Is a controlled randomised trial the non-plus-ultra design? A contribution to discussion on comparative, controlled, non-randomised trials

AbstractBackgroundClinical studies provide formalised experience for evidence-based medicine (EBM). Many people consider a controlled randomised trial (CRT, identical to a randomised controlled trial RCT) to be the non-plus-ultra design. However, CRTs also have limitations. The problem is not randomisation itself but informed consent for randomisation and masking of therapies according to today's legal and ethical standards. We do not want to de-rate CRTs, but we would like to contribute to the discussion on clinical research methodology.SituationInformed consent to a CRT and masking of therapies plainly select patients. The excellent internal validity of CRTs can be counterbalanced by poor external validity, because internal and external validity act as antagonists. In a CRT, patients may feel like guinea pigs, this can decrease compliance, cause protocol violations, reduce self-healing properties, suppress unspecific therapeutic effects and possibly even modify specific efficacy.DiscussionA control group (comparative study) is most important for the degree of evidence achieved by a trial. Study control by detailed protocol and good clinical practice (controlled study) is second in importance and randomisation and masking is third (thus the sequence CRT instead of RCT). Controlled non-randomised trials are just as ambitious and detailed as CRTs.RecommendationWe recommend clinicians and biometricians to take high quality controlled non-randomised trials into consideration more often. They combine good internal and external validity, better suit daily medical practice, show better patient compliance and fewer protocol violations, deliver estimators unbiased by alienated patients, and perhaps provide a clearer explanation of the achieved success

Risk Factors for Alveolar Echinococcosis in Humans

A case-control study of alveolar echinococcosis cases in Germany identifies several risk factors for the disease

Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice

Sepsis and septic shock, caused by an excessive systemic host-inflammatory response, are associated with high morbidity and mortality. The complement system and TLRs provide important pattern recognition receptors initiating the cytokine storm by extensive cross-talk. We hypothesized that double blockade of complement C5 and the TLR coreceptor CD14 could improve survival of experimental polymicrobial sepsis. Mice undergoing cecal ligation and puncture (CLP)–induced sepsis were treated with neutralizing anti-CD14 Ab biG 53, complement C5 inhibitor coversin (Ornithodoros moubata C inhibitor), or a combination thereof. The inflammatory study (24-h observation) revealed statistically significant increases in 22 of 24 measured plasma biomarkers in the untreated CLP group, comprising 14 pro- and anti-inflammatory cytokines and 8 chemokines, growth factors, and granulocyte activation markers. Single CD14 or C5 blockade significantly inhibited 20 and 19 of the 22 biomarkers, respectively. Combined CD14 and C5 inhibition significantly reduced all 22 biomarkers (mean reduction 85%; range 54–95%) compared with the untreated CLP group. Double blockade was more potent than single treatment and was required to significantly inhibit IL-6 and CXCL1. Combined inhibition significantly reduced morbidity (motility and eyelid movement) and mortality measured over 10 d. In the positive control CLP group, median survival was 36 h (range 24–48 h). Combined treatment increased median survival to 96 h (range 24–240 h) (p = 0.001), whereas survival in the single-treatment groups was not significantly increased (median and range for anti-CD14 and anti-C5 treatment were 36 h [24–48 h] and 48 h [24–96 h]). Combined with standard intervention therapy, specific blockade of CD14 and C5 might represent a promising new therapeutic strategy for treatment of polymicrobial sepsis

Traditionelle chinesische Arzneitherapie bei Patienten mit chronischer Rhinosinusitis - eine Therapiebeobachtung mit Berücksichtigung der Arzneimittelherkunft

BACKGROUND The use of Chinese medicinal drugs is becoming more common in Germany. However, the import from China results in aggravated quality controls and potentially jeopardized therapeutic safety. Therefore, in 1999 the Bavarian Department for Agriculture has initiated an interdisciplinary research project to cultivate and analyze important Chinese herbal plants. Currently 16 Bavarian-produced Chinese drugs are in use and distributed to patients by pharmacies. Despite a comparable quality of Bavarian pharmaceutical products, there are concerns remaining as the Bavarian medical drugs have been used for treatment purposes on patients since 2006, without their effect having been compared to the Chinese products. Therefore we performed an observational trial using a parallel group design on patients with chronic rhinosinusitis. METHODS The duration of the trial was 4 weeks. After a 4-week follow-up, the patients were interviewed via telephone. During the trial the patients were given 2 × 50 ml of a decoction of Chinese medicinal herbs, either (a) from Bavarian controlled cultivation (Bavaria group) or (b) from Chinese production (China group). The therapeutic success was evaluated using numerical rating scales. RESULTS In total, 64 patients completed the observational trial (31 Bavaria group, 33 China group). Both groups showed significant improvements in the main symptom scores of chronic rhinosinusitis as well as in secondary symptoms, such as the overall state of health or the tendency to catch a cold. There were no significant differences between the groups concerning the main symptoms scores. Overall the herbal decoctions had no severe side effects. CONCLUSION This observational trial shows that Chinese herbal drugs from Bavarian cultivation are as effective as medicinal herbs imported from China, but the effects of concomitant therapies must be considered as well. The symptom score improvements during the treatment period were obvious and should stimulate further investigation on the efficacy of this herbal formula in the treatment of chronic rhinosinusitis

Medical Statistics – Mathematics or Oracle? Farewell Lecture

Certainty is rare in medicine. This is a direct consequence of the individuality of each and every human being and the reason why we need medical statistics. However, statistics have their pitfalls, too. Fig. 1 shows that the suicide rate peaks in youth, while in Fig. 2 the rate is highest in midlife and Fig. 3 in old age. Which of these contradictory messages is right? After an introduction to the principles of statistical testing, this lecture examines the probability with which statistical test results are correct. For this purpose the level of significance and the power of the test are compared with the sensitivity and specificity of a diagnostic procedure. The probability of obtaining correct statistical test results is the same as that for the positive and negative correctness of a diagnostic procedure and therefore depends on prevalence. The focus then shifts to the problem of multiple statistical testing. The lecture demonstrates that for each data set of reasonable size at least one test result proves to be significant - even if the data set is produced by a random number generator. It is extremely important that a hypothesis is generated independently from the data used for its testing. These considerations enable us to understand the gradation of "lame excuses, lies and statistics" and the difference between pure truth and the full truth. Finally, two historical oracles are cited

STATISTICAL CONSIDERATIONS FOR LOT-BY-LOT ACCEPTANCE/REJECTION SAMPLING WITH AN ATTRIBUTE

The standard procedure for lot-by-lot acceptance/rejection sampling described in literature makes always a decision. If there are more invalid items in the sample than specified, then the lot is rejected, otherwise the lot is accepted. However, if the actual proportion of invalid items in the lot is close to the accepted quality level then it is - in principle - impossible to control the customer's and the producer's risk with a reasonable sample size. The published standard procedure can result in acceptance of the lot even if there is insufficient information. We think this is unfair to the customer. Three statistical methods with a common acceptable quality limit are proposed and discussed: A simple procedure, confidence intervals, and finally a statistical test. The idea of a statistical test, its application in lot-by-lot acceptance/rejection sampling, and the proposed statistical test are described in detail and with examples. Additionally, determination of sample size and multiple step sampling plans are characterized

Passive versus active follow-up to investigate the efficacy of primary prevention programs

Before general application of a primary prevention program its efficacy has to be demonstrated. For this purpose a randomized controlled trial with active or passive follow-up may be conducted. In the last 5 years, the ratio of controlled trials with passive versus those with active follow-up was 1:13. However, under certain circumstances a passive follow-up may be more appropriate and useful to overcome the drawbacks of an active follow-up, as e.g. high costs and many drop-outs. In a randomized controlled trial, a passive follow-up is based on the reporting of cases by physicians or hospitals instead of actively following up all study participants individually. The statistical evaluation can be carried out using a one-sample chi2-test. Advantages and limitations are discussed. A passive follow-up may be advantageous in situations with low incidence, large number of participants, complete ascertainment of conditions with obligatory notification or effective disease registries and should be preferred in such a context