Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014

INTRODUCTION: The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence. OBJECTIVE: To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). METHODS: Drug approval data were downloaded from the EMA website and the 'Drugs@FDA' database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period. RESULTS: Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time. DISCUSSION: Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators

Polarised target for Drell-Yan experiment in COMPASS at CERN, part I

In the polarised Drell-Yan experiment at the COMPASS facility in CERN pion beam with momentum of 190 GeV/c and intensity about $10^8$ pions/s interacted with transversely polarised NH$_3$ target. Muon pairs produced in Drel-Yan process were detected. The measurement was done in 2015 as the 1st ever polarised Drell-Yan fixed target experiment. The hydrogen nuclei in the solid-state NH$_3$ were polarised by dynamic nuclear polarisation in 2.5 T field of large-acceptance superconducting magnet. Large helium dilution cryostat was used to cool the target down below 100 mK. Polarisation of hydrogen nuclei reached during the data taking was about 80 %. Two oppositely polarised target cells, each 55 cm long and 4 cm in diameter were used. Overview of COMPASS facility and the polarised target with emphasis on the dilution cryostat and magnet is given. Results of the polarisation measurement in the Drell-Yan run and overviews of the target material, cell and dynamic nuclear polarisation system are given in the part II.Comment: 4 pages, 2 figures, Proceedings of the 22nd International Spin Symposium, Urbana-Champaign, Illinois, USA, 25-30 September 201

How much do we really lose?—Yield losses in the proximity of natural landscape elements in agricultural landscapes

Natural landscape elements (NLEs) in agricultural landscapes contribute to biodiversity and ecosystem services, but are also regarded as an obstacle for large‐scale agricultural production. However, the effects of NLEs on crop yield have rarely been measured. Here, we investigated how different bordering structures, such as agricultural roads, field‐to‐field borders, forests, hedgerows, and kettle holes, influence agricultural yields. We hypothesized that (a) yield values at field borders differ from mid‐field yields and that (b) the extent of this change in yields depends on the bordering structure. We measured winter wheat yields along transects with log‐scaled distances from the border into the agricultural field within two intensively managed agricultural landscapes in Germany (2014 near Göttingen, and 2015–2017 in the Uckermark). We observed a yield loss adjacent to every investigated bordering structure of 11%–38% in comparison with mid‐field yields. However, depending on the bordering structure, this yield loss disappeared at different distances. While the proximity of kettle holes did not affect yields more than neighboring agricultural fields, woody landscape elements had strong effects on winter wheat yields. Notably, 95% of mid‐field yields could already be reached at a distance of 11.3 m from a kettle hole and at a distance of 17.8 m from hedgerows as well as forest borders. Our findings suggest that yield losses are especially relevant directly adjacent to woody landscape elements, but not adjacent to in‐field water bodies. This highlights the potential to simultaneously counteract yield losses close to the field border and enhance biodiversity by combining different NLEs in agricultural landscapes such as creating strips of extensive grassland vegetation between woody landscape elements and agricultural fields. In conclusion, our results can be used to quantify ecocompensations to find optimal solutions for the delivery of productive and regulative ecosystem services in heterogeneous agricultural landscapes

Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach

Background: TRK fusion cancer results from gene fusions involving NTRK1, NTRK2 or NTRK3. Larotrectinib, the first selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% with a favorable safety profile in the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer (Drilon et al.,NEJM2018). Here, we report the clinical activity of larotrectinib in an additional 35 TRK fusion cancer patients and provide updated follow-up of the primary analysis set (PAS) of 55 patients as of 19thFeb 2018. Methods: Patients with TRK fusion cancer detected by molecular profiling from 3 larotrectinib clinical trials (NCT02122913, NCT02637687, and NCT02576431) were eligible.Larotrectinib was administered until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed using RECIST version 1.1. Results: As of Feb 2018, by independent review, 6 PRs in the PAS deepened to CRs. The median duration of response (DoR) and progression-free survival in the PAS had still not been reached, with 12.9 months median follow-up. At 1 year, 69% of responses were ongoing, 58% of patients remained progression-free and 90% of patients were alive. An additional 19 children and 25 adults (age range, 0.1-78 years) with TRK fusion cancer were enrolled after the PAS, and included cancers of the salivary gland, thyroid, lung, colon, melanoma, sarcoma, GIST and congenital mesoblastic nephroma. In 35 evaluable patients, the ORR by investigator assessment was 74% (5 CR, 21 PR, 6 SD, 2 PD, 1 not determined). In these patients, with median follow-up of 5.5 months, median DoR had not yet been reached, and 88% of responses were ongoing at 6 months, consistent with the PAS. Adverse events (AEs) were predominantly grade 1, with dizziness, increased AST/ALT, fatigue, nausea and constipation the most common AEs reported in ≥ 10% of patients. No AE of grade 3 or 4 related to larotrectinib occurred in more than 5% of patients. Conclusions: TRK fusions are detected in a broad range of tumor types. Larotrectinib is an effective age- and tumor-agnostic treatment for TRK fusion cancer with a positive safety profile. Screening patients for NTRK gene fusions in solid- and brain tumors should be actively considered

Survey of Instantaneous 1-22 GHz Spectra of 550 Compact Extragalactic Objects with Declinations from -30deg to +43deg

We present observational results for extragalactic radio sources with milliarcsecond components, obtained with the 600 meter ring radio telescope RATAN-600 from 1st to 22nd December, 1997. For each source, a six frequency broad band radio spectrum was obtained by observing simultaneously with an accuracy up to a minute at 1.4, 2.7, 3.9, 7.7, 13 and 31 cm. The observed list is selected from Preston et al. (1985) VLBI survey and contains all the sources in the declinations between -30deg and +43deg with a correlated flux density exceeding 0.1 Jy at 13 cm. The sample includes the majority of sources to be studied in the current VSOP survey and the future RadioAstron Space VLBI mission.Comment: 26 pages, 4 figures, 5 tables, published in the A&AS; figure 4 with the broad-band spectra plots is included in the preprint; tables 1 and 5, in electronic form, as well as the ReadMe file can be extracted from the preprint sourc

The 1/D Expansion for Classical Magnets: Low-Dimensional Models with Magnetic Field

The field-dependent magnetization m(H,T) of 1- and 2-dimensional classical magnets described by the $D$-component vector model is calculated analytically in the whole range of temperature and magnetic fields with the help of the 1/D expansion. In the 1-st order in 1/D the theory reproduces with a good accuracy the temperature dependence of the zero-field susceptibility of antiferromagnets \chi with the maximum at T \lsim |J_0|/D (J_0 is the Fourier component of the exchange interaction) and describes for the first time the singular behavior of \chi(H,T) at small temperatures and magnetic fields: \lim_{T\to 0}\lim_{H\to 0} \chi(H,T)=1/(2|J_0|)(1-1/D) and \lim_{H\to 0}\lim_{T\to 0} \chi(H,T)=1/(2|J_0|)

On the mean-field spherical model

Exact solutions are obtained for the mean-field spherical model, with or without an external magnetic field, for any finite or infinite number N of degrees of freedom, both in the microcanonical and in the canonical ensemble. The canonical result allows for an exact discussion of the loci of the Fisher zeros of the canonical partition function. The microcanonical entropy is found to be nonanalytic for arbitrary finite N. The mean-field spherical model of finite size N is shown to be equivalent to a mixed isovector/isotensor sigma-model on a lattice of two sites. Partial equivalence of statistical ensembles is observed for the mean-field spherical model in the thermodynamic limit. A discussion of the topology of certain state space submanifolds yields insights into the relation of these topological quantities to the thermodynamic behavior of the system in the presence of ensemble nonequivalence.Comment: 21 pages, 5 figure

RATAN-600 7.6-cm Deep Sky Strip Surveys at the Declination of the SS433 Source During the 1980-1999 Period. Data Reduction and the Catalog of Radio Sources in the Right-Ascension Interval 7h < R.A. < 17h

We use two independent methods to reduce the data of the surveys made with RATAN-600 radio telescope at 7.6 cm in 1988-1999 at the declination of the SS433 source. We also reprocess the data of the "Cold" survey (1980-1981). The resulting RCR (RATAN COLD REFINED) catalog contains the right ascensions and fluxes of objects identified with those of the NVSS catalog in the right-ascension interval 7h < R.A. < 17h. We obtain the spectra of the radio sources and determine their spectral indices at 3.94 and 0.5 GHz. The spectra are based on the data from all known catalogs available from the CATS, Vizier, and NED databases, and the flux estimates inferred from the maps of the VLSS and GB6 surveys. For 245 of the 550 objects of the RCR catalog the fluxes are known at two frequencies only: 3.94 GHz (RCR) and 1.4 GHz (NVSS). These are mostly sources with fluxes smaller than 30 mJy. About 65% of these sources have flat or inverse spectra (alpha > -0.5). We analyze the reliability of the results obtained for the entire list of objects and construct the histograms of the spectral indices and fluxes of the sources. Our main conclusion is that all 10-15 mJy objects found in the considered right-ascension interval were already included in the decimeter-wave catalogs.Comment: 26 pages, 18 figure

RC J0311+0507: A Candidate for Superpowerful Radio Galaxies in the Early Universe at Redshift z=4.514

A strong emission line at 6703A has been detected in the optical spectrum for the host galaxy (R=23.1) of the radio source RC J0311+0507 (4C+04.11). This radio galaxy, with a spectral index of 1.31 in the frequency range 365-4850 MHz, is one of the ultrasteep spectrum objects from the deep survey of a sky strip conducted with RATAN-600 in 1980-1981. We present arguments in favor of the identification of this line with Ly\alpha at redshift z=4.514. In this case, the object belongs to the group of extremely distant radio galaxies of ultrahigh radio luminosity (P_{1400}=1.3 x 10^{29}W Hz^{-1}). Such power can be provided only by a fairly massive black hole (~10^9M_\sun}) that formed in a time less than the age of the Universe at the observed z(1.3 Gyr) or had a primordial origin.Comment: 8 pages, 3 figure