Expertise In Clinical Trials Research Articles

Putting Contract Research Organisations on the Radar: An Exploratory Study on Outsourcing of Clinical Trials by Pharmaceutical Companies To Contract Research Organisations in Non-Traditional Trial Regions

It is a trend for pharmaceutical companies to contract third parties to conduct their clinical trials in order to test their drugs. This trend is referred to as ‘outsourcing’, and the companies that carry out the work are called ‘contract research organisations’ (CROs). In addition, clinical trials are increasingly conducted in non-traditional trial regions, which are mainly low- and middle-income countries. This trend is called ‘offshoring’. It is widely agreed that the offshoring of clinical trials to these regions should be scrutinised from an ethical perspective because of the vulnerability of the trial population. What happens when offshoring is combined with outsourcing? Do additional ethical risks arise when clinical trials are contracted out? Virtually all pharmaceutical companies publicly declare that they test their drugs in accordance with the highest ethical guidelines, such as the Declaration of Helsinki. But how do pharmaceutical companies safeguard their commitments when they outsource clinical trial activities to CROs in poor regions? These are the central questions that are addressed in this report. The report is based on research conducted in India, Argentina, Brazil and Peru, and combined with interviews with pharmaceutical companies and clinical trial experts. The research experiences demonstrate that the pharmaceutical sector is generally not transparent, which hinders the definitive answering of the research questions. Nevertheless, the secondary and interview data collected in India, Argentina, Brazil and Peru provides some valuable insights into the way the CRO sector is developing in these countries. Furthermore, the report demonstrates that pharmaceutical companies have elaborate systems in place to manage their supply chain responsibility, although their functioning can not be independently verified. In addition, experts, authorities and clinical trial practitioners in the selected non-traditional trial regions still expressed grave concerns about the implementation of clinical trials in these countries.

Excellence in Family Paediatricians: the FIMP-MCRN (Medicines for Children Research Network) becomes a member of ENPR-EMA (European Network of Paediatric Research at the European Medicines Agency)

One of the objectives of the Paediatric Regulation (EC) No 1901/2006, is to foster high quality ethical research on medicinal products to be used in children. To achieve this objective, the EMA is responsible for developing a European paediatric network of existing national and European networks and centres with specific expertise in research and clinical trials relating to paediatric medicines. The purpose of this article is to disseminate knowledge of the structure and goals of ENPR-EMA and to highlight the cultural and organizational difficulties for its implementation.Following the publication of research quality requirements, a set of recognition criteria, which have to be fulfilled to become a member of ENPR-EMA were agreed. So far, 32 networks and centres (of 62 identified networks) submitted self-assessment reports indicating whether or not they fulfill the agreed minimum criteria. Sixteen networks (26% of 62 identified networks) fulfilled all minimum criteria and became therefore members of ENPR-EMA. The Family Paediatricians Medicines for Children Research Network (FIMP-MCRN), established with the aim of developing competence, infrastructure, networking and education for paediatric clinical trials, became member of the ENPR-EMA responding satisfactorily to all the points of the self-assessment report.

Striving to Improve Outcomes in Oncology: Unmet Expectations in a Complex Disease

This article is featured in Highlights of This Issue, p. 5915Parallels between life and art are often drawn, and the words of Cézanne sum up very well our cancer research enterprise, in particular our attempts to deliver better therapies to cancer patients. This issue of CCR Focus deals with several facets of the targeted therapy revolution in oncology. Beginning with imatinib for chronic myelogenous leukemia (CML), our field has embraced the notion that cancer cells can be best managed with therapies aimed at blocking the 1 or 2 signaling pathways that are responsible for maintaining that tumor type. Administering the correct targeted therapy has been termed personalized medicine. However, the latter is more a goal than a reality, and imatinib in CML, as important as it was, likely represents a specific treatment in an incompletely developed malignancy and not a paradigm for all malignancies. Coincident with the development of therapies that would target critical signaling pathways, we also witnessed the endorsement of a second goal—“cancer as a chronic disease.” Unfortunately, we have come to understand that, unlike CML, the majority of cancers are much more complex than we had imagined, a fact underscored by accumulating sequence data, as shown in the Figure 1. On a very practical level, these approaches have left physicians and patients with new agents but unmet expectations.This issue of CCR Focus examines outcomes-–our difficulty in determining true clinical benefit; the increase in clinical trial size that achieves statistical significance without a meaningful advantage; the difficulty in determining a priori the subgroup that will actually benefit, and the subgroup that may be harmed; the importance of recognizing when palliative care is the right choice; the extraordinary costs of some drugs that provide marginal benefit in unselected populations; the critical need for health care reform that supports clinical trials; and the need to maintain equity as we generate ever more expensive therapies. Our guest editors, LoRusso, Wolf, Averbuch, and Schnipper, experts in clinical trials and in ethics, representing both academia and industry, have joined together with a number of experts in the field to summarize these topics in this CCR Focus on marginal outcomes. They urge the community to do more. We hope, as with every issue of CCR Focus, that this issue educates but also stimulates and challenges those working in clinical and translational oncology.

Liposomal Amphotericin B: A Review of its use in the Treatment of Invasive Fungal Infections

Amphotericin B has been the mainstay of antifungal therapy for more than 50 years, but its associated toxicity often delayed or limited its use. In general, formulating this drug with phospholipids has greatly improved its safety and maintained its efficacy. In particular incorporating amphotericin B into a liposome produced a unique pharmacokinetic profile that altered its distribution, enhanced its safety and maintained its overall effectiveness in the treatment of infections due to pathogenic yeasts and invasive molds. Clinical trial experience and expert opinion suggest there are likely few differences between the lipid amphotericin B formulations. Although the composition of liposomal amphotericin B could improve the ability of amphotericin B to treat CNS fungal infections, to date human data do not completely corroborate findings in animals. This report summarizes the pharmacology, pharmacokinetics, clinical trial data and the Infectious Disease Society of America (IDSA) guidelines regarding the use of liposomal amphotericin B to treat systemic and invasive fungal infections.

The Ties That Bind: Maternal-Infant Interactions and the Neural Circuitry of Postpartum Depression

The Ties That Bind: Maternal-Infant Interactions and the Neural Circuitry of Postpartum Depression

P.7.a.012 Dyskinesia in naïve children and adolescents treated with olanzapine, risperidone and quetiapine: three months follow up

In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the ‘New Frontiers Meeting’ on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.

Individualizing therapies in type 2 diabetes mellitus based on patient characteristics: what we know and what we need to know.

Type 2 diabetes is heterogeneous in its clinical features, pathogenesis, and predisposing or causal genetic factors. This report examines what is known and what needs to be learned about the potential to individualize glycemic therapies in type 2 diabetes, based on phenotypes and genotypes. A 29-member international working group with expertise in diabetes epidemiology, physiology, genetics, clinical trials, and clinical care participated in formal presentations and discussions at a conference on April 16-17, 2009. A writing group subsequently prepared this summary and recommendations. The conference was coendorsed by The Endocrine Society and the American Diabetes Association and was supported by an unrestricted educational grant from Novo Nordisk. Participants reviewed and discussed published literature, plus their own unpublished data. The summary and recommendations were supported unanimously by the writing group as representing the majority or unanimous opinions of the working group. Recent advances in genetics, such as the identification of Kir6.2 mutations and the responsible genes for several forms of maturity onset diabetes of the young (MODY), have established precedents linking specifically effective therapies to defined diabetes subtypes. The recent increase in identified polygenic factors related to type 2 diabetes and our understanding of the pathogenesis of diabetes provide potential opportunities to individualize therapy. To further this process, we recommend expanded analysis of existing data sources and the development of new basic and clinical research studies, including a greater focus on identifying type 2 diabetes subtypes, their response to different therapies, and quantitation of cost-effectiveness.

Diabetes, Obesity and Erectile Dysfunction: Field Overview and Research Priorities

We provide an overview of basic, clinical and epidemiological research in the field of erectile dysfunction and important research priorities presented at the 2009 National Institute of Diabetes and Digestive and Kidney Diseases symposium on Urological Complications of Diabetes and Obesity. Experts in molecular biology, physiology, pharmacology, clinical trials, epidemiology and urological surgery highlighted current knowledge on erectile dysfunction associated with diabetes mellitus and obesity. Predictable associations between erectile dysfunction, and poor diabetic control and modifiable risk factors, including body mass index, have not yet been translated into randomized trials in the United States. The relationship between erectile dysfunction and metabolic syndrome, and surrogate markers for erectile dysfunction requires further investigation. Basic research aimed at discovering disease mechanisms and therapeutic targets has focused on autonomic neuropathy, vascular dysfunction, smooth muscle contractile function and matrix. However, significant gaps exist in regard to the integration of molecular, cellular and functional data. Animal models of type 2 diabetes and obesity associated erectile dysfunction require investigation because most basic science studies have used rodent models of type 1 diabetes. Studies are needed to synthesize a systems biology understanding of erectile function/dysfunction, and characterize and disseminate rodent models of erectile dysfunction associated with type 2 diabetes and obesity. Clinical studies are needed of promising intervention and prevention strategies. Leveraging existing and future cohort phenotypes, and biological samples is needed for risk factor analysis, biomarker discovery and genome wide association studies.

Report from the Radiation Therapy Committee of the Southwest Oncology Group (SWOG): Research Objectives Workshop 2008.

Strategic planning for the Radiation Therapy Committee of the Southwest Oncology Group (SWOG) is comprehensively evaluated every six years in an effort to maintain a current and relevant scientific focus, and to provide a standard platform for future development of protocol concepts. Participants in the 2008 Strategic Planning Workshop included clinical trial experts from multiple specialties, industry representatives from both pharmaceuticals and equipment manufacturers, and basic scientists. High-priority research areas such as image-guided radiation therapy for control of limited metastatic disease, analysis of biomarkers for treatment response and late toxicity, assessment of novel agents in combination with radiation, standardization of radiation target delineation, and the assessment of new imaging techniques to individualize cancer therapy, were discussed. Research priorities included clinical study designs featuring translational end points that identify patients most likely to benefit from combined modality therapy; intervention including combination radiation with standard chemotherapy; radiation with radiosensitizing molecular-targeted therapies; and stereotactic radiation for treatment of patients with regard to asymptomatic metastasis and radiation-induced tumor autoimmunity. The Committee concluded that the future research opportunities are among the most exciting to have developed in the last decade, and work is in progress to embark on these plans.

Biomarkers of sepsis

A complex network of biological mediators underlies the clinical syndrome of sepsis. The nonspecific physiologic criteria of sepsis syndrome or the systemic inflammatory response syndrome do not adequately identify patients who might benefit from either conventional anti-infective therapies or from novel therapies that target specific mediators of sepsis. Validated biomarkers of sepsis may improve diagnosis and therapeutic decision making for these high-risk patients. To develop a methodologic framework for the identification and validation of biomarkers of sepsis. A small group meeting of experts in clinical epidemiology, biomarker development, and sepsis clinical trials; selective narrative review of the biomarker literature. The utility of a biomarker is a function of the degree to which it adds value to the available clinical information in the domains of screening, diagnosis, risk stratification, and monitoring of the response to therapy. We identified needs for greater standardization of biomarker methodologies, greater methodologic rigor in biomarker studies, wider integration of biomarkers into clinical studies (in particular, early phase studies), and increased collaboration among investigators, pharmaceutical industry, biomarker industry, and regulatory agencies. Biomarkers promise to transform sepsis from a physiologic syndrome to a group of distinct biochemical disorders. This transformation could aid therapeutic decision making, and hence improve the prognosis for patients with sepsis, but will require an unprecedented degree of systematic investigation and collaboration.

Outcomes Research in Cardiovascular Imaging: Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Outcomes Research in Cardiovascular Imaging

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Outcomes Research in Cardiovascular Imaging: Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Outcomes Research in Cardiovascular Imaging: Report of a Workshop Sponsored by the National Heart, Lung, and Blood Institute

In July of 2008, the National Heart, Lung, and Blood Institute convened experts in noninvasive cardiovascular imaging, outcomes research, statistics, and clinical trials to develop recommendations for future randomized controlled trials of the use of imaging in: 1) screening the asymptomatic patient for coronary artery disease; 2) assessment of patients with stable angina; 3) identification of acute coronary syndromes in the emergency room; and 4) assessment of heart failure patients with chronic coronary artery disease with reduced left ventricular ejection fraction. This study highlights several possible trial designs for each clinical situation.

Cost-Effectiveness of Patient Selection Using Penumbral-Based MRI for Intravenous Thrombolysis

Better selection of patients for intravenous recombinant tissue plasminogen activator (IV tPA) treatment may improve clinical outcomes. We examined the cost-effectiveness of adding penumbral-based MRI to usual computed tomography (CT)-based methods to identify patients for IV tPA treatment. A decision-analytic model estimated the lifetime costs and outcomes associated with penumbral-based MRI selection in a patient population similar to that enrolled in the IV tPA clinical trials. Inputs were obtained from published literature, clinical trial data, claims databases, and expert opinion. Outcomes included cost per life-year saved and cost per quality-adjusted life-year (QALY) gained. Costs and outcomes were discounted at 3% annually. Sensitivity analyses were conducted. The addition of penumbral-based MRI selection increased total cost by $103 over the patient's remaining lifetime. Penumbral-based MRI selection resulted in favorable outcomes (modified Rankin Scale <or=1) more often than CT-based selection (36.66% versus 35.06%) with an incremental cost per life year of $1840 and an incremental cost per QALY of $1004. Multivariate sensitivity analysis predicted cost-effectiveness (<or=$50,000 per QALY) in 99.7% of simulation runs. Selecting ischemic stroke patients for IV tPA treatment using penumbral-based MRI after routine CT may increase overall acute care costs, but the benefit is large enough to make this highly cost-effective. This economic analysis lends further support to the consideration of a paradigm shift in acute stroke evaluation.

Unconventional End Points in Cardiovascular Clinical Trials: Should We Be Moving Away From Morbidity and Mortality?

Background Mortality and irreversible or major morbid events are the end points conventionally chosen for cardiovascular clinical trials because they are considered to reflect the effects of intervention on the natural history of disease. Other end points are now being considered and implemented because of the recognized limitations associated with using mortality and morbidity as the sole measures of therapeutic efficacy. Methods and Results This article reflects the discussion and recommendations regarding nontraditional end points for cardiovascular trials generated from a meeting of clinical trial experts convened to discuss this issue. Less common end points that have been used in cardiovascular clinical trials include composite clinical scores integrating measures of quality of life with mortality and morbidity or using the function of vital organs as end points. Appropriate measurement and applications of such end points is controversial. Conclusions More experience is needed in applying and analyzing results with these nontraditional end points to enable their optimal use in clinical trials in cardiology, but such approaches have the potential to redress many of the conceptual and actual deficiencies inherent in conventional measures of outcome.

Antidepressant drugs for narcolepsy

Narcolepsy is a disorder of the central nervous system, the main symptoms of which are excessive daytime sleepiness (EDS) and cataplexy (an abrupt and reversible decrease in or loss of muscle tone, affecting the limbs or trunk or both, elicited by emotional stimuli). Narcolepsy has an adverse impact on people's quality of life. Together with stimulant drugs (used to control EDS), antidepressants are usually recommended to counteract cataplexy. In addition, some antidepressants are also reported to improve EDS. To evaluate the effects of antidepressant drugs on EDS, cataplexy, quality of life, and their side effects in people with narcolepsy. We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), MEDLINE (1966 to 2007), EMBASE (1980 to 2007), PsycINFO (1872 to 2007), and CINAHL (1981 to 2007). Bibliographies of identified articles were reviewed to find additional references. Unpublished randomised trials were searched for by consulting governmental and non-governmental clinical trial registers, disease-specific websites, investigators and experts in the field, pharmaceutical companies/manufacturers. Parallel or cross-over randomised or quasi-randomised controlled trials testing the treatment of narcolepsy with any type of antidepressant drug versus no treatment, placebo, or another antidepressant drug. Two review authors independently assessed trial quality and extracted data. Three cross-over and two parallel trials were included with a total of 246 participants. The methodological quality of all studies was unclear. As the trials tested different comparisons, or had a different design or dealt with different outcome measures, meta-analysis was not performed. In one cross-over trial (10 participants) femoxetine had no significant effect in eliminating or reducing EDS but significantly reduced cataplexy. Mild and transient side effects were reported in the femoxetine treatment period by two participants. In a second cross-over trial (56 participants) viloxazine significantly reduced EDS and cataplexy. In a third cross-over trial the authors inappropriately treated the trial design as a parallel study and no conclusions can be reached in favour of either drug. Two more trials with parallel design tested ritanserin versus placebo without finding differences of effectiveness in reducing EDS or cataplexy. There was no good quality evidence that antidepressants are effective for narcolepsy or improve quality of life. Despite the clinical consensus recommending antidepressants for cataplexy there is scarce evidence that antidepressants have a positive effect on this symptom. There is a clear need for well-designed randomised controlled trials to assess the effect of antidepressants on narcolepsy.

International Symposium on Adaptive Clinical Trial Designs

The BioLogue International Symposium on Adaptive Clinical Trials was held October 10, 2006, in Copenhagen, Denmark. This symposium brought together clinical trialists and trial experts from academia, industry, and regulatory agencies to initiate a dialogue on opportunities, scope, and challenges regarding adaptive clinical trials.

Conceptualizing Functional Cognition in Stroke

Background. Up to 65% of individuals demonstrate poststroke cognitive impairments, which may increase hospital stay and caregiver burden. Randomized stroke clinical trials have emphasized physical recovery over cognition. Neuropsychological assessments have had limited utility in randomized clinical trials. These issues accentuate the need for a measure of functional cognition (the ability to accomplish everyday activities that rely on cognitive abilities, such as locating keys, conveying information, or planning activities). Objective. The aim of the study was to present the process used to establish domains of functional cognition for development of computer adaptive measure of functional cognition for stroke. Methods. Functional cognitive domains involved in identifying relevant neuropsychological constructs from the literature were conceptualized and finalized after advisory panel feedback from experts in neurology, neuropsychology, aphasiology, clinical trials, and epidemiology. Results. The following 17 domains were proposed: receptive aphasia, expressive aphasia, agraphia, alexia, calculation, visuospatial, visuoperceptual, visuoconstruction, attention, language usage, executive functions, orientation, processing speed, memory, working memory, mood, awareness and abstract reasoning. The advisory panel recommended retaining the first 12 domains. Recommended changes included: to address only encoding and retrieval of recent information in the memory domain; to add domains for limb apraxia and poststroke depression; and to keep orientation as a separate domain or reclassify it under memory or attention. The final 10 domains included: language, reading and writing, numeric/calculation, limb praxis, visuospatial function, social use of language, emotional function, attention, executive function, and memory. Conclusion. Conceptualizing domains of functional cognition is the first step in developing a computer adaptive measure of functional cognition for stroke. Additional steps include developing, refining, and field-testing items, psychometric analysis, and computer adaptive test programming.

Proposal for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials: The STEEP System

Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies. A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used. The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites.