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Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist used for the management of type 2 diabetes and obesity. It was the first GLP-1 receptor agonist to be approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of obesity. To date, numerous skin adverse reactions to liraglutide have been reported, but data regarding hypersensitivity reactions are scarce, raising concerns about its safety and clinical management. We present the case of a 56-year-old female patient with class 3 obesity who was started on subcutaneous liraglutide (Saxenda) by her endocrinologist. One month after starting the aforementioned treatment, the patient presented well-defined, round, erythematous pruriginous plaques surrounding the injection site, around 24 hours after the drug administration. A liraglutide-induced, delayed-type hypersensitivity reaction was suspected, which could be subsequently confirmed by allergy testing and histopathological study. This paper explores the clinical use of liraglutide, the occurrence of hypersensitivity reactions, diagnosis, management, and implications for future research. Understanding and managing liraglutide hypersensitivity is crucial to ensuring the safety and efficacy of this medication. [ABSTRACT FROM AUTHOR]

Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process. [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]

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]

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 product Teysuno™ (S-1) contains tegafur, a prodrug of 5-fluorouracil (5-FU), and two modulators of 5-FU metabolism, gimeracil and oteracil. The main clinical study in this application was a randomized controlled study comparing S-1 plus cisplatin with 5-FU plus cisplatin. In this study, median overall survival times of 8.6 months and 7.9 months for S-1 plus cisplatin and 5-FU plus cisplatin, respectively, were observed (hazard ratio, 0.92; 95% confidence interval, 0.80 -1.05). The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded that S-1 in combination with cisplatin (75 mg/m2) was noninferior to 5-FU plus cisplatin (100 mg/m2) in patients with advanced gastric cancer and adopted a positive opinion recommending the marketing authorization for this product for the treatment of advanced gastric cancer when given in combination with cisplatin. The recommended dose of S-1 is 25 mg/m2 (expressed as tegafur content) twice a day, for 21 consecutive days followed by 7 days rest (one treatment cycle), in combination with 75 mg/m2 cisplatin i.v. administered on day 1. This treatment cycle is repeated every 4 weeks. The most common side effects reported in the pivotal study were anemia, neutropenia, vomiting, diarrhea, abdominal pain, weight decrease, anorexia, and fatigue. The objective of this paper is to summarize the scientific review of the application leading to approval in the EU. The full scientific assessment report and the summary of product characteristics are available on the European Medicines Agency website (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

On April 19, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union (EU) for ofatumumab (Arzerra®; Glaxo Group Ltd, Greenford, Middlesex, U.K.). The decision was based on the favorable opinion of the Committee for Medicinal Products for Human Use recommending a conditional marketing authorization for ofatumumab for the treatment of chronic lymphocytic leukemia (CLL) in patients refractory to fludarabine and alemtuzumab. A conditional marketing authorization means that additional data to confirm the benefit-risk balance of ofatumumab are awaited. The active substance of Arzerra® is ofatumumab, a monoclonal antibody medicinal product (ATC code L01XC10). The recommended dose is 300 mg of atumumab for the first infusion and 2,000 mg of atumumabfor all subsequent infusions. The infusion schedule is eight consecutive weekly infusions, followed 4-5 weeks later by four consecutive monthly (i.e., every 4 weeks) infusions. Ofatumumab targets CD20, a cell surface marker of B lymphocytes, which is followed by cell lysis via complement- dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. The benefit of ofatumumab is the control of CLL in patients who are refractory to both fludarabine and alemtuzumab, which was indicated by a high response rate. The most common side effects are infections and infusion reactions. The objective of this paper is to summarize 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 EMAwebsite (http://www.ema.europa.eu). [ABSTRACT FROM AUTHOR]

The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis. They found that Th-17 immune cells increased with very low exposure to BPA and used this endpoint to revise the TDI to be human health protective. A number of regulatory agencies including the European Medicines Agency (EMA) have written formal disagreements with several elements of EFSA's proposal. The European Commission will now decide whether to accept EFSA's recommendation over the objections of EMA. If the Commission accepts EFSA's recommendation, it will be a landmark action using knowledge acquired through independent scientific studies focused on biomarkers of chronic disease to protect human health. The goal of this Perspective is to clearly articulate the monumental nature of this debate and decision and to explain what is at stake. Our perspective is that the weight of evidence clearly supports EFSA's proposal to reduce the TDI by 20 000-fold. [ABSTRACT FROM AUTHOR]

The classical approach to analyze pharmacokinetic (PK) data in bioequivalence studies aiming to compare two different formulations is to perform noncompartmental analysis (NCA) followed by two one-sided tests (TOST). In this regard, the PK parameters area under the curve (AUC) and $C_{\max}$ are obtained for both treatment groups and their geometric mean ratios are considered. According to current guidelines by the U.S. Food and Drug Administration and the European Medicines Agency, the formulations are declared to be sufficiently similar if the $90\%$ confidence interval for these ratios falls between $0.8$ and $1.25 $. As NCA is not a reliable approach in case of sparse designs, a model-based alternative has already been proposed for the estimation of $\rm AUC$ and $C_{\max}$ using nonlinear mixed effects models. Here we propose another, more powerful test than the TOST and demonstrate its superiority through a simulation study both for NCA and model-based approaches. For products with high variability on PK parameters, this method appears to have closer type I errors to the conventionally accepted significance level of $0.05$, suggesting its potential use in situations where conventional bioequivalence analysis is not applicable. [ABSTRACT FROM AUTHOR]

Background Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life, especially in older age. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA). Methods Fifteen therapeutic areas which commonly lead to relevant mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA until September 2020 were examined for mobility endpoints included in their 'main studies'. Clinical study registries and primary scientific publications for these studies were also reviewed. Results Four hundred and eighty-four EPARs yielded 186 relevant documents with 402 'main studies'. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes and 13 composite endpoints) were used. Only 15.7% of those tools distinctly informed on patients' mobility status. Out of 402, 105 (26.1%) of the 'main studies' did not have any mobility assessment. Furthermore, none of these studies included a digital mobility outcome. Conclusions For conditions with a high impact on mobility, mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores susceptible to reporting biases were predominantly used. [ABSTRACT FROM AUTHOR]

Time is of the essence in evaluating potential drugs and biologics for the treatment and prevention of COVID‐19. There are currently 876 randomized clinical trials (phase 2 and 3) of treatments for COVID‐19 registered on clinicaltrials.gov. Covariate adjustment is a statistical analysis method with potential to improve precision and reduce the required sample size for a substantial number of these trials. Though covariate adjustment is recommended by the U.S. Food and Drug Administration and the European Medicines Agency, it is underutilized, especially for the types of outcomes (binary, ordinal, and time‐to‐event) that are common in COVID‐19 trials. To demonstrate the potential value added by covariate adjustment in this context, we simulated two‐arm, randomized trials comparing a hypothetical COVID‐19 treatment versus standard of care, where the primary outcome is binary, ordinal, or time‐to‐event. Our simulated distributions are derived from two sources: longitudinal data on over 500 patients hospitalized at Weill Cornell Medicine New York Presbyterian Hospital and a Centers for Disease Control and Prevention preliminary description of 2449 cases. In simulated trials with sample sizes ranging from 100 to 1000 participants, we found substantial precision gains from using covariate adjustment–equivalent to 4–18% reductions in the required sample size to achieve a desired power. This was the case for a variety of estimands (targets of inference). From these simulations, we conclude that covariate adjustment is a low‐risk, high‐reward approach to streamlining COVID‐19 treatment trials. We provide an R package and practical recommendations for implementation. [ABSTRACT FROM AUTHOR]

Background Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. Methods This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3–5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52–104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)—hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration—change in Hb from BL to the average Hb level during Weeks 28–52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. Results A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48–58.93] and change in Hb from BL [roxadustat – placebo: +1.692 (95% CI 1.52–1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). Conclusions Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable. [ABSTRACT FROM AUTHOR]

On August 25, 2020, a marketing authorization valid through the European Union was issued for belantamab mafodotin monotherapy for the treatment of multiple myeloma (MM) in adult patients who have received at least four prior therapies, whose disease is refractory to at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and an anti‐CD38 monoclonal antibody (mAb), and who have demonstrated disease progression on the last therapy. Belantamab mafodotin is an antibody‐drug conjugate that combines a mAb, which binds specifically to B‐cell maturation antigen, with maleimidocaproyl monomethyl auristatin F, which is a cytotoxic agent. It was evaluated in Study 205678 (DREAMM‐2), an open‐label, two arm, phase II, multicenter study in patients with MM who had relapsed following treatment with at least three prior therapies, who were refractory to an IMiD, a PI, and an anti‐CD38 mAb alone or in combination. Patients were randomized to receive 2.5 mg/kg (n = 97) or 3.4 mg/kg (n = 99) belantamab mafodotin by intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. Belantamab mafodotin achieved an overall response rate (ORR) of 32% (97.5% confidence interval [CI]: 22–44) with a median duration of response (DoR) of 11 months (95% CI: 4.2 to not reached). The most frequently (≥20%) reported adverse reactions grades 3–4 with belantamab mafodotin were keratopathy (31%), thrombocytopenia (22%), and anemia (21%). With regard to the corneal risks associated with belantamab mafodotin, patients would need to undergo specific ophthalmic examinations so that any findings can be promptly and adequately managed. The scientific review concluded that a 32% ORR and a median DoR of 11 months observed with belantamab mafodotin was considered clinically meaningful. Given the manageable toxicity profile and considering that belantamab mafodotin has a mechanism of action that is different from that of authorized treatments in this group of highly pretreated patients whose disease is refractory to three classes of agents, the benefit risk for belantamab mafodotin monotherapy was considered positive, although the efficacy and safety evidence were not as comprehensive as normally required. Implications for Practice: Belantamab mafodotin (Blenrep, GlaxoSmithKline, St. Louis, MO, U.S.A) was approved in the European Union as monotherapy for the treatment of adult patients with refractory/relapsed multiple myeloma. Belantamab mafodotin resulted in durable response in highly pretreated patients whose disease is refractory to three classes of agents. Belantamab mafodotin is a monoclonal antibody against B‐cell maturation antigen conjugated with the potent antimitotic agent maleimidocaproyl monomethyl auristatin. This is the first monoclonal antibody to target this antigen in multiple myeloma, which represents a true novelty from a pharmacological point of view. This article summarizes the scientific review of the application leading to regulatory approval of belantamab mafodotin in the EU. [ABSTRACT FROM AUTHOR]

On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310‐301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin‐cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60–75 years with untreated high‐risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin‐cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52–0.90; one‐sided p =.003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. Implications for Practice: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia‐related changes and therapy‐related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML. This article addresses development and authorization of Vyxeos for the treatment of acute myeloid leukemia, summarizing the scientific review of the application leading to regulatory approval in the European Union. [ABSTRACT FROM AUTHOR]

Summary: Statistical methodology plays a crucial role in drug regulation. Decisions by the US Food and Drug Administration or European Medicines Agency are typically made based on multiple primary studies testing the same medical product, where the two‐trials rule is the standard requirement, despite shortcomings. A new approach is proposed for this task based on the harmonic mean of the squared study‐specific test statistics. Appropriate scaling ensures that, for any number of independent studies, the null distribution is a χ2‐distribution with 1 degree of freedom. This gives rise to a new method for combining one‐sided p‐values and calculating confidence intervals for the overall treatment effect. Further properties are discussed and a comparison with the two‐trials rule is made, as well as with alternative research synthesis methods. An attractive feature of the new approach is that a claim of success requires each study to be convincing on its own to a certain degree depending on the overall level of significance and the number of studies. The new approach is motivated by and applied to data from five clinical trials investigating the effect of carvedilol for the treatment of patients with moderate to severe heart failure. [ABSTRACT FROM AUTHOR]

Maraviroc (Pfizers UK-427857, Selzentry or Celsentri outside the USA) is the first agent in the new class of oral HIV-1 entry inhibitors to acquire approval by the US Food and Drug Administration and the European Medicine Agency. Considering the mechanism of action, it is expected that this drug will be effective only in a subpopulation of HIV-1-infected people, namely those harbouring the R5 virus. The favourable toxicity profile of the drug has been demonstrated in Phase III clinical trials in treatment-naive (MERIT) and treatment-experienced (MOTIVATE) patients. In the latter population, maraviroc showed a superior antiviral efficacy and immunological activity compared with optimized backbone therapy placebo. However, in MERIT, a prospective double-blind, randomized trial in treatment-naive patients, maraviroc zidovudine/lamivudine failed to prove non-inferiority to efavirenz zidovudine/lamivudine as standard of care regimen in the 48 week intention-to-treat analysis. Using an assay with higher sensitivity for minority CXCR4-using (X4) HIV variants (the enhanced Trofile™ assay—Monogram), non-inferiority was reached for the maraviroc- versus efavirenz-based combination. These data indicate the important impact of the sensitivity of tropism testing on treatment outcome of maraviroc-containing regimens. This paper discusses both the prospective and retrospective analyses of the MERIT data and highlights the impact of these results on daily practice in HIV care. [ABSTRACT FROM AUTHOR]

The objectives of this study were to evaluate the injection site pathology and determine tissue residue depletion of tulathromycin in calves following pneumatic dart administration and to calculate the associated extralabel withdrawal interval (WDI). Castrated male Holstein calves were injected with ~2.6 mg/kg tulathromycin via pneumatic dart administration. At 1 (n = 2), 6, 12, 18, and 24 d after drug injection (n = 3/time point), calves were euthanized, and muscle, liver, kidney, fat, and injection site samples were harvested and analyzed for tulathromycin concentrations using a LC-MS/MS method. Gross pathology and histopathology evaluations on the injection site samples were also performed. Pneumatic dart administration of tulathromycin caused severe localized lesions of hemorrhage and edema on days 1 and 6, as well as severe pathological reactions in the subcutaneous muscle on days 1, 6, and 12. Slight to moderate reactions were still observed in the majority of the skin or subcutaneous/muscle samples on day 24. Measured tulathromycin concentrations were converted to calculate the concentrations of the marker residue CP-60,300 by dividing a conversion factor of 1.4. The data were used to calculate extralabel WDIs based on the guidelines from U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The results showed that tulathromycin concentrations were the highest in the liver (4,877.84 ± 65.33 µg/kg), kidney (5,819.52 ± 1,087.00 µg/kg), muscle (1,717.04 ± 140.35 µg/kg), injection site (51,884.05 ± 7,529.34 µg/kg), and fat (161.69 ± 36.48 µg/kg) at 6, 1, 1, 1, and 1 d, respectively, after treatment. Tulathromycin concentrations remained above the limit of quantification of 5 µg/kg in all tissues at 24 d. The calculated WDIs based on kidney data were 26 d using EMA method, 36 d using FDA method based on CP-60,300 data, and 45 d using FDA method based on tulathromycin data. These results suggest that pneumatic dart administration of tulathromycin causes injection site reactions in calves and an extended WDI is needed. One limitation of this study was the small sample size of 3 that did not meet FDA guideline requirement. Therefore, the calculated WDIs should be considered as preliminary and additional studies that use a larger number of animals and directly measure the concentrations of the marker residue CP-60,300 are needed to make a more conclusive recommendation on the extralabel WDI. [ABSTRACT FROM AUTHOR]

Background Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. Methods Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. Results An overall number of 33 240 (e.g. 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. Conclusion Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications. [ABSTRACT FROM AUTHOR]

There is growing evidence from Phase III randomized clinical trials of the cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in patients with diabetes mellitus. It is hypothesized that these benefits are mediated by mechanisms other than glucose control. To address this, we performed a systematic review of data from preclinical studies examining the direct cardioprotective effects of SGLT2 inhibitors. Medline, EMBASE, CINAHL, and International Pharmaceutical Abstracts databases were searched for preclinical studies that examined the potential cardioprotective effects of SGLT2 inhibitors. Submission documents to the US Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceutical and Medical Devices Agency for the registration of SGLT2 inhibitors were also reviewed. A total of 36 reports were included in the final analysis. The potential direct cardiovascular benefits of SGLT2 inhibitors include: augmentation of signal transducer and activator of transcription 3; inhibition of sodium hydrogen exchange; reduction of atherosclerosis; modulation of natriuretic peptides; vasodilation; modulation of sympathetic tone; and reduction of inflammation, oxidative stress, endoplasmic reticulum stress, and cardiac glucose uptake via down-regulation of SGLT1 expression. There are a number of mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits beyond glycaemic control. [ABSTRACT FROM AUTHOR]

Abstract: On May 20, 2016, a conditional marketing authorization valid through the European Union (EU) was issued for daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who had demonstrated disease progression on the last therapy. The review of daratumumab was conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, especially from the point of view of therapeutic innovation. Daratumumab monotherapy achieved an overall response rate of 29.2% (95% confidence interval [CI] 20.8 to 38.9) in patients with multiple myeloma who had received at least three prior lines of therapy (including a PI and IMiD) or were double refractory to a PI and an IMiD (Study MMY2002). In patients with multiple myeloma relapsed from or refractory to two or more different prior therapies, including IMiDs (e.g., thalidomide, lenalidomide) and PI, an overall response was observed in 15 patients (35.7%, 95% CI: 21.6 to 52.0) (Study GEN501). On April 28, 2017, the therapeutic indication was extended to include the use of daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. This was based on two subsequent phase III studies of daratumumab in combination with lenalidomide/low‐dose dexamethasone (MMY3003) and bortezomib/low dose dexamethasone (MMY3004). The most common side effects (grade 3–4) associated with daratumumab included neutropenia (37%), thrombocytopenia (23%), anemia (16%), pneumonia (10%), lymphopenia (8%), infusion‐related reactions (6%), upper respiratory tract infection (5%), and fatigue (5%). The objective of this study was to summarize the scientific review done by the CHMP of the application leading to regulatory approval in the EU. The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website ( www.ema.europa.eu). Implications for Practice: A conditional Marketing authorization was issued in the European Union for daratumamb as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, based on the response rate data from two single‐agent studies. Darzalex, a novel monoclonal antibody targeted against CD38, demonstrated a durable response rate in a heavily pre‐treated population with limited treatment options based on the response rate data from two single‐agent studies. The addition of daratumumab to lenalidomide and dexamethasone (study MMY3003), or bortezomib and dexamethasone (MMY3004), demonstrated a positive effect on progression‐free survival in patients with multiple myeloma who had received at least one prior therapy. Following submission of the controlled data of the MMY3003 and MMY3004 studies, the efficacy and safety of daratumumab was confirmed and the approval of daratumumab was converted to standard approval. [ABSTRACT FROM AUTHOR]

The in vitro hollow fiber system model has been qualified by the European Medicines Agency as a methodology for use in support of selection and development of antituberculosis regimens. More data are expected to be generated in the future to further characterize its value. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article informs that the European Medicines Agency has approved the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. It mentions that alirocumab and evolocumab are human monoclonal antibodies, that bind selectively to PCSK9, a protein that regulates the recycling of LDL receptors on the surface of liver cells.

On March 27, 2013, a conditional marketing authorization valid throughout the European Union was issued for bosutinib (Bosulif) for the treatment of adult patients with chronic-phase, accelerated-phase, and blast-phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) previously treated with one tyrosine kinase inhibitor or more and for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options. Bosutinib is a kinase inhibitor that targets the BCR-ABL kinase. The recommended dose is 500 mg of bosutinib once daily. The main evidence of efficacy for bosutinib was based on a CML subgroup analysis of study 3160A4-200, a phase I/II study of bosutinib in Ph+ leukemia in imatinib-resistant or intolerant CML. The subgroup was defined based on the presence of a BCR-ABL kinase domain mutation that would be expected to confer resistance to dasatinib (F317, E255) or nilotinib (E255, Y253, F359) and expected to have sensitivity to bosutinib or based on the presence of medical conditions or prior toxicities that may predispose the patient to unacceptable risk in the setting of nilotinib or dasatinib therapy. A conditional marketing authorization was granted because of the limited evidence of efficacy and safety currently supporting this last-line indication. [ABSTRACT FROM AUTHOR]

Objectives Two-stage clinical designs are currently recommended by the regulatory authorities for the assessment of bioequivalence ( BE). A specific statistical methodology was recently proposed by the European Medicines Agency ( EMA). The aims of this article are to elaborate on the suggested statistical design from the EMA and to compare it with the existing statistical methods reported in the literature. Methods Monte Carlo simulations were used to simulate the conditions of a two-stage BE design. The starting sample size was either 24 or 48, whereas the coefficient of variation of the within-subject variability was equal to 20% and 40%. Several geometric mean ratio levels of the BE metric were considered. Under each condition, 1 000 000 studies were simulated. Key findings The overall performance, in terms of percentage of BE acceptance, is identical. The additional term, 'sequence × stage', suggested in the EMA method is in most cases nonsignificant. The same results were obtained regardless of the type (fixed or random) of the effect applied to the 'subjects' term. Conclusions Any BE study either finished or in progress which relies on the existing literature methodology leads to the same percentage of BE acceptance as if it was analysed with the recently proposed EMA method. [ABSTRACT FROM AUTHOR]

The article offers guidelines on the safe use of isotretinoin for the treatment of acne in Great Britain. It states that the Medicine and Healthcare Products Regulatory Agency (MHRA) adopted the recommendations of the European Medicines Agency regarding the intake of isotretinoin among pregnant women since the drug is teratogenic. It mentions that the drug is contraindicated in several conditions including hypervitaminosis, hyperlipidemia and hepatic insufficiency.

Background. Erythropoiesis-stimulating agents (ESAs) such as epoetin alfa and beta, and darbepoetin alfa have improved the management of anaemia secondary to chronic kidney disease. Numerous studies have reported a dose reduction when patients receiving dialysis were converted from epoetin to darbepoetin alfa using the starting dose conversion of 200:1 as indicated on the prescribing label by the European Medicines Agency. The objective of this meta-analysis was to summarize the existing body of scientific evidence to evaluate the potential dose savings when comparing epoetin alfa or beta to darbepoetin alfa. [ABSTRACT FROM PUBLISHER]

The article focuses on a study related to relationship of bullous pemphigoid (BP) with different neurological diseases such as multiple sclerosis. Topics discussed include cross-reactivity towards epithelial and neuronal isoforms leads to autoantibodies development in BP through adhesion complex BPAG-1; analysis of risks related to prevalence of MS among BP patients; and consideration of Dimethyl fumarate usage for treatment of BP with approval of the European Medicines Agency.