition, we consider the role of CT-P13 in therapeutic strategies for RA treatment. Expert commentary: With its highly similar efficacy and safety profile to originator infliximab and its lower price, CT-P13 is expected to be very useful in RA treatment, whether it is applied earlier or switched from originator infliximab or other biologics. Future educational initiatives will be important to overcome misunderstandings about biosimilars and to improve the implementation of CT-P13. [ABSTRACT FROM AUTHOR]

Introduction:The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment. Areas covered:The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA’s draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed. Expert commentary:We summarize how ‘one size does not fit all’ for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines. [ABSTRACT FROM AUTHOR]

The relationships among academe, publishing, and industry can facilitate commercial bias in how drug efficacy and safety data are obtained, interpreted, and presented to regulatory bodies and prescribers. Through a critique of published and unpublished trials submitted to the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval of a new antidepressant, vortioxetine, we present a case study of the “ghost management” of the information delivery process. We argue that currently accepted practices undermine regulatory safeguards aimed at protecting the public from unsafe or ineffective medicines. The economies of influence that may intentionally and unintentionally produce evidence-biased—rather than evidence-based—medicine are identified. This is not a simple story of author financial conflicts of interest, but rather a complex tale of ghost management of the entire process of bringing a drug to market. This case study shows how weak regulatory policies allow for design choices and reporting strategies that can make marginal products look novel, more effective, and safer than they are, and how the selective and imbalanced reporting of clinical trial data in medical journals results in the marketing of expensive “me-too” drugs with questionable risk/benefit profiles. We offer solutions for neutralizing these economies of influence. [ABSTRACT FROM PUBLISHER]

A decreasing number of new therapeutic drugs reaching the clinic has led to the publication of regulatory guidelines on human microdosing trials by the European Medicines Agency in 2004 and the US Food and Drug Administration in 2006. Microdosing trials are defined by the administration of 1/100th of the therapeutic dose and designed to investigate basic drug properties. This review investigates the current application of phase 0 trials in medical research. Thirty-three studies found in PubMed and EMBASE were systematically reviewed for aim and analytical method. Pharmacokinetic studies have been a major focus of phase 0 trials, but drug distribution, drug–drug interactions, imaging and pharmacogenomics have also been investigated. Common analytical methods were tandem mass liquid chromatography, accelerator mass spectrometry and positron emission tomography. New ongoing trials are investigating the pharmacodynamics and chemoresistance of marketed drugs, suggesting that the application of phase 0 trials is still evolving. [ABSTRACT FROM AUTHOR]

Subcutaneous liraglutide (Victoza®, Novo Nordisk) was approved for the treatment of Type 2 diabetes mellitus (T2DM) in Europe in 2009 and in the USA in 2010. In December 2014, liraglutide 3.0 mg was approved by the Food and Drug Administration (FDA) and in March 2015 by the European Medicines Agency (EMA) for the treatment of chronic weight management under the brand name Saxenda® Novo Nordisk. Liraglutide causes a glucose-dependent increase in insulin secretion, decreases glucagon secretion and promotes weight loss by inhibiting appetite. Liraglutide probably induces satiety through activation of different areas in the hind brain and possibly by preserving free leptin levels. Recently, liraglutide has been suggested to protect against prediabetes and seems to prevent bone loss by increasing bone formation following diet-induced weight loss in obesity. This article not only covers the major clinical trials evaluating the effects of liraglutide in obesity and T2DM but also provides novel insights into the pharmacological mechanisms of liraglutide. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In recent years, quantitative evaluation for biosimilarity has been taken seriously due to the development of biosimilar products. The concept for assessment of biological products is very different from that of small-molecule drug products because of the variability with respect to the manufacturing process and environmental factors of the biological products. In this article, we propose an estimate method for a biosimilar index and the related lower bound based on the concept of reproducibility probability by assessing power. In addition, some approximations are proposed and compared in regard to simplicity and accuracy. [ABSTRACT FROM AUTHOR]

The European Commission has recently issued a marketing authorisation valid throughout the European Union for 5-aminolaevulinic acid (Ameluz). The decision was based on the favorable opinion of the CHMP recommending a marketing authorization for 5-aminolaevulinic acid for treatment of actinic keratosis of mild to moderate intensity on the face and scalp. The active substance is a sensitizer used in photodynamic/radiation therapy (ATC code L01XD04). The gel should cover the lesions and approximately 5 mm of the surrounding area with a film of about 1 mm thickness. The entire treatment area should be illuminated with a red light source, either with a narrow spectrum around 630 nm and a light dose of approximately 37 J/cm2 or a broader and continuous spectrum in the range between 570 and 670 nm with a light dose between 75 and 200 J/cm2. One session of photodynamic therapy should be administered for single or multiple lesions. Non- or partially responding lesions should be retreated in a second session 3 months after the first treatment. 5-aminolaevulinic acid is metabolized to protoporphyrin IX, a photoactive compound which accumulates intracellularly in the treated actinic keratosis lesions. Protoporphyrin IX is activated by illumination with red light of a suitable wavelength and energy. In the presence of oxygen, reactive oxygen species are formed which causes damage of cellular components and eventually destroys the target cells. The benefit with 5-aminolaevulinic acid is its ability to improve the complete response rate of actinic keratosis lesions. The most common side effects are reactions at the site of application. The objective of this article is to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the EMA website (). [ABSTRACT FROM AUTHOR]

Since the European Paediatric Regulation was introduced in 2007, companies developing new medicinal products or new indications/routes of administration/pharmaceutical forms are obliged to present age-appropriate formulations for the pediatric population within a Paediatric Investigation Plan (PIP) to the European Medicines Agency. Our review highlights a number of discrepancies between what is proposed by applicants and what is considered acceptable by regulators, taking a sample of PIP applications assessed by a specialized Formulation Working Group (FWG) of the Paediatric Committee in 2009. This Working Group assessed 43% of the total number of validated PIP applications during that year. Ninety-two percent of the formulations assessed raised at least one issue, mainly relating to excipients, appropriateness of the route of administration or pharmaceutical form, dosing accuracy and patient's acceptability. A stronger focus on all these aspects, considering the targeted age range, the severity of the disease and the treatment duration, could streamline the development process. [ABSTRACT FROM AUTHOR]

The role of the kidney in blood glucose-level regulation was until recently underestimated. Renal gluconeogenesis, renal glucose uptake and tubular glucose reabsorption are the three ways of renal involvement in glucose homeostasis. In the postabsorptive state, 20% of total glucose release is attributed to renal gluconeogenesis. Tubular glucose reabsorption is performed by the combined action of Na+/D-glucose SGLTs co-transporters and GLUT-facilitated diffusion glucose transporters. SGLT2 inhibitors are a new family of agents, which occlude the path of SGLT2 glucose reabsorption and cause glucosuria. Efficacy of SGLT2 inhibitors includes reduction of HbA1c, fasting and postprandial blood glucose level and slight body weight and systolic blood pressure decrease. The most common adverse events of them are genital mycotic and urinary tract infections. Dapagliflozin and canagliflozin are the first agents of this class, approved from the European Medicine Agency and FDA, respectively. [ABSTRACT FROM AUTHOR]

The need to evaluate medicines for children is widely acknowledged due to pervasive unlicensed medicine use in the pediatric setting. The EU Paediatric Regulation was developed to address these considerations, which subsequently led to the establishment of the National Institute of Health Research (NIHR) Medicines for Children Research Network (MCRN) in England. MCRN supports public and industry studies, and facilitates feasibility, site setup, recruitment and other services. The MCRN and other networks are members of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). Enpr-EMA was established to foster and coordinate research, and develop collaborations across Europe. MCRN works with Enpr-EMA, industry and others to improve the conduct of research for the benefit of children's health. [ABSTRACT FROM AUTHOR]

Rothmann et al. (2003) proposed a method for the statistical inference of fraction retention noninferiority (NI) hypothesis. A fraction retention hypothesis is defined as a ratio of the new treatment effect verse the control effect in the context of a time to event endpoint. One of the major concerns using this method in the design of an NI trial is that with a limited sample size, the power of the study is usually very low. This makes an NI trial not applicable particularly when using time to event endpoint. To improve power, Wang et al. (2006) proposed a ratio test based on asymptotic normality theory. Under a strong assumption (equal variance of the NI test statistic under null and alternative hypotheses), the sample size using Wang's test was much smaller than that using Rothmann's test. However, in practice, the assumption of equal variance is generally questionable for an NI trial design. This assumption is removed in the ratio test proposed in this article, which is derived directly from a Cauchy-like ratio distribution. In addition, using this method, the fundamental assumption used in Rothmann's test, that the observed control effect is always positive, that is, the observed hazard ratio for placebo over the control is greater than 1, is no longer necessary. Without assuming equal variance under null and alternative hypotheses, the sample size required for an NI trial can be significantly reduced if using the proposed ratio test for a fraction retention NI hypothesis. [ABSTRACT FROM AUTHOR]

Oral tissue engineering aims to treat and fill tissue deficits caused by congenital defects, facial trauma, or malignant lesion surgery, as well as to study the biology of oral mucosa. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require a large animal model to evaluate cell-based devices, including tissue-engineered oral mucosa, prior to initiating human clinical studies. Porcine oral mucosa is non-keratinized and resembles that of humans more closely than any other animal in terms of structure and composition; however, there have not been any reports on the reconstruction of a porcine oral mucosa equivalent, probably due to the difficulty to culture porcine fibroblasts. In this study, we demonstrate the feasibility of a 3D porcine oral mucosa equivalent based on a collagen-GAG-chitosan scaffold, as well as reconstructed porcine epithelium by using an amniotic membrane as support, or without any support in form of epithelial cell sheets by using thermoresponsive culture plates. Explants technique was used for the isolation of the porcine fibroblasts and a modified fibroblast medium containing 20% fetal calf serum was used for their culture. The histological and transmission electron microscopic analyses of the resulting porcine oral mucosa models showed the presence of non-keratinized epithelia expressing keratin 13, the major differentiation marker of non-keratinized oral mucosa, in all models, and the presence of newly synthesized collagen fibers in the lamina propria equivalent of the full-thickness model, indicating the functionality of porcine fibroblasts. [ABSTRACT FROM AUTHOR]

The assessment of endometrial safety is one of the key requirements for the clinical development of new products for hormone therapy (HT) to treat menopausal symptoms in women who have a uterus. Both the Food and Drug Administration (FDA) in the United States and the European Medicines Agency (EMA) provide detailed guidance on the requirements for the evaluation of biopsies to prove endometrial safety. However, there are some discrepancies between the European and the US requirements, making it difficult to fulfil both guidelines simultaneously. In order to facilitate multinational clinical trials performed within clinical programs to develop novel HT products, we developed an approach considering both guidance documents as far as possible and proposed solutions for issues that are inconsistently described in these guidelines. A table with the required sample sizes is given. Our recommendation for a unified approach for the estimation of the hyperplasia rate for hormone therapies fulfils the intent of the recommendations of both the FDA and the EMA and thus leads to a globally harmonized drug development for hormone therapies. [ABSTRACT FROM AUTHOR]

The article offers news briefs related to clinical immunology as of September 1, 2013. The European Medicines Agency certified anticancer drug rituximab for treatment of microscopic polyangiitis and granulomatosis with polyangiitis (GPA). Researchers from the University of Edinburgh conducted a study on the role of macrophages in multiple sclerosis (MS) remyelination. Researchers at the Icahn School of Medicine at Mount Sinai discovered a mouse model for autoimmune hepatitis investigation.