Determination of the target population in early benefit assessments in Germany: challenges for non-small-cell lung cancer.

OBJECTIVES: Dossiers submitted for early benefit assessments in Germany also provide information on the precise determination of the target population (patients eligible for a drug). The situation is complex for non-small-cell lung cancer (NSCLC) due to highly specific therapeutic indications. Our aim was to compare the different methodological steps applied to determine the target population in dossiers on drugs for NSCLC. METHODS: We analysed NSCLC dossiers assessed by the German Institute for Quality and Efficiency in Health Care (IQWiG) between 01.01.2011 and 31.12.2017. Methodological details regarding the determination of the target population were extracted and compared. RESULTS: We analysed 23 NSCLC dossiers. In all dossiers, the target population was determined using the number of all patients with lung cancer as the basis for calculations. This patient population was further reduced in several successive steps by assuming proportions of patients with a specific characteristic (e.g. disease stage). The most important calculation steps were patients with NSCLC (n = 23 dossiers), with a specific disease stage (n = 23), with a specific tumour mutation (n = 14), with a specific tumour histology (n = 7), without prior treatment (n = 15), with pretreatment in second or further treatment lines (n = 17), and/or with specific pretreatments (n = 9). The proportions of patients determined within the same calculation step varied considerably between dossiers. DISCUSSION: The calculation methods applied and the target population sizes reported in NSCLC dossiers vary considerably. A consensus with regard to the databases and calculation methods used to determine the target population in NSCLC would be helpful to reduce variations.

Field study on bovine paratuberculosis using real-time PCR and liquid culture for testing environmental and individual fecal samples implemented in dairy cow management.

Bovine paratuberculosis (Johne's disease) is a bacterial, chronic, and wasting intestinal disease caused by Mycobacterium avium ssp. paratuberculosis (MAP). Johne's disease causes severe losses in dairy farm productivity and is also suspected to be a potential trigger for Crohn's disease in humans. The fecal-oral infection of MAP to neonates is recognized as an important within-herd transmission route. Our objective was to recommend diagnostic methods for herds with suspected paratuberculosis requiring fast results, as well as for herds with breeding programs or others that aim at being nonsuspected of paratuberculosis infection. We determined a period of 8 wk from sampling to diagnostic findings suitable for testing of cows during the dry period. We therefore tested environmental and individual fecal samples with one rapid and one highly sensitive diagnostic method. Environmental samples (boot swabs) were taken as a first step in 3 herds and tested using a DNA extraction protocol for feces and subsequent real-time PCR (referred to as fecal PCR). Additionally, cultivation in liquid medium for 6 wk was performed and verified with real-time PCR (referred to as liquid culture). Automation of DNA extraction based on magnetic beads and the PCR setup was performed with pipetting robots. As a result, we successfully detected MAP in boot swabs of all herds by both methods. In a second step, 245 individual fecal samples from the 3 herds were examined using also fecal PCR and liquid culture. The results obtained by fecal PCR were compared with detection of MAP using cultivation in liquid medium for 6 wk. Testing individual cows, we identified MAP-specific DNA in 53 fecal samples using the liquid culture. Using fecal PCR, we revealed 43 positive samples of which 39 also tested positive in the liquid culture, revealing MAP-positive cows in all 3 herds. The fecal PCR procedure allows rapid detection of MAP-specific DNA with 74% of the sensitivity of liquid culture. For the purpose of testing with maximal sensitivity, cultivation in liquid medium is recommended. Cultivation of MAP in liquid medium M7H9C means a significant time gain in comparison to cultivation on solid media, which requires twice as much time. Thus, this testing fits within the 6- to 8-wk dry period of gravid cows and provides test results before calving, a prerequisite to prevent fecal-oral transmission to newborn calves.

Enhanced sensitivity and fast turnaround time in laboratory diagnosis for bovine paratuberculosis in faecal samples.

Bovine paratuberculosis (Johne's disease in cattle) is caused by the pathogen Mycobacterium avium subsp. paratuberculosis (MAP) and is a widespread chronic bacterial infectious disease in cattle. Due to the peculiarities of the pathogen, detection of MAP in faeces remains difficult. DNA extraction and real-time PCR for detection of MAP in bovine faeces (direct PCR) have been refined and feasible procedures for rapid, sensitive and automatable detection of the pathogen agent have been developed. Accordingly, in a first step we tested 20 faecal samples using two MAP complete kits (DNA extraction kits based on magnetic beads combined with real-time PCR assays) and six other DNA extraction kits for faeces. MAP-specific DNA was detected by real-time PCR assays. Cultivation of MAP on the solid medium HEYM and in the liquid medium M7H9C served as reference standards. The two complete kits detected significantly more MAP-DNA positive samples than the other procedures applied (p < 0.04). Ct values of 37 and 38 served as cut-off for the respective real-time PCR assays calculated on the basis of standard curves and droplet digital PCR (ddPCR). In a second step, the two MAP complete kits were employed for a comprehensive study including 107 positive and 50 negative faecal samples which had been previously tested on HEYM cultivation. The MAP complete kits yielded sensitivity values of 86% and 89% and specificity values of 100% compared to cultivation of MAP in the liquid medium M7H9C. In detail, cultivation of MAP in M7H9C detected the pathogen in 97% and 100% of the samples tested after an incubation period of six and twelve weeks, respectively. However, the cultivation of MAP on HEYM succeeded in only 74% after twelve weeks of incubation. In all these solid culture positive samples, MAP was also detected using the two complete kits. Additionally, the impact of repeated freezing and thawing of samples on re-cultivation of MAP was tested using 20 faecal samples and resulted in a reduction to 75% and 25% of bacterial growth when using liquid medium M7H9C and solid medium HEYM, respectively. The results of this study show that complete kits with refined automatable protocols for DNA extraction in combination with real-time PCR assays for detection of MAP can compete with sensitive cultivation of the pathogen in liquid medium.

[Decision of the Federal Joint Committee on screening for chorionicity - benefit assessment in the absence of screening studies]. / Die Beratungen des Gemeinsamen Bundesausschusses zum Screening auf Chorionizität - Nutzenbewertung beim Fehlen von Screeningstudien.

The main decision-making body of the self-government system in Germany is the Federal Joint Committee (G-BA). In line with the principles of evidence-based medicine, randomised controlled trials with patient-relevant endpoints (in particular mortality, morbidity, quality of life) are preferred for the G-BA assessment of medical treatments and procedures. During this analysis of ultrasound screening for monochorionicity in multiple pregnancies, no studies were identified directly comparing a group with screening vs. a group without screening. Therefore, a 3-step process, which assesses the single components of screening (risk factors, relevant outcome for the patient, existence of a confirmed diagnosis, application of an effective therapy), was used. On the basis of these results the G-BA decided that the statutory health insurance should include the determination of chorionicity in their reimbursement catalogue.

[IQWiG's methods for the cost-benefit assessment : Comparison with an international reference scenario]. / Wo steht die Kosten-Nutzen-Bewertung des IQWiG : Abgleich mit einem internationalen Referenzszenario?

Standardization of international health economic guidelines has been repeatedly requested. In this context, an international reference case was proposed, which constitutes an agreed approach for the key elements of health economic evaluation including study perspective, comparators, source of effectiveness data, role of modeling, main (economic) outcome, source of utilities, characterizing uncertainty. It is, however, questionable whether such a reference scenario can reasonably be applied across all health care systems. Our analysis pursues the question to which degree the Institute for Quality and Efficiency in Health Care's (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) "General methods for evaluating the relation between cost and benefit" comply with the key elements of the reference case. In case of divergences, they will be described and discussed in light of the German social legislation and in consideration of current scientific evidence. In conclusion, the analysis revealed that IQWiG complied with the reference case in almost all aspects. Differences were found only with respect to the choice of main (economic) outcome and the source of utilities. These differences seem justified and well explained in the context of the German social legislation as well as in view of the weaknesses of the quality-adjusted life year (QALY) concept.

Changes in testicular histology and sperm quality in llamas (Lama glama), following exposure to high ambient temperature.

The aim of the study was to investigate whether a moderately elevated ambient temperature (29 degrees C, 4 weeks, 24hperday) has an effect on the spermatogenesis in male llamas (Lama glama) and to monitor the recrudescence of spermatogenesis. Thirteen llamas were used. Semen parameters were monitored in four of the llamas and six animals were castrated at different times after the heat treatment. An additional three llamas were used as control animals and were castrated without any treatment. Spermatogenesis was found to be severely impaired due to the high environmental temperature. Sperm concentration declined from 97.5 million to 10 million spermatozoa/ml. Sperm motility declined from 63.1% to 15.0% and the percentage of morphologically abnormal sperm cells increased from 26.3% up to 50.5%. The changes in sperm parameters corresponded to the histological analysis of the testes. We found an increase in destroyed tubules, where no stage of the spermatogenic cycle could be established from 1.8% up to 38.2%, and a reduction of the spermatogonial proliferation rate (Ki-67 histochemistry) represented by tubules with proliferating spermatogonia from 79.5% to 45.7% directly after the heat treatment. Apoptosis (TUNEL assay) showed no significant changes during the experiment. The recrudescence of spermatogenesis within 6 weeks after the heat treatment was found to be due to an increase of mitotic proliferation of spermatogonia and not due to a decrease in the apoptotic rate. Our data indicate that in llamas the thermoregulatory ability is not sufficient enough to prevent heat caused damage to the testis at longer acting ambient temperature of 29 degrees C.