The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations.

Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

Outcomes and endpoints in trials of cancer treatment: the past, present, and future.

Cancer treatment should allow patients to live better or longer lives, and ideally, both. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Alternative endpoints such as progression-free survival, disease-free survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is controversial. In this Review we discuss the measurement, assessment, and benefits and limitations of trial endpoints in use for cancer treatment. Many stakeholders are affected, including regulatory agencies, industry partners, clinicians, and most importantly, patients. In an accompanying Review, reflections from individual stakeholders are incorporated into a discussion of what the future holds for clinical trial endpoints and design.

Novel approaches are needed to develop tomorrow's antibacterial therapies.

Society faces a crisis of rising antibiotic resistance even as the pipeline of new antibiotics has been drying up. Antibiotics are a public trust; every individual's use of antibiotics affects their efficacy for everyone else. As such, responses to the antibiotic crisis must take a societal perspective. The market failure of antibiotics is due to a combination of scientific challenges to discovering and developing new antibiotics, unfavorable economics, and a hostile regulatory environment. Scientific solutions include changing the way we screen for new antibiotics. More transformationally, developing new treatments that seek to disarm pathogens without killing them, or that modulate the host inflammatory response to infection, will reduce selective pressure and hence minimize resistance emergence. Economic transformation will require new business models to support antibiotic development. Finally, regulatory reform is needed so that clinical development programs are feasible, rigorous, and clinically relevant. Pulmonary and critical care specialists can have tremendous impact on the continued availability of effective antibiotics. Encouraging use of molecular diagnostic tests to allow pathogen-targeted, narrow-spectrum antibiotic therapy, using short rather than unnecessarily long course therapy, reducing inappropriate antibiotic use for probable viral infections, and reducing infection rates will help preserve the antibiotics we have for future generations.

A decade of innovation in pharmaceutical R&D: the Chorus model.

Chorus is a small, operationally independent clinical development organization within Eli Lilly and Company that specializes in drug development from candidate selection to clinical proof of concept. The mission of Chorus is to achieve proof of concept rapidly and at a low cost while positioning successful projects for 'pharma-quality' late-stage development. Chorus uses a small internal staff of experienced drug developers and a network of external vendors to design and implement chemistry, manufacturing and control processes, preclinical toxicology and biology, and Phase I/II clinical trials. In the decade since it was established, Chorus has demonstrated substantial productivity improvements in both time and cost compared to traditional pharmaceutical research and development. Here, we describe its development philosophy, organizational structure, operational model and results to date.

The Year in Cardiology 2013: arrhythmias.

The Year in Cardiology 'arrhythmias' presents an update on the latest studies and innovations published in the field within the last 12 months. Recent advances in the management of atrial fibrillation and novel treatment strategies and technologies are presented. New consensus documents to improve the diagnosis and treatment of patients with inherited cardiac arrhythmias and for paediatric patients with cardiac arrhythmias are summarized. Great progress has also been made in the field of cardiac implantable electronic devices: improvements in implantation techniques and novel technologies have been introduced and successfully applied. In addition, novel data on prevention of implantable cardioverter defibrillator-shocks and cardiac resynchronization therapy will certainly help to improve the quality of care for patients with cardiac arrhythmias and heart failure.

Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.

In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds.

Advances from clinical trials in juvenile idiopathic arthritis.

Treatments available to children with juvenile idiopathic arthritis (JIA) have improved dramatically in the past 15 years, largely because of the development of powerful new biologic treatments. However, the seeds of this development were sewed over 40 years ago with the formation of a group of paediatric rheumatologists who understood the necessity of performing clinical trials in children with JIA. From there, international paediatric rheumatology networks have grown, and are dedicated to and highly experienced in performing such clinical trials. Development of validated outcomes and methodologies has also been critical. The ability to perform these trials stems from legislation enabling the FDA and the European Medicines Agency to require studies to be performed in children before they can be licensed for use in children. Current efforts to enhance the understanding of treatment options for patients with JIA include the development of disease-specific rather than drug-specific consolidated registries, studies in personalized predictive medicine and the development of treatment protocols for regular clinical care of these patients.

[Complementary medicine and scientific pluralism--from governmental research funding to the dialogue forum of pluralism in medicine]. / Komplementärmedizin und Wissenschaftspluralismus--von der staatlichen Forschungsförderung zum Dialogforum Pluralismus in der Medizin.

Medicine is based on a pluralism of different ways of thinking and practical approaches. Given this assumption, the history and experiences of the 2 German governmental research funding programs 'Unconventional Methods of Cancer' (UMK) and 'Unconventional Medicine Directions' (UMR) are described from the perspective of the project supporter of 2 working groups that were based at the University of Witten/Herdecke, Germany, on behalf of the federal government. The results of a nationwide inventory analysis conducted under my direction in the years 1989­1992 showed a distinct lack of human and infrastructural resources for competitive research for complementary medicine at that time. The field of complementary medicine was found to be very heterogeneous and was divided into procedures without any visible research interest, but also contained approaches nourishing mainstream medicine by its different paradigm. The representatives of complementary medicine were and still are recognizably interested in evaluative, empirical research. The following contains our funding recommendations made for the relevant ministries, the advertised funding issues, and the research activities carried out. Although this governmental research funding was limited, a signal function can be awarded, retrospectively. For the subsequent period, there has been a significant improvement in infrastructural, staff, and research conditions. This development led to a significant increase in the level of quality and the acceptability of research results. As a result of an increased willingness for cooperations, the foundations, concerns, and activities of the 'dialogue forum pluralism in medicine' set up in 2000 are presented and compared with the situation at the time of research funding by government. 'Integrative Medicine' is currently being favored and welcomed as a sign of better mutual acceptance. Nevertheless, complementary medicine is still seen as being creative, enriching medical and health care, improving the patient-centeredness, and thus as an educational (unrest) element (of agitation).

Tumor treating fields: a new frontier in cancer therapy.

Tumor treating fields (TTFields) is a noninvasive, regional antimitotic treatment modality that has been approved for the treatment of recurrent glioblastoma by the U.S. FDA and has a CE mark in Europe. TTFields therapy delivers low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields to the tumor using transducer arrays placed on the skin around the region of the body containing the tumor. TTFields therapy affects metaphase, by disrupting mitotic spindle formation, and anaphase, by dielectrophoretic dislocation of intracellular constituents, resulting in apoptosis. TTFields therapy is frequency tuned to specific cancer cell types. The antimitotic effect of TTFields therapy has been demonstrated in multiple cell lines when the appropriate frequency was utilized. A phase III trial of TTFields monotherapy compared to active chemotherapy in recurrent glioblastoma patients established that TTFields therapy is associated with minimal toxicity, better quality of life, and comparable efficacy to chemotherapy. Ongoing and future trials will evaluate TTFields in newly diagnosed glioblastoma, solid tumor brain metastases, nonsmall cell lung cancer, and ovarian and pancreatic cancers.

[Path to the execution of explorative clinical researches in National Cerebral and Cardiovascular Center (NCVC)].

In the Ministry of Health, Labour and Welfare's (MHLW) "5-year plan for activating clinical trials", we have put in place the infrastructure including human resources for supporting not only commercial clinical trials but also those initiated by academic researchers, including clinical research coordinator (CRC) support and consultation for planning clinical trial with biostatistician. We also prepared a data management unit and trained data managers for academic clinical trials. In 2011, the National Cerebral and Cardiovascular Center (NCVC) was selected one of the sites of the MHLW project of structure improvement to execute early phase clinical trials. To clinically develop medical devices invented by the NCVC researchers involved in the project, animal experiments which meet the GLP standards must be finished before the first-in-human clinical trial. We are planning to create the units containing human resources for developing medical devices such as professionals in regulatory affairs, safety tests, and Good Laboratory Practice (GLP) systems. Creation of a smooth pathway from the preclinical to the clinical phases will be key to the efficient development of new medical devices.

The future of monitoring in clinical research - a holistic approach: linking risk-based monitoring with quality management principles.

Since several years risk-based monitoring is the new "magic bullet" for improvement in clinical research. Lots of authors in clinical research ranging from industry and academia to authorities are keen on demonstrating better monitoring-efficiency by reducing monitoring visits, monitoring time on site, monitoring costs and so on, always arguing with the use of risk-based monitoring principles. Mostly forgotten is the fact, that the use of risk-based monitoring is only adequate if all mandatory prerequisites at site and for the monitor and the sponsor are fulfilled.Based on the relevant chapter in ICH GCP (International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use - Good Clinical Practice) this publication takes a holistic approach by identifying and describing the requirements for future monitoring and the use of risk-based monitoring. As the authors are operational managers as well as QA (Quality Assurance) experts, both aspects are represented to come up with efficient and qualitative ways of future monitoring according to ICH GCP.

A pharmacokinetic evaluation of topotecan as a cervical cancer therapy.

INTRODUCTION: Topotecan was initially approved for the treatment of recurrent ovarian cancer. In cervical cancer, it has been investigated for its potential as part of systemic therapy for advanced and/or recurrent disease and in combination with cisplatin and radiation as a first-line treatment for advanced disease. As a topoisomerase I (topo I) inhibitor, its activity is predicted to be schedule-dependent and potentiated in a schedule-dependent manner by its interaction with DNA damaging agents. AREAS COVERED: The cytotoxicity of topotecan is believed to be due to double-stranded DNA damage produced when the DNA replication 'fork' on the opposing DNA strand is interrupted by the ternary complex formed by topotecan, topoisomerase I and DNA. This review focuses on: i) combination studies of cisplatin + topotecan both as neoadjuvant and with concomitant radiation; ii) adding this drug as a radiosensitizer in pilot studies for locally advanced disease and iii) topotecan as part of non-cisplatin combinations in metastatic disease. EXPERT OPINION: Cervical cancer continues to claim many victims among parts of the world where early detection and/or vaccination programs are not systemically applied. Topotecan is an attractive building block for improving therapy against advanced disease.

Post SELECT: selenium on trial.

Selenium is an essential trace element for humans and other animals that is required in very small amounts for proper growth and functioning. Several selenium compounds have shown promise as cancer chemopreventive and chemotherapeutic agents. However, the negative outcome of the SELECT trial to some extent dampened the enthusiasm of selenium-related drug development. A look at the selenium compounds, their diverse mechanism of action, bioavailability and efficacy based on chemical structure, however, suggests that failure of SELECT that used selenomethionine supplement to prevent prostate cancer was not a failure of selenium compounds as a whole. This is certainly true in regard to therapeutic applications of selenium compounds. This article puts these arguments in perspective, and based on the literature reports, especially several newly developed selenium compounds, emphasizes the importance of selenium in the development of chemopreventive and particularly chemotherapeutic drugs for cancer in near future.

Cancer chemoprevention with green tea catechins: from bench to bed.

Many epidemiological studies and a large number of experimental studies using a variety of animal models have observed that consumption or administration of green tea appears to exert cancer chemopreventive activity. Based on the results of numerous laboratory cell culture investigations, several mechanisms have been hypothesized to underlie the anti-cancer activity of green tea catechins, especially that of (-)-epigallocatechin-3-gallate (EGCG), the most abundant and active constituent in green tea. These mechanisms include promotion of anti-oxidant activity, inhibition of NF-κB and AP-1, regulation of the cell cycle, inhibition of receptor tyrosine kinase pathways, control of epigenetic modifications, and modulation of the immune system. Several recent interventional studies examining the anti-carcinogenic properties of green tea catechins in humans have yielded promising results that suggest the possibility of their application to human clinical trials. This review article analyzes the results of these studies to explicate the effects of consumption or administration of green tea and its constituents on malignancies observed to date and discuss future directions in this research field.

Carcinoembryonic antigen (CEA)-based cancer vaccines: recent patents and antitumor effects from experimental models to clinical trials.

Carcinoembryonic antigen (CEA), a glycosylated protein of MW 180 kDa, is overexpressed in a wide range of human carcinomas, including colorectal, gastric, pancreatic, non-small cell lung and breast carcinomas. Accordingly, CEA is one of several oncofetal antigens that may serve as a target for active anti-cancer specific immunotherapy. Experimental results obtained by employing animal models have supported the design of clinical trials using a CEA-based vaccine for the treatment of different types of human cancers. This review reports findings from experimental models and clinical evidence on the use of a CEA-based vaccine for the treatment of cancer patients. Among the diverse CEA-based cancer vaccines, DCs- and recombinant viruses-based vaccines seem the most valid. However, although vaccination was shown to induce a strong immune response to CEA, resulting in a delay in tumor progression and prolonged survival in some cancer patients, it failed to eradicate the tumor in most cases, owing partly to the negative effect exerted by the tumor microenvironment on immune response. Thus, in order to develop more efficient and effective cancer vaccines, it is necessary to design new clinical trials combining cancer vaccines with chemotherapy, radiotherapy and drugs which target those factors responsible for immunosuppression of immune cells. This review also discusses relevant patents relating to the use of CEA as a cancer vaccine.

Future trends in drugs for migraine prophylaxis.

Migraine prevention hinges on a variety of non-specific drugs that mainly reduce neuronal hyperexcitability, the putative pathophysiological hallmark for migraine. The improved knowledge about migraine circuitry and neurobiology has prompted research to develop new specific migraine preventive medications targeted to innovative sites and mechanisms. Drugs designed to inhibit cortical spreading depression, for example tonabersat, might offer a useful option for the management of migraine with aura but not for migraine without aura. Inducible nitric-oxide synthase (iNOS) inhibition seems ineffective as a prophylactic strategy. Results are awaited from recent and ongoing phase II trials with glutamate receptor antagonists, third-generation antiepileptics, melatonin agonists, vitamin D3 and statins.

Therapeutic approaches in the improvement of cognitive performance in Down syndrome: past, present, and future.

Clinical trials with drugs aimed at treatment of Alzheimer disease to decelerate cognitive decline and translated mimetically to demented and young nondemented Down syndrome patients have been unable to demonstrate improvements in cognitive performance and functioning. Unfortunately, results from clinical trials do not support the use of NMDA antagonists like memantine and we should await at the development of safer GABA(A) antagonists to conclude about the efficacy of approaching Down syndrome therapeutics by modulating neurotransmission systems altered in this pathology. The use of folinic acid or antioxidants in DS patients is not supported by scientific evidence and do not provide improvement in cognitive performance to patients. Alternatively to the modulation of neurotransmission systems, future therapeutic approaches should focus at normalizing the expression levels or function of candidate molecules. Epigallocatechin gallate, a green tea polyphenol, that modulates DYRK1A functioning has already shown preliminarily that this approach may prove useful in therapeutics.