Critical shortage of new antibiotics in development against multidrug-resistant bacteria-Time to react is now.

Two commercial databases (Pharmaprojects and Adis Insight R&D) were queried for antibacterial agents in clinical development. Particular attention was given to antibacterial agents for systemic administration. For each agent, reviewers were requested to indicate whether its spectrum of activity covered a set of selected multidrug-resistant bacteria, and whether it had a new mechanism of action or a new target. In addition, PubMed was searched for antibacterial agents in development that appeared in review articles. Out of 90 agents that were considered to fulfil the inclusion criteria for the analysis, 66 were new active substances. Fifteen of these could be systemically administered and were assessed as acting via a new or possibly new mechanism of action or on a new or possibly new target. Out of these, 12 agents were assessed as having documented in vitro activity against antibiotic-resistant Gram-positive bacteria and only four had documented in vitro activity against antibiotic-resistant Gram-negative bacteria. Of these four, two acted on new or possibly new targets and, crucially, none acted via new mechanisms of action. There is an urgent need to address the lack of effective treatments to meet the increasing public health burden caused by multidrug-resistant bacteria, in particular against Gram-negative bacteria.

Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency.

PURPOSE: To identify factors associated with success of Market Authorisation Applications (MAAs) for pharmaceutical drugs submitted to the European Medicines Agency (EMEA), with an emphasis on the Scientific Advice (SA) given by the Committee for Human Medicinal Products (CHMP). METHODS: MAAs with a CHMP decision (outcome) between 1 January 2004 and 31 December 2007 were included in the analysis. Factors evaluated were: company size, orphan drug (OD) status, product type, existence of SA, compliance with SA, therapeutic area and year of outcome. Compliance with SA was retrospectively assessed with reference to three critical clinical variables in pivotal studies: choice of primary endpoint, selection of control and statistical methods. RESULTS: Of 188 MAAs with an outcome, 137 (72.9%) were approved, whereas 51 (27.1%) were not approved or were withdrawn by the company. In the simple logistic regression analysis, company size [odds ratio (OR) 2.96, 95% confidence interval (CI) 1.92; 4.56, p < 0.0001) was positively correlated with a positive outcome, whereas OD status (OD vs. non-OD: OR 0.38, 95% CI 0.19; 0.77, p = 0.0067) was negatively correlated. A total of 59 (31.4%) MAAs had obtained SA related to one or more of the three critical variables. Thirty-nine of these were assessed as being compliant with SA. Obtaining an SA per se was not associated with outcome (SA vs. no-SA: OR 0.96, 95% CI 0.49; 1.88, p = 0.92), but complying with SA was significantly associated with positive outcome (compliant with SA vs. no-SA: OR 14.71, 95% CI 1.95; 111.2; non-compliant with SA vs. no-SA: OR 0.17, 95% CI 0.06; 0.47, p < 0.0001). Stepwise regression analysis revealed that company size and SA compliance were independent predictors of outcome. The proportion of the MAAs that had received SA increased from 22% in 2004 to 47% in 2007. Company size and product type were associated with the frequency of requesting SA (26, 33 and 46% for small, medium-sized and large companies, respectively; 16, 39 and 48% for known chemical substances, new chemical substances and biologics, respectively). Factors related to compliance with SA were company size and OD status (25, 60 and 84% for small, medium-sized, and large companies, respectively; 77 and 38% for non-OD and OD status, respectively). CONCLUSIONS: The strong association between company size and outcome suggests that resources and experience in drug development and obtaining regulatory approval are critical factors for a successful MAA. In addition, obtaining and complying with SA appears to be a predictor of outcome. Based on this analysis, companies, particularly smaller ones and those developing orphan drugs, are recommended to engage in a dialogue with European regulators via the SA procedure. Obtaining SA early in development and at major transition points as well as compliance with the advice given by the CHMP are recommended.

Clinical trials for registration in the European Union: the EMEA 5-year experience in oncology.

The evaluation of quality, safety and efficacy of medicinal products by regulatory agencies is a necessary step for obtaining marketing authorisation in the European Union (EU). The objective of this paper is to outline some key aspects of the EU regulatory system relevant to the field of oncology. Regulatory standards in oncology and the experience with anti-neoplastic and endocrine therapy agents in the centralised EU review system are presented. Also, the most common pitfalls encountered with oncology applications that were rejected are illustrated. The review is based on the first 5 years (1995-1999) of operation of the European Agency for the Evaluation of Medicinal Products (EMEA). Nineteen out of 30 different oncology drugs submitted during this period were approved, based on the recommendations of the Committee for Proprietary Medicinal Products (CPMP), which is the main scientific body within the EMEA responsible for evaluating medicines for human use. Although, in general, randomised trials to test the benefit of the new drug are a prerequisite for approval, this series showed that in strictly defined situations, approval could be obtained based on non-randomised trials measuring surrogate endpoints, provided the applicant agreed to the completion of a further programme of studies. These situations were the majority in our series and the CPMP has produced a guideline in oncology to address these specific requirements. Eleven out of the 30 oncology applications did not establish a positive benefit/risk profile of the drug in the proposed therapeutic indication, and were therefore rejected. Failure generally occurred because applications were based on too small series of patients or relied on the results of exploratory analyses after pre-defined analyses had failed to produce the expected results or, particularly for diagnostic agents, due to the fact that the effect of the agent had been measured only in terms of endpoints that were of unclear relevance.

Adhesion of Pseudomonas aeruginosa strains to untreated and oxygen-plasma treated poly(vinyl chloride) (PVC) from endotracheal intubation devices.

Pseudomonas aeruginosa pneumonia is a life threatening complication in mechanically ventilated patients that requires the ability of the bacteria to adhere to, and colonize the endotracheal intubation device. New strategies to prevent or reduce these nosocomial infections are greatly needed. We report here the study of a set of P. aeruginosa clinical isolates, together with specific mutants, regarding their adhesion on native and chemically modified poly(vinyl chloride) (PVC) surfaces from endotracheal intubation devices. The adhesion of the different strains to untreated PVC varied widely, correlating with several physico-chemical characteristics known to influence the attachment of bacteria to inert surfaces. The adhesion patterns were compared to the calculations obtained with the DLVO theory of colloidal stability. These results illustrate the importance of testing different clinical isolates when investigating bacterial adhesion. Oxygen plasma treatment of the PVC pieces yielded a hydrophilic surface and reduced the number of adhering bacteria by as much as 70%. This reduction is however unlikely to be sufficient to prevent P. aeruginosa colonization of endotracheal intubation devices.

Haemocompatibility evaluation of DLC- and SiC-coated surfaces.

Diamond-like carbon (DLC) and silicon carbide (SiC) coatings are attractive because of low friction coefficient, high hardness, chemical inertness and smooth finish, which they provide to biomedical devices. Silicon wafers (Si(waf)) and silicone rubber (Si(rub)) plates were coated using plasma-enhanced chemical vapour deposition (PE-CVD) techniques. This article describes: 1- the characterization of modified surfaces using attenuated total reflection-Fourier transform infrared spectroscopy (ATR/FTIR) and contact angle measurements, 2- the results of three in-vitro haemocompatibility assays. Coated surfaces were compared to uncoated materials and various substrates such as polymethylmethacrylate (PMMA), polyethylene (LDPE), polydimethylsiloxane (PDMS) and medical steel (MS). Thrombin generation, blood platelet adhesion and complement convertase activity tests revealed the following classification, from the most to the least heamocompatible surface: Si(rub)/ DLC-Si(rub)/ DLC-Si(waf)/ LDPE/ PDMS/ SiC-Si(waf)/ Si(waf)/ PMMA/ MS. The DLC coating surfaces delayed the clotting time, tended to inhibit the platelet and complement convertase activation, whereas SiC-coated silicon wafer can be considered as thrombogenic. This study has taken into account three events of the blood activation: coagulation, platelet activation and inflammation. The response to those events is an indicator of the in vitro haemocompatibility of the different surfaces and it allows us to select biomaterials for further in vivo blood contacting investigations.

Bone response to surface-modified titanium implants: studies on the early tissue response to implants with different surface characteristics.

In a series of experimental studies, the bone formation around systematically modified titanium implants is analyzed. In the present study, three different surface modifications were prepared and evaluated. Glow-discharge cleaning and oxidizing resulted in a highly stoichiometric TiO2 surface, while a glow-discharge treatment in nitrogen gas resulted in implants with essentially a surface of titanium nitride, covered with a very thin titanium oxide. Finally, hydrogen peroxide treatment of implants resulted in an almost stoichiometric TiO2, rich in hydroxyl groups on the surface. Machined commercially pure titanium implants served as controls. Scanning Auger Electron Spectroscopy, Scanning Electron Microscopy, and Atomic Force Microscopy revealed no significant differences in oxide thickness or surface roughness parameters, but differences in the surface chemical composition and apparent topography were observed. After surface preparation, the implants were inserted in cortical bone of rabbits and evaluated after 1, 3, and 6 weeks. Light microscopic evaluation of the tissue response showed that all implants were in contact with bone and had a large proportion of newly formed bone within the threads after 6 weeks. There were no morphological differences between the four groups. Our study shows that a high degree of bone contact and bone formation can be achieved with titanium implants of different surface composition and topography.

The review of drug applications submitted to the European Medicines Evaluation Agency: frequently raised objections, and outcome.

OBJECTIVE: To study the issues raised during the review of drug applications submitted to the European Medicines Evaluation Agency for approval in the European Union and to identify important predictors of outcome. METHODS: All consecutive applications submitted since September 1997 and which had reached an outcome by May 2001 were included. The factors considered in this exploratory analysis were: year of submission, anatomical therapeutic chemical classification (ATC code), type of medicinal product (biopharmaceuticals vs. new chemical entities), and common "major objections" raised during the review. Predictors were identified using multivariate logistic regression on outcome (positive opinion vs. negative opinion or withdrawal). Examples have been provided to illustrate some of the weaknesses of the applications received, the types of objections raised by the reviewers, and the strategies used to address them. RESULTS: This series consisted of 111 successive applications for which the review had started between September 1997 and April 2000. It included 73 (66%) new chemical entities and 38 (34%) biopharmaceuticals, the most represented agents being anti-neoplastic and immunomodulating agents, and anti-infectives for systemic use, with 25 (22%), and 19 (17%) applications, respectively. Overall the proportion of drug applications that failed to reach a positive outcome was 32/111 (29%). The most frequent major objections raised were those related to the safety database and to serious adverse events. These clinical safety objections were raised in 54 (48.6%) applications. Another frequent objection was the clinical efficacy objection on the lack of adequate randomised controlled trials, which was raised in 47 (42.3%) applications. This clinical efficacy objection was the only factor that was retained after multivariate selection (P<0.01). The odds of a positive outcome for an application lacking adequate randomised controlled trials were: 0.46 (95% confidence interval 0.29-0.71) times the odds of an application without this objection (P=0.0006). CONCLUSIONS: Despite the existence of various mechanisms that allow important deficiencies to be resolved, failure to establish clinical efficacy due to the lack of adequate randomised controlled trials remained problematic, leading to a high risk of rejection.