A teaching tool about the fickle p value and other statistical principles based on real-life data.

A poor understanding of statistical analysis has been proposed as a key reason for lack of replicability of many studies in experimental biomedicine. While several authors have demonstrated the fickleness of calculated p values based on simulations, we have experienced that such simulations are difficult to understand for many biomedical scientists and often do not lead to a sound understanding of the role of variability between random samples in statistical analysis. Therefore, we as trainees and trainers in a course of statistics for biomedical scientists have used real data from a large published study to develop a tool that allows scientists to directly experience the fickleness of p values. A tool based on a commonly used software package was developed that allows using random samples from real data. The tool is described and together with the underlying database is made available. The tool has been tested successfully in multiple other groups of biomedical scientists. It can also let trainees experience the impact of randomness, sample sizes and choice of specific statistical test on measured p values. We propose that live exercises based on real data will be more impactful in the training of biomedical scientists on statistical concepts.

Why Are New Drugs Expensive and How Can They Stay Affordable?

Increasing life expectancy leading to a higher median age causes an increasing need for healthcare resources, which is aggravated by an increasing prevalence of preventable diseases such as type 2 diabetes. This includes increasing expenditures for medicines, although these increases when expressed as a share of overall societal wealth are more moderate than often claimed. An increasing use of generic medicines (currently about 90% of all prescriptions) means that costs for discovery and development of innovative drugs must be recovered on a shrinking percentage of prescriptions. However, the key challenge to affordable drugs is exponentially increasing costs to bring a new medicine to the market, which in turn are largely driven by an about 90% attrition rate after start of clinical development. While many factors will be required in concert to keep innovative medicines affordable, reducing attrition appears to be the factor with the greatest potential to contain escalating drug development costs and thereby medication expenditures.

Innovation in cardiovascular disease in Europe with focus on arrhythmias: current status, opportunities, roadblocks, and the role of multiple stakeholders.

The European Heart Rhythm Association (EHRA) held an Innovation Forum in February 2016, to consider issues around innovation. The objective of the forum was to extend the innovation debate outside of the narrow world of arrhythmia specialists and cardiology in general, and seek input from all stakeholders including regulators, strategists, technologists, industry, academia, health providers, medical societies, payers, and patients. Innovation is indispensable for a continuing improvement in health care, preferably at higher efficacy and lower costs. It requires people who have been trained in a good scientific environment, high-quality research for achieving ground breaking inventions and the certainty of return on innovation investments. In the context of cardiovascular disease, innovation can imply better risk assessment and stratification, device technology, drug development, and process design. Several areas of promising developments were identified as well as several roadblocks to innovation. To drive innovation forward all stakeholders need to play a significant role. In a globalized and extremely competitive world, the leading role of Europe in medical innovation can only be achieved through a combined and well-coordinated effort from all involved parties.

Expectations and satisfaction of academic investigators in nonclinical collaboration with the pharmaceutical industry.

In light of a growing role of research collaborations between academia and the pharmaceutical industry, we have explored expectations and experience of academic investigators with preclinical collaborations. Researchers from Western Europe, North America, and Japan with preclinical publications in the obstructed airways or diabetes fields were invited to anonymously participate in a web-based survey. A total of 134 investigators (28 % of invitees) participated in the two sequentially performed surveys with similar responses in both therapeutic areas. A secondary but prespecified subgroup analysis was based on region of residence, gender, and career level of the investigator. Across all groups, responders considered freedom to publish, obtaining funding and obtaining compounds to be the most important objectives of nonclinical collaborations with the pharmaceutical industry, whereas cultivating professional relationships, getting external scientific input, direct relationship to disease treatment, and involvement with drug development were less important. Among eight attributes of the primary contact person in the company, trustworthiness ranked highest, followed by a collaborative spirit and transparent information sharing; supportiveness, scientific qualification, accessibility, and timeliness of responses ranked lower, and friendliness, lowest. Related to their most recent collaboration, investigators also expressed the highest level of satisfaction with the trustworthiness attribute. On the other hand, the process of reaching a contract was often considered too long and difficult, for which both university and company legal departments were reported as culprits. We conclude that academic researchers are generally satisfied with their preclinical collaboration with the pharmaceutical industry but look for improved contracting procedures.

A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis.

CONTEXT: Nocturia is a common urologic symptom that has been covered in a variety of reported studies in the literature but is not specifically covered in current guidelines. OBJECTIVE: To comprehensively review the literature pertaining to the definition, etiologies, and consequences of nocturia and assess the evidence supporting the use of conservative medical and interventional therapy. EVIDENCE ACQUISITION: A literature search was conducted using the keyword nocturia, restricted to articles in the English language, after 2000 and before April 2012, in PubMed/Medline, Embase, Scopus, Web of Science, and Cochrane Library databases. Regarding treatment modalities, studies were included only if nocturia was a primary end point and if the studies were designed as randomized controlled trials without limit of date. When suitable, a meta-analysis was conducted. Papers covering treatment options for nocturia specifically related to nonurologic conditions were excluded. EVIDENCE SYNTHESIS: Nocturia is still defined as the symptom of wakening from sleep once or more often to void. The prevalence is high in both genders and increases with age. Frequency-volume charts, which are the pivotal tool of clinical assessment, detect 24-h polyuria, nocturnal polyuria (NP), or reduced nocturnal bladder capacity and help to target specific nonurologic etiologies. Nocturia is a morbid condition that significantly affects quality of life and increases mortality. Besides behavioral measures, validated treatment options include oral desmopressin, which is superior to placebo in treating NP. While the level of evidence for desmopressin is high, limited data support the use of α1-blockers and antimuscarinics; however, only rarely has nocturia been a primary end point when studying these drug classes, and studies have not consistently controlled for the effect of NP. CONCLUSIONS: Our knowledge of nocturia, its etiology, and its management has substantially improved in recent years. The evidence available on the management of nocturia remains limited; contributory factors include (1) the complexity of associated conditions, (2) the underuse of objective evaluation tools, and (3) the lack of specific focus on nocturia in clinical trials.

Medical expulsive therapy for distal ureteral stones.

Although minimally invasive treatments for ureteral stones are efficacious, they are not free of complications and are associated with high cost. Medical expulsive therapy (MET) has recently emerged as an alternative strategy for the initial management of small distal ureteral stones. A MEDLINE search was undertaken to evaluate all currently available data on efficacy and safety of MET therapy in such patients. The specific mechanism of action on the ureteral smooth muscle and the emerging evidence of the efficacy (defined as either an increase in expulsion rate or a decrease in time to expulsion) and low-risk profile suggest that alpha-adrenergic receptor antagonists (alpha-blockers) and calcium channel antagonists should be the initial medical treatment in patients amenable to conservative therapy. NSAIDs and anticholinergics have not shown efficacy as single agents or in combination with alpha-blockers or nifedipine. Corticosteroids may provide a small additive effect when combined with either alpha-blockers or nifedipine.

Evidence why paroxetine dose escalation is not effective in major depressive disorder: a randomized controlled trial with assessment of serotonin transporter occupancy.

Dose escalation is often used in depressed patients who fail to respond to standard doses of selective serotonin reuptake inhibitors, but clinical efficacy is equivocal. We aimed to reassess the efficacy of paroxetine dose escalation and quantify whether paroxetine dose escalation increases occupancy of the serotonin transporter (SERT) more than placebo dose escalation in a randomized controlled trial. We recruited 107 nonpsychotic, unipolar depressed outpatients (18-70 years; Hamilton Depression Rating Scale (HDRS(17)) >18) from primary care and psychiatric outpatient departments. After 6 weeks, open-label paroxetine 20 mg per day (T0), nonresponding patients (HDRS(17) decrease <50%; n=60) were randomized to double-blind paroxetine (30-50 mg per day as tolerable) or placebo dose escalation (paroxetine 20 mg per day+placebo). Patients were followed until 6 weeks after randomization (T1). Forty-nine patients, drug free at study entry, underwent single-photon emission-computed tomography (SPECT) scanning before treatment and were scanned repeatedly at T0 and T1. Paroxetine serum concentrations and SERT occupancy were determined at T0 and T1 (n=32). We terminated the dose-escalation trial after an interim analysis. Thirty nonresponding patients were randomized to paroxetine (46.7+/-5.5 mg per day), 27 to placebo dose escalation. Response rates were 10/30 (33.3%) and 10/27 (37.0%), respectively. Repeated measurement analyses showed no significant effect for treatment (p=0.88, exceeding a priori stopping rules for futility (p>0.5)). Overall dropout was higher for placebo (26.7%) than paroxetine (3.3%; p=0.03). Paroxetine dose escalation increased paroxetine serum concentrations (p<0.001). SPECT measurements (12 patients randomized to paroxetine (46.9+/-4.8 mg) and 14 to placebo dose escalation) showed no significant increase of midbrain SERT occupancy (2.5+/-26.4%, paroxetine; 3.1+/-25.8% placebo; p=0.687) nor in diencephalon (p=0.529). Paroxetine dose escalation in depressed patients has no clinical benefit over placebo dose escalation. This is explained by the absence of significant increases of SERT occupancy by paroxetine dose escalation, despite increased paroxetine serum concentrations (ISRCTN44111488).

A benefit-risk assessment of extended-release oxybutynin.

Oxybutynin is a muscarinic receptor antagonist, which has been available for a number of years in its original immediate-release (IR) formulation. While oxybutynin IR has proven effective for the treatment of overactive bladder, its extended use can be limited by adverse effects, particularly dry mouth. An extended-release (ER) formulation of oxybutynin based on the OROS system has recently become available, which allows once daily administration. In direct comparison to oxybutynin IR, oxybutynin ER has an increased oral bioavailability for the parent compound oxybutynin which is accompanied by a reduced bioavailability for the active metabolite N-desethyl-oxybutynin. The latter has been implicated in mediating a major part of the adverse effects of oxybutynin treatment. Two double-blind, placebo-controlled, randomised studies in patients with overactive bladder have demonstrated that oxybutynin ER has a similar efficacy as oxybutynin IR but with improved tolerability. This is in line with clinical pharmacological studies demonstrating a smaller impairment of saliva production with oxybutynin ER than with oxybutynin IR. Thus, the ER formulation of oxybutynin maintains the therapeutic benefits and concomitantly improves tolerability.