Proposed best practice for statisticians in the reporting and publication of pharmaceutical industry-sponsored clinical trials

In this paper we set out what we consider to be a set of best practices for statisticians in the reporting of pharmaceutical industry-sponsored clinical trials. We make eight recommendations covering: author responsibilities and recognition; publication timing; conflicts of interest; freedom to act; full author access to data; trial registration and independent review. These recommendations are made in the context of the prominent role played by statisticians in the design, conduct, analysis and reporting of pharmaceutical sponsored trials and the perception of the reporting of these trials in the wider community.

The potential for bias in reporting of industry-sponsored clinical trials

Concerns about potentially misleading reporting of pharmaceutical industry research have surfaced many times. The potential for duality (and thereby conflict) of interest is only too clear when you consider the sums of money required for the discovery, development and commercialization of new medicines. As the ability of major, mid-size and small pharmaceutical companies to innovate has waned, as evidenced by the seemingly relentless decline in the numbers of new medicines approved by Food and Drug Administration and European Medicines Agency year-on-year, not only has the cost per new approved medicine risen: so too has the public and media concern about the extent to which the pharmaceutical industry is open and honest about the efficacy, safety and quality of the drugs we manufacture and sell. In 2005 an Editorial in Journal of the American Medical Association made clear that, so great was their concern about misleading reporting of industry-sponsored studies, henceforth no article would be published that was not also guaranteed by independent statistical analysis. We examine the precursors to this Editorial, as well as its immediate and lasting effects for statisticians, for the manner in which statistical analysis is carried out, and for the industry more generally.

Identifying and investigating pesticide application types to promote a more sustainable pesticide use: the case of smallholders in Boyacá, Colombia

The present paper investigates pesticide application types adopted by smallholder potato producers in the Department of Boyacá , Colombia. In this region, environmental, health and adverse economic effects due to pesticide mis- or over-use respectively have been observed. Firstly, pesticide application types were identified based on input-effectiveness. Secondly, their determinants of adoption were investigated. Finally suggestions were given to develop intervention options for transition towards a more sustainable pesticide use. Three application types were identified for fungicide and insecticide. The types differed in terms of input (intensity of pesticide application), effect (damage control), frequency of application, average quantity applied per application, chemical class, and productivity. Then, the determinants of different pesticide application types were investigated with a multinomial logistic regression approach and applying the integrative agent centred (IAC) framework. The area of the plot, attendance at training sessions and educational and income levels were among the most relevant determinants. The analysis suggested that better pesticide use could be fostered to reduce pesticide-related risks in the region. Intervention options were outlined, which may help in targeting this issue. They aim not only at educating farmers, but to change their social and institutional context, by involving other agents of the agricultural system (i.e. pesticide producers), facilitating new institutional settings (i.e. cooperatives) and targeting social dynamics (i.e. conformity to social norms).

Suitability of pesticide risk indicators for less developed countries: a comparison

Pesticide risk indicators provide simple support in the assessment of environmental and health risks from pesticide use, and can therefore inform policies to foster a sustainable interaction of agriculture with the environment. For their relative simplicity, indicators may be particularly useful under conditions of limited data availability and resources, such as in Less Developed Countries (LDCs). However, indicator complexity can vary significantly, in particular between those that rely on an exposure–toxicity ratio (ETR) and those that do not. In addition, pesticide risk indicators are usually developed for Western contexts, which might cause incorrect estimation in LDCs. This study investigated the appropriateness of seven pesticide risk indicators for use in LDCs, with reference to smallholding agriculture in Colombia. Seven farm-level indicators, among which 3 relied on an ETR (POCER, EPRIP, PIRI) and 4 on a non-ETR approach (EIQ, PestScreen, OHRI, Dosemeci et al., 2002), were calculated and then compared by means of the Spearman rank correlation test. Indicators were also compared with respect to key indicator characteristics, i.e. user friendliness and ability to represent the system under study. The comparison of the indicators in terms of the total environmental risk suggests that the indicators not relying on an ETR approach cannot be used as a reliable proxy for more complex, i.e. ETR, indicators. ETR indicators, when user-friendly, show a comparative advantage over non-ETR in best combining the need for a relatively simple tool to be used in contexts of limited data availability and resources, and for a reliable estimation of environmental risk. Non-ETR indicators remain useful and accessible tools to discriminate between different pesticides prior to application. Concerning the human health risk, simple algorithms seem more appropriate for assessing human health risk in LDCs. However, further research on health risk indicators and their validation under LDC conditions is needed.

Why don’t pesticide applicators protect themselves? Exploring the use of personal protective equipment among Colombian smallholders

The misuse of personal protective equipment (PPE) during pesticide application was investigated among smallholders in Colombia. The integrative agent-centered (IAC) framework and a logistic regression approach were adopted. The results suggest that the descriptive social norm was significantly influencing PPE use. The following were also important: (1) having experienced pesticide-related health problems; (2) age; (3) the share of pesticide application carried out; and (4) the perception of PPE hindering work. Interestingly, the influence of these factors differed for different pieces of PPE. Since conformity to the social norm is a source of rigidity in the system, behavioral change may take the form of a discontinuous transition. In conclusion, five suggestions for triggering a transition towards more sustainable PPE use are formulated: (1) diversifying targets/tools; (2) addressing structural aspects; (3) sustaining interventions in the long-term; (4) targeting farmers’ learning-by-experience; and (5) targeting PPE use on a collective level.

Exploring behavioural change through an agent-oriented system dynamics model: the use of personal protective equipment among pesticide applicators in Colombia

The misuse of Personal Protective Equipment results in health risk among smallholders in developing countries, and education is often proposed to promote safer practices. However, evidence point to limited effects of education. This paper presents a System Dynamics model which allows the identification of risk-minimizing policies for behavioural change. The model is based on the IAC framework and survey data. It represents farmers' decision-making from an agent-oriented standpoint. The most successful intervention strategy was the one which intervened in the long term, targeted key stocks in the systems and was diversified. However, the results suggest that, under these conditions, no policy is able to trigger a self sustaining behavioural change. Two implementation approaches were suggested by experts. One, based on constant social control, corresponds to a change of the current model's parameters. The other, based on participation, would lead farmers to new thinking, i.e. changes in their decision-making structure.

A practical comparison of blinded methods for sample size reviews in survival data clinical trials.

This paper presents practical approaches to the problem of sample size re-estimation in the case of clinical trials with survival data when proportional hazards can be assumed. When data are readily available at the time of the review, on a full range of survival experiences across the recruited patients, it is shown that, as expected, performing a blinded re-estimation procedure is straightforward and can help to maintain the trial's pre-specified error rates. Two alternative methods for dealing with the situation where limited survival experiences are available at the time of the sample size review are then presented and compared. In this instance, extrapolation is required in order to undertake the sample size re-estimation. Worked examples, together with results from a simulation study are described. It is concluded that, as in the standard case, use of either extrapolation approach successfully protects the trial error rates. Copyright © 2012 John Wiley & Sons, Ltd.

Linking pesticide exposure and spatial dynamics: An individual-based model of wood mouse (Apodemus sylvaticus) populations in agricultural landscapes

The wood mouse is a common and abundant species in agricultural landscape and is a focal species in pesticide risk assessment. Empirical studies on the ecology of the wood mouse have provided sufficient information for the species to be modelled mechanistically. An individual-based model was constructed to explicitly represent the locations and movement patterns of individual mice. This together with the schedule of pesticide application allows prediction of the risk to the population from pesticide exposure. The model included life-history traits of wood mice as well as typical landscape dynamics in agricultural farmland in the UK. The model obtains a good fit to the available population data and is fit for risk assessment purposes. It can help identify spatio-temporal situations with the largest potential risk of exposure and enables extrapolation from individual-level endpoints to population-level effects. Largest risk of exposure to pesticides was found when good crop growth in the “sink” fields coincided with high “source” population densities in the hedgerows. Keywords: Population dynamics, Pesticides, Ecological risk assessment, Habitat choice, Agent-based model, NetLogo

Conditionally unbiased estimation in phase II/III clinical trials with early stopping for futility

Seamless phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages, with stage 1 used to answer phase II objectives such as treatment selection and stage 2 used for the confirmatory analysis, which is a phase III objective. Although seamless phase II/III clinical trials are efficient because the confirmatory analysis includes phase II data from stage 1, inference can pose statistical challenges. In this paper, we consider point estimation following seamless phase II/III clinical trials in which stage 1 is used to select the most effective experimental treatment and to decide if, compared with a control, the trial should stop at stage 1 for futility. If the trial is not stopped, then the phase III confirmatory part of the trial involves evaluation of the selected most effective experimental treatment and the control. We have developed two new estimators for the treatment difference between these two treatments with the aim of reducing bias conditional on the treatment selection made and on the fact that the trial continues to stage 2. We have demonstrated the properties of these estimators using simulations

Motivations behind farmers’ pesticide use in Bangladesh rice farming

This paper addresses the motivations behind farmers’ pesticide use in two regions of Bangladesh. The paper considers farmers’ knowledge of arthropods and their perceptions about pests and pest damage, and identifies why many farmers do not use recommended pest management practices. We propose that using the novel approach of classifying farmers according to their motivations and constraints rather than observed pesticide use can improve training approaches and increase farmers’ uptake and retention of more appropriate integrated pest management technologies.