Deborah Ashby

Imperial College London, Londinium, England, United Kingdom

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Publications (79)657.12 Total impact

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    ABSTRACT: Purpose: The purpose of this study is to draw on the practical experience from the PROTECT BR case studies and make recommendations regarding the application of a number of methodologies and visual representations for benefit-risk assessment. Methods: Eight case studies based on the benefit-risk balance of real medicines were used to test various methodologies that had been identified from the literature as having potential applications in benefit-risk assessment. Recommendations were drawn up based on the results of the case studies. Results: A general pathway through the case studies was evident, with various classes of methodologies having roles to play at different stages. Descriptive and quantitative frameworks were widely used throughout to structure problems, with other methods such as metrics, estimation techniques and elicitation techniques providing ways to incorporate technical or numerical data from various sources. Similarly, tree diagrams and effects tables were universally adopted, with other visualisations available to suit specific methodologies or tasks as required. Every assessment was found to follow five broad stages: (i) Planning, (ii) Evidence gathering and data preparation, (iii) Analysis, (iv) Exploration and (v) Conclusion and dissemination. Conclusions: Adopting formal, structured approaches to benefit-risk assessment was feasible in real-world problems and facilitated clear, transparent decision-making. Prior to this work, no extensive practical application and appraisal of methodologies had been conducted using real-world case examples, leaving users with limited knowledge of their usefulness in the real world. The practical guidance provided here takes us one step closer to a harmonised approach to benefit-risk assessment from multiple perspectives. Copyright © 2016 John Wiley & Sons, Ltd.
    No preview · Article · Jan 2016 · Pharmacoepidemiology and Drug Safety
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    ABSTRACT: Background: The PROTECT Benefit-Risk group is dedicated to research in methods for continuous benefit-risk monitoring of medicines, including the presentation of the results, with a particular emphasis on graphical methods. Methods: A comprehensive review was performed to identify visuals used for medical risk and benefit-risk communication. The identified visual displays were grouped into visual types, and each visual type was appraised based on five criteria: intended audience, intended message, knowledge required to understand the visual, unintentional messages that may be derived from the visual and missing information that may be needed to understand the visual. Results: Sixty-six examples of visual formats were identified from the literature and classified into 14 visual types. We found that there is not one single visual format that is consistently superior to others for the communication of benefit-risk information. In addition, we found that most of the drawbacks found in the visual formats could be considered general to visual communication, although some appear more relevant to specific formats and should be considered when creating visuals for different audiences depending on the exact message to be communicated. Conclusion: We have arrived at recommendations for the use of visual displays for benefit-risk communication. The recommendation refers to the creation of visuals. We outline four criteria to determine audience-visual compatibility and consider these to be a key task in creating any visual. Next we propose specific visual formats of interest, to be explored further for their ability to address nine different types of benefit-risk analysis information. Copyright © 2015 John Wiley & Sons, Ltd.
    No preview · Article · Nov 2015 · Pharmacoepidemiology and Drug Safety
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    ABSTRACT: Structured frameworks for benefit-risk analysis in drug licensing decisions are being implemented across a number of regulatory agencies worldwide. The aim of these frameworks is to aid the analysis and communication of the benefit-risk assessment throughout the development, evaluation, and supervision of medicines. In this review, authors from regulatory agencies, pharmaceutical companies, and academia share their views on the different frameworks and discuss future directions.
    No preview · Article · Aug 2015 · Clinical Pharmacology &#38 Therapeutics
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    ABSTRACT: In Vitro Fertilization (IVF) treatment is an effective therapy for infertility, but can result in the potentially life-threatening complication 'ovarian hyperstimulation syndrome' (OHSS). To investigate whether kisspeptin-54 can be used to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS. Phase 2 multi-dose open label randomized clinical trial carried out during 2013-2014. Hammersmith Hospital IVF unit, London, UK. Sixty women at high risk of developing OHSS. Following a standard recombinant FSH/GnRH antagonist protocol, patients were randomized to receive a single injection of kisspeptin-54 to trigger oocyte maturation using an adaptive design for dose allocation (3.2nmol/kg, n=5; 6.4nmol/kg, n=20; 9.6nmol/kg, n=15; 12.8nmol/kg, n=20). Oocytes were retrieved 36hrs after kisspeptin-54 administration, assessed for maturation, and fertilized by intra-cytoplasmic sperm injection (ICSI) with subsequent transfer of one or two embryos. Women were routinely screened for the development of OHSS. Oocyte maturation was measured by oocyte yield (percentage of mature oocytes retrieved from follicles ≥14mm on ultrasound). Secondary outcomes include rates of OHSS and pregnancy. Oocyte maturation occurred in 95% of women. Highest oocyte yield (121%) was observed following 12.8nmol/kg kisspeptin-54, which was +69% (CI -16%,+153%) greater than following 3.2nmol/kg. At all doses of kisspeptin-54, biochemical pregnancy, clinical pregnancy and live birth rates per transfer (n=51) were 63%, 53% and 45%, respectively. Highest pregnancy rates were observed following 9.6nmol/kg kisspeptin-54 (85%, 77% and 62%, respectively). No woman developed moderate, severe or critical OHSS. Kisspeptin-54 is a promising approach to effectively and safely trigger oocyte maturation in women undergoing IVF treatment at high risk of developing OHSS.
    No preview · Article · Jul 2015 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis. We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0·9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867. Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3·7%, 95% CI 0·1-7·3; p=0·046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups. Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials. Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme. Copyright © 2015 Alton et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.
    No preview · Article · Jul 2015
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    ABSTRACT: 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 a sense of the variability of the benefit-risk balance. Here, we present a Bayesian statistical method that directly models the outcomes observed in randomized placebo-controlled trials and uses this to infer indirect comparisons between competing active treatments. The resulting treatment effects estimates are suitable for use within the MCDA setting, and it is possible to derive the distribution of the overall benefit-risk balance through Markov Chain Monte Carlo simulation. The method is illustrated using a case study of natalizumab for relapsing-remitting multiple sclerosis.
    No preview · Article · Jan 2015 · Biometrical Journal
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    ABSTRACT: The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. NCT00750438. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Full-text · Article · Dec 2014 · Gut

  • No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: 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 prevention of patients with atrial fibrillation.Methods We used the qualitative framework BRAT as the starting point of the benefit–risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi-criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making.ResultsOur benefit–risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit–risk balance is fairly robust to differences in preferences. The probability of a favourable benefit–risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data.In this case study, we identified major challenges related to the identification of relevant benefit–risk criteria and taking into account the diversity and quality of evidence available to inform the benefit–risk assessment.Conclusion The main challenges in applying formal methods for medical benefit–risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large. Copyright © 2014 John Wiley & Sons, Ltd.
    No preview · Article · Sep 2014 · Pharmacoepidemiology and Drug Safety
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    ABSTRACT: Patients with mutations that inactivate kisspeptin signaling are infertile. Kisspeptin-54, the major circulating isoform of kisspeptin in humans, potently stimulates reproductive hormone secretion in humans. Animal studies suggest that kisspeptin is involved in generation of the luteinizing hormone surge, which is required for ovulation; therefore, we hypothesized that kisspeptin-54 could be used to trigger egg maturation in women undergoing in vitro fertilization therapy. METHODS Following superovulation with recombinant follicle-stimulating hormone and administration of gonadotropin-releasing hormone antagonist to prevent premature ovulation, 53 women were administered a single subcutaneous injection of kisspeptin-54 (1.6 nmol/kg, n = 2; 3.2 nmol/kg, n = 3; 6.4 nmol/kg, n = 24; 12.8 nmol/kg, n = 24) to induce a luteinizing hormone surge and egg maturation. Eggs were retrieved transvaginally 36 hours after kisspeptin injection, assessed for maturation (primary outcome), and fertilized by intracytoplasmic sperm injection with subsequent transfer of one or two embryos. RESULTS Egg maturation was observed in response to each tested dose of kisspeptin-54, and the mean number of mature eggs per patient generally increased in a dose-dependent manner. Fertilization of eggs and transfer of embryos to the uterus occurred in 92% (49/53) of kisspeptin-54-treated patients. Biochemical and clinical pregnancy rates were 40% (21/53) and 23% (12/53), respectively. CONCLUSION This study demonstrates that a single injection of kisspeptin-54 can induce egg maturation in women with subfertility undergoing in vitro fertilization therapy. Subsequent fertilization of eggs matured following kisspeptin-54 administration and transfer of resulting embryos can lead to successful human pregnancy. TRIAL REGISTRATION ClinicalTrials.gov NCT01667406.
    No preview · Article · Jul 2014 · Journal of Clinical Investigation
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    ABSTRACT: Introduction Vasopressin is an alternative vasopressor in the management of septic shock. It spares catecholamine use but whether it improves outcome remains uncertain. Current evidence suggests that it may be most effective if used early and possibly in conjunction with corticosteroids. This trial will compare vasopressin to noradrenaline as initial vasopressor in the management of adult septic shock and investigate whether there is an interaction of vasopressin with corticosteroids. Methods and analysis This is a multicentre, factorial (2×2), randomised, double-blind, placebo-controlled trial. 412 patients will be recruited from multiple UK intensive care units and randomised to receive vasopressin (0–0.06 U/min) or noradrenaline (0–12 µg/min) as a continuous intravenous infusion as initial vasopressor therapy. If maximum infusion rates of this first study drug are reached, the patient will be treated with either hydrocortisone (initially 50 mg intravenous bolus six-hourly) or placebo, before additional open-label catecholamine vasopressors are prescribed. The primary outcome of the trial will be the difference in renal failure-free days between treatment groups. Secondary outcomes include need for renal replacement therapy, survival rates, other organ failures and resource utilisation. Ethics and dissemination The trial protocol and information sheets have received a favourable opinion from the Oxford A Research Ethics Committee (12/SC/0014). There is an independent Data Monitoring and Ethics Committee and independent membership of the Trial Steering Committee including patient and public involvement. The trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. Trial registration number: ISRCTN 20769191 and EudraCT 2011-005363-24.
    Full-text · Article · Jul 2014 · BMJ Open
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    ABSTRACT: Background The need for formal and structured approaches for benefit–risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit–risk balance of medicines. We systematically collected, appraised and classified available benefit–risk methodologies to facilitate and inform their future use.MethodsA systematic review of publications identified benefit–risk assessment methodologies. Methodologies were appraised on their fundamental principles, features, graphical representations, assessability and accessibility. We created a taxonomy of methodologies to facilitate understanding and choice.ResultsWe identified 49 methodologies, critically appraised and classified them into four categories: frameworks, metrics, estimation techniques and utility survey techniques. Eight frameworks describe qualitative steps in benefit–risk assessment and eight quantify benefit–risk balance. Nine metric indices include threshold indices to measure either benefit or risk; health indices measure quality-of-life over time; and trade-off indices integrate benefits and risks. Six estimation techniques support benefit–risk modelling and evidence synthesis. Four utility survey techniques elicit robust value preferences from relevant stakeholders to the benefit–risk decisions.Conclusions Methodologies to help benefit–risk assessments of medicines are diverse and each is associated with different limitations and strengths. There is not a ‘one-size-fits-all’ method, and a combination of methods may be needed for each benefit–risk assessment. The taxonomy introduced herein may guide choice of adequate methodologies. Finally, we recommend 13 of 49 methodologies for further appraisal for use in the real-life benefit–risk assessment of medicines. Copyright © 2014 John Wiley & Sons, Ltd.
    Full-text · Article · Jul 2014 · Pharmacoepidemiology and Drug Safety
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    ABSTRACT: Objective: Meta-analyses of epidemiologic studies have suggested that metformin may reduce cancer incidence, but randomized controlled trials did not support this hypothesis. Research design and methods: A retrospective cohort study, Clinical Practice Research Datalink, was designed to investigate the association between use of metformin compared with other antidiabetes medications and cancer risk by emulating an intention-to-treat analysis as in a trial. A total of 95,820 participants with type 2 diabetes who started taking metformin and other oral antidiabetes medications within 12 months of their diagnosis (initiators) were followed up for first incident cancer diagnosis without regard to any subsequent changes in pharmacotherapy. Cox proportional hazards models were used to estimate multivariable-adjusted hazard ratios (HR) and 95% CI. Results: A total of 51,484 individuals (54%) were metformin initiators and 18,264 (19%) were sulfonylurea initiators, and 3,805 first incident cancers were diagnosed during a median follow-up time of 5.1 years. Compared with initiators of sulfonylurea, initiators of metformin had a similar incidence of total cancer (HR 0.96; 95% CI 0.89-1.04) and colorectal (HR 0.92; 95% CI 0.76-1.13), prostate (HR 1.02; 95% CI 0.83-1.25), lung (HR 0.85; 95% CI 0.68-1.07), or postmenopausal breast (HR 1.03; 95% CI 0.82-1.31) cancer or any other cancer. Conclusions: In this large study, individuals with diabetes who used metformin had a similar risk of developing cancer compared with those who used sulfonylureas.
    Full-text · Article · Jun 2014 · Diabetes Care
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    ABSTRACT: Background Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients. Methods/Design This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg-1.min-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom. Discussion This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action. Trial registration Current controlled trials ISRCTN12776039 (19 September 2013)
    Full-text · Article · Jun 2014 · Trials
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    ABSTRACT: Vasopressin and corticosteroids are both commonly used adjunctive therapies in septic shock. Retrospective analyses have suggested that there may be an interaction between these drugs, with higher circulating vasopressin levels and improved outcomes in patients treated with both vasopressin and corticosteroids. We aimed to test for an interaction between vasopressin and corticosteroids in septic shock. Prospective open-label randomized controlled pilot trial. Four adult ICUs in London teaching hospitals. Sixty-one adult patients who had septic shock. Initial vasopressin IV infusion titrated up to 0.06 U/min and then IV hydrocortisone (50 mg 6 hourly) or placebo. Plasma vasopressin levels were measured at 6-12 and 24-36 hours after hydrocortisone/placebo administration. Thirty-one patients were allocated to vasopressin + hydrocortisone and 30 patients to vasopressin + placebo. The hydrocortisone group required a shorter duration of vasopressin therapy (3.1 d; 95% CI, 1.1-5.1; shorter in hydrocortisone group) and required a lower total dose of vasopressin (ratio, 0.47; 95% CI, 0.32-0.71) compared with the placebo group. Plasma vasopressin levels were not higher in the hydrocortisone group compared with the placebo group (64 pmol/L difference at 6- to 12-hour time point; 95% CI, -32 to 160 pmol/L). Early vasopressin use was well tolerated with only one serious adverse event possibly related to study drug administration reported. There were no differences in mortality rates (23% 28-day mortality in both groups) or organ failure assessments between the two treatment groups. Hydrocortisone spared vasopressin requirements, reduced duration, and reduced dose, when used together in the treatment of septic shock, but it did not alter plasma vasopressin levels. Further trials are needed to assess the clinical effectiveness of vasopressin as the initial vasopressor therapy with or without corticosteroids.
    Full-text · Article · Feb 2014 · Critical care medicine
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    ABSTRACT: Although in-vitro fertilisation (IVF) treatment allows infertile couples to conceive, it can result in a potentially life-threatening condition termed the ovarian hyperstimulation syndrome (OHSS). The major cause of OHSS is use of human chorionic gonadotropin (hCG) in current IVF protocols for initiating oocyte maturation. The development of a more physiological stimulus for oocyte maturation would avoid this dangerous side-effect and thus improve safety of IVF treatment. Kisspeptin is a recently identified hypothalamic hormone that acutely and potently increases endogenous secretion of luteinising hormone in a gonadotropin-releasing hormone (GnRH)-dependent manner. We aimed to investigate whether kisspeptin can induce oocyte maturation in IVF treatment.
    No preview · Article · Feb 2014 · The Lancet
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    ABSTRACT: Objectives: Domperidone and metoclopramide are pro-kinetics commonly prescribed off-label to infants and younger children in an attempt to treat gastro-oesophageal reflux symptoms. Another pro-kinetic drug, cisapride, was used but withdrawn in 2000 in the UK due to serious arrhythmic adverse events. MHRA issued safety warnings for domperidone in May 2012, and restricted its indications. We report here national primary care prescribing trends and safety signals of these drugs in children. Methods: We used data from the General Practices Research Database between 1990 and 2006 for children <18 years. Descriptive statistics and Poisson regressions were performed to characterise prescribing trends. We examined safety signals in nested case-controls studies. Results: The proportion of children <2 years old being precribed one of the medications doubled during the study period. Prescriptions of domperidone increased 10-fold, mainly following the withdrawal of cisapride in 2000. Prescriptions of metoclopramide did not significantly change. Despite the increase in prescriptions of domperidone no new safety signals were identified. Conclusions: These data showed dramatic changes in prescribing of cisapride and domperidone despite the lack of good quality supporting evidence. It is possible these prescribing trends were influenced by published guidelines. Even if produced without robust efficacy and safety evidence, published guidelines can influence clinicians and consequently impact prescribing. Therefore, improving the evidence base on pro-kinetics to inform future guidelines is vital. The lack of new safety signals over this period would support the development of suitable powered clinical studies.
    No preview · Article · Jan 2014 · Journal of Pediatric Gastroenterology and Nutrition
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    ABSTRACT: www.protectbenefitrisk.eu In support of the goal to strengthen the monitoring of the benefit-risk balance of medicines in Europe, four years of research was conducted by a public-private partnership under the auspices of the EU and coordinated by the EMA and representatives of the pharmaceutical industry. The results of this work confirmed the added value of using more formal and structured approaches to the benefit-risk assessment of medicines to improve the transparency and communicability of this process. Under the umbrella of the IMI PROTECT consortium, members have advanced the understanding of both the integration and visual representation of benefit and risk data. Following a robust review of the literature, selected methodologies and visualisation techniques were applied in several case studies, each one constructed from publicly available data and representative of the more challenging benefit-risk assessments encountered throughout the life cycle of a drug. The experience of the case study teams has been distilled into a clear set of practical recommendations for benefit-risk decision processes and supporting tools, and these are organised around the five stages of a generic benefit-risk assessment roadmap: (I) Planning: This stage encourages stakeholders to focus on critical issues related to benefit-risk assessment, including the purpose and context of the assessment. Clear documentation of discussions allows future analyses and updates to utilise the same foundations. Useful methodologies included frameworks, such as the Benefit-Risk Action Team (BRAT) and Problem, Objectives, Alternatives, Consequences, Trade-offs, Uncertainty, Risk and Linked decisions (PrOACT-URL) frameworks that organise data, with tree diagrams and structured tables providing useful means of visualisation. (II) Evidence gathering and data preparation: This stage identifies data sources and extracts evidence relevant to the benefit-risk assessment, and may include aggregation of multiple sources of evidence, which may require the use of estimation techniques. It encourages the systematic handling of missing data and requires engagement of clinical, statistical, epidemiological, and database expertise. Useful methodologies include Indirect/Mixed Treatment Comparison (ITC/MTC) and Probabilistic Simulation Method (PSM), and visualisation techniques such as structured and colour-coded tables, and network graphs to enhance the communication of data. (III) Analysis: In this stage, the data are evaluated, quantifying the magnitudes of benefits and risks, and perhaps weighing and/or integrating favourable and unfavourable effects as required by a given approach. Useful methodologies for analysis include metric indices which provide numerical representations of benefits and risks (Number Needed to Treat / Number Needed to Harm (NNT/NNH), Impact numbers), quantitative frameworks which model benefit-risk trade-off and balance benefits and risks (Multi-Criteria Decision Analysis (MCDA), Stochastic Multi-criteria Acceptability Analysis (SMAA)), and utility survey techniques which elicit stakeholders’ preference information (Discrete Choice Experiment (DCE)). Visualisations recommended for the analysis stage include visualisation techniques specific for eliciting value preferences (tree diagram, method-specific visualisations such as MACBETH grid, Analytic Hierarchy Process (AHP) table, swing-weighting ‘thermometer’ scale, drop-down list), and visualisations for presenting analysis results (tables, forest/interval plots for qualitative or partially quantitative analyses; ‘Difference display’ (MCDA), and stacked or grouped bar charts for quantitative analyses). (IV) Exploration: This stage assesses the robustness and sensitivity of the main results to various assumptions and sources of uncertainties, considers impact or added value of risk minimisation measures, and likely requires both statistical and clinical input. Useful methodologies include ITC/MTC, utility survey techniques (DCE, AHP, Swing-weighting, MACBETH), PSM, and SMAA. Preferred visualisation techniques include the box, distribution, scatter, and forest/interval plots; tornado diagram; and most importantly, techniques that are interactive with the user. (V) Conclusion and Dissemination: This is the point at which, after considering all the information in the previous four stages, a conclusion is reached. The results and consensus from the benefit-risk assessment are then explicitly communicated to a wider audience, providing a transparent audit trail of the whole assessment process and bringing all aspects together in a holistic fashion. The content of the communication and visualisation methods used should match the needs of the intended audience. While no single benefit-risk methodology can fully capture all aspects of a benefit-risk assessment, the choice of a single approach or combination of methodologies should be matched to the complexity of the problem. Application of a simple descriptive framework can provide a clear and easily communicable benefit-risk assessment, could be sufficient for the majority of benefit-risk problems, and can be enhanced for clarity with varying degrees of quantification. For more complex problems, a framework supplemented by quantitative models can facilitate consideration of trade-offs amongst the benefits and risks, address uncertainty, and potentially lead to a more comprehensive overall assessment. To understand the perspective of a particular stakeholder, elicitation of preference values for weighing benefits and risks may be required. Several ongoing initiatives are examining the role of formal benefit-risk assessment methods, and PROTECT’s experience makes what we believe is a unique contribution which complements and builds on these other efforts. The recommendations provided should serve as a valuable guide for readers who are new to the world of benefit-risk assessment as they highlight key issues and considerations that are common to many approaches.
    Full-text · Technical Report · Nov 2013
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    ABSTRACT: To test whether offering financial incentives to patients with psychotic disorders is effective in improving adherence to maintenance treatment with antipsychotics. Cluster randomised controlled trial. Community mental health teams in secondary psychiatric care in the United Kingdom. Patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder, who were prescribed long acting antipsychotic (depot) injections but had received 75% or less of the prescribed injections. We randomly allocated 73 teams with a total of 141 patients. Primary outcome data were available for 35 intervention teams with 75 patients (96% of randomised) and for 31 control teams with 56 patients (89% of randomised). Participants in the intervention group were offered £15 (€17; $22) for each depot injection over a 12 month period. Participants in the control condition received treatment as usual. The primary outcome was the percentage of prescribed depot injections given during the 12 month intervention period. 73 teams with 141 consenting patients were randomised, and outcomes were assessed for 131 patients (93%). Average baseline adherence was 69% in the intervention group and 67% in the control group. During the 12 month trial period adherence was 85% in the intervention group and 71% in the control group. The adjusted effect estimate was 11.5% (95% confidence interval 3.9% to 19.0%, P=0.003). A secondary outcome was an adherence of ≥95%, which was achieved in 28% of the intervention group and 5% of the control group (adjusted odds ratio 8.21, 95% confidence interval 2.00 to 33.67, P=0.003). Although differences in clinician rated clinical improvement between the groups failed to reach statistical significance, patients in the intervention group had more favourable subjective quality of life ratings (β=0.71, 95% confidence interval 0.26 to 1.15, P=0.002). The number of admissions to hospital and adverse events were low in both groups and did not show substantial differences. Offering modest financial incentives to patients with psychotic disorders is an effective method for improving adherence to maintenance treatment with antipsychotics. Current Controlled Trials ISRCTN77769281.
    Full-text · Article · Oct 2013 · BMJ (online)
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    ABSTRACT: Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.
    Full-text · Article · Mar 2013

Publication Stats

2k Citations
657.12 Total Impact Points

Institutions

  • 2009-2016
    • Imperial College London
      • Department of Primary Care and Public Health
      Londinium, England, United Kingdom
  • 2001-2012
    • University of Liverpool
      • Department of Clinical Sciences
      Liverpool, England, United Kingdom
  • 2002-2010
    • University of London
      Londinium, England, United Kingdom
  • 2003-2008
    • Institut for Sygdomsforebyggelse
      København, Capital Region, Denmark
  • 2001-2008
    • Queen Mary, University of London
      • • Centre for Environmental and Preventive Medicine
      • • Barts and The London School of Medicine and Dentistry
      • • Wolfson Institute of Preventive Medicine
      Londinium, England, United Kingdom
  • 2005
    • University of Bristol
      Bristol, England, United Kingdom
  • 2001-2005
    • Alder Hey Children's Healthcare Hospital
      Liverpool, England, United Kingdom