Approaches to interim analysis of cancer randomised clinical trials with time to event endpoints: A survey from the Italian National Monitoring Centre for Clinical Trials

<p>Abstract</p> <p>Background</p> <p>Although interim analysis approaches in clinical trials are widely known, information on current practice of planned monitoring is still scarce. Reports of studies rarely include details on the strategies for both data monitoring and interim analysis. The aim of this project is to investigate the forms of monitoring used in cancer clinical trials and in particular to gather information on the role of interim analyses in the data monitoring process of a clinical trial. This study focused on the prevalence of different types of interim analyses and data monitoring in cancer clinical trials.</p> <p>Methods</p> <p>Source of investigation were the protocols of cancer clinical trials included in the Italian registry of clinical trials from 2000 to 2005. Evaluation was restricted to protocols of randomised studies with a time to event endpoint, such as overall survival (OS) or progression free survival (PFS). A template data extraction form was developed and tested in a pilot phase. Selection of relevant protocols and data extraction were performed independently by two evaluators, with differences in the data assessment resolved by consensus with a third reviewer, referring back to the original protocol. Information was obtained on a) general characteristics of the protocol b) disease localization and patient setting; c) study design d) interim analyses; e) DSMC.</p> <p>Results</p> <p>The analysis of the collected protocols reveals that 70.7% of the protocols incorporate statistical interim analysis plans, but only 56% have also a DSMC and be considered adequately planned. The most concerning cases are related to lack of any form of monitoring (20.0% of the protocols), and the planning of interim analysis, without DSMC (14.7%).</p> <p>Conclusion</p> <p>The results indicate that there is still insufficient attention paid to the implementation of interim analysis.</p

Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries

<p>Abstract</p> <p>Background</p> <p>Shifts in clinical trial application rates over time indicate if the attractiveness of a country or region for the conduct of clinical trials is growing or decreasing. The purpose of this observational study was to track changes in drug trial application patterns across several EU countries in order to analyze the medium-term impact of the EU Clinical Trials Directive 2001/20/EC on the conduct of drug trials.</p> <p>Methods</p> <p>Rates of Clinical Trial Applications (CTA) for studies with medicinal products in those six countries in the EU, which authorize on average more than 500 trials per year, were analyzed. Publicly available figures on the number of annually submitted CTA, the distribution of trials per phase and the type of sponsorship were tracked; missing data were provided by national drug agencies.</p> <p>Results</p> <p>Since 2001, the number of CTA in Italy and Spain increased significantly (5.0 and 2.5% average annual growth). For Italy, the gain was driven by a strong increase of applications from academic trial sponsors; Spain's growth was due to a rise in trials run by commercial sponsors. The Netherlands, Germany, France and the UK saw a decline (1.9, 2.3, 3.0 and 5.3% average annual diminution; significant (<it>P </it>< 0.05) except for Germany) in clinical drug trials. The decrease in the UK was caused by a sharp fall in academic trial activities. Across the six analyzed countries, no EU-wide trial-phase-specific patterns or trends were observed.</p> <p>Conclusions</p> <p>The EU Clinical Trials Directive 2001/20/EC did not achieve the harmonization of clinical trial requirements across Europe. Rather, it resulted in the leveling of clinical trial activities caused by a continuing decrease in CTA rates in the Netherlands, Germany, France and the UK. Southern European countries, Italy and Spain, benefited to some extent from policy changes introduced by the Directive. In Italy's case, national funding measures helped to considerably promote the conduct of non-commercial trials. On the other hand, the EU Directive-driven transition from liberal policy environments, based on non-explicit trial approval through notifications, towards red-taped processes of trial authorization, contributed to the decreases in trial numbers in Germany and the UK. In the latter case, national research governance concerns had a share in the country's marked decline. However, different EU member states successfully developed best practices, which a new European legislation should take into consideration to resume Europe's attractiveness and international competitiveness for the conduct of clinical trials.</p

Floristic analysis of a high-speed railway embankment in a Mediterranean landscape

We analyzed the floristic composition of a 4.5 km-long segment of a high-speed railway in Lazio, central Italy, which travels on an artificial embankment through an intensively-farmed landscape. In total, 287 vascular plant species were recorded. The life-form distribution was found to be similar to that of the regional species pool, with high percentages of therophytes (38%) and phanerophytes (13%). In the chorological spectrum the Mediterranean floristic element prevailed (44%), while alien species were 8% of the flora. The phytosociological spectrum showed a high diversity of characteristic species from the class Stellarietea mediae or its subordinate syntaxa (26%), and in particular from the order Thero-Brometalia (Mediterranean, sub-nitrophilous annual communities). Species from forest syntaxa had a relatively high diversity (9%). These results suggest that the ecological filtering provided by the Mediterranean regional climate controlled species assemblage even in a completely artificial habitat, preventing floristic homogenization: the flora of the studied railway section is only partially »ruderalized«, while it keeps strong links with the regional (semi-) natural plant communities. However, in contrast to what is observed in central and north Europe, the railway sides studied in the present paper do not seem to represent a refugial habitat for rare species from grassland communities, mainly because in Italy semi-natural dry grasslands are still widely represented

Chronic cocaine enhances defensive behaviour in the laboratory mouse: involvement of D2 dopamine receptors.

C57BL/6 male mice injected with a challenge dose (20 mg/kg) of cocaine 72 h after the end of chronic intermittent treatment with the psychostimulant (two daily injections of 20 mg/kg for 10 days) exhibited a clear-cut increase in defensive upright and sideways postures and escape when confronted with a non-drugged conspecific. Treated mice spent 40\% of time showing defensive acts over the 5-min testing session. Administration of the selective D2 receptor antagonist (-)-sulpiride (25 mg/kg) before the challenge dose of cocaine completely antagonized the increase in defensive behaviour, while the selective D1 receptor antagonist SCH 23390 (0.25-0.50 mg/kg) did not significantly affect defensive behavioural patterns. These results suggest the involvement of D2 receptors in cocaine-induced hyperdefensiveness. The hypothesis that alteration in D2 receptor functioning produced by chronic cocaine administration may produce hyperdefensiveness possibly due to altered perceptive processes is discussed

Behavioural data on dermorphins in mice

Dermorphin, an opioid peptide occuring in amphibian skin, exerted a depressive effect on locomotor activity of C57B1/6 mice and an analgesic effect when injected intravenously. Intracerebroventricular injections of dermorphin enhanced locomotor activity and resulted in analgesia. A stimulating effect of intracerebroventricular administration on locomotor activity was also induced by shorter homologues of dermorphin and [D-Ala2, Leu5]enkephalinamide, while β-endorphin produced a depression. It is suggested that dermorphin acts on central receptor populations activated by morphine and enkephalins. © 1982

Festuca valesiaca Schleich. ex Gaudin newly discovered in the Central Apennines (Italy): a further example of steppe relict in the Abruzzo “dry valleys”

Festuca valesiaca Schleich. ex Gaudin subsp. valesiaca is acknowledged as one of the most characteristic grasses of the continental grasslands and steppes of Eurasia. In Italy, the species was known almost only from the continental valleys of the Alpine chain (with the exception of two small populations at the northernmost edge of the Apennines). Here, we report on the first confirmed finding of F. valesiaca subsp. valesiaca in the surroundings of the Fucino Basin, Central Apennines. This finding expands by c. 400 km southwards the species’ range in Italy. The identity of the species was first ascertained by means of leaf cross-sections and stomata measurements, and then confirmed by chromosome count. Its habitat preferences within the area were found to match well with those described in the literature for C-Europe. After discussing some identification issues and the population’s ecological niche, we present the main biogeographic implications of our finding. By recalling and discussing similar examples, we conclude that during the Holocene forest spread some Apennine “dry valleys” performed as refugia for a number of Pleistocene steppic taxa. The grasslands of these areas may thus be ancient and valuable ecosystems maintained by climate and disturbance throughout the Holocene

Steppes of Southern Siberia - Experiences from the 6th EDGG Research Expedition to Khakassia, Russia (22 July – 1 August 2013)

The 6th EDGG Research Expedition took place in summer 2013 in the Kuznetsky Alatau Mountains, part of the Altai-Sayanian mountain region (Republic of Khakassia, Russia). A group of 14 scientists from seven countries studied the variety of steppe vegetation in two regions of the "Khakassky" Reserve – Lake Itkul (Shira region) and Podzaploty (Ordzhenikidzevsky region). Standardised sampling procedures including nested-plot series and phytosociological relevés of 10-m2 plots were used to sample steppes of European-Siberian (Festuco-Brometea) and Central Asian (Cleistogenetea squarrosae) types. All terricolous plants present in the plots were sampled, including perennial and annual vascular plants, bryophytes, and lichens. The data will be used for analyses of scale-dependent diversity patterns and species-area relationships, as well as for studying vegetation-environment relationships and performing phytosociological classification

Steppes of Southern Siberia - Experiences from the 6th EDGG Research Expedition to Khakassia, Russia (22 July – 1 August 2013)

The 6th EDGG Research Expedition took place in summer 2013 in the Kuznetsky Alatau Mountains, part of the Altai-Sayanian mountain region (Republic of Khakassia, Russia). A group of 14 scientists from seven countries studied the variety of steppe vegetation in two regions of the "Khakassky" Reserve – Lake Itkul (Shira region) and Podzaploty (Ordzhenikidzevsky region). Standardised sampling procedures including nested-plot series and phytosociological relevés of 10-m2 plots were used to sample steppes of European-Siberian (Festuco-Brometea) and Central Asian (Cleistogenetea squarrosae) types. All terricolous plants present in the plots were sampled, including perennial and annual vascular plants, bryophytes, and lichens. The data will be used for analyses of scale-dependent diversity patterns and species-area relationships, as well as for studying vegetation-environment relationships and performing phytosociological classification