Regulatory approval of pharmaceuticals without a randomised controlled study: analysis of EMA and FDA approvals 1999-2014

INTRODUCTION: The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence. OBJECTIVE: To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). METHODS: Drug approval data were downloaded from the EMA website and the 'Drugs@FDA' database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period. RESULTS: Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time. DISCUSSION: Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators

Baseline characteristics and treatment-emergent risk factors associated with cerebrovascular event and death with risperidone in dementia patients

BACKGROUND: Use of antipsychotics to treat behavioural symptoms of dementia has been associated with increased risks of mortality and stroke. Little is known about individual patient characteristics that might be associated with bad or good outcomes. AIMS: We examined the risperidone clinical trial data to look for individual patient characteristics associated with these adverse outcomes. METHOD: Data from all double-blind randomised controlled trials of risperidone in dementia patients (risperidone n = 1009, placebo n = 712) were included. Associations between characteristics and outcome were analysed based on crude incidences and exposure-adjusted incidence rates, and by time-to-event analyses using Cox proportional hazards regression. Interactions between treatment (risperidone or placebo) and characteristic were analysed with a Cox proportional hazards regression model with main effects for treatment and characteristic in addition to the interaction term. RESULTS: Baseline complications of depression (treatment by risk factor interaction on cerebrovascular adverse event (CVAE) hazard ratio (HR): P = 0.025) and delusions (P = 0.043) were associated with a lower relative risk of CVAE in risperidone-treated patients (HR = 1.47 and 0.54, respectively) compared to not having the complication (HR = 5.88 and 4.16). For mortality, the only significant baseline predictor in patients treated with risperidone was depression, which was associated with a lower relative risk (P<0.001). The relative risk of mortality was increased in risperidone patients treated with anti-inflammatory medications (P = 0.021). CONCLUSIONS: Only anti-inflammatory medications increased mortality risk with risperidone. The reduced risks of CVAE in patients with comorbid depression and delusions, and of mortality with depression, may have clinical implications when weighing the benefits and risks of treatment with risperidone in patients with dementia

Automated Detection of Radiology Reports that Document Non-routine Communication of Critical or Significant Results

The purpose of this investigation is to develop an automated method to accurately detect radiology reports that indicate non-routine communication of critical or significant results. Such a classification system would be valuable for performance monitoring and accreditation. Using a database of 2.3 million free-text radiology reports, a rule-based query algorithm was developed after analyzing hundreds of radiology reports that indicated communication of critical or significant results to a healthcare provider. This algorithm consisted of words and phrases used by radiologists to indicate such communications combined with specific handcrafted rules. This algorithm was iteratively refined and retested on hundreds of reports until the precision and recall did not significantly change between iterations. The algorithm was then validated on the entire database of 2.3 million reports, excluding those reports used during the testing and refinement process. Human review was used as the reference standard. The accuracy of this algorithm was determined using precision, recall, and F measure. Confidence intervals were calculated using the adjusted Wald method. The developed algorithm for detecting critical result communication has a precision of 97.0% (95% CI, 93.5–98.8%), recall 98.2% (95% CI, 93.4–100%), and F measure of 97.6% (ß = 1). Our query algorithm is accurate for identifying radiology reports that contain non-routine communication of critical or significant results. This algorithm can be applied to a radiology reports database for quality control purposes and help satisfy accreditation requirements

Gender perspectives on views and preferences of older people on exercise to prevent falls: a systematic mixed studies review

Background: To offer fall prevention exercise programs that attract older people of both sexes there is a need to understand both womens and mens views and preferences regarding these programs. This paper aims to systematically review the literature to explore any underlying gender perspectives or gender interpretations on older peoples views or preferences regarding uptake and adherence to exercise to prevent falls. Methods: A review of the literature was carried out using a convergent qualitative design based on systematic searches of seven electronic databases (PubMed, CINAHL, Amed, PsycINFO, Scopus, PEDro, and OTseeker). Two investigators identified eligible studies. Each included article was read by at least two authors independently to extract data into tables. Views and preferences reported were coded and summarized in themes of facilitators and barriers using a thematic analysis approach. Results: Nine hundred and nine unique studies were identified. Twenty five studies met the criteria for inclusion. Only five of these contained a gender analysis of mens and womens views on fall prevention exercises. The results suggests that both women and men see women as more receptive to and in more need of fall prevention messages. The synthesis from all 25 studies identified six themes illustrating facilitators and six themes describing barriers for older people either starting or adhering to fall prevention exercise. The facilitators were: support from professionals or family; social interaction; perceived benefits; a supportive exercise context; feelings of commitment; and having fun. Barriers were: practical issues; concerns about exercise; unawareness; reduced health status; lack of support; and lack of interest. Considerably more women than men were included in the studies. Conclusion: Although there is plenty of information on the facilitators and barriers to falls prevention exercise in older people, there is a distinct lack of studies investigating differences or similarities in older womens and mens views regarding fall prevention exercise. In order to ensure that fall prevention exercise is appealing to both sexes and that the inclusion of both men and women are encouraged, more research is needed to find out whether gender differences exists and whether practitioners need to offer a range of opportunities and support strategies to attract both women and men to falls prevention exercise.Funding Agencies|Swedish Research Council [2015-03481]; Strategic Research Programme in Care Sciences, Umea University; Karolinska Institute, Sweden; Umea University</p

Systematic review of antiepileptic drugs’ safety and effectiveness in feline epilepsy

Understanding the efficacy and safety profile of antiepileptic drugs (AEDs) in feline epilepsy is a crucial consideration for managing this important brain disease. However, there is a lack of information about the treatment of feline epilepsy and therefore a systematic review was constructed to assess current evidence for the AEDs’ efficacy and tolerability in cats. The methods and materials of our former systematic reviews in canine epilepsy were mostly mirrored for the current systematic review in cats. Databases of PubMed, CAB Direct and Google scholar were searched to detect peer-reviewed studies reporting efficacy and/or adverse effects of AEDs in cats. The studies were assessed with regards to their quality of evidence, i.e. study design, study population, diagnostic criteria and overall risk of bias and the outcome measures reported, i.e. prevalence and 95% confidence interval of the successful and affected population in each study and in total

Pulmonary valve endocarditis caused by right ventricular outflow obstruction in association with sinus of valsalva aneurysm: a case report

<p>Abstract</p> <p>Background</p> <p>Right-sided infective endocarditis is uncommon. This is primarily seen in patients with intravenous drug use, pacemaker or central venous lines, or congenital heart disease. The vast majority of cases involve the tricuspid valve. Isolated pulmonary valve endocarditis is extremely rare. We report the first case of a pulmonary valve nonbacterial thrombotic endocarditis caused by right ventricular outlflow tract (RVOT) obstruction in association with a large sinus of Valsalva aneurysm.</p> <p>Case presentation</p> <p>A 60-year-old man with a six-week history of fever, initially treated as pneumonia and sinusitis with levofloxacin, was admitted to the hospital with a new onset of a heart murmur. An echocardiogram showed thickening of the pulmonary valve suggestive of valve vegetation. A dilated aortic root and sinus of Valsalva aneurysm measuring at least 6.4 cm were also identified. The patient was empirically treated for infective endocarditis with vancomycin and gentamycin for 28 days. Four months later, the patient underwent resection of a large aortic root aneurysm and exploration of the pulmonary valve. During the surgery, vegetation of the pulmonary valve was confirmed. Microscopic pathological examination revealed fibrinous debris with acute inflammation and organizing fibrosis with chronic inflammation, compatible with a vegetation. Special stains were negative for bacteria and fungi.</p> <p>Conclusion</p> <p>This is the first case report of a pulmonary valve nonbacterial endocarditis caused by RVOT obstruction in association with a sinus of Valsalva aneurysm. We speculate that jets created by the RVOT obstruction and large sinus of Valsalva aneurysm hitting against endothelium of the pulmonary valve is the etiology of this rare nonbacterial thrombotic endocarditis.</p

Image perception and interpretation of abnormalities; can we believe our eyes? Can we do something about it?

The radiologist’s visual impression of images is transmitted, via non-visual means (the report), to the clinician. There are several complex steps from the perception of the images by the radiologist to the understanding of the impression by the clinician. With a process as complex as this, it is no wonder that errors in perception, cognition, interpretation, transmission and understanding are very common. This paper reviews the processes of perception and error generation and possible strategies for minimising them

Exercise therapy for chronic low back pain:protocol for an individual participant data meta-analysis

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) is one of the leading causes of disability and has a major socioeconomic impact. Despite a large amount of research in the field, there remains uncertainty about the best treatment approach for chronic LBP, and identification of relevant patient subgroups is an important goal. Exercise therapy is a commonly used strategy to treat chronic low back pain and is one of several interventions that evidence suggests is moderately effective.</p> <p>In parallel with an update of the 2005 Cochrane review, we will undertake an individual participant data (IPD) meta-analysis, which will allow us to standardize analyses across studies and directly derive results, and to examine differential treatment effects across individuals to estimate how patients’ characteristics modify treatment benefit.</p> <p>Methods/design</p> <p>We will use standard systematic review methods advocated by the Cochrane Collaboration to identify relevant trials. We will include trials evaluating exercise therapy compared to any or no other interventions in adult non-specific chronic LBP. Our primary outcomes of interest include pain, functional status, and return-to-work/absenteeism. We will assess potential risk of bias for each study meeting selection criteria, using criteria and methods recommended by the Cochrane BRG.</p> <p>The original individual participant data will be requested from the authors of selected trials having moderate to low risk of bias. We will test original data and compile a master dataset with information about each trial mapped on a pre-specified framework, including reported characteristics of the study sample, exercise therapy characteristics, individual patient characteristics at baseline and all follow-up periods, subgroup and treatment effect modifiers investigated. Our analyses will include descriptive, study-level meta-analysis and meta-regression analyses of the overall treatment effect, and individual-level IPD meta-analyses of treatment effect modification. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies.</p> <p>Discussion</p> <p>We will analyze IPD across a large number of LBP trials. The resulting larger sample size and consistent presentation of data will allow additional analyses to explore patient-level heterogeneity in treatment outcomes and prognosis of chronic LBP.</p

Barking up the same tree: a comparison of ethnomedicine and canine ethnoveterinary medicine among the Aguaruna

<p>Abstract</p> <p>Background</p> <p>This work focuses on plant-based preparations that the Aguaruna Jivaro of Peru give to hunting dogs. Many plants are considered to improve dogs' sense of smell or stimulate them to hunt better, while others treat common illnesses that prevent dogs from hunting. This work places canine ethnoveterinary medicine within the larger context of Aguaruna ethnomedicine, by testing the following hypotheses: H1 -- Plants that the Aguaruna use to treat dogs will be the same plants that they use to treat people and H2 -- Plants that are used to treat both people and dogs will be used for the same illnesses in both cases.</p> <p>Methods</p> <p>Structured interviews with nine key informants were carried out in 2007, in Aguaruna communities in the Peruvian department of Amazonas. Informants provided freelists of plants given to dogs and explained the purpose, preparation and route of administration used. For each plant, informants also described any uses for treating people. Botanical voucher specimens were collected and additional informal observations were made, accompanying people on hunting trips.</p> <p>Results</p> <p>Out of 35 plant species given to dogs, 29 (83%) are also given to humans for some medicinal purpose, while five are used only for dogs. However, the same plant is used to treat the same illness in both humans and dogs in only 53% of the cases. Forty-three percent of plants used to treat a particular illness for both dogs and people are administered in the same manner for both.</p> <p>Conclusion</p> <p>Results suggest that Aguaruna canine ethnoveterinary medicine is, at least partly, an independent cognitive domain. Some of the difference in plant use between dogs and people can be explained by the fact that certain diseases mentioned only apply to dogs. Although reports of canine ethnoveterinary medicine are very sparse in the literature, Aguaruna practices show some similarities with a few trends reported for other Amazonian societies, particularly, in the prevalence of the nasal route of administration, the use of plant-based psychoactives and in the importance of ants and wasps, in some form, for training dogs.</p