Authorization For Use Research Articles

Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. From November 2015 to November 2016, patients receiving in our institution palbociclib+fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. 60 patients were treated accordingly; median age was 61years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3months, median progression-free survival (mPFS) was 5.8months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4months (HR 1.00; 95% CI 0.55-1.83; P=1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8months with the same magnitude of benefit for fulvestrant-pretreated patients.

Mechanical properties of cement and cement-asphalt matrices with rubber powder

Cement matrices are known from concrete testing. Cement-asphalt matrices made of cement and asphalt emulsion are used in mineral-cement-emulsion mixes (MCEM). The matric strength in MCEM mixtures has not been studied so far. Cement-asphalt matrices with 0/1 mm rubber powder are proposed by the author for use in the MCEM [3, 26]. In this paper the results of the investigation of the mechanical properties of matrices are presented for comparative purposes and for the preliminary evaluation of their suitability for MCEM. The following tests were made: indirect tensile strength, bending strength, compressive strength and rigidity modules in NAT and 4 PB-PR.

The French Compassionate Program "Temporary Authorization For Use" And Thereafter... How Can It Affect Drug Market Access?

The French Compassionate Program "Temporary Authorization For Use" And Thereafter... How Can It Affect Drug Market Access?

OISO, traitement informatisé de la prise en charge en oncogénétique clinique

Oncogenetics is a long-term process, which requires a close relation between patients and medical teams, good familial links allowing lifetime follow-up. Numerous documents are exchanged in between the medical team, which has to frequently interact. We present here a new tool that has been conceived specifically for this management. The tool has been developed according to a model-view-controler approach with the relational system PostgreSQL 9.3. The web site used PHP 5.3, HTML5 and CSS3 languages, completed with JavaScript and jQuery-AJAX functions and two additional modules, FPDF and PHPMailer. The tool allows multiple interactions, clinical data management, mailing and emailing, follow-up plannings. Requests are able to follow all patients and planning automatically, to send information to a large number of patients or physicians, and to report activity. The tool has been designed for oncogenetics and adapted to its different aspects. The CNIL delivered an authorization for use. Secured web access allows the management at a regional level. Its simple concept makes it evolutive according to the constant updates of genetic and clinical management of patients.

Experimental Research on the Manufactureof Parts Composing a Technical System Using Polymer Composite Materials

Abstract The article presents experimental research conducted by the authors for use of polymer composite materials to manufacture pressure parts of subassemblies composition of technical systems, currently manufactured from nonferrous materials. The research aimed to identify and establish a manufacturing technology specific for polymer composite materials and conducting testing and verification of resistance of manufactured parts, including their real operation conditions under pressure. The final part of the article highlights the authors’ conclusions, insisting on the advantages and disadvantages of the proposed method.

49 Lumacaftor/ivacaftor (LUM/IVA) treatment in patients (pts) with cystic fibrosis (CF) aged ≥12 years homozygous for F508del-CFTR: description of a French Temporary Authorization for Use (ATU) cohort

49 Lumacaftor/ivacaftor (LUM/IVA) treatment in patients (pts) with cystic fibrosis (CF) aged ≥12 years homozygous for F508del-CFTR: description of a French Temporary Authorization for Use (ATU) cohort

Safety of the proposed amendment of the specifications for the food additive polyvinyl alcohol-polyethylene glycol-graft-co-polymer (E1209).

The European Commission asked EFSA to provide a scientific opinion on the request for a modification of the EU specifications for polyvinyl alcohol‐polyethylene glycol‐graft‐co‐polymer (PVA‐PEG graft‐co‐polymer) (E 1209) and its possible impact on the safety. In accordance with Annex II to Regulation (EC) No 1333/2008, PVA‐PEG graft‐co‐polymer (E 1209) has a single authorisation for use as a food additive in the EU, in the food category food supplements in solid form. According to the current EU specifications, ethylene glycol and diethylene glycol can be present as impurities in other food additives authorised in the EU, namely in polysorbates (E 432–436) and polyethylene glycol (E 1521). The exposure to ethylene glycol and diethylene glycol from their presence in E 1209 and in the other food additives was estimated considering the maximum limit permitted according to the EU specifications and the new proposed maximum limit in E 1209 of 620 mg/kg for the ethylene glycol individually or in combination with diethylene glycol in E 1209. This proposed request would result in a total exposure from food additive uses below the group tolerable daily intake (TDI) of 0.5 mg/kg body weight (bw) per day allocated by the Scientific Committee on Food (SCF) for these contaminants. Therefore, the Panel concluded that the requested amendment of the EU specifications for E 1209 would not result in a safety concern. The Panel noted that the analytical results provided were consistently and considerably lower (up to 360 mg/kg) than the proposed level of 620 mg/kg for ethylene glycol individually or in combination with diethylene glycol in the EU specifications for E 1209.

Metformin in pregnancy

Metformin in pregnancy

Are additive effects of dietary surfactants on intestinal tight junction integrity an overlooked human health risk? – A mixture study on Caco-2 monolayers

Surfactants may cause dysfunction of intestinal tight junctions (TJs), which is a common feature of intestinal autoimmune diseases. Effects of dietary surfactants on TJ integrity, measured as trans-epithelial resistance (TEER), were studied in Caco-2 cell monolayers. Cytotoxicity was assessed as apical LDH leakage. Monolayers were apically exposed for 60 min to the dietary surfactants solanine and chaconine (SC, potato glycoalkaloids, 0–0.25 mM), perfluorooctane sulfonic acid (PFOS, industrial contaminant, 0–0.8 mM), and sucrose monolaurate (SML, food emulsifier E 473, 0–2.0 mM) separately and as a mixture. Dose-response modelling of TEER EC50 showed that SC were 2.7- and 12-fold more potent than PFOS and SML, respectively. The mixture was composed of 1 molar unit SC, 2.7 units PFOS and 12 units SML (“SC TEER equivalent” proportions 1:1:1). Mixture exposure (0–0.05 mM SC equivalents) dose-response modelling suggested additive action on TJ integrity. Increasing SC and SML concentrations caused increased LDH leakage, but PFOS decreased LDH leakage at intermediate exposure concentrations. In the mixture PFOS appeared to protect from extensive SC- and SML-induced LDH leakage. Complex mixtures of surfactants in food may act additively on intestinal TJ integrity, which should be considered in risk assessment of emulsifier authorisation for use in food production.

Safety and efficacy of Bacillussubtilis PB6 (Bacillussubtilis ATCC PTA-6737) as a feed additive for sows.

Bacillus subtilis PB6 is a feed additive based on viable spores of a strain of Bacillus subtilis. EFSA has already issued several opinions on the safety and efficacy of the additive when used in the feed for a number of avian and porcine species/categories. The applicant is now seeking authorisation for use in sows in order to have benefits in piglets. In the course of previous assessments, no evidence of a toxigenic potential or resistance to relevant antibiotics was found. Consequently, the strain of B. subtilis in the additive, following the qualified presumption of safety approach to safety assessment, is presumed safe for target animals including sows and their offspring, consumers and the environment. In a previous assessment, it was also concluded that the additive is not a skin/eye irritant or a skin sensitiser and that there were no concerns on respiratory sensitisation. The use of the additive with feed for sows is considered unlikely to introduce hazards for users of the product not already considered. Five studies are described in which groups of sows given the additive for a minimum period from the last 3 weeks of pregnancy, throughout farrowing and lactation, until weaning of piglets were compared with a control group. In only two of five studies, there was a significant beneficial effect seen in terms of piglet performance. However, when data from the four similar were pooled and analysed, significant increases in weaned weight and average daily gain were indicated for piglets from sows given the additive. Consequently, the FEEDAP Panel concludes that Bacillus subtilis PB6 when added to diets of sows from 3 weeks before parturition until weaning of piglets at a dose of 1 × 108 CFU/kg complete feed has the potential to improve the growth of piglets from birth to weaning.

A role for strategies in urban climate change adaptation planning: Lessons from London

Global cities are taking a leadership role in climate change adaptation. Increasing numbers of cities are creating climate adaptation plans and strategies, and a wide range of international organizations are developing tools and programs to promote and support further planning, despite the fact that the few studies to date that have evaluated adaptation planning have found it to be ineffective: focused more on broad visions than specific actions. To understand why cities continue to engage in adaptation planning, what benefits planners anticipate, and whether these benefits can be achieved through vision-oriented strategies as well as action-based plans, this study reports on a qualitative case study of the creation and adoption of the 2011 London, United Kingdom, Climate Change Adaptation Strategy. Results from interviews with participants and stakeholders indicate the London Strategy was consciously developed as a vision-setting strategy and was successful in: raising awareness of cross-sectoral risks, coordinating pre-existing adaptation efforts, validating stakeholder engagement, providing political authorization for use of resources and personnel, and creating continuity of purpose across changing political administrations. To accurately capture these benefits in other urban adaptation planning efforts will require a new evaluation approach. Based on the London case, this paper proposes future adaptation strategies be evaluated according to how well they build the adaptive capacity of city institutions to enable ongoing adaptation.

Substances of Very High Concern in Food Contact Materials: Migration and Regulatory Background

Food contact materials (FCMs) are needed to produce, transport, process and store our food. Although essential for handling and protecting food from farm to fork, FCMs are often not inert, and chemical components may partition into food. In Europe, FCMs are regulated under the FCM Framework Regulation 1935/2004 which covers their effects on human health. Environmental effects of FCM substances are included in the scope of the European Chemicals Regulation [Regulation (EC) No 1907/2006 on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)] which aims at substituting Substances of Very High Concern (SVHCs) by safer alternatives. In this study, we focus on 10 FCM substances that are SVHCs and already included in the authorization list of REACH (Annex XIV): We show their possible application in the manufacture of FCMs and give evidence or highlight the absence thereof for migration into food or food simulants. An overview on migration of four phthalates (diisobutyl phthalate, dibutyl phthalate, benzyl butyl phthalate and bis(2‐ethylhexyl) phthalate) and 4,4′‐methylenedianiline from FCMs is provided, based on peer‐reviewed studies and notifications from the Rapid Alert System for Food and Feed. Different approaches in evaluating and handling SVHCs under REACH and the European FCM legislation are discussed, and recommendations on how to increase the safety of FCMs are included. Combining better enforcement, an explicit ban of SVHCs without specific authorization for use in FCMs, and re‐evaluations of previously authorized FCM substances could lead to safer FCMs. In conclusion, a harmonization between REACH and European FCM legislation is desirable for improving legal certainty for FCM users as well as in the interest of public health. Copyright © 2017 John Wiley & Sons, Ltd.

Similar Biologics: Global Opportunities and Issues.

The invention and use of a large number of biologics during the last three decades for treating various deficiencies and chronic disorders has resulted in great benefit to human health. Abundant use of these biologics has been considerably constrained due to the reasons of their increased prices, charged by the inventors up to the time up to which their use were/are protected by intellectual property rights (IPR).Some of these biologics are presently being manufactured by the existing and newer companies as "similar biologics" after the IPR on these products have expired and as a result the prices of several such medicines are coming down."Similar biologics" are also referred to as "biosimilars" and other related names in different parts of the world. The regulatory authorities of different countries have authorized use of "similar biologics" based on comparative evaluation of each of such medicines with the inventor's biologics; these are approved when considered to be closely similar to the inventor's biologics in properties, quality and efficacy. By 2020, a dozen of "inventor's biologicals" having estimated market sale-value of over USD 79 billion are going out of protection of IPR. This would drive entrepreneurs to enter in to the field and the prices are going to crash considerably due to market competition. In course of time more "biosimilars" would go out of IPR. Different proactive governments and the regulatory agencies all over the world are trying to harness the existing and future opportunities by creating regulatory guidelines to ease faster authorization for use of "similar biologics" in their territories. Up to the present time, a small number of "similar biologics" have been approved for use in different countries all over the major parts of the world. More efficient technologies for manufacture of "similar biologics" are also getting developed. Together, these efforts are anticipated to ease the availability of "similar biologics" at more affordable prices to the users/ payers the world over.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

A prospective observational study on the attitude and experience of community pharmacists towards off-label and unlicensed prescriptions for the pediatric population

Off-label is defined as any drug use outside the terms of product license; while the unlicensed use refers to using a drug in children when it has not received marketing authorization for use in them. The objective of the study was to determine the attitude and experience of community pharmacists towards off-label and unlicensed prescriptions for the pediatric population. This study was carried out as a prospective observational study for a period of six months at the community pharmacies in and around Chennai. Validated questionnaire to assess the attitude and experience of community pharmacists towards unlicensed and off-label prescriptions for the paediatric population was given to those community Pharmacists who have registered in the State Pharmacy Council as Pharmacist. Questionnaires issued were self administered by the community pharmacists and the answers recorded by them were collected and then assessed. Over 70% of respondents were familiar with the concept of off-label prescribing, primarily through dispensing experience rather than education. Over 60% of respondents had been asked by the public to sell paediatric over-the-counter medicines, such as antihistamines, analgesics and steroid preparations for off-label use. Most common off-label drug was paracetamol being 32% (BNFC) of all prescribed in this manner. Most common information sources was British national formulary for children (BNFC), Current index medical specialities(CIMS) and local formularies. The majority of respondents (74%) admitted to being familiar with the concept of off-label prescribing .The majority of respondents, 88% agreed or strongly agreed that the pharmacist has a responsibility to inform the prescriber that they are prescribing off-label medicines for children, and 32% unsure that pharmacist also has a responsibility to inform the parents that the medicines prescribed for their children are off-label. Dispensing labeled and licensed drugs in pediatric patients should be promoted among the community pharmacist as well as pediatricians in order to avoid exposing children to unnecessary risk. Participation in Continuing Medical Education should be encouraged among community pharmacist to keep their knowledge updated.

A differentiated approach to the risk assessment from exposure to radon

The paper presents the methods of risk assessment from exposure to radon. Proposed methods implement a differentiated approach to the risk estimates calculation procedure which depends on the purpose of risk assessment. This approach is based on the analysis of the results of practical tests of different risk assessment models on arrays Russian medical and demographic data with and without consideration of the synergistic effect of smoking, in simple and complex exposure scenarios. All of these tests were performed in previous 5 years (results are available elsewhere). In this work the evaluation of effectiveness of radon mitigation actions in schools was used as a test task and results obtained using 4 models («EPA-2003», «Wismut-2006», «FCZ» and «Tomasek-2014») were compared. If it is important to evaluate the effect of reduction of radon concentration on the health of children and adolescents in terms of lifetime lung cancer risk, «Tomasek-2014» model will be the best choice. It is as sensitive as «FCZ» model and ERR is close to that from «Wismut-2006» model, which was earlier proposed by other authors for use with some modifications in Russia. If the data on radon concentration are limited (for example data from radiation-hygienic passports of territories) and constant lifelong exposure scenario is considered, it seems reasonable to apply more simple «Darby-2005» model. Thus, the proposed methods could be used by specialists in various fields in a wide range of tasks, from the risk assessment for the purposes of radiation-hygienic certification and comparative assessment of radiation safety of the population of different regions of Russia on the basis of the generalized statistical data, to the risk assessment in practical works where large amounts of measurement data on the radon concentration and complex exposure scenarios are used.

Role of vitamin B6 in idiopathic burning mouth syndrome: some clinical observations

Introduction : Idiopathic burning mouth syndrome (iBMS) is a chronic oral pain syndrome mainly characterized by a burning sensation in the oral mucosa and an etiopathogenesis that remains unclear, with therapeutic options that are disappointing. Any clinical observation providing insight into the disorder can therefore be of interest. Among metabolic factors, deficiencies of vitamins have been pointed out, but only a few studies have focused on the role of vitamin B6 (vitB6) in this syndrome. In this report, we aimed to highlight the involvement of increased but not decreased vitB6 serum levels in a subgroup of BMS Patients. Patients and Methods : Medical files of patients who attended the chronic orofacial pain consultation, in the dental departement of the Groupe Hospitalier Pitie-Salpetriere (GHPS) in Paris (France) between 09/03/2008 and 12/19/2015 were retrieved from the hospital database and analyzed. This retrospective study was approved by the board of the dental department and authorization for use of patient data was obtained from the National Personal Data Protection Committee (Commission Nationale de l’Informatique et des Libertes (CNIL)) (#1913570). Results : Seven per- or postmenopausal female patients out of 42 diagnosed with iBMS (17%) displayed an increase in their serum levels of vitB6, one to six times the upper normal limits. There was a statistically significant correlation between pain and vitB6 levels. Moreover, in two patients, the reversal of vitB6 levels to normal values resulted in significant decreases in pain severity. Conclusion : These clinical observations report for the first time a potential implication of elevated vitB6 serum levels in the burning sensation which might be specific to a subgroup of iBMS patients.

Safety and Efficacy of Blinatumomab Used in Children with B-Precursor Acute Lymphoblastic Leukemia (ALL) Treated in French Hematological Centers

Blinatumomab is a monoclonal bispecific antibody, combining two binding sites: a CD3 site for T cells and a CD19site for the target B cells. Blinatumomab has demonstrated efficacy and safety in adult relapsed/refractory B-precursor ALL (R/R ALL) populations, but also in the pediatric R/R ALL population as shown by interim results from the Phase 1b/2 study MT103-205 (Gore L et al, ASH 2014).Patients and methods: this retrospective study aims to evaluate safety and efficacy of Blinatumomab in 17 pediatric pts with B-precursor ALL treated in 4 french hematological centers between April 2013 and December 2015 within a compassionate use frame. These 17 pts represent the whole population of French children treated with Blinatumomab outside a clinical trial but under a Temporary Authorization for Use (ATU) given by the French Regulatory Agency (ANSM) within this period. Median age was 6.6 years (8 months - 16.6 years).Results: 1)7 pts (41%) received Blinatumomab at a dose of 15 mcg/m2/day for 28 days/cycle in first or second complete remission for minimal residual disease (MRD) persistence. Six of those 7 pts had a molecular remission (MRD <10-4) after 1 or 2 cycles of Blinatumomab. Those 6 responders could be led to allo-HSCT. One of these died of invasive aspergillosis 131 days after allo-HSCT, without bone marrow relapse. Three pts had no relapse with a median follow-up time of 147 days (142 - 240 days). Time to relapse for the 2 remaining pts was respectively 75 and 86 days after allo-HSCT. One non responder pt was not led to allo-HSCT and died of ALL progression. 2) Ten pts (59%) with R/R ALL received Blinatumomab at a dose of 5-15 mcg/m2/day for 28 days during the first cycle then at a dose of 15 mcg/m2/day for all subsequent cycles; 2 of them being in marrow relapse after allo-HSCT. Four of those 10 pts achieved a molecular remission after 1 or 2 cycles and could receive an allo-HSCT. Two of those 4 pts had a bone marrow relapse respectively 89 and 135 days after allo-HSCT. One patient had an isolated meningeal relapse 141 days after allo-HSCT. Of note no marrow relapse has been observed in this patient with a follow-up of 2.7 years after allo-HSCT. One patient was free of disease with a short follow-up (69 days after allo-HSCT). The 6 pts who did not achieve molecular remission after one or two cycles of Blinatumomab died from ALL progression.3) In total, 10 of 17 pts have achieved a molecular remission after 1 or 2 cycles of Blinatumomab. Four of those 10 pts are alive without any further relapse, with a median follow-up time of 144 days after allo-HSCT (69 - 240 days). The 7 pts who were not in molecular remission after 1 or 2 cycles of Blinatumomab all died of ALL progression.4) Safety: regarding treatment-related adverse events of grade ≥2, 5 of 17 pts (29%) had a cytokine release syndrome of grade ≥ 2 (grade 2= 3, grade 4= 2). Five pts (29%) had an infection: 2 pts had a grade 3 viral infection (HSV oral recurrence, n=1 and herpes zoster, n=1). Two pts had grade 3 sepsis (<i>Enterococcus faecalis<i/>, n=1 and <i>Staphylococcus haemolyticus<i/>, n=1). One patient had a grade 3 soft tissue mucormycosis. Three pts (18%) had hepatic toxicity (≥ grade 3 increased ALAT, n=2). One patient had a grade 4 pericarditis without documented infection. No neurological event was observed.Conclusion: Although our numbers are small 1) Blinatumomab is an effective bridge to HSCT for pts with persisting high MRD after intensive chemotherapy. 2) A 40% MRD response rate has been found for R/R pts but with a dismal final outcome. 3) Toxicity is manageable with a low neurological event rate (none in this study). Blinatumomab should be developed in less advanced B lineage ALL in children. DisclosuresBaruchel:Amgen: Consultancy. Brethon:Amgen: Consultancy.

Military Force and Violence, but Neither War nor Hostilities

Against all hope for change, President Barack Obama has been a war president and a vigorous one at that. This Article considers the legality of his uses of force in Libya and against ISIS. When the President waged war against Libya in 2011, he acted contrary to the Constitution and its allocation of the declare war power to Congress. In simple terms, the President unconstitutionally declared war against Libya. Moreover, the aerial bombardment of Libyan forces constituted hostilities under the War Powers Resolution. Given that Resolution’s time constraint on hostilities, the President’s failure to halt the war against Libya infringed that Resolution. With respect to ISIS, however, I believe that the President’s continuing war is legal. The 2001 Authorization for Use of Military Force sanctions the use of necessary and appropriate force against those organizations that conducted the 9/11 attacks. Because al Qaeda perpetrated the 9/11 attacks, when the predecessor of ISIS joined al Qaeda in 2004, the predecessor thereby made itself a lawful target under the 2001 Authorization. Though ISIS splintered from al Qaeda in 2014, it retains the stigma of its former association with al Qaeda and remains subject to uses of military force by the United States.

1234P - Osimertinib in EGFR T790M positive advanced NSCLC (aNSCLC) – real–life data from the French temporary authorization for use (ATU) program

1234P - Osimertinib in EGFR T790M positive advanced NSCLC (aNSCLC) – real–life data from the French temporary authorization for use (ATU) program

Obama's AUMF Legacy

Despite massive changes in the geographical scope of the conflict that began on 9/11, the strategy and tactics employed, and the identity of the enemy, the 2001 Authorization for Use of Military Force (“AUMF”) remains the principal legal foundation under U.S. domestic law for the President to use force against and detain members of terrorist organizations. For many years, President Obama proclaimed that he wanted to repeal the AUMF and end the AUMF-authorized conflict. By the closing year of his presidency, however, his administration had established the AUMF as the legal foundation for an indefinite conflict against Al Qaeda and associated groups and extended that foundation to cover a significant new conflict against the Islamic State. This transformation of the AUMF is one of the most remarkable legal developments in American public law in the still-young twenty-first century, and it will stand as one of President Obama’s primary legal legacies. In addition to establishing this descriptive claim, this Essay considers how the Obama administration has invoked international law in making arguments about the scope of the AUMF. As the Essay explains, although the Obama administration often maintained that international law was an important constraint on its actions, on a range of issues where international law was unsettled it interpreted it in ways that supported presidential discretion and flexibility under the AUMF.