Inference and Decision Making for 21st-Century Drug Development and Approval

ABSTRACT

The cost and time of pharmaceutical drug development continue to grow at rates that many say are unsustainable. These trends have enormous impact on what treatments get to patients, when they get them and how they are used. The statistical framework for supporting decisions in regulated clinical development of new medicines has followed a traditional path of frequentist methodology. Trials using hypothesis tests of “no treatment effect” are done routinely, and the p-value < 0.05 is often the determinant of what constitutes a “successful” trial. Many drugs fail in clinical development, adding to the cost of new medicines, and some evidence points blame at the deficiencies of the frequentist paradigm. An unknown number effective medicines may have been abandoned because trials were declared “unsuccessful” due to a p-value exceeding 0.05. Recently, the Bayesian paradigm has shown utility in the clinical drug development process for its probability-based inference. We argue for a Bayesian approach that employs data from other trials as a “prior” for Phase 3 trials so that synthesized evidence across trials can be utilized to compute probability statements that are valuable for understanding the magnitude of treatment effect. Such a Bayesian paradigm provides a promising framework for improving statistical inference and regulatory decision making.     

Modelling daily multivariate pollutant data at multiple sites

Summary. This paper considers the spatiotemporal modelling of four pollutants measured daily at eight monitoring sites in London over a 4-year period. Such multiple-pollutant data sets measured over time at multiple sites within a region of interest are typical. Here, the modelling was carried out to provide the exposure for a study investigating the health effects of air pollution. Alternative objectives include the design problem of the positioning of a new monitoring site, or for regulatory purposes to determine whether environmental standards are being met. In general, analyses are hampered by missing data due, for example, to a particular pollutant not being measured at a site, a monitor being inactive by design (e.g. a 6-day monitoring schedule) or because of an unreliable or faulty monitor. Data of this type are modelled here within a dynamic linear modelling framework, in which the dependences across time, space and pollutants are exploited. Throughout the approach is Bayesian, with implementation via Markov chain Monte Carlo sampling.     

Bayesian analysis of mixture modelling using the multivariate t distribution

A finite mixture model using the multivariate t distribution has been shown as a robust extension of normal mixtures. In this paper, we present a Bayesian approach for inference about parameters of t-mixture models. The specifications of prior distributions are weakly informative to avoid causing nonintegrable posterior distributions. We present two efficient EM-type algorithms for computing the joint posterior mode with the observed data and an incomplete future vector as the sample. Markov chain Monte Carlo sampling schemes are also developed to obtain the target posterior distribution of parameters. The advantages of Bayesian approach over the maximum likelihood method are demonstrated via a set of real data.     

Maintaining the connection: Parenting as a noncustodial father

The purpose of this study was to identify relevant factors associated with the noncustodial father's frequency of contact with his child following divorce. The findings of the research revealed that a combination of demographic, personal characteristics, and psychosocial factors are related to the father's frequency of contact with the child.     

ATSDR Science Panel on the Bioavailability of Mercury in Soils: Lessons Learned

On the basis of discussion and analysis during and following an ATSDR science panel on the bioavailability of mercury in soils, it is apparent that the default assumption of 100% relative bioavailability for mercury-contaminated soils is excessively conservative. However, current knowledge does not allow the development of default assumptions or guidelines for determining relative bioavailability of mercury in soils. Until such default assumptions or guidelines can be developed, site-specific assays of bioavailability, preferably using either animal bioassays or validated in vitro techniques, may provide the best approach for estimating soil-mercury bioavailability.     

Championing the interface between mental health and child protection: evaluation of a service initiative to improve joint working in northern Ireland

The importance of establishing effective inter‐agency working between adult mental health services and child care services in order to safeguard children has been repeatedly identified by research, policy, inquiries and inspection reports. This article reports on the evaluation of an initiative in one health and social care trust in Northern Ireland that aimed to facilitate joint working and so improve service provision and protection for children and families. The Champions Initiative involved identifying a Champion in each multidisciplinary community mental health team and in each family and child care team that would have responsibility for providing information, promoting joint working and identifying any obstacles to better cooperation. The evaluation of this Initiative assessed levels of experience, training, confidence, understanding and awareness in the Champions and their team members at baseline. The Champions and their Team Leaders were then followed up after six months to obtain their qualitative views of the impact of the initiative. The results include comparisons between mental health and child care staff, and crucially, views about whether the initiative has had any impact on working together. This study also generated recommendations for further service development in this complex and important area of practice. Copyright © 2010 John Wiley & Sons, Ltd.

‘Identifying a Champion in each multidisciplinary community mental health team and in each family and child care team’

Citing Literature

Number of times cited according to CrossRef: 15

• Kerry McVeigh, The Think Family Social Work Assessment: outcomes of a family-focused initiative using The Family Model, Advances in Mental Health, 10.1080/18387357.2020.1825969, (1-15), (2020). Crossref
• Billie Lever Taylor, Liberty Mosse, Nicky Stanley, Experiences of social work intervention among mothers with perinatal mental health needs, Health & Social Care in the Community, 10.1111/hsc.12832, 27 , 6, (1586-1596), (2019). Wiley Online Library
• Lelia Fitzsimons, The role of champions in promoting family focused practice across adult mental health and children's services, Advances in Mental Health, 10.1080/18387357.2019.1661783, (1-10), (2019). Crossref
• Nicky Stanley, Khatidja Chantler, Rachel Robbins, Children and Domestic Homicide, The British Journal of Social Work, 10.1093/bjsw/bcy024, 49 , 1, (59-76), (2018). Crossref
• Sanne Rumping, Leonieke Boendermaker, Doret J. Ruyter, Stimulating interdisciplinary collaboration among youth social workers: A scoping review, Health & Social Care in the Community, 10.1111/hsc.12589, 27 , 2, (293-305), (2018). Wiley Online Library
• Robin Mason, Janice Du Mont, Maeve Paterson, Ilene Hyman, Experiences of child protection workers in collaborating with adult mental health providers: An exploratory study from Ontario, Canada, Children and Youth Services Review, 10.1016/j.childyouth.2018.02.005, 86 , (271-276), (2018). Crossref
• Andani Thakhathi, Champions of Change and Organizational Development: A Return to Schön and Typology for Future Research and Practice, Research in Organizational Change and Development, 10.1108/S0897-301620180000026007, (265-306), (2018). Crossref
• Phillip Tchernegovski, Andrea E. Reupert, Darryl J. Maybery, How do Australian adult mental health clinicians manage the challenges of working with parental mental illness? A phenomenological study, Child & Family Social Work, 10.1111/cfs.12426, 23 , 3, (381-389), (2017). Wiley Online Library
• Eeva Timonen-Kallio, Juha Hämäläinen, Eila Laukkanen, Interprofessional Collaboration in Finnish Residential Child Care: Challenges in Incorporating and Sharing Expertise Between the Child Protection and Health Care Systems, Child Care in Practice, 10.1080/13575279.2016.1158153, 23 , 4, (389-403), (2016). Crossref
• Barry Luckock, Jane Barlow, Chris Brown, Developing innovative models of practice at the interface between the NHS and child and family social work where children living at home are at risk of abuse and neglect: a scoping review, Child & Family Social Work, 10.1111/cfs.12228, 22 , S4, (62-69), (2015). Wiley Online Library
• Joe Duffy, Gavin Davidson, Damien Kavanagh, Applying the recovery approach to the interface between mental health and child protection services, Child Care in Practice, 10.1080/13575279.2015.1064358, 22 , 1, (35-49), (2015). Crossref
• Estela Arcos, Ximena Sanchez, Maria Cecilia Toffoletto, Margarita Baeza, Patricia Gazmuri, Luz Angélica Muñoz, Antonia Vollrath, Social protection systems in vulnerable families: their importance for the public health, Revista de Saúde Pública, 10.1590/S0034-8910.2014048005131, 48 , 3, (398-405), (2014). Crossref
• Oi Ling Wong, Integrative Family and Systems Treatment with Parental Mental Illness: A Hong Kong Chinese Family, Contemporary Family Therapy, 10.1007/s10591-014-9298-2, 36 , 2, (242-249), (2014). Crossref
• Peter Sidebotham, Rethinking Filicide, Child Abuse Review, 10.1002/car.2303, 22 , 5, (305-310), (2013). Wiley Online Library
• Jane V. Appleton, Peter Sidebotham, Child Protection and Mental Health, Child Abuse Review, 10.1002/car.2220, 21 , 3, (153-156), (2012). Wiley Online Library

Volume 21 , Issue 3 May/June 2012

Pages 157-172     

Taking Stock of Neighbourhood Planning in England 2011–2016

Neighbourhood planning (NP) as enabled by the 2011 Localism Act in England has precipitated a considerable literature discussing its potential, limitations and likely shortcomings referenced against government rhetoric and the reporting of initial experiences of the process. This paper provides an overview of the current literature on neighbourhood planning and sets out how it has been received and practised across England drawing on empirical evidence. The extent of take-up and the experience of those involved in the first five years of neighbourhood planning is used to consider how community-led planning may be designed and used following operational principles of inclusivity, capacity-building and adding value.     

Improved bridge constructs for stochastic differential equations

We consider the task of generating discrete-time realisations of a nonlinear multivariate diffusion process satisfying an Itô stochastic differential equation conditional on an observation taken at a fixed future time-point. Such realisations are typically termed diffusion bridges. Since, in general, no closed form expression exists for the transition densities of the process of interest, a widely adopted solution works with the Euler–Maruyama approximation, by replacing the intractable transition densities with Gaussian approximations. However, the density of the conditioned discrete-time process remains intractable, necessitating the use of computationally intensive methods such as Markov chain Monte Carlo. Designing an efficient proposal mechanism which can be applied to a noisy and partially observed system that exhibits nonlinear dynamics is a challenging problem, and is the focus of this paper. By partitioning the process into two parts, one that accounts for nonlinear dynamics in a deterministic way, and another as a residual stochastic process, we develop a class of novel constructs that bridge the residual process via a linear approximation. In addition, we adapt a recently proposed construct to a partial and noisy observation regime. We compare the performance of each new construct with a number of existing approaches, using three applications.     

The reification of celebrity: global newspaper coverage of the death of David Bowie*

This paper examines global English-language newspaper coverage of the death of David Bowie. Drawing upon the concept of reification, it is argued that the notion of celebrity is discursively (re)produced and configured through a ‘public face’ that is defined, maintained and shaped via media reports and public responses that aim to know and reflect upon celebrity. The findings highlight how Bowie’s reification was supported by discourses that represented him as an observable, reified form. Here, Bowie’s ‘reality’, that is, his authentic/veridical self, was obscured behind a façade of mediation, interpretation and representation that debated and decided his ‘authenticity’ as a cultural icon. Such debates, however, were engagements with a reified image, enveloped in continual (re)interpretation. As a result, Bowie’s reification was grounded in a polysemous process that allowed numerous versions of ‘himself’ to be aesthetically reimagined, reinvented and repeated.