Richard M Nixon

Richard M Nixon
Novartis · Modeling and Simulation

Ph.D.

About

74
Publications
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Publications

Publications (74)
Article
Full-text available
Background and aim Diclofenac is widely prescribed for the treatment of pain. Several network meta-analyses (NMA), largely of published trials have evaluated the efficacy, tolerability, and safety of non-steroidal anti-inflammatory drugs (NSAIDs). The present NMA extends these analyses to unpublished older (legacy) diclofenac trials. Methods We id...
Article
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Researchers in clinical trials in rheumatoid arthritis (RA) and osteoarthritis (OA) often measure pain levels with a visual analogue scale (VAS). Of interest to clinical practice and future clinical trial design are associations of change from baseline (CFB) between time points with predictive ability of earlier response for long-term treatment ben...
Article
Drug development involves complex, high-value decisions with lasting consequences. These decisions are made in the context of uncertainty, with information of many different types and from many different sources. A project team making a decision regarding the development of a drug needs to structure and synthesize this information in this context a...
Article
Full-text available
Background Diclofenac, a traditional NSAID was developed 40 years back by Novartis for the treatment of acute and chronic pain. NSAIDs are used for pain management in osteoarthritis (OA), and have recently been under scrutiny due to possible safety risks. Both benefits and risks of different treatments should be analyzed to inform clinical decision...
Article
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Network meta-analysis (NMA) is a methodology for indirectly comparing, and strengthening direct comparisons of two or more treatments for the management of disease by combining evidence from multiple studies. It is sometimes not possible to perform treatment comparisons as evidence networks restricted to randomized controlled trials (RCTs) may be d...
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There is argument over the benefits and risks of drugs for treating chronic musculoskeletal pain. This study compared the efficacy, safety, and tolerability of diclofenac, ibuprofen, naproxen, celecoxib, and etoricoxib for patients with pain caused by osteoarthritis (OA) or rheumatoid arthritis (RA). A systematic literature review used Medline and...
Article
Quantitative decision models such as multiple criteria decision analysis (MCDA) can be used in benefit-risk assessment to formalize trade-offs between benefits and risks, providing transparency to the assessment process. There is however no well-established method for propagating uncertainty of treatment effects data through such models to provide...
Article
While benefit-risk assessment is a key component of the drug development and maintenance process, it is often described in a narrative. In contrast, structured benefit-risk assessment builds on established ideas from decision analysis and comprises a qualitative framework and quantitative methodology. We compare two such frameworks, applying multi-...
Article
Full-text available
Two treatments, ranibizumab and dexamethasone implant, for visual impairment due to macular oedema (ME) secondary to retinal vein occlusion (RVO) have recently been studied in clinical trials. There have been no head to head comparisons of the two treatments, and improvement measured as gain in Best Corrected Visual Acuity (BCVA) was reported using...
Article
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No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies. No evidence of disease activity (NEDA) was ev...
Article
PurposeDifficulties may be encountered when undertaking a benefit–risk assessment for an older product with well-established use but with a benefit–risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit–risk framework to assess the benefit–risk balance of warfarin for primary...
Article
Multilevel models provide a flexible modelling framework for cost-effectiveness analyses that use cluster randomised trial data. However, there is a lack of guidance on how to choose the most appropriate multilevel models. This paper illustrates an approach for deciding what level of model complexity is warranted; in particular how best to accommod...
Article
Statistical methods have been developed for cost-effectiveness analyses of cluster randomised trials (CRTs) where baseline covariates are balanced. However, CRTs may show systematic differences in individual and cluster-level covariates between the treatment groups. This paper presents three methods to adjust for imbalances in observed covariates:...
Article
Full-text available
Cost-effectiveness analyses (CEAs) may use data from cluster randomized trials (CRTs), where the unit of randomization is the cluster, not the individual. However, most studies use analytical methods that ignore clustering. This article compares alternative statistical methods for accommodating clustering in CEAs of CRTs. Our simulation study compa...
Article
Full-text available
The best data for cost-effectiveness analyses (CEAs) of group-level interventions often come from cluster randomized trials (CRTs), where randomization is by cluster (e.g., the hospital attended), not by individual. for these CEAs need to recognize both the correlation between costs and outcomes and that these data may be dependent on the cluster....
Article
Cost-effectiveness analyses (CEA) alongside randomised controlled trials commonly estimate incremental net benefits (INB), with 95% confidence intervals, and compute cost-effectiveness acceptability curves and confidence ellipses. Two alternative non-parametric methods for estimating INB are to apply the central limit theorem (CLT) or to use the no...
Article
The development of a new drug is a major undertaking and it is important to consider carefully the key decisions in the development process. Decisions are made in the presence of uncertainty and outcomes such as the probability of successful drug registration depend on the clinical development programmme. The Rheumatoid Arthritis Drug Development M...
Article
Cost-effectiveness analyses (CEA) may be undertaken alongside cluster randomized trials (CRTs) where randomization is at the level of the cluster (for example, the hospital or primary care provider) rather than the individual. Costs (and outcomes) within clusters may be correlated so that the assumption made by standard bivariate regression models,...
Article
Full-text available
To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension. Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs)...
Article
A model is presented to generate a distribution for the probability of an ACR response at six months for a new treatment for rheumatoid arthritis given evidence from a one- or three-month clinical trial. The model is based on published evidence from 11 randomized controlled trials on existing treatments. A hierarchical logistic regression model is...
Article
To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States. Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS....
Article
Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered inflixima...
Article
To derive robust estimates for the cost of multiple sclerosis (MS) based on a variety of cost factors across a number of different cost perspectives. This is essential to perform credible pharmacoeconomic evaluations of alternative MS therapies. Here we present a detailed analysis of previously published MS cost data for the UK to which we fit a se...
Article
Full-text available
To evaluate the cost effectiveness of TNF-alpha antagonist therapies for rheumatoid arthritis (RA) in the United Kingdom using data from the British Society for Rheumatology Biologics Registry (BSRBR). A simulation model is constructed to quantify the cost effectiveness of the TNF-alpha antagonist therapies (infliximab, etanercept and adalimumab) a...
Article
Multilevel models (MLMs) have been recommended for estimating incremental net benefits (INBs) in multicentre cost-effectiveness analysis (CEA). However, these models have assumed that the INBs are exchangeable and that there is a common variance across all centres. This paper examines the plausibility of these assumptions by comparing various MLMs...
Article
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New treatments that inhibit the cytokines tumour necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1) in the treatment of rheumatoid arthritis have proven clinical effect against placebo and methotrexate (MTX) in several clinical trials in early and late-stage disease and different severity groups. Since there are no head-to-head randomized co...
Article
Overall assessments of cost-effectiveness are now commonplace in informing medical policy decision making. Analyses may be biased by case-mix differences, and it is important to attempt to adjust the inference for this especially if the evaluation is conducted in the context of an observation study. It is also often important also to investigate ho...
Article
Mixed treatment comparison (MTC) is a generalization of meta-analysis. Instead of the same treatment for a disease being tested in a number of studies, a number of different interventions are considered. Meta-regression is also a generalization of meta-analysis where an attempt is made to explain the heterogeneity between the treatment effects in t...
Article
Estimated progression rates for people with active relapsing-remitting multiple sclerosis (RRMS) are essential for resource management but are poorly quantified according to disability severity. In this study data from the placebo arm of the AFFIRM study were used to estimate rates for a population of active RRMS patients and for a rapidly evolving...
Article
Because published utility estimates in multiple sclerosis (MS) are concentrated in people with moderate to severe disease severity and focus on specific types of MS, we conducted a cross-sectional study of people with MS to estimate the utility associated with disease, functional status as measured by the Adapted Patient Determined Disease Steps (A...
Article
Differences in the mean, spread and skewness of cost data collected from different countries present problems for analysis and interpretation. Here we develop generalised linear multilevel models to estimate the effects of patient and national characteristics on costs. Using gamma distributions and multiplicative effects for patient characteristics...
Article
This cost-of-illness analysis for the United Kingdom is part of a Europe-wide study on the costs of multiple sclerosis (MS). The objective was to analyze the costs and quality of life (utility) related to the level of disease severity. People with MS from a database administered by a UK charity (the MS Trust) were asked to participate in the survey...
Article
Potential biochemical indicators of long-term undernutrition in cattle, which could be used objectively, reliably and routinely, were investigated by evaluating frequently analysed metabolites in cattle. In an initial study, a meta-regression of literature data for glucose, urea, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB) agai...
Article
Overall assessments of cost-effectiveness are now commonplace in informing medical policy decision making. It is often important, however, also to investigate how cost-effectiveness varies between patient subgroups. Yet such analyses are rarely undertaken, because appropriate methods have not been sufficiently developed. We propose a coherent set o...
Article
Cost-effectiveness analyses of clinical trial data are based on assumptions about the distributions of costs and effects. Cost data usually have very skewed distributions and can be difficult to model. The authors investigate whether choice of distribution can make a difference to the conclusions drawn. The authors compare 3 distributions for cost...
Article
Recently, commentators have suggested that the distributional form of cost data should be explicitly modelled to gain efficiency in estimating the population mean. We perform a series of simulation experiments to evaluate the usual sample mean and the mean estimator of a lognormal distribution, in the context of both theoretical distributions and t...
Article
Critical limits for cadmium in parts of the human food chain are considered to have too small margins of safety and some limits are regularly exceeded. There is concern about the exposure of some sections of the population to cadmium in the human food chain, in particular regarding offal, which is a major source of cadmium to some sectors. The kidn...
Article
Multinational economic evaluations often calculate a single measure of cost-effectiveness using cost data pooled across several countries. To assess the validity of pooling international cost data the reasons for cost variation across countries need to be assessed. Previously, ordinary least-squares (OLS) regression models have been used to identif...
Article
The cost of medical resources used is often recorded for each patient in clinical studies in order to inform decision-making. Although cost data are generally skewed to the right, interest is in making inferences about the population mean cost. Common methods for non-normal data, such as data transformation, assuming asymptotic normality of the sam...
Article
Human cadmium intake derives mainly from food sources, and cadmium can be present in high concentrations in some offal. A meta-analysis using random effects modeling was carried out to integrate the results of 21 controlled randomized trials in which sheep were fed diets with elevated cadmium levels and cadmium concentrations in their livers and ki...
Article
Full-text available
The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former...
Article
Analysis of covariance models, which adjust for a baseline covariate, are often used to compare treatment groups in a controlled trial in which individuals are randomized. Such analysis adjusts for any baseline imbalance and usually increases the precision of the treatment effect estimate. We assess the value of such adjustments in the context of a...
Article
The mean sojourn time (the duration of the period during which a cancer is symptom free but potentially detectable by screening) and the screening sensitivity (the probability that a screen applied to a cancer in the preclinical screen detectable period will result in a positive diagnosis) are two important features of a cancer screening programme....
Article
To compare the diagnostic accuracy of clinical assessment with transabdominal ultrasound in the management of secondary postpartum haemorrhage (PPH). A prospective cohort study. Fifty-three women who presented to a teaching hospital obstetric unit with secondary PPH were studied. Patients were divided into those in whom retained placental tissue wa...
Article
The development of breast cancer control strategies in women at high genetic risk of breast cancer is an important issue. The likely benefit of chemopreventive approaches is of particular interest. Tamoxifen tends to be more effective in both prevention and treatment of oestrogen receptor positive tumours than oestrogen receptor negative. In this s...
Article
Cross-design synthesis usually refers to the inclusion in a meta-analysis of studies addressing the same question but using different designs, for example, combining results from randomised trials with those from case-control studies. Here we describe a procedure for combining information from studies addressing different but clinically related que...
Article
Women are frequently referred to genetic clinics because of a family history of breast or ovarian cancer, conferring a moderate increased risk of the disease, but not sufficient in itself to indicate gene mutation analysis. One possible management strategy is to offer regular mammographic screening, possibly earlier in life and more frequently than...
Article
Moderate to severe undermasculinized genitalia was recently shown to be associated with longer polyglutamine repeats within the androgen receptor [AR(Gln)n]. However, it was unknown whether this was because longer AR(Gln)n contributed to the: 1) etiology; 2) severity; and/or 3) testicular maldescent. Therefore, AR(Gln)n length in 175 males with abn...
Article
The Anglia menorrhagia education study tests the effectiveness of an education package for the treatment of menorrhagia given to doctors at a primary care level. General practices were randomized to receive or not receive the package. It is hoped that this intervention will reduce the proportion of women suffering from menorrhagia that are referred...
Article
Full-text available
Menorrhagia is an important healthcare problem for women.1 In primary care menorrhagia is a considerable burden on resources and may ultimately lead to referral and surgery.1,2 There is a gap between research and practice, with best evidence not uniformly applied. The Anglia menorrhagia education study, a randomised controlled trial of an education...
Article
The objective of this study is to compare the effectiveness of mammographic screening in women with a family history of breast cancer to those without. In the invited arm of a randomised trial of breast cancer screening, data on family history of breast cancer were available on 29.179 women aged 40-74 attending for screening. Among those women, 358...
Article
Full-text available
The androgen receptor (AR) is essential to the normal development of the male internal and external genitalia. Consequently, impairment of AR function can result in undermasculinized genitalia that vary from a completely female appearance to isolated hypospadias. Since in vitro studies demonstrate that AR function is reduced by expansion of the pol...
Article
In the Swedish two-county trial women aged 40-74 years from two counties in Sweden were randomised to invitation to mammographic screening for breast cancer. This paper uses random effects logistic regression models to analyse recent data from the trial. The analysis accounts for the structure of the trial, where small geographical units are random...
Article
Full-text available
To determine whether an educational package could influence the management of menorrhagia, increase the appropriateness of choice of non-hormonal treatment, and reduce referral rates from primary to secondary care. Randomised controlled trial. General practices in East Anglia. 100 practices (348 doctors) in primary care were recruited and randomise...
Article
Full-text available
Summary Decision-makers require appropriate measures of the sampling uncertainty that surround the results of cost-effectiveness analysis. This paper uses the central limit theorem to derive 95% confidence intervals around the incremental net benefit, cost-effectiveness acceptability curves and confidence ellipses when data is collected from a sing...

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