De-risking in Tier I CNS safety assessments is the primary function of study design and technical training of laboratory staff observers.

Derisking is not a pharmaceutical industry strategy to reduce time, effort, or costs in drug development. Derisking strategies originated within the National Institutes of Health as a predicate to good science. There is a growing sentiment within drug development programs to diminish the importance of behavioral measures in toxicological studies and in the Tiered Safety assessment plans of the U.S. Regulatory Agencies and the International Commission on Harmonization. The validity and reliability of the Functional Observational Batter (FOB) is critically dependent on consistency and technical quality in each risk assessment plan. US Federal and International drug approval organizations have universally adopted the concept of principles of test construction rather than delineating specific behavioral assay endpoints for inclusion of the FOB in nonclinical safety protocols. The validity and reliability of behavioral observations in standardized neurotoxicity screening is critically dependent on the FOB developed by the Study Director with the Sponsor throughout all stages of testing.. The individual risk factors selected for observation to be included in the early Tier 1 safety program should be determined by the mechanism and mode of action of the test article. The results of Tier I testing are the basis for Tier II testing designs. Critical to the compliance with Good Laboratory Practices is the documentation of training of the operational staff scheduled to conduct all aspects of the established protocol.

Are we on the cusp of a fourth research paradigm? Predicting the future for a new approach to methods-use in medical and health services research.

BACKGROUND: The dominant medical and health research paradigm continues to be quantitative. While the authors sense a sea-change in opinion about mixed-method research, underpinned by two decades of highly-cited publications in medical journals, much of the medical literature still widely favours the Randomised Control Trial. MAIN BODY: This debate article examines whether it is the beginning of the end of the dominant quantitative paradigm and the interest this holds for researchers and clinicians at the forefront of care delivery. It examines the Third Research Paradigm, signifying the importance of mixed-methods, and discusses the power of the patient voice and person-focused research activity. The authors discern the coming of age of a Fourth Research Paradigm integrating mixed-methods with data collected 'on the hoof'. Within this new paradigm, the article explores the power of available, real time, and emergent data - from smart phones, wearable devices, and social media, as well as more creative approaches to data collection. The Fourth Research Paradigm will require the support of multi-disciplinary teams, moving through the world alongside their research subjects. The impact of a Fourth Research Paradigm on the health researcher is assessed, as the researcher's gaze moves away from considerations of methodological superiority to re-considerations of their role in the brave new world of research multiplicity. CONCLUSION: The Fourth Research Paradigm offers extensive opportunities to tell more complete research stories in real-time settings. It concentrates on contextual notions of everyday happenings within the ever-changing world of healthcare delivery. There will be challenges ahead, not least the management of large, complex datasets and adaptive study designs. But rigorous planning will enable unique insights into the relationships played out in the world of the patient and healthcare provider. Better care and new delivery models are likely to result, but how this will manifest is not yet clear.

Participation in research improves overall patient management: insights from the Global Rheumatic Heart Disease registry (REMEDY).

BACKGROUND: Rheumatic heart disease (RHD) is a major public health problem in low- and middle-income countries (LIMCs), with a paucity of high-quality trial data to improve patient outcomes. Investigators felt that involvement in a recent large, observational RHD study impacted positively on their practice, but this was poorly defined. AIM: The purpose of this study was to document the experience of investigators and research team members from LMICs who participated in a prospective, multi-centre study, the global Rheumatic Heart Disease Registry (REMEDY), conducted in 25 centres in 14 countries from 2010 to 2012. METHOD: We conducted an online survey of site personnel to identify and quantify their experiences. Telephone interviews were conducted with a subset of respondents to gather additional qualitative data. We asked about their experiences, positive and negative, and about any changes in RHD management practices resulting from their participation in REMEDY as a registry site. RESULTS: The majority of respondents in both the survey and telephone interviews indicated that participation as a registry site improved their management of RHD patients. Administrative changes included increased attention to follow-up appointments and details in patient records. Clinical changes included increased use of penicillin prophylaxis, and more frequent INR monitoring and contraceptive counselling. CONCLUSION: Our study demonstrates that participation in clinical research on RHD can have a positive impact on patient management. Furthermore, REMEDY has led to increased patient awareness and improved healthcare workers' knowledge and efficiency in caring for RHD patients.

A Journey Toward Cultural Competence: The Role of Researcher Reflexivity in Indigenous Research.

This article highlights the personal journey of reflective development that a non-Aboriginal White researcher and health professional underwent to be "fully positioned" in the everyday lives of a rural Australian Aboriginal community in Western Australia. The article explains the researcher's personal development in areas important to building respect, building relationships, and ensuring reciprocity while undertaking Aboriginal research. The researcher reports on the reflective evaluation of her worldview. Understanding that judgment is a natural tendency, the researcher used reflexivity as a tool to examine and contextualize her judgments, presumptions, and preconceptions, which positioned her to be open to differing viewpoints and actively explore alternate perspectives. The researcher explores her evolutionary understanding that cultural competence is not a destination but a continual journey, and she details her knowledge development regarding the Aboriginal research paradigm, which requires that all the learning, sharing, and growth taking place is reciprocal and engages all parties actively.

TB questions, East Kwaio answers: community-based participatory research in a remote area of Solomon Islands.

INTRODUCTION: East Kwaio is a remote region on the island of Malaita, Solomon Islands. Atoifi Adventist Hospital (the Hospital) is the only hospital and tuberculosis (TB) services provider in the region. If people come to the Hospital with TB, they are usually admitted for the two-month intensive phase of treatment as there are no community-based TB services. Most people walk or travel by canoe to the Hospital as there are no roads. East Kwaio is known to have high rates of TB; however, it has a low case detection rate and low treatment completion. The aims of this study were to explore why people with TB, especially from the mountain areas, present to the Hospital so late in their illness or do not present at all. The study was part of a larger project to strengthen the research capacity of local health workers and community leaders, supported by visiting researchers from Australia. METHODS: Semi-structured interviews with TB patients, a focus group of key informants and direct interaction with a community with a history of TB were used to explore reasons why people present to the Hospital late in their TB illness. RESULTS: Four interviews and a focus group of 12 key informants were conducted and a mountain hamlet with a history of TB was visited. The results represent the data from the interviews and the focus group. The time delay in presenting to the Hospital from when participants first became unwell ranged between two and three years. In the mountain hamlet, two additional people with probable TB were seen who had not presented to the Hospital during illnesses of five and nine months. Reasons for delays included: seeking care from traditional healers; the challenge of accessing health services due to distance, cost and cultural issues different from the Hospital's worldview; social isolation when in hospital; and being old so not having long to live. Delays in diagnosis of people with TB will increase the risk of transmission to family and through hamlets and villages. This study has led to plans being developed to build a more culturally appropriate TB ward and community treatment program. CONCLUSIONS: The study has identified TB questions that need East Kwaio answers. It has shown that a small project can inform the development of important changes to TB services, such as the redevelopment and relocation of the TB ward. To enable TB control, the local health services need to develop an understanding of, and appropriately engage with, traditional beliefs that influence how people interact with Hospital TB treatment and management. This is the case even if the beliefs are based on a worldview different than that of the health service providers. Ongoing operational research is required into TB diagnosis and treatment services and the many factors that contribute to the high TB burden in this remote area.

Opinions on the preclinical evaluation of novel therapies for spinal cord injury: a comparison between researchers and spinal cord-injured individuals.

We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for SCI.