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Good pharmacovigilance practices (GVP) of the Eurasian Economic Union (EAEU) were prepared based on the GVP of the European Medicines Agency that have been in force in the European Union (EU) since 2012. The EAEU GVP have been in force in the Russian Federation and the other EAEU member states since 2016. It is important to identify potential differences between the current regulations in order to harmonise requirements for the pharmacovigilance systems in the EU and EAEU. The aim of the study was to analyse and compare GVP requirements in the EU and EAEU. The analysis helped to identify differences in the structure and contents of GVP sections, the definitions of terms (EU GVP definitions are more detailed and supported by examples, subsections, and references to other documents). Moreover, supplements and annexes to the EU GVP contain figures, templates, examples, algorithms, and tables, which are missing in the EAEU GVP. Expert analysis of these differences as applied to assessment of the pharmacovigilance systems’ effectiveness, and practical activities of marketing authorisation holders, medicine developers, and regulatory authorities, demonstrated that the two GVPs are sufficiently harmonised and have very few differences. However, the number of differences between the documents increases, as changes are made to the EU GVP. A more comprehensive harmonisation of the EAEU GVP with the current version of the EU GVP will make it possible to develop and use uniform pharmacovigilance documents in the EU and EAEU, and will facilitate the introduction of EAEU medicines into the global pharmaceutical market.

Trends in Daily Heart Rate Variability Fluctuations Are Associated with Longitudinal Changes in Stress and Somatisation in Police Officers

In this 13th annual installment of the annual ‘Antibodies to Watch’ article series, we discuss key events in commercial antibody therapeutics development that occurred in 2021 and forecast events that might occur in 2022. Regulatory review of antibody therapeutics that target the SARS-CoV-2 coronavirus proceeded at an unprecedented pace in 2021, resulting in both emergency use authorizations and full approvals for sotrovimab, regdanvimab, REGEN-COV2, as well as others, in numerous countries. As of November 1, a total of 11 antibody therapeutics had been granted first approvals in either the United States or European Union in 2021 (evinacumab, dostarlimab loncastuximab tesirine, amivantamab, aducanumab, tralokinumab, anifrolumab, bimekizumab, tisotumab vedotin, regdanvimab, REGEN-COV2). The first global approvals of seven products, however, were granted elsewhere, including Japan (pabinafusp alfa), China (disitamab vedotin, penpulimab, zimberelimab), Australia (sotrovimab, REGEN-COV2), or the Republic of Korea (regdanvimab). Globally, at least 27 novel antibody therapeutics are undergoing review by regulatory agencies. First actions by the Food and Drug Administration on the biologics license applications for faricimab, sutimlimab, tebentafusp, relatlimab, sintilimab, ublituximab and tezepelumab are expected in the first quarter of 2022. Finally, our data show that, with antibodies for COVID-19 excluded, the late-stage commercial clinical pipeline of antibody therapeutics grew by over 30% in the past year. Of those in late-stage development, marketing applications for at least 22 may occur by the end of 2022.

Advanced Therapy Medicinal Products (ATMPs) comprising cell, gene, and tissue-engineered therapies have demonstrated enormous therapeutic benefits. However, their development is complex to be managed efficiently within currently existing regulatory frameworks. Legislation and regulation requirements for ATMPs must strike a balance between the patient safety while promoting innovations to optimize exploitation of these novel therapeutics. This paradox highlights the importance of on-going dynamic dialogue between all stakeholders and regulatory science to facilitate the development of pragmatic ATMP regulatory guidelines.

Pancreatic cancer has a dismal prognosis and only a few treatment options are available. In the European Union, pancreatic cancer classifies as a rare disease, allowing drug developers to apply for orphan medicinal product (OMP) designation. The aim of this study was to provide more detail on OMPs for pancreatic cancer. All applications for OMP designation submitted to the EMA between 2000 and 2019 were identified. For each medicinal product that received an OMP designation, the mode of drug action, use of protocol assistance, and current life cycle status was determined. Fifty-two medicinal products received an OMP designation. At the time of submission, eighteen OMPs were at the non-clinical and 34 OMPs were at the clinical stage of development. At least fourteen kinds of mode of action were explored in the condition. For eighteen out of 52 OMPs protocol assistance was sought. At the time of data analysis, one OMP received marketing authorisation and 24 OMPs were ongoing in development. Many medicinal products for pancreatic cancer received an OMP designation and the majority of these products was already in the clinical stage of development. Nonetheless, the success rate of OMPs for pancreatic cancer that reach the market is low, and increasing this rate is something to aspire. Fortunately, development is still ongoing for a part of the OMPs, and a few developers are planning to submit a marketing authorisation application in the near future. This however does not guarantee success, as pancreatic cancer remains a difficult disease to treat. Developers are advised to make optimal use of incentives such as protocol assistance, establishing (early) dialogue between regulators and drug developers and to agree on important topics such as clinical trial design.

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.

Seasonal influenza vaccines are frequently reformulated, leading to specific challenges for continuous benefit/risk monitoring. In 2014, the European Medicines Agency started requiring annual enhanced safety surveillance (ESS). This article provides a perspective on ESS studies conducted ever since and aims to map existing initiatives used to monitor adverse events following influenza immunization. Of 11 ESS studies, reporting surveillance data of at least five different vaccine brands during four seasons, all were able to rapidly capture vaccine-specific adverse events of interest reports. However, challenges have been identified during study implementation, including recruitment of sufficient participants, enrolling younger age groups, collecting data of vaccine batch numbers, comparing observed with expected rates and achieving adequate return of reported events. Harmonizing safety monitoring standards across countries, and bridging between routine pharmacovigilance and ESS, is likely to allow more comprehensive assessments of influenza vaccine safety, requiring close collaboration between regulators, public health, and manufacturers.

Background: Prior studies investigated regulatory actions that reflected a negative impact on drug risks. We aimed to evaluate occurrence of regulatory actions that reflected a negative or positive impact on benefits or risks, as well as relations between them. Research design and methods: We followed EMA-approved innovative drugs from approval (2009���2010) until July 2020 or withdrawal to identify regulatory actions. We assessed these for impact on benefits or risks and relations between actions. Additionally, we scrutinized drug lifecycles for time-variant characteristics that may contribute to specific patterns of regulatory actions. Results: We identified 14 letters and 361 label updates for 40 drugs. Of the label updates, 85 (24%) reflected a positive impact, mostly concerning indications, and 276 (76%) a negative impact, mostly adverse drug reactions. Many updates (54%) occurred simultaneously with other updates, also if these reflected a different impact. Furthermore, levels of patient exposure, innovativeness, needs for regulatory learning and unexpected risks may contribute to patterns of regulatory actions. Conclusions: Almost a quarter of regulatory actions reflected a positive impact on benefits and risks. Also, simultaneous learning about benefits and risks suggests an important role for drug development in risk characterization. These findings may impact regulatory analyses and decision-making.

Background: The approval process of every drug regulatory agency differs, and hence, the time required for the approval of a new drug varies. This results in a drug lag and India is no exception to this phenomenon. A drug lag precludes Indian patients from accessing new medicines at the same time as they are approved elsewhere. Against this backdrop, we assessed the absolute and relative drug lags of the Indian regulator relative to three regulators in mature markets, namely United States (US), European Union (EU), and Japan. Methods: International nonproprietary names were used to identify new drugs. Their dates of approval (2004-2018) from the online database of four regulatory agencies were identified. Both absolute and relative drug lags were calculated for India as compared to US, EU, and Japan as well for all the agencies relative to the Indian regulator. Results: We identified a total of 453, 473, 424, and 472 new drugs approved over the study period in India, US, EU, and Japan, respectively. The absolute drug lag of Central Drugs Standard Control Organization (CDSCO) was 19 and 18 relative to the US Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA), respectively. The relative drug lag for the CDSCO vis-a-vis the US FDA, European Medicines Agency, and PMDA was 43.2 (2.1–1287.8), 25.6 (0.03–1310.5), and 30.3 (1.2–1242) months, respectively. Conclusion: Our study shows a significant drug lag between India and other three developed nations (US, EU, and Japan). However, in some therapeutic areas, Indian regulator has proactively approved new drugs much before other agencies. The New Drugs and Clinical Trials Rule of 2019 has brought hope for reduction in drug lag in the near future.

In this 12th annual installment of the Antibodies to Watch article series, we discuss key events in antibody therapeutics development that occurred in 2020 and forecast events that might occur in 2021. The coronavirus disease 2019 (COVID-19) pandemic posed an array of challenges and opportunities to the healthcare system in 2020, and it will continue to do so in 2021. Remarkably, by late November 2020, two anti-SARS-CoV antibody products, bamlanivimab and the casirivimab and imdevimab cocktail, were authorized for emergency use by the US Food and Drug Administration (FDA) and the repurposed antibodies levilimab and itolizumab had been registered for emergency use as treatments for COVID-19 in Russia and India, respectively. Despite the pandemic, 10 antibody therapeutics had been granted the first approval in the US or EU in 2020, as of November, and 2 more (tanezumab and margetuximab) may be granted approvals in December 2020.* In addition, prolgolimab and olokizumab had been granted first approvals in Russia and cetuximab saratolacan sodium was first approved in Japan. The number of approvals in 2021 may set a record, as marketing applications for 16 investigational antibody therapeutics are already undergoing regulatory review by either the FDA or the European Medicines Agency. Of these 16 mAbs, 11 are possible treatments for non-cancer indications and 5 are potential treatments for cancer. Based on the information publicly available as of November 2020, 44 antibody therapeutics are in late-stage clinical studies for non-cancer indications, including 6 for COVID-19, and marketing applications for at least 6 (leronlimab, tezepelumab, faricimab, ligelizumab, garetosmab, and fasinumab) are planned in 2021. In addition, 44 antibody therapeutics are in late-stage clinical studies for cancer indications. Of these 44, marketing application submissions for 13 may be submitted by the end of 2021. *Note added in proof on key events announced during December 1-21, 2020: margetuximab-cmkb and ansuvimab-zykl were approved by FDA on December 16 and 21, 2020, respectively; biologics license applications were submitted for ublituximab and amivantamab.

Entre los diversos efectos secundarios del Brexit, la Comisión Europea reubicó la Agencia Europea de Medicamentosen Amsterdam. Las ciudades candidatas diseñaron diferentes campañas de comunicación política/institucional paraconvencer a los países miembros a su favor. Esta investigación compara estas campañas políticas/organizacionales onliney destaca las temáticas y variables en cuestión durante el proceso de selección. A través de un análisis combinadode contenido preferentemente cuantitativo, el estudio pretende validar la medida en que las teorías resource push oresource pull aplicadas a las compañas organizacionales, tuvieron correlación con la decisión final de reubicar la agenciaen Amsterdam. Among the diverse side effects of Brexit, the European Commission relocated the European Medicines Agency (EMA) to Amsterdam. Host bids designed different political/institutional communication campaigns to persuade member states in their favor. This investigation compares and contrasts these institutional political online campaigns and highlights the themes and variables under discussion during the selection process. Through a preferred quantitative content analysis, the aims to validate the extent to which resource push or resource pull theories are correlated with the final decision to relocate the Agency to Amsterdam.

Entre los diversos efectos secundarios del Brexit, la Comisión Europea reubicó la Agencia Europea de Medicamentosen Amsterdam. Las ciudades candidatas diseñaron diferentes campañas de comunicación política/institucional paraconvencer a los países miembros a su favor. Esta investigación compara estas campañas políticas/organizacionales onliney destaca las temáticas y variables en cuestión durante el proceso de selección. A través de un análisis combinadode contenido preferentemente cuantitativo, el estudio pretende validar la medida en que las teorías resource push oresource pull aplicadas a las compañas organizacionales, tuvieron correlación con la decisión final de reubicar la agenciaen Amsterdam. Among the diverse side effects of Brexit, the European Commission relocated the European Medicines Agency (EMA) to Amsterdam. Host bids designed different political/institutional communication campaigns to persuade member states in their favor. This investigation compares and contrasts these institutional political online campaigns and highlights the themes and variables under discussion during the selection process. Through a preferred quantitative content analysis, the aims to validate the extent to which resource push or resource pull theories are correlated with the final decision to relocate the Agency to Amsterdam.

For the past 10 years, the annual ‘Antibodies to watch’ articles have provided updates on key events in the late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred in the year before publication or were anticipated to occur during the year of publication. To commemorate the 10th anniversary of the article series and to celebrate the 2018 Nobel Prizes in Chemistry and in Physiology or Medicine, which were given for work that is highly relevant to antibody therapeutics research and development, we expanded the scope of the data presented to include an overview of all commercial clinical development of antibody therapeutics and approval success rates for this class of molecules. Our data indicate that: 1) antibody therapeutics are entering clinical study, and being approved, in record numbers; 2) the commercial pipeline is robust, with over 570 antibody therapeutics at various clinical phases, including 62 in late-stage clinical studies; and 3) Phase 1 to approval success rates are favorable, ranging from 17–25%, depending on the therapeutic area (cancer vs. non-cancer). In 2018, a record number (12) of antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) that treat a wide variety of diseases were granted a first approval in either the European Union (EU) or United States (US). As of November 2018, 4 antibody therapeutics (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) were being considered for their first marketing approval in the EU or US, and an additional 3 antibody therapeutics developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) were in regulatory review in China. In addition, our data show that 3 product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter regulatory review by the end of 2018, and at least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) may enter regulatory review in 2019. Finally, we found that approximately half (18 of 33) of the late-stage pipeline of antibody therapeutics for cancer are immune checkpoint modulators or antibody-drug conjugates. Of these, 7 (tremelimumab, spartalizumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, and depatuxizumab mafodotin) are being evaluated in clinical studies with primary completion dates in late 2018 and in 2019, and are thus ‘antibodies to watch’. We look forward to documenting progress made with these and other ‘antibodies to watch’ in the next installment of this article series.

Nucleoside and nucleotide analogues (NUCs) targeting hepatitis B virus are capable of selecting resistant viruses upon long-term administration as monotherapies. The prevalence of resistance-associated substitutions (RASs) and fitness-associated substitutions at baseline of NUC therapy and their impact on treatment responses remain unknown. A total of 232 treatment-naïve patients chronically infected with hepatitis B virus (HBV) consecutively referred for the first time to one of French reference centres were included. The nearly full-length HBV reverse transcriptase was sequenced by means of deep sequencing, and the sequences were analysed. RASs were detected in 25% of treatment-naïve patients, generally representing low proportions of the viral quasispecies. All amino acid positions known to be associated with HBV resistance to currently approved NUCs or with increased fitness of resistant variants were affected, except position 80. RASs at positions involved in lamivudine, telbivudine and adefovir resistance were the most frequently detected. All patients with RASs detectable by next-generation sequencing at baseline who were treatment-eligible and treated with currently recommended drugs achieved a virological response. The presence of pre-existing HBV RASs has no impact on the outcome of therapy if potent drugs with a high barrier to resistance are used.

Childhood-onset systemic lupus erythematosus (cSLE) is rare in many regions of the world, including Europe. Access to approved medications for cSLE is currently limited, among others, due to a lack of high-quality evidence from clinical trials. The objectives of the study were to evaluate the current regulatory framework regarding medication approvals, delineate barriers to clinical trial conduct, and strategies to improve access to new medications for cSLE. Relevant methodological and regulatory aspects, epidemiological data, study designs and outcome measures are reviewed, and the results of a survey among Paediatric Rheumatology International Trials Organisation/Pediatric Rheumatology Collaborative Study Group investigators are presented. Laws and regulations in the USA and Europe necessitate that novel medicines are studied in paediatric populations, if similar or the same diseases in adults have been found to benefit from them. Regulatory agencies consider cSLE the paediatric form of SLE in adults. For medicines that have been found safe and effective in adult SLE, paediatric extrapolation strategies can limit the number and complexity of studies needed to support the labelling of these medicines for use in cSLE. In this setting, specialised research networks, validated outcome measures, stakeholder input, study designs as well as statistical methods successfully used in other uncommon diseases will help improve study efficiency in an effort to enhance the speed with which new drugs for cSLE can be studied. Open-label pharmacokinetic-pharmacodynamic studies are preferred by paediatric rheumatologists over double-blind parallel designs for cSLE trials. Appropriate infrastructure, outcome measures and sufficient numbers of patients are available for the testing of new medicines for children with cSLE.

The pace of antibody therapeutics development accelerated in 2017, and this faster pace is projected to continue through 2018. Notably, the annual number of antibody therapeutics granted a first approval in either the European Union (EU) or United States (US) reached double-digits (total of 10) for the first time in 2017. The 10 antibodies granted approvals are: brodalumab, dupilumab, sarilumab, guselkumab, benralizumab, ocrelizumab, inotuzumab ozogamicin, avelumab, duvalumab, and emicizumab. Brodalumab, however, had already been approved in Japan in 2016. As of December 1, 2017, nine antibody therapeutics (ibalizumab, burosumab, tildrakizumab, caplacizumab, erenumab, fremanezumab, galcanezumab, romosozumab, mogamulizumab) were in regulatory review in the EU or US, and regulatory actions on their marketing applications are expected by the end of 2018. Based on company announcements and estimated clinical study primary completion dates, and assuming the study results are positive, marketing applications for at least 12 antibody therapeutics that are now being evaluated in late-stage clinical studies may be submitted by the end of 2018. Of the 12 candidates, 8 are for non-cancer indications (lanadelumab, crizanlizumab, ravulizumab, eptinezumab, risankizumab, satralizumab, brolucizumab, PRO140) and 4 are for cancer (sacituzumab govitecan, moxetumomab pasudotox, cemiplimab, ublituximab). Additional antibody therapeutics to watch in 2018 include 19 mAbs undergoing evaluation in late-stage studies with primary completion dates in late 2017 or during 2018. Of these mAbs, 9 are for non-cancer indications (lampalizumab, roledumab, emapalumab, fasinumab, tanezumab, etrolizumab, NEOD001, gantenerumab, anifrolumab) and 10 are for cancer indications (tremelimumab, isatuximab, BCD-100, carotuximab, camrelizumab, IBI308, glembatumumab vedotin, mirvetuximab soravtansine, oportuzumab monatox, L19IL2/L19TNF). Positive clinical study results may enable marketing application submissions in 2018. Brief summaries of these antibody therapeutics are provided in this installment of the ‘Antibodies to watch’ article series.

Background: The prevalence of narrow-band ultraviolet B (NB-UVB) use in Europe for moderate and severe psoriasis is unknown, because national registries for psoriasis do not monitor this treatment. Objectives: To quantify the use of phototherapy, biologics or conventional treatments in psoriasis, in a setting where European Medicines Agency (EMA) eligibility criteria for biologics were strictly applied, and phototherapy was included among first-line treatments. Methods: We followed a cohort of 1,090 patients who were referred to the only centre entitled to prescribe biologics and phototherapy during a 5-year period. Results: The cumulative number of treatment cycles was: 1,047 with NB-UVB phototherapy, 650 with systemic treatments and 239 with biologics; 754 patients received at least 1 course of NB-UVB phototherapy, 422 at least 1 course with a systemic treatment and 137 with a biologic; 595 patients were treated only with phototherapy. Conclusions: Regular use of NB-UVB as first-line treatment for moderate and severe psoriasis and adherence to the EMA eligibility criteria for biologics led to a relatively restricted use of biologics.

Introduction Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation. Methods Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes of interest, the relationship between the RMMs in place and (1) implementation measures, such as clinical knowledge or physicians` compliance to recommendations contained in the RMMs; and (2) occurrence or reduced severity of the adverse drug reactions for which the RMMs were required. Results Of 59 eligible studies (24 completed, 35 ongoing), 44 assessed implementation measures, whereas only 15 assessed safety outcomes (1 study as a single endpoint and 14 studies with other endpoints). Fifty-one studies used non-experimental designs and 25 studies employed electronic healthcare databases for analysis. Of the 24 completed studies, 17 were considered satisfactory and supported immediate regulatory decision making, 6 were considered inconclusive and required new evaluations, and 1 was terminated early because new safety restrictions were required, thereby necessitating a new evaluation. Compliance with agreed deadlines was considered acceptable in 21 of 24 completed studies; the average time for a submission was 37 months (standard deviation ± 17), with differences observed by type of data source employed. Conclusions Three important gaps in the evaluation plans of RMMs were identified: lack of early feedback on implementation, limited evaluation of safety outcomes, and inability to provide information on the effectiveness from an integrated measurement of different elements of a set of risk minimization tools. More robust evidence is needed to advance regulatory science and support more rapid adjustment of risk minimization strategies as needed. Electronic supplementary material The online version of this article (doi:10.1007/s40264-017-0604-4) contains supplementary material, which is available to authorized users.

This article summarizes the scientific review of panobinostat that led to regulatory approval in the European Union., On August 28, 2015, a marketing authorization valid through the European Union was issued for panobinostat, in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDAC proteins at nanomolar concentrations. HDAC proteins catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins. Inhibition of HDAC activity results in increased acetylation of histone proteins, an epigenetic alteration that results in a relaxing of chromatin, leading to transcriptional activation. The recommended starting dose of panobinostat is 20 mg, taken orally in a cyclical manner for up to 48 weeks. The use of panobinostat in combination with bortezomib and dexamethasone was studied in a randomized, double‐blind, placebo‐controlled, multicenter phase III study (PANORAMA I) in 768 patients with relapsed or relapsed and refractory multiple myeloma who had received one to three prior lines of therapies. In the subgroup of patients who have received at least two prior regimens including bortezomib and an IMiD, there was a difference of 7.8 months in the progression‐free survival in favor of the experimental arm (12.5 months for panobinostat + bortezomib + dexamethasone vs. 4.7 months for placebo + bortezomib + dexamethasone; hazard ratio = 0.47, 95% confidence interal 0.31–0.72; log‐rank p value = .0003). The incidence of grade 3–4 adverse events suspected to be related to study drug was 76.9% vs. 51.2%, for the panobinostat and the placebo group, respectively. The most common side effects (grade 3–4) associated with panobinostat included diarrhea (18.9%), fatigue (14.7%), nausea (4.5%), vomiting (5.5%), thrombocytopenia (43.6%), anemia (7.9%), neutropenia (16.5%) and lymphopenia (8.1%). This article summarizes the scientific review of the application leading to regulatory approval in the European Union. The full scientific assessment report and product information, including the Summary of Product Characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/medicines/medicines_landing_page.jsp&mid=). Implications for Practice. Farydak was approved in the European Union in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD). The addition of panobinostat to bortezomib and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression‐free survival compared with bortezomib and dexamethasone, and an additional therapeutic option with a new mechanism of action was considered valuable. Although the toxicity associated with panobinostat combination was significant, at the time of the marketing authorization of panobinostat, it was considered that it was acceptable and that it should be left to the clinician and the patient to decide whether the panobinostat combination is the preferred treatment option or not.

Innovation is a major pillar in bringing new, targeted medicines to patients. In the health arena, this means the translation of knowledge into what we can call “value.” The latter covers the value to patients but must also take into account value to healthcare systems, society and, of course, manufacturers. The EU has recognised that innovations in healthcare can contribute to the health and well-being of citizens and patients through access to new products, services and treatments with added value. It is also aware that in order to stimulate development, there is a need to facilitate the translation of scientific advances into innovative medicinal products that meet regulatory standards, accelerate patients' access to new therapies and are affordable to Member States' health systems. Early dialogue between technology developers, regulators, health technology assessment and, where relevant, pricing bodies will promote innovation and quicker access to medicines at affordable prices, for the benefit of patients. But while uncertainties in healthcare policy still exist, a request by the European Ombudsman to the European Medicines Agency to provide more information about its early dialogue procedures questions the above “early dialogue” principal. It raises the issue of what the EU aims to do with its health regulation in bringing innovation to the patient. Is this added uncertainty about the hereto trusted role of the EMA a welcome development? Not necessarily.

The issue of translational education of healthcare professionals is a major one. It is clear that a great degree of upskilling is already required and, to keep pace with the science, this must be ongoing. Stakeholders need to achieve this together - with agreed-on standards across the board so that no patient is denied a suitable, virtually tailor-made treatment due to a lack of knowledge or understanding on behalf of the healthcare professional treating and diagnosing him or her. A key partner in tackling this is the healthcare community, and one way to achieve the goal is through increased EU-wide investment in translational education and training of healthcare professionals.

Purpose The European Medicines Agency developed an algorithm to detect unexpected increases in frequency of reports, to enhance the ability to detect adverse events that manifest as increases in frequency, in particular quality defects, medication errors, and cases of abuse or misuse. Methods An algorithm based on a negative binomial time-series regression model run on 6 sequential observations prior to the monitored period was developed to forecast monthly counts of reports. A heuristic model to capture increases in counts when the previous 4 observations were null supplemented the regression. Count data were determined at drug-event combination. Sensitivity analyses were run to determine the effect of different methods of pooling or stratifying count data. Positive retrospective detections and positive predictive values (PPVs) were determined. Results The algorithm detected 8 of the 13 historical concerns, including all concerns of quality defects. The highest PPV (1.29%) resulted from increasing the lower count threshold from 3 to 5 and including literature reports in the counts. Both the regression model and the heuristic model components to the algorithm contributed to the detection of concerns. Sensitivity analysis indicates that stratification by commercial product reduces the PPV but suggests that pooling counts of related events may improve it. Conclusion The results are encouraging and suggest that the algorithm could be useful for the detection of concerns that manifest as changes in frequency of reporting; however, further testing, including in prospective use, is warranted.

This 2020 installment of the annual ‘Antibodies to Watch’ series documents the antibody therapeutics approved in 2019 and in regulatory review in the United States or European Union, as well as those in late-stage clinical studies, as of November 2019*. At this time, a total of 5 novel antibody therapeutics (romosozumab, risankizumab, polatuzumab vedotin, brolucizumab, and crizanlizumab) had been granted a first approval in either the US or EU, and marketing applications for 13 novel antibody therapeutics (eptinezumab, teprotumumab, enfortumab vedotin, isatuximab, [fam-]trastuzumab deruxtecan, inebilizumab, leronlimab, sacituzumab govitecan, satralizumab, narsoplimab, tafasitamab, REGNEB3 and naxituximab) were undergoing review in these regions, which represent the major markets for antibody therapeutics. Also as of November 2019, 79 novel antibodies were undergoing evaluation in late-stage clinical studies. Of the 79 antibodies, 39 were undergoing evaluation in late-stage studies for non-cancer indications, with 2 of these (ublituximab, pamrevlumab) also in late-stage studies for cancer indications. Companies developing 7 (tanezumab, aducanumab, evinacumab, etrolizumab, sutimlimab, anifrolumab, and teplizumab) of the 39 drugs have indicated that they may submit a marketing application in either the US or EU in 2020. Of the 79 antibodies in late-stage studies, 40 were undergoing evaluation as treatments for cancer, and potentially 9 of these (belantamab mafodotin, oportuzumab monatox, margetuximab, dostarlimab, spartalizumab, 131I-omburtamab, loncastuximab tesirine, balstilimab, and zalifrelimab) may enter regulatory review in late 2019 or in 2020. Overall, the biopharmaceutical industry’s clinical pipeline of antibody therapeutics is robust, and should provide a continuous supply of innovative products for patients in the future. *Note on key updates through December 18, 2019: 1) the US Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv (Padcev) on December 18, 2019, bringing the total number of novel antibody therapeutics granted a first approval in either the US or EU during 2019 to 6; 2) the European Commission approved romosozumab on December 9, 2019; 3) the European Medicines Agency issued a positive opinion for brolucizumab; 4) Sesen Bio initiated a rolling biologics license application (BLA) on December 6, 2019; 5) GlaxoSmithKline submitted a BLA for belantamab mafodotin; and 6) the status of the Phase 3 study (NCT04128696) of GSK3359609, a humanized IgG4 anti-ICOS antibody, in patients with head and neck squamous cell carcinoma was updated to recruiting from not yet recruiting.

On 18 September 2017, a marketing authorisation valid through the European Union (EU) was issued for midostaurin in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are Fms-like tyrosine kinase 3 mutation positive and as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL). The recommended dose of midostaurin is 50 mg orally twice daily for AML and 100 mg orally twice daily for ASM, SM-AHN and MCL. Midostaurin was evaluated in two pivotal studies. Study A2301 (RATIFY) included 717 patients with AML. Overall survival (OS) was statistically significantly different between the two groups, and the median OS was 74.7 months in the midostaurin+daunorubicin+cytarabine group and 25.6 months in the placebo+daunorubicin+cytarabine group (HR 0.774; 95% CI 0.629 to 0.953; p=0.0078). Study D2201 included 116 patients with ASM, SM-AHN or MCL. An overall response rate, by IWG-MRT/ECNM (international working group – myelofibrosis research and treatment/European competence network on mastocytosis) criteria of 28.3% was observed in all patients and 60.0%, 20.8% and 33.3% in patients with ASM, SM-AHN and MCL respectively. The most common adverse drug reactions (ADRs) with midostaurin treatment in AML were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and fever. In ASM, SM-AHN, MCL the most common ADRs were nausea, vomiting, diarrhoea, peripheral oedema and fatigue. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU.

On 21 November 2016, the European Commission issued a marketing authorisation valid throughout the European Union for ixazomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Ixazomib was evaluated in one, randomised, double-blind, phase III study comparing ixazomib plus lenalidomide and dexamethasone (n=360; ixazomib arm) versus placebo plus lenalidomide and dexamethasone (n=362; placebo arm) in adult patients with relapsed and/or refractory multiple myeloma who had received at least one prior therapy. The median progression-free survival (PFS) in the intent-to-treat population was 20.6 months in patients treated with ixazomib compared with 14.7 months for patients in the placebo arm (stratified HR=0.742, 95% CI 0.587 to 0.939, stratified p-value=0.012). The most frequently reported adverse reactions (≥20%) within the ixazomib and placebo arms were diarrhoea (42% vs 36%), constipation (34% vs 25%), thrombocytopaenia (28% vs 14%), peripheral neuropathy (28% vs 21%), nausea (26% vs 21%), peripheral oedema (25% vs 18%), vomiting (22% vs 11%) and back pain (21% vs 16%). The scientific review concluded that the gain in PFS of 5.9 months observed with ixazomib was considered clinically meaningful. Concerning the possible uncertainty about the magnitude of the effect, this uncertainty was acceptable given the favourable toxicity profile, and considering that ixazomib is the first agent to allow oral triple combination therapy in this patient population which represents a therapeutic innovation in terms of convenience for patients. Therefore, the benefit–risk for ixazomib in combination with lenalidomide and dexamethasone was considered positive, although the efficacy evidence was not as comprehensive as normally required.

Defined Daily Doses (DDD) and Defined Course Doses (DCD) have been established in both human and veterinary medicine in order to standardize the measurement of treatments in a population. In 2016 the European Medicines Agency published average defined daily dose (DDDvet) and defined course dose (DCDvet) values for antimicrobial agents used in livestock production. Similarly, national defined doses (DDDch and DCDch) for the pig sector in Switzerland have recently been determined. The aim of this study was to compare the outcome of calculating antimicrobial consumption based on either DDDvet/DCDvet or DDDch/DCDch. Data from 227 Swiss pig farms describing antimicrobial use in 2015 was collected. The numbers of treatment days and treatments were calculated using DDDvet/DCDvet and DDDch/DCDch respectively, for each farm in total and for different antimicrobial classes. Associations between calculated numbers of DDDvet/DCDvet and DDDch/DCDch on farm level were investigated. In addition, differences concerning antimicrobial use were investigated between different production types of farms (piglet-producer, finishing farm or farrow-to-finishing farm). Using DDDch/DCDch values we calculated 1,805,494 treatment days and 433,678 treatments compared to 1,456,771 treatment days (19% ratio) and 303,913 treatments (30% ratio) based on DDDvet/DCDvet. Penicillins (21.4/26.6%), polypeptides (18.6/27.6%) and fluoroquinolones (9.5/8.8%) were the most frequently used classes of antimicrobials based on calculation using both DDDch and DDDvet. Similar findings were observed for complete treatments (DCDch/vet) (penicillins: 52.8/39.6%; polypeptides: 7.8/14.2%; fluoroquinolones: 13.2/12.9%). The number of treatment days or treatments per farm was higher for piglet-producers and farrow-to-finishing farms compared to finisher farms regardless of whether Swiss or European DDD or DCD values were used for the calculation (each P < 0.001). Similar results for antimicrobial use (AMU) obtained at farm level were observed when calculated either by Swiss or European definitions. Nevertheless, marked differences could be observed in the assessment of the use of specific antimicrobial classes in the field based on DDDvet/DCDvet compared to DDDch/DCDch.

Neurodegenerative disorders are characterized by progressive degeneration of nerve cells resulting in functional decline of cognition and/or movement. As the prevalence of many of these disorders increases with the aging global population, there is an urgent need for disease-modifying drugs that will halt or slow the progression of these devastating diseases. A summary of the scientific information needed to guide the safe and effective use of a drug is provided in the product label in which the indication section should clearly state the treatment concept, e.g., distinguish between symptomatic, preventive, and curative treatments. However, a review of the United States (US) and European Union (EU) product labels for disease-modifying multiple sclerosis (MS) drugs reveals that the indications are not aligned with the regulatory guidance on labeling. Indication claims such as "delay of accumulation of disability" and "slowing of disease progression" were previously accepted by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, all recently approved MS drugs include no such specification of the treatment concept in the label indication sections despite similar clinical data packages supporting the approvals. Coincidently, the FDA and EMA therapeutic guidelines pertaining to development of drugs for treatment of neurodegenerative disorders have changed from providing recommendations for specific disease modification label claims to a more general focus on the clinical development approach. Our analysis of MS drug labels could imply that the FDA and EMA may be unlikely to accept disease modification-related indication claims for drugs to treat neurodegenerative disorders in general. We envision that a potential disease-modifying effect is more likely to be inferred from the label descriptions of the mechanism of action, clinical efficacy data and trial design, and target patient population. This poses a challenge for communication of the clinical benefit in a language that can be easily understood by patients and prescribers.

Applicants for marketing authorisation for human medicinal products in the European Union must submit an environmental risk assessment which is assessed by assessors from the national competent authorities. The EMA guideline on the environmental risk assessment of medicinal products for human use came into effect on 1 December 2006. After 12 years’ experience with the guideline, the EMA has released for public consultation a draft revision of the guideline. The revision proposes significant substantive and structural changes to the guideline. The major changes proposed in the revision are outlined together with the rationale for the changes and the expected impact on stakeholders.

The use of biosimilar drugs for multiple sclerosis (MS) has become widespread in Latin America, with the goal of reducing costs of treatments, promoting the sustainability of healthcare systems, and improving patient access to these therapies. There is currently a need to define and comply with requirements to guarantee the efficacy, safety, and quality of these drugs. Thus, the objective of the present study was to compile up-to-date information from each Latin American country assessed on (a) approval of biosimilar drugs by regulatory agencies; (b) use of biosimilar drugs, pharmacovigilance plans, risk management; and (c) update in the knowledge on different molecules. To do so, a group of experts from Argentina, Bolivia, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Panama, Peru, Uruguay, and Venezuela met to discuss the current situation regarding good practices and risks associated with the use of biosimilar drugs in their respective countries. Regulation, risk management plans, and pharmacovigilance in the whole continent must guide the strategies on the commercialization and access of biosimilar drugs and copies of complex molecules. Current regulations must be implemented for the registration of biosimilar drug products and complex molecules. It is paramount to ensure that new products follow the best quality standards at all stages beyond being safe and efficient. Uncontrolled interchangeability between original biological and biosimilar should be avoided. Latin America requires the implementation and full use of strong pharmacovigilance programs. National and multinational clinical studies are required to demonstrate the similarity in safety, efficacy, and immunogenicity profiles of complex molecules, as well as biological and biosimilar products. Plain Language Summary Plain language summary available for this article.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

Over 50 investigational monoclonal antibody (mAb) therapeutics are currently undergoing evaluation in late-stage clinical studies, which is expected to drive a trend toward first marketing approvals of at least 6–9 mAbs per year in the near-term. In the United States (US), a total of 6 and 9 mAbs were granted first approvals during 2014 and 2015, respectively; all these products are also approved in the European Union (EU). As of December 1, 2016, 6 mAbs (atezolizumab, olaratumab, reslizumab, ixekizumab, bezlotoxumab, oblitoxaximab) had been granted first approvals during 2016 in either the EU or US. Brodalumab, was granted a first approval in Japan in July 2016. Regulatory actions on marketing applications for brodalumab in the EU and US are not expected until 2017. In 2017, first EU or US approvals may also be granted for at least nine mAbs (ocrelizumab, avelumab, Xilonix, inotuzumab ozogamicin, dupilumab, sirukumab, sarilumab, guselkumab, romosozumab) that are not yet approved in any country. Based on announcements of company plans for regulatory submissions and the estimated completion dates for late-stage clinical studies, and assuming the study results are positive, marketing applications for at least 6 antibody therapeutics (benralizumab, tildrakizumab, emicizumab, galcanezumab, ibalizumab, PRO-140) that are now being evaluated in late-stage clinical studies may be submitted during December 2016* or 2017. Other ‘antibodies to watch' in 2017 include 20 mAbs are undergoing evaluation in pivotal studies that have estimated primary completion dates in late 2016 or during 2017. Of these, 5 mAbs are for cancer (durvalumab, JNJ-56022473, ublituximab, anetumab ravtansine, glembatumumab vedotin) and 15 mAbs are for non-cancer indications (caplacizumab, lanadelumab, roledumab, tralokinumab, risankizumab, SA237, emapalumab, suptavumab, erenumab, eptinezumab, fremanezumab, fasinumab, tanezumab, lampalizumab, brolucizumab). Positive results from these studies may enable submission of marketing applications in 2017 or 2018, or provide justification for additional studies. *See note added in proof for update through December 31, 2016.

National and international medicines agencies have developed innovative methods to expedite promising new medicines to the market and facilitate early patient access. Some of these approval pathways are the conditional approval and the adaptive pathways by the European Medicines Agency (EMA); the Promising Innovative Medicine (PIM) designation and the Early Access to Medicines Scheme (EAMS) by the Medicines and Healthcare Products Regulatory Agency (MHRA), as well as the Fast Track, Breakthrough or Accelerated Approval methods by the Food and Drug Administration (FDA). However, at least in Europe, these methods cannot achieve the goal of improving timely access for patients to new medicines on their own; the reimbursement process also has to become adaptive and flexible. In the past 2 years, the effective access (national patient access) to newly approved oncology drugs ranged from 1 to 30 months, with an extremely high variability between European countries. The goal of early patient access in Europe can only be achieved if the national health technology assessment bodies, such as NICE (ENG), HAS (FR), G-BA (DE) or AIFA (IT), provide harmonized, transparent, flexible, conditional and adaptive methods that adopt the level of evidence accepted by the medicines agencies. The efforts from medicines agencies are welcome but will be in vain if health technology assessments do not follow with similar initiatives, and the European ‘postcode' lottery will continue.

ObjectiveThe aim of this study was to assess the marketing status of the new paediatric medicinal products listed in the 10-year report as initially authorised between 2007 and 2016, reflecting the product availability in four Nordic countries.DesignThis is a cross-sectional study.SettingAnalysis of the national medicine agency’s databases in Denmark, Finland, Norway and Sweden.Data sourceNew medicinal products with paediatric indications and new paediatric formulations listed in the Annex of European Medicines Agency’s EU Paediatric Regulation 10-year report.Data analysisThe products were classified according to national marketing status between January 2019 and March 2019, whether a product was authorised and whether the product was marketed.Main outcome measuresThe percentages of the new medicinal products with paediatric indications and new paediatric formulations having a valid marketing authorisation and being marketed, both in terms of the sums of all countries and separately for each country.ResultsAcross the four countries, 21%–32% (16/76–24/76) of the new medicinal products were not marketed. Of the new formulations relevant to children, 29%–50% (16/56–28/56) were not marketed, and a significant proportion of these products had never been marketed.ConclusionsThis study reflects the reality of the implementation of the Paediatric Regulation. The results show that several new paediatric medicines and new formulations are not marketed. This affects the product availability. Similar data from other countries are needed to evaluate the overall European status to find remedies to current situation and increase the availability of the medicines for children.

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.

Background: Relenza represents the first neuraminidase inhibitor (NI), a class of drugs that also includes the drug Tamiflu. Although heralded as breakthrough treatments in influenza, NI efficacy has remained highly controversial. A key unsettled question is why the United States Food and Drug Administration (FDA) has approved more cautious efficacy statements in labelling than European regulators for both drugs. Methods: We conducted a qualitative analysis of United States and European Union regulatory appraisals for Relenza to investigate the reasons for divergent regulatory interpretations, pertaining to Relenza's capacity to alleviate symptoms and reduce frequency of complications of influenza. Results: In Europe, Relenza was evaluated via the so-called national procedure with Sweden as the reference country. We show that FDA reviewers, unlike their European (i.e. Swedish) counterpart, (1) rejected the manufacturer's insistence on pooling efficacy data, (2) remained wary of subgroup analyses, and (3) insisted on stringent statistical analyses. These differences meant that the FDA was less likely to depart from prevailing regulatory and scientific standards in interpreting trial results. We argue that the differences are explained largely by divergent institutionalised review methodologies, i.e. the European regulator's reliance on manufacturer-compiled summaries compared to the FDA's examination of original data and documentation from trials. Conclusions: The FDA's more probing and meticulous evaluative methodology allowed its reviewers to develop 'deep' knowledge concerning the clinical and statistical facets of trials, and more informed opinions regarding suitable methods for analysing trial results. These findings challenge the current emphasis on evaluating regulatory performance mainly in terms of speed of review. We propose that persistent uncertainty and knowledge deficits regarding NIs could have been ameliorated had regulators engaged in the public debates over the drugs' efficacy and explained their contrasting methodologies and judgments. Regulators use major resources to evaluate drugs, but if regulators' assessments are not effectively disseminated and used, resources are used inefficiently.

Background: Despite a steady stream of headlines suggesting they will transform the future of healthcare, high-tech regenerative medicines have, to date, been quite inaccessible to patients, with only eight having been granted an EU marketing licence in the last 7 years. Here, we outline some of the historical reasons for this paucity of licensed innovative regenerative medicines. We discuss the challenges to be overcome to expedite the development of this complex and rapidly changing area of medicine, together with possible reasons to be more optimistic for the future. Discussion: Several factors have contributed to the scarcity of cutting-edge regenerative medicines in clinical practice. These include the great expense and difficulties involved in planning how individual therapies will be developed, manufactured to commercial levels and ultimately successfully delivered to patients. Specific challenges also exist when evaluating the safety, efficacy and cost-effectiveness of these therapies. Furthermore, many treatments are used without a licence from the European Medicines Agency, under "Hospital Exemption" from the EC legislation. For products which are licensed, alternative financing approaches by healthcare providers may be needed, since many therapies will have significant up-front costs but uncertain benefits and harms in the long-term. However, increasing political interest and more flexible mechanisms for licensing and financing of therapies are now evident; these could be key to the future growth and development of regenerative medicine in clinical practice. Conclusions: Recent developments in regulatory processes, coupled with increasing political interest, may offer some hope for improvements to the long and often difficult routes from laboratory to marketplace for leading-edge cell or tissue therapies. Collaboration between publicly-funded researchers and the pharmaceutical industry could be key to the future development of regenerative medicine in clinical practice; such collaborations might also offer a possible antidote to the innovation crisis in the pharmaceutical industry.

This article summarizes the scientific review of the application leading to regulatory approval of carfilzomib in combination with lenalidomide and dexamethasone in the European Union., On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy. In a phase III trial in patients with relapsed MM, median progression‐free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0.69; 95% confidence interval, 0.57–0.83; one‐sided log‐rank p value

The routine use of recombinant erythropoiesis-stimulating agents (ESA) over the past three decades has enabled the partial correction of anaemia in most patients with end-stage renal disease (ESRD). Since ESA use frequently leads to iron deficiency, almost all ESA-treated haemodialysis patients worldwide receive intravenous iron (IV) to ensure sufficient available iron during ESA therapy. Patients with inflammatory bowel disease (IBD) are also often treated with IV iron preparations, as anaemia is common in IBD. Over the past few years, liver magnetic resonance imaging (MRI) has become the gold standard method for non-invasive diagnosis and follow-up of iron overload diseases. Studies using MRI to quantify liver iron concentration in ESRD have shown a link between high infused iron dose and risk of haemosiderosis in dialysis patients. In September 2017, the Pharmacovigilance Committee (PRAC) of the European Medicines Agency (EMA) considered convergent publications over the last few years on iatrogenic haemosiderosis in dialysis patients and requested that companies holding marketing authorization for iron products should investigate the risk of iron overload, particularly in patients with end-stage renal disease on dialysis and, by analogy, patients with IBD. We present a narrative review of data supporting the views and decision of the EMA, and then give our expert opinion on this controversial field of anaemia therapeutics.

Objectives: To identify differences in the recommendations for targeted cancer therapies (TCT) in three distinctive European health care systems: Serbian, Scottish and Dutch, and to examine the role of cost effectiveness analyses (CEA) in such recommendations. Methods: A list of currently approved TCTs cited from the European Medicines Agency (EMA) was cross-referenced with the drug reimbursement reports issued by Health Insurance Fund (RFZO) for Serbia, Scottish Medicines Consortium (SMC) for Scotland and Health Institute (ZI) for the Netherlands. The following key variables were gathered from the reports: drug indication, registration status, reimbursement status and outcome of the cost effectiveness evaluation. Results: There were 44 TCTs indicated for 75 cancer sites and approved by EMA. Out of total number of drugs per indication (d/i= 75), 20 were reimbursed in Serbia, and 15 are still without the decision from RFZO. Remaining majority of TCTs is not registered in Serbia. None of submissions neither CEAs were publically available. SMC positively assessed 25 d/i and rejected as much as 30. All appraisals were published, and majority contained full CEAs. Finally, Dutch ZI accepted total of 59 d/i and disapproved use of only 5 d/i. The majority of reimbursed drugs were exempted from CEA in accordance with the policy for expensive hospital drugs. Conclusions: Although data collected for Serbia did not allow us to evaluate practiced policy in broader extent, it is certainly surrounding with the smallest number of reimbursed TCTs. Surprisingly, TCTs in Scotland were comparable to this number, yet reasons for such an outcome were fairly different. It seems that full application of CEA in TCTs submission contributed to 55% of SMC negative recommendations. Its Dutch counterpart, ZI, issued only 8% of negative decisions to TCTs. The mode for a success rate in the Netherlands was special policy that enabled reimbursement of TCTs without CEA.

Objective 1) To compare the Food and Drug Administration's (FDA's) Risk Evaluation and Mitigation Strategies (REMS) and European Medicines Agency's (EMA's) Risk Management Plan (RMP) guidances and 2) to compare REMS and RMPs for specific chemical entities and biological products. Methods FDA, EMA, and pharmaceutical company Web sites were consulted for details pertaining to REMS and RMPs. REMS requirements include medication guides, communication plans, elements to ensure safe use, implementation systems, and specified assessment intervals. RMP requirements are increased pharmacovigilance and risk minimization activities. We compared these requirements for drugs requiring both REMS and RMPs. Results We identified 95 drugs on FDA's REMS list as of March 2010. Of these, there were 29 drugs (11 biologics and 18 new chemical entities) with EMA RMPs. REMS and RMPs are similar in objectives, with comparable toolkits. Both allow flexibility in product-specific actions, recognizing adverse effects of potential concern. Of the 29 drugs reviewed, REMS requirements not included in RMPs were patient medication guides (100% of the drugs), provider communication plans (38%), and routine monitoring of REMS (66%). RMP requirements not included in REMS were specific adverse event reporting (45% of the drugs), prospective registry studies (34%), prospective epidemiology studies (24%), additional trial data (28%), and Summary of Product Characteristics contraindications (76%). Conclusions Both REMS and RMPs provide positive guidance for identification, monitoring, and minimization of risk to patient safety. Currently, neither agency provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively.

Scientific knowledge and our understanding of the human body and diseases have limited any possible treatment tailoring to each patient. The technological advances enabling the integration of various data sets (e.g. ‘-omics', microbiome, epigenetics and environmental exposure) have facilitated a greater understanding of the human body, the molecular basis of disease and all the factors influencing disease onset, progression and response to treatment, thereby ushering in the era of personalized medicine. We evaluate the regulatory approaches available to facilitate early patient access to efficacious and safe compounds in the EU and the USA in order to make more informed recommendations in the future as to the gaps in regulations for early patient access. An in-depth analysis of conditional approvals (EU) and accelerated approvals (USA) is performed based on the publicly available information (European public assessment reports and a summary review of products approved under both programmes). The types of product, indications, time to approval and type of evidence submitted were analysed. Between 2007 and early 2015, 17 products were conditionally approved in the EU and 25 in the USA, most of them in the area of oncology and based on evidence from phase II clinical trial data. Early approval of promising products based on data from early phases of development is already possible in the EU and the USA. Some of the improvements could entail implementing a rolling assessment of evidence in Europe and extending the scope of early dialogues.

Background Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population. Methods Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50 % of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence. Results As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments. Conclusions Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based, endpoints.

In Europe, new medicines are approved or rejected on the basis of the results of studies carried out by the manufacturer and submitted to the European Medicines Agency (EMA). This article briefly presents the main roles and responsibilities of the EMA and the key rules that govern the approval process. The main scientific limitations of this process are highlighted, together with some suggestions for dealing with them.

ObjectivesThe research and development process in the field of rare diseases is characterised by many well-known difficulties, and a large percentage of orphan medicinal products do not reach the marketing approval.This work aims at identifying orphan medicinal products that failed the developmental process and investigating reasons for and possible factors influencing failures.DesignDrugs designated in Europe under Regulation (European Commission) 141/2000 in the period 2000–2012 were investigated in terms of the following failures: (1) marketing authorisation failures (refused or withdrawn) and (2) drugs abandoned by sponsors during development.Possible risk factors for failure were analysed using statistically validated methods.ResultsThis study points out that 437 out of 788 designations are still under development, while 219 failed the developmental process. Among the latter, 34 failed the marketing authorisation process and 185 were abandoned during the developmental process. In the first group of drugs (marketing authorisation failures), 50% reached phase II, 47% reached phase III and 3% reached phase I, while in the second group (abandoned drugs), the majority of orphan medicinal products apparently never started the development process, since no data on 48.1% of them were published and the 3.2% did not progress beyond the non-clinical stage.The reasons for failures of marketing authorisation were: efficacy/safety issues (26), insufficient data (12), quality issues (7), regulatory issues on trials (4) and commercial reasons (1). The main causes for abandoned drugs were efficacy/safety issues (reported in 54 cases), inactive companies (25.4%), change of company strategy (8.1%) and drug competition (10.8%). No information concerning reasons for failure was available for 23.2% of the analysed products.ConclusionsThis analysis shows that failures occurred in 27.8% of all designations granted in Europe, the main reasons being safety and efficacy issues. Moreover, the stage of development reached by drugs represents a specific risk factor for failures.

PURPOSE: Targeted cancer therapies (TCTs) are drugs that specifically act on molecular targets within the cancer cell, causing its regression and/or destruction. Although TCTs offer clinically important gains in survival in one of the most challenging therapeutic areas, these gains are followed by considerable increases in health care expenditures. The aim of this study was to identify differences in the recommendations for TCTs in 3 European health care systems (Serbian, Scottish, and Dutch) and to examine the role of pharmacoeconomic (PE) assessments in such recommendations.METHODS: A list of currently approved TCTs cited from the European Medicines Agency was cross-referenced with drug reimbursement reports issued by the National Health Insurance Fund for Serbia, the Scottish Medicines Consortium for Scotland, and the National Health Institute for the Netherlands. The following key variables were gathered from the reports: drug indication, registration status, reimbursement status, and outcome of the PE evaluation.FINDINGS: There were 41 TCTs approved by the European Medicines Agency for 70 cancer indications. Of the total number of TCT indications, 20 were reimbursed in Serbia, and 25 are still without a decision from the national agency. The remaining TCT indications (n = 25) are not registered in Serbia. None of the submissions or the PE analyses were publicly available. The Scottish Medicines Consortium positively assessed 26 TCT indications and rejected 30. All appraisals were published, and the majority contained full PE assessments. Finally, the Dutch agency accepted 60 TCT indications and disapproved the use of 1. The majority of reimbursed drugs were exempted from PE evaluation in accordance with 2 recent policies regarding expensive hospital drugs.IMPLICATIONS: In the 3 examined health care systems, the reimbursement status of the TCTs differed significantly. Level of PE application within the TCT evaluation procedures seemed to largely affect the final reimbursement decisions. Although, there are special policies in the Netherlands that enabled fast access for 98% of the TCTs that applied for reimbursement, a clear definition of cost-effectiveness threshold and strict requirements for full cost utility assessments in Scotland led to acceptance of only 46% of the TCT submissions. More precise PE guidelines must still be designed for TCT reimbursement in Serbia. Guidelines must account for specific epidemic and economic conditions of the country and could build on the experiences of Scotland and the Netherlands.

Malaria remains a major public health challenge with almost half of the world's population exposed to the risk of contracting the illness. Prompt, effective and well tolerated treatment remains one of the cornerstones in the disease management, with artemisinin-based combination therapy the recommended option for non-severe malaria in endemic areas with predominant Plasmodium falciparum infections. Recent experience has been obtained at the European Medicines Agency with regulatory approval of two such antimalarial fixed combination products. For these cases, two different regulatory pathways were applied. As such, the present contribution describes this experience, emphasising main differences and applicability offered by these regulatory choices.

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.

New initiatives have been introduced in Europe and the USA to encourage more rapid development of antibiotics. The need to ensure these new antibiotics can be safely used in children, and especially neonates, is important owing to high antimicrobial resistance in these patient groups. This review aims to determine what lessons can be learnt from the recent regulatory processes to speed up access to new medicines for children, focusing on antibiotics licensed for adults by the EMA since 2000. For the 11 newly approved antibiotics, 31 clinical trials enrolling children in Europe were identified. However, many of these trials included both adults and children but did not provide a subset analysis for paediatrics, limiting the relevance of their findings. Some studies have been prematurely terminated and others are apparently active but are still not yet recruiting patients. Among paediatric-specific studies, 18 evaluate safety and efficacy of new compounds, 4 are pharmacokinetic studies, but only 2 focus on neonates. Nearly all studies with an agreed Paediatric Investigation Plan have just started or are not yet recruiting. For most antibiotics, despite adult phase 3 studies being completed, with specific concerns for particular drugs already noted, it will take another 3-5 years before adequate prescribing information becomes available for paediatricians. Evidence from this review suggests that we could do better. Lessons should be learnt from paediatric antiretroviral development, with neonatal and paediatric pharmacokinetic, clinical trial and pharmacovigilance drug development programmes being run directly in parallel with adult studies-not a decade behind.