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

Assessment of OMT-28, a synthetic analog of omega-3 epoxyeicosanoids, in patients with persistent atrial fibrillation: Rationale and design of the PROMISE-AF phase II study.

We designed a placebo controlled, double-blind, randomized, dose-finding phase II study on OMT-28 in the maintenance of sinus rhythm after electrical cardioversion (DCC) in patients with persistent atrial fibrillation (PROMISE-AF). OMT-28 is a first-in-class, synthetic analog of 17,18-epoxyeicosatetetraenoic acid, a bioactive lipid mediator generated by cytochrome P450 enzymes from the omega-3 fatty acid eicosapentaenoic acid. OMT-28 improves Ca2+-handling and mitochondrial function in cardiomyocytes and reduces pro-inflammatory signaling. This unique mode of action may provide a novel approach to target key mechanism contributing to AF pathophysiology. In a recent phase I study, OMT-28 was safe and well tolerated and showed favorable pharmacokinetics. The PROMISE-AF study (NCT03906799) is designed to assess the efficacy (primary objective), safety, and population pharmacokinetics (secondary objectives) of three different doses of OMT-28, administered once daily, versus placebo until the end of the follow-up period. Recruitment started in March 2019 and the study will include a total of 120 patients. The primary efficacy endpoint is the AF burden (% time with any AF), evaluated over a 13-week treatment period after DCC. AF burden is calculated based on continuous ECG monitoring using an insertable cardiac monitor (ICM). The primary efficacy analysis will be conducted on the modified intention-to-treat (mITT) population, whereas the safety analysis will be done on the safety population. Although ICMs have been used in other interventional studies to assess arrhythmia, PROMISE-AF will be the first study to assess antiarrhythmic efficacy and safety of a novel rhythm-stabilizing drug after DCC by using ICMs

A bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer

© 2014 Chan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear

Removal of dental amalgam restorations in patients with health complaints attributed to amalgam: A prospective cohort study

Background The Norwegian Ministry of Health and Care Services initiated a project including experimental treatment for patients with health complaints attributed to amalgam restorations. Objective The aim was to evaluate changes of general health complaints in patients who participated in the project and had all amalgam restorations removed. Methods The project was designed as a prospective cohort study and organised by the Dental Biomaterials Adverse Reaction Unit in Bergen, Norway. The dental treatment was provided by the patient's local dentist. The main target group consisted of patients with medically unexplained physical symptoms, attributed to dental amalgam restorations (Amalgam cohort). The primary comparison group consisted of patients with medically unexplained physical symptoms without attribution to dental amalgam restorations (MUPS cohort). Primary outcome was self-reported general health complaints (GHC index) at follow-up 12-months after completed amalgam removal. Results In the Amalgam cohort, a significant reduction of GHC index from 43.3 (SD 17.8) at baseline to 30.5 (SD 14.4) at follow-up (mean reduction 12.8, SD 15.9; n = 32; P < .001) was observed. The change scores for GHC index indicated that the reduction of complaints was significantly higher (P = .004) in the Amalgam cohort compared with the MUPS cohort (mean reduction 1.2, SD 12.3, n = 28). After adjustment for age, gender, education and baseline GHC index, the mean adjusted difference was −8.0 (95% confidence interval from −15.4 to −0.5; P = .036). Conclusion In a group of patients with medically unexplained physical symptoms, which they attributed to dental amalgam restorations, removal of amalgam restorations was followed by a significant reduction of health complaints.publishedVersio

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

Evidence synthesis as the key to more coherent and efficient research

<p>Abstract</p> <p>Background</p> <p>Systematic review and meta-analysis currently underpin much of evidence-based medicine. Such methodologies bring order to <it>previous </it>research, but <it>future </it>research planning remains relatively incoherent and inefficient.</p> <p>Methods</p> <p>To outline a framework for evaluation of health interventions, aimed at increasing coherence and efficiency through i) making better use of information contained within the existing evidence-base when designing future studies; and ii) maximising the information available and thus potentially reducing the need for future studies.</p> <p>Results</p> <p>The framework presented insists that an up-to-date meta-analysis of existing randomised controlled trials (RCTs) should always be considered before future trials are conducted. Such a meta-analysis should inform critical design issues such as sample size determination. The contexts in which the use of individual patient data meta-analysis and mixed treatment comparisons modelling may be beneficial before further RCTs are conducted are considered. Consideration should also be given to how any newly planned RCTs would contribute to the totality of evidence through its incorporation into an updated meta-analysis. We illustrate how new RCTs can have very low power to change inferences of an existing meta-analysis, particularly when between study heterogeneity is taken into consideration.</p> <p>Conclusion</p> <p>While the collation of existing evidence as the basis for clinical practice is now routine, a more coherent and efficient approach to planning future RCTs to strengthen the evidence base needs to be developed. The framework presented is a proposal for how this situation can be improved.</p

College of Radiology, Academy of Medicine of Malaysia position on whole body screening CT scans in healthy asymptomatic individuals (2008)

To date, the College of Radiology (CoR) does not see any clear benefit in performing whole body screening computed tomography (CT) examinations in healthy asymptomatic individuals. There are radiation risk issues in CT and principles of screening should be adhered to. There may be a role for targeted cardiac screening CT that derives calcium score, especially for asymptomatic medium-risk individuals and CT colonography when used as part of a strategic programme for colorectal cancer screening in those 50 years and older. However, population based screening CT examinations may become appropriate when evidence emerges regarding a clear benefit for the patient outweighing the associated radiation risks

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research

Radiation Exposure from CT Examinations in Japan

<p>Abstract</p> <p>Background</p> <p>Computed tomography (CT) is the largest source of medical radiation exposure to the general population, and is considered a potential source of increased cancer risk. The aim of this study was to assess the current situation of CT use in Japan, and to investigate variations in radiation exposure in CT studies among institutions and scanners.</p> <p>Methods</p> <p>Data-sheets were sent to all 126 hospitals and randomly selected 14 (15%) of 94 clinics in Gunma prefecture which had CT scanner(s). Data for patients undergoing CT during a single month (June 2008) were obtained, along with CT scan protocols for each institution surveyed. Age and sex specific patterns of CT examination, the variation in radiation exposure from CT examinations, and factors which were responsible for the variation in radiation exposure were determined.</p> <p>Results</p> <p>An estimated 235.4 patients per 1,000 population undergo CT examinations each year, and 50% of the patients were scanned in two or more anatomical locations in one CT session. There was a large variation in effective dose among hospitals surveyed, particularly in lower abdominal CT (range, 2.6-19.0 mSv). CT examinations of the chest and upper abdomen contributed to approximately 73.2% of the collective dose from all CT examinations. It was estimated that in Japan, approximately 29.9 million patients undergo CT annually, and the estimated annual collective effective dose in Japan was 277.4 *10³Sv person. The annual effective dose per capita for Japan was estimated to be 2.20 mSv.</p> <p>Conclusions</p> <p>There was a very large variation in radiation exposure from CT among institutions surveyed. CT examinations of the chest and upper abdomen were the predominant contributors to the collective dose.</p