Effect of Crossover in Oncology Clinical Trials on Evidence Levels in Early Benefit Assessment in Germany.

BACKGROUND: In oncology clinical trials, crossover is used frequently but may lead to uncertainties regarding treatment effects. OBJECTIVE: To investigate the handling of evidence from crossover trials by the European Medicines Agency (EMA) and the German Federal Joint Committee (G-BA). METHODS: For oncology medicines with early benefit assessments before January 2015, presence of crossover, clinical data, EMA requests for additional data, and G-BA benefit ratings/evidence levels were analyzed from manufacturers' dossiers, G-BA appraisals, European Public Assessment Reports, and original publications. RESULTS: Eleven of 21 benefit assessments included crossover trials. Significant intergroup differences (P < 0.05) in overall survival (OS) were noted in 7 of 11 trials with and 7 of 10 without crossover. For 6 of 11 medicines with crossover, these were demonstrated before crossover. Treatment effects generally worsened with increasing proportions of crossover. The EMA requested additional data more frequently if crossover was performed, particularly if no OS data were available before crossover. The G-BA granted a considerable benefit to 73% of medicines with crossover and 40% of those without. Evidence levels were intermediate for 50% and 75%, respectively. None of the medicines received the highest evidence level. CONCLUSIONS: In G-BA appraisals, oncology medicines with crossover received better additional benefit ratings, but were assigned lower evidence levels, than those without. The five medicines with crossover after progression were assigned lower evidence levels than the six medicines with crossover after demonstration of superior OS, indicating that the way in which crossover is implemented may be one factor influencing the assignment of evidence levels by the G-BA.

Inconsistent approaches of the G-BA regarding acceptance of primary study endpoints as being relevant to patients - an analysis of three disease areas: oncological, metabolic, and infectious diseases.

BACKGROUND: Previous evaluations of oncological medicines in the German early benefit assessment (EBA) procedure have demonstrated inconsistent acceptance of endpoints by regulatory authorities and the Federal Joint Committee (G-BA). Accepted standard endpoints for regulatory purposes are frequently not considered as patient-relevant in the German EBA system. In this study the acceptance of clinically acknowledged primary endpoints (PEPs) from regulatory trials in EBAs conducted by the G-BA was evaluated across three therapeutic areas. METHODS: Medicines for oncological, metabolic and infectious diseases with EBAs finalised before 25 January 2016 were evaluated. Respective manufacturer's dossiers, regulatory assessments, G-BA appraisals and oral hearing minutes were reviewed, and PEPs were examined to determine whether they were considered relevant to patients by the G-BA. Furthermore, the acceptance of symptomatic vs asymptomatic PEPs was also analysed. RESULTS: A total of 65 EBAs were evaluated. Mortality PEPs were widely accepted as patient-relevant but were only used in a minority of EBAs and exclusively in oncological diseases. Morbidity PEPs constituted around 72 % of assessed PEPs, but were excluded from the EBA in over half of the corresponding assessments as they were not considered patient-relevant. Symptomatic endpoints were largely deemed patient-relevant, whereas acceptance of asymptomatic endpoints varied between therapeutic areas. CONCLUSIONS: This evaluation identified inconsistencies in patient relevance of morbidity-related PEPs as well as in acceptance of asymptomatic endpoints by the G-BA in all three disease areas examined. Better harmonisation between the regulatory authorities and the G-BA is still required after 5 years of AMNOG health technology assessment in Germany.

Aetiology, comorbidities and cofactors of chronic leg ulcers: retrospective evaluation of 1 000 patients from 10 specialised dermatological wound care centers in Germany.

Numerous comorbidities and cofactors have been known to influence wound healing processes. In this multicentre study, clinical data of 1 000 patients with chronic leg ulcers from ten specialised dermatological wound care centers were analysed. The patient cohort comprised 567 females and 433 males with an average age of 69·9 years. The wounds persisted on average for 40·8 months and had a mean size of 43·7 cm(2) . Venous leg ulcers represented the most common entity accounting for 51·3% of all chronic wounds, followed by mixed-type ulcers in 12·9% and arterial ulcerations in 11·0% of the patients. Vasculitis was diagnosed in 4·5%, trauma in 3·2%, pyoderma gangrenosum in 2·8%, lymphoedema in 1·7%, neoplasia in 1·0% and delayed post-surgical wound healing in 0·6% of the included patients. In total, 70·5% of patients suffered from arterial hypertension, 45·2% were obese, 27·2% had non-insulin dependent diabetes, and 24·4% dyslipidaemia. Altogether 18·4% suffered from metabolic syndrome. Cofactors and comorbidities of patients with chronic leg ulcers have previously been studied but not in detail. Here, we were able to demonstrate the existence of several potentially relevant cofactors, comorbidities of their associations and geographical distributions, which should be routinely examined in patients with chronic leg ulcers and - if possible - treated.

Randomized placebo-controlled human pilot study of cold atmospheric argon plasma on skin graft donor sites.

Cold atmospheric plasma has already been shown to decrease the bacterial load in chronic wounds. However, until now it is not yet known if plasma treatment can also improve wound healing. We aimed to assess the impact of cold atmospheric argon plasma on the process of donor site healing. Forty patients with skin graft donor sites on the upper leg were enrolled in our study. The wound sites were divided into two equally sized areas that were randomly assigned to receive either plasma treatment or placebo (argon gas) for 2 minutes. Donor site healing was evaluated independently by two blinded dermatologists, who compared the wound areas with regard to reepithelialization, blood crusts, fibrin layers, and wound surroundings. From the second treatment day onwards, donor site wound areas treated with plasma (n = 34) showed significantly improved healing compared with placebo-treated areas (day 1, p = 0.25; day 2, p = 0.011; day 3, p < 0.001; day 4, p < 0.001; day 5, p = 0.004; day 6, p = 0.008; day 7, p = 0.031). Positive effects were observed in terms of improved reepithelialization and fewer fibrin layers and blood crusts, whereas wound surroundings were always normal, independent of the type of treatment. Wound infection did not occur in any of the patients, and no relevant side effects were observed. Both types of treatment were well tolerated. The mechanisms contributing to these clinically observed effects should be further investigated.

Bacteriological pathogen spectrum of chronic leg ulcers: Results of a multicenter trial in dermatologic wound care centers differentiated by regions.

BACKGROUND: In almost every chronic wound different bacteria species can be detected. PATIENTS AND METHODS: Retrospective, multicenter evaluation of bacterial swab results from 2010 and 2011 in patients with chronic leg ulcer treated in 10 dermatologic wound care centers from 5 regions in Germany. RESULTS: Data of 970 patients were analyzed. Staphylococcus aureus was detected in 47.6 % of the patients, 8.6% of these were methicillin-resistant (MRSA). Pseudomonas aeruginosa was found in 31.1 %, enterobacteria in 28.6 % and Proteus mirabilis in 13.7 % of the patients. The regional comparison showed a significant south-north gradient for S. aureus, P. aeruginosa, and enterobacteria. Moreover, a highly significant west-east gradient for MRSA was found with detection rates of 13.5 % in the west to 4.0 % in the east. Furthermore, nationally there was a significant negative correlation between S. aureus and P. aeruginosa or P. mirabilis, respectively, as well as a positive correlation of P. aeruginosa with respect to wound size and duration. In addition to climatic and therapeutic conditions, different regional health care structures are discussed as potentially relevant reasons for these significantly different regional detection rates. CONCLUSIONS: Our data show the regional variability of the spectrum of currently detected bacteria in patients with chronic leg ulcers in Germany.

Cold atmospheric air plasma sterilization against spores and other microorganisms of clinical interest.

Physical cold atmospheric surface microdischarge (SMD) plasma operating in ambient air has promising properties for the sterilization of sensitive medical devices where conventional methods are not applicable. Furthermore, SMD plasma could revolutionize the field of disinfection at health care facilities. The antimicrobial effects on Gram-negative and Gram-positive bacteria of clinical relevance, as well as the fungus Candida albicans, were tested. Thirty seconds of plasma treatment led to a 4 to 6 log(10) CFU reduction on agar plates. C. albicans was the hardest to inactivate. The sterilizing effect on standard bioindicators (bacterial endospores) was evaluated on dry test specimens that were wrapped in Tyvek coupons. The experimental D(23)(°)(C) values for Bacillus subtilis, Bacillus pumilus, Bacillus atrophaeus, and Geobacillus stearothermophilus were determined as 0.3 min, 0.5 min, 0.6 min, and 0.9 min, respectively. These decimal reduction times (D values) are distinctly lower than D values obtained with other reference methods. Importantly, the high inactivation rate was independent of the material of the test specimen. Possible inactivation mechanisms for relevant microorganisms are briefly discussed, emphasizing the important role of neutral reactive plasma species and pointing to recent diagnostic methods that will contribute to a better understanding of the strong biocidal effect of SMD air plasma.

Contact-free inactivation of Candida albicans biofilms by cold atmospheric air plasma.

Candida albicans is one of the main species able to form a biofilm on almost any surface, causing both skin and superficial mucosal infections. The worldwide increase in antifungal resistance has led to a decrease in the efficacy of standard therapies, prolonging treatment time and increasing health care costs. Therefore, the aim of this work was to demonstrate the applicability of atmospheric plasma at room temperature for inactivating C. albicans growing in biofilms without thermally damaging heat-sensitive materials. This so-called cold atmospheric plasma is produced by applying high voltage to accelerate electrons, which ionize the surrounding air, leading to the production of charged particles, reactive species, and photons. A newly developed plasma device was used, which exhibits a large plasma-generating surface area of 9 by 13 cm (117 cm(2)). Different time points were selected to achieve an optimum inactivation efficacy range of ≥3 log(10) to 5 log(10) reduction in CFU per milliliter, and the results were compared with those of 70% ethanol. The results obtained show that contact-free antifungal inactivation of Candida biofilms by cold atmospheric plasma is a promising tool for disinfection of surfaces (and items) in both health care settings and the food industry, where ethanol disinfection should be avoided.

Plasma medicine: possible applications in dermatology.

As a result of both the better understanding of complex plasma phenomena and the development of new plasma sources in the past few years, plasma medicine has developed into an innovative field of research showing high potential. While thermal plasmas have long been used in various medical fields (for instance for cauterization and sterilization of medical instruments), current research mainly focuses on application of non-thermal plasmas. Experiments show that cold atmospheric plasmas (CAPs) allow efficient, contact-free and painless disinfection, even in microscopic openings, without damaging healthy tissue. Plasmas influence biochemical processes and offer new possibilities for the selective application of individually designable medically active substances. In dermatology, new horizons are being opened for wound healing, tissue regeneration, therapy of skin infections, and probably many more diseases. First clinical trials show the efficacy and tolerability of plasma in treating infected chronic wounds. A major task will be the introduction of plasma into clinical medicine and, simultaneously, the further investigation of the mechanisms of action of plasma at the cellular level.

A case of multiple familial trichoepitheliomas responding to treatment with the Hedgehog signaling pathway inhibitor vismodegib.

Multiple familial trichoepitheliomas (MFT) is an autosomal dominantly inherited disease characterized by multiple skin appendage tumors. We describe a patient showing a continuous spectrum of follicular differentiated neoplasms including classical trichoepitheliomas but also infiltrative growing and finally metastasizing malignant follicular differentiated tumors. Germline mutation analysis revealed a nonsense mutation in the cylindromatosis (CYLD) gene. Gene expression analysis by real-time PCR of tumor tissue showed overexpression of glioma-associated oncogene Gli1 mRNA. Treatment with the Hedgehog pathway inhibitor vismodegib resulted in a significant regression of the highly differentiated trichoepitheliomas. Gli upregulation is indicative of an active Hedgehog signaling pathway. We hypothesize that its upregulation is indirectly caused by CYLD mutation which promotes tumor development. Vismodegib treatment could thus provide a new treatment option for patients with this debilitating disorder.

Cold atmospheric plasma devices for medical issues.

Cold atmospheric plasma science is an innovative upcoming technology for the medical sector. The plasma composition and subsequent effects on cells, tissues and pathogens can vary enormously depending on the plasma source, the plasma settings and the ambient conditions. Cold atmospheric plasmas consist of a highly reactive mix of ions and electrons, reactive molecules, excited species, electric fields and to some extent also UV radiation. In the last year, this partly ionized gas has been demonstrated to have a broad antimicrobial activity, while resistance and resistance development are unlikely. Furthermore, recent research has indicated that plasmas also have a strong influence on various cell lines and cell functions, including anticancer properties. This review summarizes the major plasma designs available and their main benefits, as well as assessing possible risks of this new technology.