Pharmacogenomics in early-phase clinical development.

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs.

Linking Research and Marketing: A Pharmaceutical Innovation

This chapter describes in very general terms the integration of clinical research and marketing, drawing on books by marketers and recent cases that have come to the public eye. The tools that have been used to accomplish this integration over the past half-century are various, but they all stem from a realization that in a rational world centered on health there need be no intrinsic divide between research and marketing. Most obviously, marketing drugs to physicians, who are professionals acting within their own spheres, depends crucially on research. Physicians respond, and need to see themselves as responding, to fact, figures, and studies. The well-chosen images and vehicles for marketing campaigns must be subordinated to research. Yet at the same time research is a means of increasing sales.

Sperm DNA: organization;protection and vulnerability: from basic science to clinical applications. a position rep

This paper reports the results of the most recent in a series of EHSRE workshops designed to synthesize the current state of the field in Andrology and provide recommendations for future work (ESHRE 1998; 1996). Its focus is on methods for detecting sperm DNA damage and potential application of new knowledge about sperm chromatin organization, vulnerability and repair to improve the diagnosis and treatment of clinical infertility associated with that damage. Equally important is the use and reliability of these tests to identify the extent to which environmental contaminants or pharmaceutical agents may contribute to the incidence of sperm DNA damage and male fertility problems. A working group# under the auspices of ESHRE met in May 2009 to assess the current knowledgebase and suggest future basic and clinical research directions. This document presents a synthesis of the working group’s understanding of the recent literature and collective discussions on the current state of knowledge of sperm chromatin structure and function during fertilization. It highlights the biological, assay and clinical uncertainties that require further research and ends with a series of recommendations.

Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials.

Objectives: To investigate the knowledge and views of a range of healthcare professionals (consultant paediatricians, general practitioners (GPs), community pharmacists and paediatric nurses) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials.

Methods: A regional study in which a survey instrument with 39 items was issued to 500 randomly selected GPs, all community pharmacists (n?=?512), 50 hospital consultants and 150 paediatric nurses in Northern Ireland.

Results: Approximately half (46.5%) of the 1,212 healthcare professionals approached responded to the questionnaire. The majority of respondents indicated their familiarity with the term unlicensed (82.9%) or off-label (58.6%) prescribing with the most frequently quoted reason for such prescribing being younger age (33.6%). Apart from community pharmacists, most respondents reported having gained their knowledge through personal experience. Even though a large percentage of respondents expressed concerns about the safety (77.8%) or efficacy (87.9%) of unlicensed/off-label prescribing in children, only 30.7% reported informing parents/guardians of these concerns on the use of such medicines in children. In addition, only 56% of respondents believed that unlicensed/off-label medicines should undergo clinical trials in children. Overall, 28.4% of respondents (20.1% of GPs, 41.4% of community pharmacists, 27.7% of paediatric nurses and 94% of consultant paediatricians) indicated their willingness to be actively involved in, and recruit their patients for paediatric clinical research.

Conclusion: The use of unlicensed and off-label medicines remains a major issue in paediatric medicine. Until such times as more licensed medicines are available for children, clear guidance should be developed to allow consistency in practice across the spectrum of healthcare professionals who are involved with such medicines in their routine practice.

Developmental care for high-risk newborns:Emerging science, clinical application, and continuity from newborn intensive care unit to community

Neonatology has optimized medical outcomes for high-risk newborns yet neurodevelopmental outcomes continue to be a concern. Basic science, clinical research, and environmental design perspectives have shown the impact of the caregiving environment on the developing brain and the role of professional caregivers in providing supportive intervention to both infants and their families. This recognition has prompted a focus on early developmentally supportive care (DSC) for high-risk newborns both in the hospital and in community follow up. DSC has emerged as a recognized standard of care in most neonatal intensive care units. Still, many questions remain and much integrative research is needed.

Cystic fibrosis research in allied health and nursing professions

This report is the result of the "Allied Health and Nursing Professions Working Group" meeting which took place in Verona, Italy, November 2009, which was organised by the European Cystic Fibrosis Society, and involved 32 experts. The meeting was designed to provide a "roadmap" of high priority research questions that can be addressed by Allied Health Professionals (AHP) and nursing. The other goal was to identify research skills that would be beneficial to AHP and nursing researchers and would ultimately improve the research capacity and capability of these professions. The following tasks were accomplished: 1) a Delphi survey was used to identify high priority research areas and themes, 2) common research designs used in AHP and nursing research were evaluated in terms of their strengths and weaknesses, 3) methods for assessing the clinimetric and psychometric properties, as well as feasibility, of relevant outcome measures were reviewed, and 4) a common skill set for AHPs and nurses undertaking clinical research was agreed on and will guide the planning of future research opportunities. This report has identified important areas and themes for future research which include: adherence; physical activity/exercise; nutritional interventions; interventions for the newborn with CF and evaluation of outcome measures for use in AHP and nursing research. It has highlighted the significant challenges AHPs and nurses experience in conducting clinical research, and proposes strategies to overcome these challenges. It is hoped that this report will encourage research initiatives that assess the efficacy/effectiveness of AHP and nursing interventions in order to improve the evidence base. This should increase the quality of research conducted by these professions, justify services they currently provide, and expand their skills in new areas, with the ultimate goal of improving care for patients with CF.

The geriatric minimum data set for clinical trials (GMDS)

To overcome the weak evidence base coming from often poor and insufficient clinical research in older people, a minimum data set to achieve harmonisation is highly advisable. This will lead to uniform nomenclature and to the standardisation of the assessment tools. Our primary objective was to develop a Geriatric Minimum Data Set (GMDS) for clinical research.

Guideline on the design and conduct of cystic fibrosis clinical trials: The European Cystic Fibrosis Society–Clinical Trials Network (ECFS-CTN)

We describe the rationale for disease specific research networks in general as well as the aims and function of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) specifically. The ECFS-CTN was founded in 2009 with the aim of improving the quality and quantity of clinical research in the area of cystic fibrosis (CF) in Europe. A network of 18 clinical trial sites in 8 European countries was established according to uniform state-of-the-art quality criteria. To support the ECFS-CTN in the acquisition, planning and conduct of clinical trials, the network is equipped with a coordinating centre, steering and executive committees, and committees for protocol review, standardization, training and networking as well as a data safety monitoring board. A strong partnership with European CF patient parent organizations aims to increase awareness of the need for efficient clinical research and the participation of patients in clinical trials.

Towards optimal clinical and epidemiological registration of haematological malignancies: Guidelines for recording progressions, transformations and multiple diagnoses

Haematological malignancies (HM) represent over 6% of the total cancer incidence in Europe and affect all ages, ranging between 45% of all cancers in children and 7% in the elderly. Thirty per cent of childhood cancer deaths are due to HM, 8% in the elderly. Their registration presents specific challenges, mainly because HM may transform or progress in the course of the disease into other types of HM. In the context of cancer registration decisions have to be made about classifying subsequent notifications on the same patient as the same tumour (progression), a transformation or a new tumour registration. Allocation of incidence date and method of diagnosis must also be standardised. We developed European Network of Cancer Registries (ENCR) recommendations providing specific advice for cancer registries to use haematology and molecular laboratories as data sources, conserve the original date of incidence in case of change of diagnosis, make provision for recording both the original as well as transformed tumour and to apply precise rules for recording and counting multiple diagnoses. A reference table advising on codes which reflect a potential transformation or a new tumour is included. This work will help to improve comparability of data produced by population-based cancer registries, which are indispensable for aetiological research, health care planning and clinical research, an increasing important area with the application of targeted therapies.

Multi-centre research in Australia:analysis of a recent National Health and Medical Research Council-funded project

BACKGROUND AND OBJECTIVE: Human research ethics committees provide essential review of research projects to ensure the ethical conduct of human research. Several recent reports have highlighted a complex process for successful application for human research ethics committee approval, particularly for multi-centre studies. Limited resources are available for the execution of human clinical research in Australia and around the world.

METHODS: This report overviews the process of ethics approval for a National Health and Medical Research Council-funded multi-centre study in Australia, focussing on the time and resource implications of such applications in 2007 and 2008.

RESULTS: Applications were submitted to 16 hospital and two university human research ethics committees. The total time to gain final approval from each committee ranged between 13 and 77 days (median = 46 days); the entire process took 16 months to complete and the research officer's time was estimated to cost $A34 143.

CONCLUSIONS: Obstacles to timely human research ethics committee approval are reviewed, including recent, planned and potential initiatives that could improve the ethics approval of multi-centre research.

UK publicly funded Clinical Trials Units supported a controlled access approach to share individual participant data but highlighted concerns

OBJECTIVES: Evaluate current data sharing activities of UK publicly funded Clinical Trial Units (CTUs) and identify good practices and barriers.

STUDY DESIGN AND SETTING: Web-based survey of Directors of 45 UK Clinical Research Collaboration (UKCRC)-registered CTUs.

RESULTS: Twenty-three (51%) CTUs responded: Five (22%) of these had an established data sharing policy and eight (35%) specifically requested consent to use patient data beyond the scope of the original trial. Fifteen (65%) CTUs had received requests for data, and seven (30%) had made external requests for data in the previous 12 months. CTUs supported the need for increased data sharing activities although concerns were raised about patient identification, misuse of data, and financial burden. Custodianship of clinical trial data and requirements for a CTU to align its policy to their parent institutes were also raised. No CTUs supported the use of an open access model for data sharing.

CONCLUSION: There is support within the publicly funded UKCRC-registered CTUs for data sharing, but many perceived barriers remain. CTUs are currently using a variety of approaches and procedures for sharing data. This survey has informed further work, including development of guidance for publicly funded CTUs, to promote good practice and facilitate data sharing.

Good Laboratory Practice for optimization research

Good Laboratory Practice has been a part of non-clinical research for over 40 years. Optimization Research, despite having many papers discussing standards being published over the same period of time, has yet to embrace standards that underpin its research. In this paper we argue the need to adopt standards in optimization research. Building on previous papers, many of which have suggested that the optimization research community should adopt certain standards, we suggest a concrete set of recommendations that the community should adopt. We also discuss how the proposals in this paper could be progressed.