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The North Eastern Himalayan (NEH) regions of India are considered as one of the major repositories of the ' Capsicum annuum complex' which comprises of three cultivated species namely C. annuum, C. frutescens, and C. chinense. The interspecific delimitation within this large complex is ill-defined due to poorly developed crossing barriers and lack of discontinuous morphological characters. The present study elucidates the relationship among nine different cultivars of three Capsicum species on the basis of floral morphology and karyological parameters for the first time. Different floral characteristics such as margins and constrictions of calyx, type of pedicel, flower size, and color were found to have paramount importance in the species delimitation within the studied members of ' C. annuum complex.' The present karyomorphometric study explicitly revealed differences between the observed chromosomal data such as karyotype formulae, ordering of satellite bearing chromosome pairs and total diploid chromatin length which aid in resolving interspecific relationship among the studied cultivars of Capsicum. The present analyses unambiguously distinguished all cultivars of C. annuum from the members of C. frutescens and C. chinense and also proposed that among the five cultivars of C. annuum, Ghee lanka was comparatively distant from the other four cultivars on the basis of their karyomorphological characteristics. For the first time karyotype of hottest Indian chili is included in this paper. Comprehensive knowledge on floral morphology and karyotypes of some Himalayan Capsicums not only help to conserve genetic diversity but also help capsicum breeders for their basic and applied research. [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]

The coronavirus disease 2019 (COVID‐19) pandemic and the accompanying control measures have significantly affected clinical trial (CT) conduct, and sponsors have needed to make rapid changes to their CT operations. As a result, regulatory guidance was pivotal during the initial phases of the pandemic. This study aimed to evaluate the regulatory readiness and guidance related to COVID‐19 in the European Union (EU). The European Medicines Agency (EMA) and national competent authorities' (NCAs') websites were searched in September and October 2020 for guidances on the management of CTs during the pandemic published from January 2020 onward. "Regulatory readiness" was defined as the number of days from the first European COVID‐19 case (January 24, 2020) to the first published guidance by the respective NCA. "Regulatory guidance" was evaluated by coding the guidances for the following predefined operational trial activities important for ongoing CTs: obtaining informed consent, participant information, clinic visits, home health visits, telemedicine visits, self‐monitoring, investigational medicinal product (IMP) supply, IMP adherence monitoring, CT monitoring, documentation management, regulatory management, and safety management. Twenty‐four of the 27 EU NCAs published country‐specific guidance. The time from the first European COVID‐19 case to the first published EMA guidance was 56 days and ranged from 47 to 66 days for the first national guidances. Guidance was provided most frequently for regulatory management (24/24), safety management (23/24), documentation management (22/24), and CT monitoring (22/24). The regulatory guidance provided during the pandemic, ensuring participant safety and data integrity, may now be the starting point to innovate future CT conduct. [ABSTRACT FROM AUTHOR]

Ondansetron is an effective antiemetic that is being widely used as a second‐line treatment option for severe nausea and vomiting of pregnancy in accordance with clinical guidelines. The safety of ondansetron during pregnancy has—following publication of controversial and seemingly contradictory results—been subject to considerable academic turmoil, specifically with respect to the risk of congenital cardiac malformations and oral cleft. In July 2019, the European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) released an updated, comprehensive assessment report on the use of ondansetron in the first trimester. The ensuing Summary of Product Characteristics (SmPC) was updated in November 2019 with important changes to section on "Fertility, pregnancy and lactation." The SmPC now states that ondansetron should not be used in the first trimester of pregnancy. ENTIS, The European Network of Teratology Information Services, believes that the implementation of this regulatory step—which has important clinical consequences—is insufficiently substantiated and is not serving the interest of pregnant women with severe nausea and vomiting. Herein, we discuss the underlying evidence and argue the case against the EMA decision. [ABSTRACT FROM AUTHOR]

FAF1 (FAS-associated factor 1) is involved in the activation of Fas cell surface death receptors and plays a role in apoptosis and necrosis. In patients with Parkinson's disease, FAF1 is overexpressed in dopaminergic neurons in the substantia nigra. KM-819, an FAF1 inhibitor, has shown potential for preventing dopaminergic neuronal cell death, promoting the degradation of α-synuclein and preventing its accumulation. This study aimed to develop and validate a quantitative analytical method for determining KM-819 levels in rat plasma using liquid chromatography–tandem mass spectrometry. This method was then applied to pharmacokinetic (PK) studies in rats. The metabolic stability of KM-819 was assessed in rat, dog, and human hepatocytes. In vitro metabolite identification and metabolic pathways were investigated in rat, dog, and human hepatocytes. The structural analog of KM-819, namely N-[1-(4-bromobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]-2-(phenylsulfanyl) acetamide, served as the internal standard (IS). Proteins were precipitated from plasma samples using acetonitrile. Analysis was carried out using a reverse-phase C18 column with a mobile phase consisting of 0.1% formic acid in distilled water and 0.1% formic acid in acetonitrile. The analytical method developed for KM-819 exhibited linearity within the concentration range of 0.002–10 μg/mL in rat plasma. The precision and accuracy of the intra- and inter-day measurements were <15% for the lower limit of quantification (LLOQ) and all quality control samples. KM-819 demonstrated stability under various sample storage conditions (6 h at room temperature (25 °C), four weeks at −20 °C, three freeze-thaw cycles, and pretreated samples in the autosampler). The matrix effect and dilution integrity met the criteria set by the Food and Drug Administration and the European Medicines Agency. This sensitive, rapid, and reliable analytical method was successfully applied in pharmacokinetic studies in rats. Pharmacokinetic analysis revealed the dose-independent kinetics of KM-819 at 0.5–5 mg/kg, with a moderate oral bioavailability of ~20% in rats. The metabolic stability of KM-819 was also found to be moderate in rat, dog, and human hepatocytes. Metabolite identification in rat, dog, and human hepatocytes resulted in the discovery of six, six, and eight metabolites, respectively. Glucuronidation and mono-oxidation have been proposed as the major metabolic pathways. Overall, these findings contribute to a better understanding of the pharmacokinetic characteristics of KM-819, thereby aiding future clinical studies. [ABSTRACT FROM AUTHOR]

Introduction: Over the preceding decade, an increasing number of drugs have been approved by the European Medicines Agency (EMA) with limited knowledge of their relative efficacy. This is due to the utilization of non-randomized, singlearm studies, surrogate endpoints, and shorter follow-up time. The impact of this trend on the accessibility and affordability of newly approved drugs in Europe remains uncertain. The primary objective of this study is to provide insights into the issues of accessibility and affordability of new drugs in the Norwegian healthcare system. Method: The presented study entails an analysis of all reimbursement decisions for hospital drugs in Norway spanning 2021–2022. The included drugs were approved by the EMA between 2014 and 2022, with the majority (91%) receiving approval between 2018 and 2022. The drugs were categorized based on the level of documentation of relative efficacy. Approval rates and costs (confidential netprices) were compared. Results: A total of 35% (70/199) of the reimbursement decisions were characterized by limited certainty regarding relative efficacy and as a consequence the Norwegian Health Technology Assessment (HTA) body did not present an incremental cost-effectiveness ratio (ICER) in the HTA report. Within this category, a lower percentage of drugs (47%) gained reimbursement approval compared to those with a higher certainty level, which were presented with an ICER (58%). On average, drugs with an established relative efficacy were accepted with a 4.4-fold higher cost (confidential net-prices). These trends persisted when specifically examining oncology drugs. Conclusion: Our study underscores that a substantial number of recently introduced drugs receive reimbursement regardless of the level of certainty concerning relative efficacy. However, the results suggest that payers prioritize documented over potential efficacy. Given that updated information on relative efficacy may emerge post-market access, a potential solution to address challenges related to accessibility and affordability in Europe could involve an increased adoption of market entry agreements. These agreements could allow for price adjustments after the presentation of new knowledge regarding relative efficacy, potentially resolving some of the current challenges. [ABSTRACT FROM AUTHOR]

Biosimilar insulin analogues are increasing market access for diabetic patients globally. Scientific establishment of biosimilarity is cornerstone of this key change in the medical landscape. BGL-ASP is a biosimilar insulin aspart developed by BioGenomics Limited, India. BioGenomics has considered a stepwise approach in generating the totality of evidence required to establish similarity with reference product. Insulin aspart is a recombinant rapid-acting human insulin analogue utilised in the treatment of type-1 and type-2 diabetes mellitus. The single amino acid substitution at position B28 where proline is replaced with aspartic acid results in a decreased propensity to form hexamers, thus increasing the absorption rate on subcutaneous administration compared to native insulin. In order to establish the safety and efficacy of BGL-ASP, the critical quality attributes (CQAs) of BGL-ASP are identified based on the impact created on biological activity, pharmacokinetic/pharmacodynamic (PK/PD), immunogenicity and safety. The CQAs of insulin aspart are related to product structure, purity and functionality and are characterised using a series of state-of-the-art orthogonal analytical tools. The primary protein sequence, the secondary, tertiary and quaternary structure are found to be highly similar for BGL-ASP and reference product. The product related impurities of insulin aspart and the assay content are determined using high performance liquid chromatography (HPLC) based analysis and is similar for BGL-ASP and reference insulin aspart sourced from United States of America (US), Europe Union (EU) and India. The safety, efficacy and immunogenicity of BGL-ASP is also found to be comparable with reference product and is confirmed through the clinical trials conducted as recommended by International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) and European Medicines Agency (EMA) guidelines. The data encompassed in this study demonstrates that reference insulin aspart and BGL-ASP are highly similar in terms of structural, physicochemical, and biological properties, thus confirming its safety and efficacy for usage as potential alternative economical medicinal treatment for diabetes mellitus. [ABSTRACT FROM AUTHOR]

Background. Chimeric antigen receptor (CAR) T cell therapy, a "living drug" immunotherapy, harnesses the power of T-cells from a patient (autologous) or healthy donor (allogeneic) to target and kill cancer cells and has shown unprecedented outcomes in patients with relapsed and refractory malignancies. Treatment with CAR-T cells requires the application of unique skillsets in recognised specialist centres for successful outcomes and requires management by the multidisciplinary team incorporating the specialist pharmacist. Method. A multimodal research strategy was employed for this literature review whereby PubMed, Google Scholar, Embase, Stella Library Search, EMA website, and EBMT website were sources of information. The search was limited from 2020 onwards with key terms referring to CAR-T cell therapy. Results and Discussion. There are six CAR-T cell products currently approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) which target haematological malignancies with abundant clinical trials underway exploring new and improved CAR designs and antigen targets. As CAR-T cell therapy is an advanced therapy medicinal product (ATMP), there is need for an extensive regulatory framework underpinning its safety and efficacy. The clinical pharmacist plays an integral role in the provision of safe and effective CAR-T cell therapy including governance, operational and clinical aspects of treatment. Pharmacists may also be involved through provision of "Qualified Person" (QP) expertise in clinical trials and for release within hospitals under certain circumstances. There is a need for harmonised and accessible guidance on the clinical delivery of ATMPs such as CAR-T cells, with fully delineated responsibilities of pharmacists involving the oversight and supervision of CAR-T cell treatment. Conclusion. There is an unmet need to provide suitable and applicable literature for clinical pharmacists who are involved in the delivery of CAR-T cells. We have provided an overview of T-cell biology and an explanation of CAR-T cell design and the biomanufacturing process. We reviewed the complex and multifaceted treatment cycle requiring considerable logistics, and described the involvement of the clinical pharmacist in each part of this cycle from patient selection to postinfusion care. Finally, we look to the challenges and future opportunities that will require the involvement of the clinical pharmacist. [ABSTRACT FROM AUTHOR]

Background: The nonclinical as well as clinical development of orphan drugs is difficult, owing to unknown pathophysiology and the absence of animal models. Both, the U.S. Food and Drug Administration (FDA) Guidance and European Medicines Agency (EMA) Guidelines, for orphan drug development describe non-clinical studies, but lack specific information, such as animal species and study design. Against this background, this study aimed to elucidate efficient methods for evaluating nonclinical efficacy based on a review report of orphan drugs approved in Japan. Results: A total of 184 orphan drugs, including 84 anticancer and 100 non-anticancer drugs, approved in Japan from January 2010 to December 2019 were investigated. Some anticancer drugs progressed to clinical development without distinct efficacy data in nonclinical studies. Patient-derived cells have been used for some drugs due to a lack of established cell lines. Cells used for non-clinical studies were devised for drugs indicated for cancers resistant to prior therapies, tumours with specific amino acid mutations in the target molecules, and solid tumours with specific biomarkers. For some non-anticancer drugs, similar disease animal models and normal animals were used for evaluation, since animal models did not exist. Biomarkers have been used specifically for evaluation in normal animals and as endpoints in some clinical trials. Conclusions: It was possible to evaluate drug efficacy by flexibly designing nonclinical studies according to disease characteristics for potentials orphan drugs. These approaches, which are not described in detail in the EMA Guideline or FDA Guidance, may thus lead to approval. [ABSTRACT FROM AUTHOR]

Roflumilast, a selective phosphodiesterase 4 inhibitor, was approved by the European Medicines Agency Committee for Medicinal Products for Human Use in 2010 for the treatment of severe chronic obstructive pulmonary disease. However, low solubility of Roflumilast is a question mark to design a suitable dosage form to get therapeutic objectives. The aim of this work was to enhance solubility of the drug to develop fast release oral tablet. Drug-polymer binary system was developed at 1:1 w/w ratio followed by development of immediate release tablet by direct compression method. Drug-polymer compatibility studies were assessed by Fourier-transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, and scanning electron microscopic studies. Pre and Post- compression tests and in vitro dissolutions studies in acidic (pH 1.2) and PBS pH 6.8 were performed to evaluate in vitro performance of the developed formulations. In vitro kinetic models were applied and similarity and difference factors were computed in comparison with reference product (marketed brand). Drug content was found between 95.37 to 99.57 in the developed formulations. Drug-polymer compatibility results demonstrated good compatibility among drug, polymers and other excipients. The micromeretic parameters and post compression studies results were in acceptable limit for all the developed formulations. Fast drug release behavior was observed in acidic medium. The results suggested that similarity factor (f2) values of the developed formulations were within acceptable limit (50-100). The developed binary systems may apply to overcome solubility issues of biopharmaceutical classification system class II drugs. The developed formulations are easy to scale-up. [ABSTRACT FROM AUTHOR]

As the first biologics produced by recombinant deoxyribonucleic acid (DNA) technology were approved in the late 1980s and consequently the exclusive marketing rights of most of these biological medicinal products have expired or will expire very shortly, it is quite evident that biosimilars are being developed and marketed in developed as well as developing countries in line with these expiries. Hence, there is an explosion of published papers and scientific programs on biological medicinal products and biosimilar insulins in the last decade or so. Each of these papers or scientific programs generated more questions than providing clinically useful answers. The specific aim of the medical literature or scientific programs were blurred due to lot of attention (created by the innovators) directed towards confusing terminologies, past mishaps with biosimilars (in the era with the absence of regulatory guidelines for biosimilars) diverting our attention from the matters relevant to clinicians and patients. One of the principle reason behind this phenomenon has been our poor understanding of the manufacturing process, regulatory pathways, and study endpoints involved in developing a biosimilar in the present era. This drawback resulted in a nonsystematic approach in analyzing the biosimilars and apparently resulting in confusion. This review attempts at demystifying certain facets of frequently encountered information on biosimilars and acquire a personal understanding on the same, rather than depending on conflicting versions floated at different continuing medical educations (CMEs) and Diabetes Congresses.

The article reports on the emergence of a paper from the European Medicines Agency to address the challenges arising in clinical research in 2012. The paper intents to strengthen procedures to offer assurance to regulators that clinical trials meet the needed ethical standards. The paper puts forward plans for international cooperation in clinical trials' regulation and clarifies how the regulators of the European Union (EU) can assure that ethical standards are used in clinical trials.

In June 2015, European Medicines Agency/Committee for Advanced Therapies (CAT) released the new version of the reflection paper on classification of advanced therapy medicinal products (ATMPs) established to address questions of borderline cases in which classification of a product based on genes, cells or tissues is unclear. The paper shows CAT's understanding of substantial manipulation and essential function(s) criteria that define the legal scope of cell-based medicinal products. This article aims to define the authors' viewpoint on the reflection paper. ATMP classification has intrinsic weaknesses derived from the lack of clarity of the evolving concepts of substantial manipulation and essential function(s) as stated in the EU Regulation, leading to the risk of differing interpretations and misclassification. This might result in the broadening of ATMP scope at the expense of other products such as cell/tissue transplants and blood products, or even putting some present and future clinical practice at risk of being classified as ATMP. Because of the major organizational, economic and regulatory implications of product classification, we advocate for increased interaction between CAT and competent authorities (CAs) for medicines, blood and blood components and tissues and cells or for the creation of working groups including representatives of all parties as recently suggested by several CAs. [ABSTRACT FROM AUTHOR]

On September 20, 2012, a marketing authorization valid throughout the European Union (EU) was issued for decitabine for the treatment of adult patients aged 65 years and older with newly diagnosed de novo or secondary acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy. Decitabine is a pyrimidine analog incorporated into DNA, where it irreversibly inhibits DNA methyltransferases through covalent adduct formation with the enzyme.The use of decitabine was studied in an open-label, randomized, multi-center phase III study (DACO-016) in patients with newly diagnosed de novo or secondary AML. Decitabine (n = 242) was compared with patient's choice with physician's advice (n=243) of low-dose cytarabine or supportive care alone.The primary end point of the study was overall survival. The median overall survival in the intent-to-treat (ITT) population was 7.7 months among patients treated with decitabine compared with 5.0 months for those in the control arm (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.69-1.04; p = .1079). Mature survival data after an additional year of follow-up were consistent with these results, with a median overall survival of 7.7 months in patients treated with decitabine and 5.0 months in the control arm (HR, 0.82; 95% CI, 0.68-0.99; p = .0373). Secondary endpoints, including response rates, progression-free survival, and event-free survival, were increased in favor of decitabine when compared with control treatment. The most common adverse drug reactions reported during treatment with decitabine are pyrexia, anemia, thrombocytopenia, febrile neutropenia, neutropenia, nausea, and diarrhea. This paper summarizes the scientific review of the application leading to approval of decitabine in the EU. The detailed scientific assessment report and product information (including the summary of product characteristics) for this product are available on the EMA website (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) initiative was a collaborative European project that sought to address limitations of current methods in the field of pharmacoepidemiology and pharmacovigilance. Initiated in 2009 and ending in 2015, PROTECT was part of the Innovative Medicines Initiative, a joint undertaking by the European Union and pharmaceutical industry. Thirty-five partners including academics, regulators, small and medium enterprises, and European Federation of Pharmaceuticals Industries and Associations companies contributed to PROTECT. Two work packages within PROTECT implemented research examining the extent to which differences in the study design, methodology, and choice of data source can contribute to producing discrepant results from observational studies on drug safety. To evaluate the effect of these differences, the project applied different designs and analytic methodology for six drug-adverse event pairs across several electronic healthcare databases and registries. This papers introduces the organizational structure and procedures of PROTECT, including how drug-adverse event and data sources were selected, study design and analyses documents were developed, and results managed centrally. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Therapeutic use of an unauthorised drug (or of an authorised drug for an unauthorised indication) for patients with a life-threating disease is permitted outside a clinical trial as an Expanded Access Programme (EAP).The regulations regarding EAPs is not the same all over the world. For example, the recommendation of the European Medicines Agency (EMA) in EU countries also includes within EAPs patients who have been treated in a clinical trial and who wish to continue the treatment. Nevertheless, the patients treated in a clinical trial could have the option of continuing treatment for an extended period in an Open-label Extension study, aimed to generate long-term data on efficacy, safety, tolerability and administration.The aims of this paper - based on the difficulties and incoherence encountered by an Italian Ethic Committee (EC) during the authorisation process of EAPs - are: understanding the origin of this misclassification by analysing differences and similarities among USA, European and Italian regulations concerning EAPs; and showing difficulties in classifying international study protocols as a consequence of the lack of harmonisation of definitions.We performed a critical review of the current USA, European and Italian regulations and we analysed some practical cases by retrieving protocols from Clinicaltrials.gov and the Italian Clinical Trials Registry (OsSC) containing in the title the keywords 'Expanded Access Programme', "'Expanded Access', 'Open-label Extension study' or 'Early Access'.We observed that the Food and Drug Administration ( FDA) definition of EAP is very clear while the EMA definition is similar to that of an Open-label Extension study. This lack of a clear definition generates misclassification and it is possible to find an EAP with an efficacy or safety endpoint; or an EAP managed as a clinical trial; or an EAP classified in Clinical Trials Registries as a phase II, III or IV clinical trial.The internationalisation of the studies requires a harmonisation on a global level of legislation and definitions to eliminate misclassification of protocols. For this reason, the authors suggest that: a) the EMA definition should be harmonised with the FDA definition of EAPs, b) European regulation, even if optional, should be adopted in a compulsory way by national regulations. Moreover, separate registries for both EAPs and clinical trials should be organised. [ABSTRACT FROM AUTHOR]

A three-arm parallel design has been proposed to assess the biosimilarity between a biological product and a reference product using relative distance (Kang and Chow, 2013). The three-arm parallel design consists of two arms for the reference product and one arm for the biosimilar product. This paper extended the three-arm parallel design to a (k + 1)-arm parallel design composed of k (≥ 3) arms for the reference product and one arm for the biosimilar product. A new relative distance was defined based on Euclidean distance; consequently, a corresponding test procedure was developed based on asymptotic distribution. Type I error rates and powers were investigated both theoretically and empirically. [ABSTRACT FROM AUTHOR]

Pharmaceutical residues can harm the environment. Therefore any Marketing Authorisation Application (MAA) for a medicinal product for human use shall be accompanied by an "indication of any potential risks presented by the medicinal product for the environment" according to Article 8(3)(g) of the Directive 2001/83/EC. Since 2006 a guideline document from the European Medicines Agency (EMA, formerly EMEA) is available for this task, which is now called the "Environmental Risk Assessment" (ERA). Recently the EMA released a draft revision of an updated ERA guideline. The present paper provides a summary of the intended innovation. A number of options have been discontinued, but some of them cannot be easily recognised, even though they are potentially affecting the MAA and its costs in a relevant way. A new specifically tailored experimental testing course for antibiotics and a secondary poisoning assessment is introduced. The selection of required study types is altered and the environmental fate evaluation is adapted to the scientific progress. In the recent situation it is suggested that marketing authorisation applicants may reconsider the conduct of water/sediment studies for substances not requiring these according to the guideline revision. The new tailored testing approach for antibiotics avoids any vertebrate use, because it demands no fish study, therefore it may be applied henceforth. If the new prescriptions are not yet in force at the point in time of the MAA submission, appropriate waivers should be stated in the ERA. No further HPLC-study types and acute earthworm toxicity tests should be performed, since the guideline update draft does not accept them. In preclinical toxicity and pharmacokinetic studies, additional data gathering on metabolites should be considered in order to avoid unnecessary leaflet warnings. The cost for ERA may change significantly, with a tendency to increase for generic pharmaceutical MAA, but with a possible reduction for substances of low environmental concern. Earlier consideration of ERA in the drug development process is recommended. [ABSTRACT FROM AUTHOR]

Wearable inertial sensors can be used to monitor mobility in real-world settings over extended periods. Although these technologies are widely used in human movement research, they have not yet been qualified by drug regulatory agencies for their use in regulatory drug trials. This is because the first generation of these sensors was unreliable when used on slow-walking subjects. However, intense research in this area is now offering a new generation of algorithms to quantify Digital Mobility Outcomes so accurate they may be considered as biomarkers in regulatory drug trials. This perspective paper summarises the work in the Mobilise-D consortium around the regulatory qualification of the use of wearable sensors to quantify real-world mobility performance in patients affected by Parkinson's Disease. The paper describes the qualification strategy and both the technical and clinical validation plans, which have recently received highly supportive qualification advice from the European Medicines Agency. The scope is to provide detailed guidance for the preparation of similar qualification submissions to broaden the use of real-world mobility assessment in regulatory drug trials. [ABSTRACT FROM AUTHOR]

The article reports that the European Medicines Agency (EMA) is inviting public comments on a reflection paper regarding development of medicines for older people as of January 2018.

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]

On August 5, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pomalidomide in combination with dexamethasone for the treatment of adult patients with relapsed and refractory multiple myeloma (MM) who have received at least two prior treatment regimens, including both lenalidomide and bortezomib, and have demonstrated disease progression on the last therapy. Pomalidomide is an immunomodulating agent. The recommended starting dose of pomalidomide is 4 mg once daily taken on days 1-21 of repeated 28-day cycles. The main evidence of efficacy for pomalidomide in MM was based on a phase III multicenter, randomized, open-label study (CC-4047-MM-003) in which pomalidomide plus low-dose dexamethasone therapy (POM1LoDEX) was compared with high-dose dexamethasone alone (HiDEX) in previously treated adult patients with relapsed and refractory multiple myeloma who had received at least two prior treatment regimens, including both lenalidomide and bortezomib, and had demonstrated disease progression on the last therapy. For the intent-to-treat population, median progression-free survival based on International Myeloma Working Group criteria was 15.7 weeks (95% confidence interval [CI]: 13.0-20.1) in the POM1LoDEX group versus 8.0 weeks (95% CI: 7.0-9.0) in theHiDEX group (log-rank p value,.001). Overall survival (secondary endpoint) was also different in the two treatment groups (hazard ratio 0.53 [95% CI: 0.37-0.74]).Themost commonly reported adverse reactions to pomalidomide in clinical studies were anemia (45.7%), neutropenia (45.3%) and thrombocytopenia (27%), fatigue (28.3%), pyrexia (21%), peripheral edema (13%), and infections including pneumonia (10.7%). Peripheral neuropathy adverse reactionswere reported in 12.3% of patients, and venous embolic or thrombotic (VTE) adverse reactions were reported in 3.3%of patients. Pomalidomide is expected to be teratogenic. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open-label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first-line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon-α, temsirolimus, or cytokines. In the primary analysis, a 2-month increase in median progression-free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544-0.812; p < .0001). In the subgroup of patients with a prior cytokine-containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375-0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578-0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine-containing regimens (HR: 0.813; 95% CI: 0.556-1.191) or sunitinib (HR: 0.997; 95% CI: 0.782-1.270). The most common treatment-related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar-plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

New European Union (EU) pharmacovigilance legislation, effective from July 2012, introduced new concepts and procedures to optimise the way medicines are regulated within the Union and provided new channels for public health interventions. Triggered by the EU legislation, the work done by the International Conference on Harmonisation (ICH) has provided a common standard for periodic benefit-risk evaluation reporting within the ICH regions. The present paper provides a review of the concepts behind the use of periodic benefit-risk evaluation reports (PBRER) in supporting safety evaluation and assessment of benefit-risk balance and covers essential points in the documentation of safety information, risk evaluation and benefit-risk assessment. The review incorporates the experience to-date with the PBRER at EU level led by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency. The scope of the PBRER, the main content topics and the challenges relevant to the different stakeholders are highlighted together with key success factors for the report to deliver its objectives and maximise the use of the regulatory assessment procedure. It is clear that the PBRER extends beyond new ways of data presentation and analysis and reflects a further shift in pharmacovigilance in the EU towards more integrated benefit-risk assessment of marketed medicines. [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]

The article offers information on the Reflection Paper on Risk-Based Quality Management in Clinical Trials by the European Medicines Agency (EMA) which demonstrates the need for systematic, prioritized, risk-based approach to quality management in clinical trials program. Topics discussed include need of developing central monitoring systems using statistical methodology to monitor clinical trials, analyzing individual patient data, and efficiency of contract research organization (CRO).

In the European Union, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) develop guidelines to guide drug development, supporting development of efficacious and safe medicines. A European Public Assessment Report (EPAR) is published for every medicine application that has been granted or refused marketing authorisation within the EU. In this work, we study the use of text embeddings and similarity metrics to investigate the semantic similarity between EPARs and EMA guidelines. All 1024 EPARs for initial marketing authorisations from 2008 to 2022 was compared to the 669 current EMA scientific guidelines. Documents were converted to plain text and split into overlapping chunks, generating 265,757 EPAR and 27,649 guideline text chunks. Using a Sentence BERT language model, the chunks were transformed into embeddings and fed into an in-house piecewise matching algorithm to estimate the full-document semantic distance. In an analysis of the document distance scores and product characteristics using a linear regression model, EPARs of anti-virals for systemic use (ATC code J05) and antihemorrhagic medicines (B02) present with statistically significant lower overall semantic distance to guidelines compared to other therapeutic areas, also when adjusting for product age and EPAR length. In conclusion, we believe our approach provides meaningful insight into the interplay between EMA scientific guidelines and the assessment made during regulatory review, and could potentially be used to answer more specific questions such as which therapeutic areas could benefit from additional regulatory guidance. [ABSTRACT FROM AUTHOR]

Background: The action of mesenchymal stem cells (MSCs) is the subject of intense research in the field of regenerative medicine, including their potential use in companion animals, such as dogs. To ensure the safety of canine MSC batches for their application in regenerative medicine, a quality control test must be conducted in accordance with Good Manufacturing Practices (GMP). Based on guidance provided by the European Medicines Agency, this study aimed to develop and validate a highly sensitive and robust, nucleic acid-based test panel for the detection of various canine pathogens. Analytical sensitivity, specificity, amplification efficiency, and linearity were evaluated to ensure robust assessment. Additionally, viable spike-in controls were used to control for optimal nucleic acid extraction. The conventional PCR-based and real-time PCR-based pathogen assays were evaluated in a real-life setting, by direct testing MSC batches. Results: The established nucleic acid-based assays displayed remarkable sensitivity, detecting 100–1 copies/reaction of template DNA. They also exhibited high specificity and efficiency. Moreover, highly effective nucleic acid isolation was confirmed by the sensitive detection of spike-in controls. The detection capacity of our optimized and validated methods was determined by direct pathogen testing of nine MSC batches that displayed unusual phenotypes, such as reduced cell division or other deviating characteristics. Among these MCS batches of uncertain purity, only one tested negative for all pathogens. The direct testing of these samples yielded positive results for important canine pathogens, including tick-borne disease-associated species and viral members of the canine infectious respiratory disease complex (CIRDC). Notably, samples positive for the etiological agents responsible for enteritis (CPV), leptospirosis (Leptospira interrogans), and neosporosis (Neospora caninum) were also identified. Furthermore, we conducted biosafety evaluation of 12 MSC batches intended for therapeutic application. Eleven MSC batches were found to be free of extraneous agents, and only one tested positive for a specific pathogen, namely, canine parvovirus. Conclusion: In this study, we established and validated reliable, highly sensitive, and accurate nucleic acid-based testing methods for a broad spectrum of canine pathogens. [ABSTRACT FROM AUTHOR]

Antisense oligonucleotides (ASOs) are short single stranded synthetic RNA or DNA molecules, whereas double-stranded RNA nucleotide sequences are called small interfering RNA (siRNA). ASOs bind to complementary nucleic acid sequences impacting the associated functions of the targeted nucleic acids. They represent an emerging class of drugs that, through a revolutionary mechanism of action, aim to directly regulate disease-causing genes and their variants, providing an alternative tool to traditional "protein-specific" therapies. The majority of the ASOs are designed to treat orphan genetic disorders that in most of the cases are seriously disabling and still lacking an adequate therapy. In order to translate ASOs into clinical success, constant technological advances have been instrumental in overcoming several pharmacological, toxicological and formulation limitations. Accordingly, chemical structures have been recently implemented and new bio-conjugation and nanocarriers formulation strategies explored. The aim of this work is to offer an overview of the antisense technology with a comparative analysis of the oligonucleotides approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). [ABSTRACT FROM AUTHOR]

Introduction: Numerous investigations on herbal medicine that have been undertaken in the past several years demonstrate the general acceptance of its safety. The Saudi Food and Drug Authority (SFDA) established the Herb–Drug Interaction (HDI) project to detect and assess potential HDIs to ensure safety. The aim is to detect safety signals and assess them based on available evidence. Methods: First, SFDA-registered herbal products (n = 30) were selected and prioritized based on commonly used herbs. Second, reported potential HDIs were retrieved from the World Health Organization global database of individual case safety reports (VigiBase), AdisInsight®, and the Natural Medicines database. We excluded drugs non-registered by SFDA and labeled interactions in the product information of SFDA, the US Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Finally, a comprehensive evaluation of potential HDIs was carried out using several evidence sources: literature, global cases, local cases, and other relevant documents. The Drug Interaction Probability Scale (DIPS) scale was used to assess the probability of a causal relationship between the interacting herb and drug and the event. Results: The search yielded 566 potential signals, and 41 had published evidence and were referred for assessment. The assessment results using DIPS were: 22 possible (53.6 %), 7 probable (17%), and 12 doubtful (29.2%) interactions. The recommendation was to include probable HDIs in the product information, including turmeric–tacrolimus, etoposide–Echinacea, Ginkgo biloba–ibuprofen, green tea–warfarin, and licorice–thiazides interactions. Conclusion: The HDI project assessed the screening and identification of potential HDIs. The action plan of this project can be used in post-marketing activities to identify potential drug interactions. [ABSTRACT FROM AUTHOR]

Background and Objectives: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNβ)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNβ formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNβ-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. Methods: Pregnant women with multiple sclerosis exposed to IM IFNβ-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8–12 weeks. Data were collected on IM IFNβ-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. Results: Three-hundred and two patients with a median (range) age of 31.0 (16–48) years and a median (range) gestational age at the time of enrollment of 10.1 (4–39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNβ-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2–15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8–10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNβ-1a exposure. Conclusions: This large US registry study suggests IM IFNβ-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNβ-1a use during pregnancy. Clinical Trial Registration: ClinicalTrials.gov: NCT00168714, 15 September, 2005. [ABSTRACT FROM AUTHOR]

Introduction: SB12 is a biosimilar to eculizumab reference product [SolirisTM (Soliris is a trademark of Alexion Pharmaceuticals, Inc.)] that acts as a C5 complement protein inhibitor. The infusion stability of in-use (diluted) SB12 outside the conditions stated in the reference product's label is unknown. Objective: The objective of this study was to assess the stability of SB12 after extended storage in conditions not claimed in the originator label. Methods: Infusion stability was assessed in SB12 samples (diluted in 0.9% NaCl, 0.45% NaCl, and 5% dextrose, final concentration of 5 mg/mL per clinical trial protocol and the reference product's label) kept at 5 ± 3 °C for up to 3 months, then 30 ± 2 °C/65 ± 5% relative humidity (RH) for 72 h. The product was stored in different containers [polyolefin (PO) bags, glass bottles and syringes], and the protocol followed International Conference on Harmonisation (ICH) and European Medicines Agency (EMA) requirements for stability evaluation of biological products. Stability was evaluated using complementary assays, including pH, protein concentration (A280), purity (size exclusion-high-performance liquid chromatography, capillary electrophoresis-sodium dodecyl sulfate, and imaged capillary isoelectric focusing), biological activity (C5 binding and inhibition), and safety (subvisible particles). Results: Except for charge variants in SB12 diluted in 5% dextrose, all results met the stability acceptance criteria. There were no major changes in terms of physicochemical stability, biological activity, and subvisible particles. Conclusions: The infusion stability of SB12 after extended storage (5 ± 3 °C for up to 3 months, then 30 ± 2 °C/65 ± 5% RH for 72 h) was demonstrated for longer periods and at higher temperatures than what is stated in the EU and US labels of the reference product. The physicochemical properties, biological activity, and subvisible particles of in-use SB12 diluted in 0.9% NaCl and 0.45% NaCl were maintained under the described conditions and for all tested containers. However, instability was observed for the diluted SB12 in 5% dextrose. These results may reduce the workload of clinical staff and minimize drug waste from treatment delays without any loss in product quality and biological activity. [ABSTRACT FROM AUTHOR]

(1) Background: In 2022, monkeypox (Mpox) was declared a public health emergency. The European Medicines Agency has authorized the use of Imvanex/Jynneos, a smallpox vaccine, for coverage against pox. Healthcare workers (HCWs) are all considered by the European Centre for Disease Prevention and Control to be at risk, but in Italy, vaccination was offered only to laboratory personnel. The present study aims to investigate smallpox vaccination coverage (VC) that provides protection against Mpox among HCWs in an Italian university hospital and to assess HCWs' attitudes towards the possibility of getting vaccinated against Mpox. (2) Methods: We conducted a cross-sectional survey. 336 HCWs from selected wards were asked to fill out a self-declaration to collect their sex, profession, ward, vaccination status, and attitude toward Mpox vaccination. (3) Results: 60.71% of HCWs involved provided the requested data; 38.7% of them were previously vaccinated against smallpox, which corresponds to 23.5% of the total HCWs in the wards considered. Considering those born before 1979 as vaccinated, VC increases from 23.5% to 41.7%; the percentage of HCWs who adhered to vaccination is 23%; laboratory technicians showed a lower willingness to be vaccinated. The ward with the highest willingness to vaccinate is proctological surgery. (4) Conclusions: Based on our experience, a variability in smallpox VC and in willingness to vaccination has emerged both among different job titles and age categories and across the wards analyzed. Additionally, our survey reveals that vaccination attitudes are higher among HCWs from wards that currently do not have free access to such vaccinations. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a lower motor neuron disease due to biallelic mutations in the SMN1 gene on chromosome 5. It is characterized by progressive muscle weakness of limbs, bulbar and respiratory muscles. The disease is usually classified in four different phenotypes (1–4) according to age at symptoms onset and maximal motor milestones achieved. Recently, three disease modifying treatments have received approval from the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), while several other innovative drugs are under study. New therapies have been game changing, improving survival and life quality for SMA patients. However, they have also intensified the need for accurate biomarkers to monitor disease progression and treatment efficacy. While clinical and neurophysiological biomarkers are well established and helpful in describing disease progression, there is a great need to develop more robust and sensitive circulating biomarkers, such as proteins, nucleic acids, and other small molecules. Used alone or in combination with clinical biomarkers, they will play a critical role in enhancing patients’ stratification for clinical trials and access to approved treatments, as well as in tracking response to therapy, paving the way to the development of individualized therapeutic approaches. In this comprehensive review, we describe the foremost circulating biomarkers of current significance, analyzing existing literature on non-treated and treated patients with a special focus on neurofilaments and circulating miRNA, aiming to identify and examine their role in the follow-up of patients treated with innovative treatments, including gene therapy. [ABSTRACT FROM AUTHOR]

B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance. [ABSTRACT FROM AUTHOR]

The prices of oncology drugs have been rising progressively in recent years. Despite accounting for only a small share of prescriptions, oncology drugs are the most expensive drugs on the market. However, the association between drug price and clinical benefit often remains questionable. Therefore, we set out to analyze the development of prescription and benefit assessment of protein kinase inhibitors. We identified 20 protein kinase inhibitors with oncological indications that were newly approved by the European Medicines Agency (EMA) between 2015 and 2019, based on the Arzneiverordnungsreport (AVR, Drug Prescription Report). For these 20 drugs, the number of prescriptions, sales, defined daily dose (DDD), and DDD costs were identified for the year of approval and for 2020, respectively, based on data from the Wissenschaftliches Institut der Ortskrankenkassen (WIdO, Scientific Institute of the General Local Health Insurance Fund, AOK). Moreover, the additional benefit assessments by the Gemeinsamer Bundesausschuss (GBA, Federal Joint Committee) were considered for each drug. It is shown that the share of a drug in prescriptions, sales, and DDD does not correlate with the clinical benefit of the drug as measured by the additional benefit assessment by the GBA. Lastly, the advertisement pattern of protein kinase inhibitors in a representative oncology journal does not correlate with drug benefit. In conclusion, the immense costs of oncology drugs are therefore largely caused by drugs for which no additional benefit has been proven by the GBA. In order to ensure the long-term stability of health care systems, price-regulation measures are urgently needed, especially for drugs whose additional benefit has not been proven. [ABSTRACT FROM AUTHOR]

Primula veris (cowslip) is an important medicinal–aromatic plant used traditionally for its expectorant and anti-inflammatory properties, as well as a valuable horticultural plant with ornamental value and agroalimentary interest (edible flowers and leaves). With extensive illegal harvesting across northern Greece to date, the long-term survival of Greek cowslip wild-growing populations seems compromised. With the aim to characterize the phytochemical content of locally adapted native genotypes of P. veris subsp. veris, we examined samples from 13 wild-growing populations sourced from 8 mountain areas along a longitudinal gradient of northern Greece. Flowers, leaves, and roots were separately evaluated with HPLC-PDA-MS for their chemical content to select the genotypes associated with the best phytochemical traits. The flowers were found to contain mainly flavonoids, isorhamnetin, quercetin, and kaempferol triglycosides, with varied population contents, generally higher in northwestern population samples with a colder and more humid climate; however, all in line with the European Medicines Agency's (EMA) reports. The leaves were characterized by the prevalence of kaempferol and quercetin triglycosides, being generally higher than that of the flowers. In the roots, saponins were detected in relatively low percentages, and the phenolic glycosides were found up to nearly 2%. The results of this study suggest a potential specificity of the marginal Greek genotypes being at the edge of the species' native distribution range in Europe and Asia. The phytochemical characterization herein supports the domestication process of Greek native cowslip genotypes. In turn, this may alleviate the overharvesting pressure in wild populations, thus contributing to species conservation and offering an incentive for farmers to sustainably cultivate at local scales well-adapted indigenous genotypes of high value. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic posed challenges to communicating accurate information about vaccines because of the spread of misinformation. The European Medicines Agency (EMA) tried to reassure the public by communicating early on about the development and approval of COVID-19 vaccines. The EMA surveyed patients/consumers, healthcare professional organizations, and individual stakeholders, both at the EU level and in an Italian regional context. The objectives of the study were to see if the EMA's core information materials were informative and well-understood and which communication channels were preferred by the public. The main findings showed that individual patients/consumers generally prefer to obtain information about COVID-19 vaccines from the internet or mass media, while organizations and individual healthcare professionals prefer to obtain information from national and international health authorities. Both at EU and local levels, participants had a good understanding of the key messages from regulators and found the materials useful and relevant. However, some improvements were recommended to the visual, text, and dissemination formats, including publishing more information on safety and using a more public-friendly language. Also, it was recommended to maintain the EMA's approach of using media, stakeholder engagement, and web-based formats to communicate about COVID-19 vaccines. In conclusion, user-testing of proactive communication materials aimed to prebunk misinformation during a public health crisis helps to ensure that users understand the development and safety of novel vaccine technologies. This information can then be used as a basis for further evidence-based communication activities by regulators and public health bodies in an emergency context. [ABSTRACT FROM AUTHOR]

The recruitment of therapeutics and most importantly COVID-19 vaccines has seen a measurable reduction in transmission, re-infection, severity, hospitalization and mortality associated with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The development and approval of some vaccines and therapeutics undoubtedly signaled renewed hope for public health personnel, the government, the World Health Organization (WHO) and the entire world population. At present, most countries have progressed beyond administering first and second doses to administering COVID-19 vaccine updated boosters to prevent transmission and provide protection. Notably, a bivalent COVID-19 vaccine from Pfizer-BioNTech and Moderna, also called an "updated" COVID-19 vaccine booster dose, is a formulation that houses the original virus strain and omicron BA.1, which provides broad immunity against COVID-19 including the omicron variant (BA.1) and the Paxlovid drug (Nirmatrelvir-ritonavir) authorized for use by the Food and Drug Administration (FDA) and the European Medicines Agency. This current review outlines the variant of concern (VOC), viral cell entry and pathogenesis, host immunity and viral immune evasion. In addition, we discuss the therapeutic and vaccine treatment approach, WHO and FDA authorization, vaccine storage and vaccine efficacy. In conclusion, bearing in mind the trend of continued mutations as observed on the spike (S) glycoprotein and receptor binding domain (RBD) of SARS-CoV-2, which lead to more immune-evasive strains such as BQ.1, BQ.1.1, BF.7, XBB and XBB.1, researcher and clinician attention should be tailored toward the design and development of variant-specific vaccines for future interventions. [ABSTRACT FROM AUTHOR]

Abstract Aims We have previously described the European Medicines Agency’s (EMA) and the US Food and Drug Administration’s guidelines, each for a specific psychiatric indication, on how to design pivotal drug trials used in new drug applications. Here, we report on our efforts over 3 years to retrieve conflicts of interest declarations from EMA. We wanted to assess potential internal industry influence judged as the proportion of guideline committee members with industry conflicts of interest. Methods We submitted Freedom of Information requests in February 2020 to access EMA’s lists of committee members (and their declared conflicts of interest) involved in drafting the 13 ‘Clinical efficacy and safety’ guidelines available on EMA’s website pertaining to psychiatric indications. In our request, we did not specify the exact EMA committees. Here, we describe the received documents and report the proportion of members with industry interests (i.e. defined as any financial industry relationship). It is a follow-up paper to our first report (http://doi.org/10.1017/S2045796021000147). Results After 2 years and 9 months (November 2022), the EMA sent us member lists and corresponding conflicts of interest declarations from the Committee for Medicinal Products for Human use (CHMP) from 2012, 2013 and 2017. These member lists pertained to 3 of the 13 requested guidelines (schizophrenia, depression and autism spectrum disorder). The 10 remaining guidelines were published before 2011 and EMA stated that they needed to require permission from their expert members (with unknown retrieval rate) and foresaw excessive workload and long wait. Therefore, we withdrew our request. The CHMPs from 2012, 2013 and 2017 had from 34 to 36 members; 39%–44% declared any interests and we judged 14%–18% as having industry interests. For the schizophrenia guideline, we identified two members with industry interests to companies who submitted feedback on the guideline. We did not receive declarations from the Central Nervous System (CNS) Working Party, the CHMP appointed expert group responsible for drafting and incorporating feedback into the guidelines. Conclusions After almost 3 years, we received information, which only partly addressed our request. We recommend EMA to improve transparency by publishing the author names and their corresponding conflicts of interest declarations directly in the ‘Clinical efficacy and safety’ guidelines and to not remove conflicts of interest declarations after 1 year from their website to reduce the risk of stealth corporate influence during the development of these influential guidelines.

Despite the available therapies for treatment-resistant depression (TRD), there are a limited number that are evidence-based and effective in this hard-totreat population. The European Group for the Study of Resistant Depression (GSRD) investigated in the last two decades the illness characteristics, genetic underpinnings, as well as psychopharmacotherapy of TRD. The GSRD staging model characterizing response, nonresponse and resistance to antidepressant (AD) treatment was applied to 2762 patients in eight European countries. The retrospective and prospective studies of the GSRD reporting that switching antidepressants according to different classes was not associated with better response or remission rates influenced the European Medicines Agency (EMA) that subsequently revised its definition for TRD. Accordingly, the EMA defines TRD as non-response to at least two courses of antidepressants of the same or a different substance class administered in adequate doses and duration in adherent patients (EMA, 2013). A prediction model reaching accuracy of above 0.7 highlighted symptom severity, suicidality, comorbid anxiety and lifetime MDEs as the most informative predictors for TRD. Novel associations of single nucleoid polymorphisms (SNPs) within the PPP3CC, ST8SIA2, CHL1, GAP43 and ITGB3 genes and gene pathways associated with neuroplasticity, intracellular signaling and chromatin silencing have also been found to be associated with TRD. Applying machine learning algorithms, a signature of three SNPs of the BDNF, PPP3CC and HTR2A genes and lacking melancholia predicted treatment response. Taken together, the plethora of findings substantiated by the GSRD over two decades of research offers a unique and balanced perspective on TRD. On this foundation, further research will elaborate on specific clinical and genetic hypotheses, as well as treatment strategies within appropriate study-designs, especially interaction-based models for studying treatment outcome predictors and RCTs for investigating efficacy of particular psychopharmacotherapeutic strategies and prediction models. [ABSTRACT FROM AUTHOR]

Pertuzumab is a recombinant humanized monoclonal antibody that specifically targets the extracellular dimerization domain (subdomain II) of HER2. Based on the positive opinion from the European Medicines Agency (EMA) on March 4, 2013, a marketing authorization valid throughout the European Union (EU) was issued for pertuzumab (Perjeta) for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.The demonstration of clinical benefit for pertuzumab was based on a single, phase III, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel in previously untreated patients with locally advanced or metastatic HER2-positive breast cancer. In the primary analysis, median progression-free survival was 18.5 months in the pertuzumab group compared with 12.4 months in the placebo group (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.51-0.75; p < .0001). For the secondary endpoints, overall survival (HR: 0.66; 95%CI:0.52-0.84; p = .0008) and objective response rate (80.2% vs. 69.3%) were also favored in the pertuzumab group. Toxicity was similar between groups except for higher incidence of diarrhea, rash, mucosal inflammation, dry skin, and neutropenia for pertuzumab compared with placebo. This paper summarizes the scientific review of the application leading to approval in the EU.The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website (http://www.ema.europa.eu). The Oncologist 2014;19:766-773 [ABSTRACT FROM AUTHOR]

The first biosimilar monoclonal antibody (infliximab, CT-P13) was registered by the European Medicines Agency in 2013 for the treatment of several inflammatory conditions including rheumatoid arthritis (RA). Biosimilar infliximab is first being marketed in the Central and Eastern European countries. This paper presents the estimated budget impact of the introduction of biosimilar infliximab in RA over a 3-year time period in six selected countries, namely Bulgaria, the Czech Republic, Hungary, Poland, Romania and Slovakia. A prevalence-based model was constructed for budget impact analysis. Two scenarios were compared to the reference scenario (RSc) where no biosimilar infliximab is available: biosimilar scenario 1 (BSc1), where interchanging the originator infliximab with biosimilar infliximab is disallowed, and only patients who start new biological therapy are allowed to use biosimilar infliximab; as well as biosimilar scenario 2 (BSc2), where interchanging the originator infliximab with biosimilar infliximab is allowed, and 80 % of patients treated with originator infliximab are interchanged to biosimilar infliximab. Compared to the RSc, the net savings are estimated to be €15.3 or €20.8 M in BSc1 and BSc2, respectively, over the 3 years. If budget savings were spent on reimbursement of additional biosimilar infliximab treatment, approximately 1,200 or 1,800 more patients could be treated in the six countries within 3 years in the two biosimilar scenarios, respectively. The actual saving is most sensitive to the assumption of the acquisition cost of the biosimilar drug and to the initial number of patients treated with biological therapy. The study focused on one indication (RA) and demonstrated that the introduction of biosimilar infliximab can lead to substantial budget savings in health care budgets. Further savings are expected for other indications where biosimilar medicines are implemented. [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]

Background In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. Results 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. Conclusions Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities. [ABSTRACT FROM AUTHOR]

Background: Data sharing from clinical trials can be key to the development and approval of medicines for rare diseases. Many events during the first half of 2013 have contributed to the movement for increased transparency. These include the development of the European Medicines Agency's new data publication policy, the creation of the AllTrials petition and GlaxoSmithKline's choice to sign it, the launch of GlaxoSmithKline's system for access to patient-level clinical trial data and Roche's commitment to create a similar system, the release of results from the Yale University Open Data Access project's first medicine analysis for Medtronic, and the creation of the Reg4All website. Aims/Objectives: This paper summarises major developments in clinical trial transparency between January and June 2013 and analyses the composition of datasets released by GlaxoSmithKline. Methods: GlaxoSmithKline's database of available trials was tabulated and graphs of relevant trial characteristics were produced. Results/Conclusions: Due to current transparency initiatives, it is likely that much more data will be made available over the next few years through systems similar to GlaxoSmithKline's. Although some aspects of GlaxoSmithKline's model could limit its usefulness, the data currently listed is diverse and could be promising for researchers interested in rare disease treatment. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]