Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

The predictive utility of the plant phylogeny in identifying sources of cardiovascular drugs

Context: Cardiovascular disease (CVD) is the number one cause of death globally, responsible for over 17 million (31%) deaths in the world. Novel pharmacological interventions may be needed given the high prevalence of CVD.

Objective: In this study, we aimed to find potential new sources of cardiovascular (CV) drugs from phylogenetic and pharmacological analyses of plant species that have experimental and traditional CV applications in the literature.

Materials and methods: We reconstructed the molecular phylogeny of these plant species and mapped their pharmacological mechanisms of action on the phylogeny.

Results: Out of 139 plant species in 71 plant families, seven plant families with 45 species emerged as phylogenetically important exhibiting common CV mechanisms of action within the family, as would be expected given their common ancestry: Apiaceae, Brassicaceae, Fabaceae, Lamiaceae, Malvaceae, Rosaceae and Zingiberaceae. Apiaceae and Brassicaceae promoted diuresis and hypotension; Fabaceae and Lamiaceae had anticoagulant/thrombolytic effects; Apiaceae and Zingiberaceae were calcium channel blockers. Moreover, Apiaceae, Lamiaceae, Malvaceae, Rosaceae and Zingiberaceae species were found to possess anti-atherosclerotic properties.

Discussion and conclusions: The phylogeny identified certain plant families with disproportionately more species, highlighting their importance as sources of natural products for CV drug discovery. Though there were some species that did not show the same mechanism within the family, the phylogeny predicts that these species may contain undiscovered phytochemistry, and potentially, the same bioactivity. Evolutionary pharmacology, as applied here, may guide and expedite our efforts in discovering sources of new CV drugs.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

Lidocaine 5% medicated plaster for localized neuropathic pain in thoracic surgical patients

Context: Neuropathic pain is a common and distressing symptom in thoracic surgical patients. When it consistently presents with measurable sensory changes in a circumscribed area, neuropathic pain can be diagnosed as localized neuropathic pain (LNP).

Objective: The purpose of this study was to report the efficacy of lidocaine 5% medicated plaster (Lido5%P) in the treatment of LNP in thoracic surgical patients.

Methods: We retrospectively reviewed the records of sixteen cancer and noncancer thoracic patients treated with Lido5%P for LNP. Patients had been assessed before and during treatment with standardized forms and questionnaires for pain intensity, sleep quality, drug dosages and adverse events.

Results: Treatment with Lido5%P yielded a significant and lasting improvement in pain symptomatology. In oncological patients as an add-on therapy, Lido5%P improved pain intensity and sleep quality, and delayed opioid dose escalation. In non-oncological patients as monotherapy or in association with antineuropathic drugs, Lido5%P attenuated LNP. No local or systemic adverse events were recorded.

Conclusions: Lido5%P was effective in relieving thoracic LNP, and was well tolerated.     

Cognitive defusion versus experiential avoidance in the reduction of smoking behaviour: an experimental and preliminary investigation

Background: Brief procedures that reduce smoking behaviour may be useful in reaching the many people that do not seek help for smoking addiction.

Objectives: The current study aimed to determine if one component of Acceptance and Commitment Therapy (ACT), cognitive defusion, could be useful in reducing smoking behaviour in a sample of students.

Methods: The study employed a between-subjects three-arm design. For one week, participants were asked to reduce their cigarette consumption. To aid them in their reduction, participants were randomly allocated to one of three conditions: the first received a defusion procedure, the second received an experiential avoidance procedure and a control condition received no procedure. For a second week, the instruction to reduce cigarette consumption was lifted. During both weeks participants were required to monitor their smoking behaviour via a tally diary system.

Results: The defusion condition smoked significantly less than the control condition during week one and significantly less than the control and experiential avoidance conditions during week two.

Conclusion: Results are discussed in terms of the potential utility of defusion in this domain, and the limitations of this preliminary research that would need to be addressed in future investigations.     

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.

Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented.

In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.

Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.

Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.     

Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies

Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients.

Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice.

Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered.

Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05)

Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.     

Incarceration history,social network composition,and substance use among homeless youth in Los Angeles

Background: Homeless youth in the United States have high rates of substance use. Existing research has identified social network composition and street-associated stressors as contributing factors. Incarceration is a highly prevalent stressor for homeless youth. Its effect on youth’s social network composition and substance use, however, has been neglected.

Aims: This study investigated the direct and indirect associations between incarceration history and substance use (through social networks) among homeless youth in Los Angeles, California.

Methods: A sample of 1047 homeless youths were recruited between 2011 and 2013. Computerized self-administrated surveys and social network interviews were conducted to collect youth’s sociodemographic characteristics, incarceration history, social network composition, and substance use. Bootstrapping was used to identify the direct and indirect associations between youth’s incarceration history and substance use.

Results: Incarceration history was positively associated with youth’s cannabis, methamphetamine, and injection drug use. The percentage of cannabis-using peers partially mediated the associations between incarceration history and youth’s cannabis, cocaine, and heroin use. The percentage of methamphetamine-using peers partially mediated the associations between incarceration history and youth's methamphetamine, cocaine, and injection drug use. The percentage of heroin-using peers partially mediated the association between incarceration history and youth’s heroin use. Moreover, the percentage of peers who inject drugs partially mediated the associations between incarceration history and youth’s methamphetamine, heroin, and injection drug use.

Discussion: Incarceration history should be taken to a more central place in future research and practice with homeless youth in the United States.     

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative.

Areas covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis.

Expert opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 – 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 – 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.     

Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions,biological properties and clinical efficacy

Context: Cardiometabolic risks are regarded as the crucial factors associated with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Regarding an increased attention to medicinal plants in the current healthcare system, the effects of mulberry (Morus spp., Moraceae) leaves on cardiometabolic risks have been consecutively considered in scientific research.

Objective: The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.

Methods: Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using ‘mulberry leaves’ ‘Morus spp.’, ‘hyperglycemia’, ‘hyperlipidemia’, ‘obesity’, ‘hypertension’, ‘oxidative stress’, ‘atherosclerosis’ and ‘cardiovascular diseases’ as the keywords. The relevant articles published over the past two decades were identified and reviewed.

Results: Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.

Conclusions: Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses.     

Echinacea biotechnology: advances,commercialization and future considerations

Context: Plants of the genus Echinacea (Asteraceae) are among the most popular herbal supplements on the market today. Recent studies indicate there are potential new applications and emerging markets for this natural health product (NHP).

Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.

Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.

Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.

Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities.     

Successful administration of BI 695501, an adalimumab biosimilar,using an autoinjector (AI): results from a Phase II open-label clinical study (VOLTAIRE®-RL)

Background: This study examined the patient handling experience and self-injection success of patients with rheumatoid arthritis (RA) administering BI 695501 using an AI.

Methods: This Phase II, 7-week, open-label, interventional study (NCT02636907) included adult patients with moderately to severely active RA not adequately controlled by DMARDs, with no experience of self-injecting with AI/pen. Patients self-injected BI 695501 via AI every 2 weeks in the AI Assessment Period (AAP). Training was given on first injection; AI handling events were recorded. Percentage of self-injection success was the primary end point. Patients could enter a 42-week pre-filled syringe (PFS) safety extension.

Results: The AAP was completed by 73/77 patients. In total, 216/218 (99.1%) self-injections on Days 15, 29, and 43, were successful. Nine (11.7%) patients had drug-related adverse events (AEs). Two patients reported four serious AEs (SAEs), none drug-related. Overall (in the AAP and PFS extension), 28 (36.4%) patients had drug-related AEs; nine patients had SAEs, one was considered drug-related. Five (6.5%) patients reported injection-site reactions in the AAP; 13 (18.1%) in the PFS extension.

Conclusions: After training, almost all patients were successfully able to self-administer BI 695501 using an AI. BI 695501 via AI (and via PFS in the extension) was well tolerated.

Clinical Trial Registration: NCT02636907     

An ethnopharmacological study of aromatic Uyghur medicinal plants in Xinjiang,China

Context: An ethnobotanical survey was completed in a remote village and surrounding country of Xinjiang, where most Uyghur medicinal plants could be collected. This work clarifies and increases ethnobotanical data.

Objectives: We surveyed and organized aromatic medicinal plants that are commonly used in clinical settings to provide a significant reference for studying new medical activities.

Materials and methods: In the survey, informants who have traditional knowledge on aromatic Uyghur medicinal plants were interviewed between March 2014 and September 2014. Aromatic medicinal plant species and pertinent information were collected. Some therapeutic methods and modes of preparation of traditional aromatic medicinal plants were found.

Results: A total of 86 aromatic medicinal plant species belonging to 36 families were included in our study. We identified 34 plant species introduced from different regions such as Europe, India and Mediterranean areas. Fruits and whole plants were the most commonly used parts of plant, and most aromatic medicinal plants could be applied as medicine and food. We assigned the medicinal plants a use value (UV). Knowing the UV of species is useful in determining the use reliability and pharmacological features of related plants.

Conclusions: Xinjiang is an area in which indigenous aromatic medicinal plants are diversely used and has therefore established a sound dimensional medical healthcare treatment system. Some aromatic Uyghur medicinal plants are on the verge of extinction. Hence, further strategies for the conservation of these aromatic medicinal plants should be prioritized.     

Conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis: a randomized clinical trial

Objective: Efficacy of the conventional- versus high-dose vancomycin regimen in patients with acute bacterial meningitis was compared.

Methods: In a randomized clinical trial 44 patients with acute bacterial meningitis were randomly assigned to the conventional- or high-dose vancomycin groups. Clinical and laboratory parameters were used for evaluation of response to the treatment regimens.

Results: In the high-dose group, leukocytosis and fever resolved significantly faster than those in the conventional group. Furthermore, the length of hospitalization was shorter and Glasgow Coma Scale at the end of 10th day was significantly lower in the high dose compared to the conventional group. Trend of creatinine clearance changes did not differ significantly between the two groups.

Conclusion: In comparison to the conventional-dose regimen, the high-dose vancomycin regimen was associated with significantly more favorable clinical response without increase in the incidence of nephrotoxicity in patients with acute bacterial meningitis.     

Induction therapy for the management of early relapsing forms of multiple sclerosis. A critical opinion

Introduction: The therapeutic approach in multiple sclerosis (MS) is radically changing. From the early stages of MS, a hard-hitting approach to treatment is taken with strong anti-inflammatory drugs being a possible therapeutic option.

Areas covered: The concept of induction therapy is emerging in the MS therapeutic scenario.

Expert opinion: Not all the MS licensed drugs are suitable candidates for induction therapy. The upcoming challenge will be to identify, after a careful and individual assessment of risk/benefit ratio, the ideal patient who is a candidate to such aggressive therapeutic approach.     

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept

Background and purpose: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects.

Experimental approach: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models.

Results: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)).

Conclusion and implications: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.     

Potential mechanisms underlying CDK5 related Osteosarcoma progression

Objectives: Identification of new prognostic biomarkers and therapeutic targets is of crucial importance for patients with osteosarcoma. Cyclin-dependent kinase 5 (CDK5) is overexpressed in several tumor types. However, the exact role CDK5 plays in osteosarcoma is still unknown.

Methods: In this study, we explored the association between CDK5 expression and the prognosis of osteosarcoma patients using publicly available gene expression datasets. Potential molecular mechanisms underlying its pro-malignant role in cancer progression were also discussed.

Results: We demonstrated that tricarboxylic acid (TCA) cycle is activated while antigen presentation is repressed in patients with CDK5 overexpression and poor survival. This results indicated that sufficient energy production and tumor immune escape are important characteristics and potential therapeutic targets for this subgroup of osteosarcoma patients. Furthermore, several critical hub genes that are associated with CDK5 related osteosarcoma progression such as MELK were identified.

Conclusion: This study discussed the pro-malignant role of CDK5 and potential mechanisms involved. Further preclinical and clinical studies to develop CDK5 based treatments are warranted.     

The influence of excipients on physical and pharmaceutical properties of oral lyophilisates containing a pregabalin-acetaminophen combination

Objectives: The purpose of the study was to investigate and characterize the oral lyophilisates containing the pregabalin-acetaminophen drug combination and as xcipients mannitol with microcrystalline cellulose or hydroxypropyl methylcellulose, in order to conclude upon drug-excipient interactions and their stability implications, impact of excipients on drug release and on the physicochemical and mechanical properties of the pharmaceutical formulations.

Methods: The oral tablets were made by using a Christ freeze-dryer alpha 2–4-LSC lyophilizer, and evaluated for stability, drug-excipient compatibility and homogeneity of the prepared pharmaceutical formulations. The formulations were evaluated for in vivo absorption in rabbits by histopathological exams.

Results: FTIR and thermogravimetric analyses, DLS technique, SEM and NIR-CI studies confirmed the compatibility between compounds. From the determined physical and biochemical parameters of the formulations it was established that they are stable, homogeneous, and meet the conditions for orally disintegrating tablets.

Conclusion: In the case of the investigated pharmaceutical formulations the study evidenced the assembling through physical bonds between the excipients and the ‘codrug’ complex, which do not affect the release of the bioactive compounds.     

Regulation of cytochrome P450 gene expression by ketamine: a review

Introduction: Although used as an anesthetic drug for decades, ketamine appears to have garnered renewed interest due to its potential therapeutic uses in pain therapy, neurology, and psychiatry. Ketamine undergoes extensive oxidative metabolism by cytochrome P450 (CYP) enzymes. Considerable efforts have been expended to elucidate the ketamine-induced regulation of CYP gene expression. The safety profile of chronic ketamine administration is still unclear. Understanding how ketamine regulates CYP gene expression is clinically meaningful.

Areas covered: In this article, the authors provide a brief review of clinical applications of ketamine and its metabolism by CYP enzymes. We discuss the effects of ketamine on the regulation of CYP gene expression, exploring aspects of cytoskeletal remodeling, mitochondrial functions, and calcium homeostasis.

Expert opinion: Ketamine may inhibit CYP gene expression through inhibiting calcium signaling, decreasing ATP levels, producing excessive reactive oxygen species, and subsequently perturbing cytoskeletal dynamics. Further research is still needed to avoid possible ketamine–drug interactions during long-term use in the clinic.