Precision Dosing Priority Criteria: Drug, Disease, and Patient Population Variables.

The administered dose of a drug modulates whether patients will experience optimal effectiveness, toxicity including death, or no effect at all. Dosing is particularly important for diseases and/or drugs where the drug can decrease severe morbidity or prolong life. Likewise, dosing is important where the drug can cause death or severe morbidity. Since we believe there are many examples where more precise dosing could benefit patients, it is worthwhile to consider how to prioritize drug-disease targets. One key consideration is the quality of information available from which more precise dosing recommendations can be constructed. When a new more precise dosing scheme is created and differs significantly from the approved label, it is important to consider the level of proof necessary to either change the label and/or change clinical practice. The cost and effort needed to provide this proof should also be considered in prioritizing drug-disease precision dosing targets. Although precision dosing is being promoted and has great promise, it is underutilized in many drugs and disease states. Therefore, we believe it is important to consider how more precise dosing is going to be delivered to high priority patients in a timely manner. If better dosing schemes do not change clinical practice resulting in better patient outcomes, then what is the use? This review paper discusses variables to consider when prioritizing precision dosing candidates while highlighting key examples of precision dosing that have been successfully used to improve patient care.

Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Utility of Model-Based Approaches for Informing Dosing Recommendations in Specific Populations: Report From the Public AAPS Workshop.

This report summarizes the discussions and recommendations of the workshop titled "Specific Population Drug Dosing Recommendations: Shifting from Clinical Studies to Predict and Confirm," which preceded the 2015 American Association of Pharmaceutical Scientists annual meeting. Participants from the pharmaceutical industry, regulatory agencies (FDA and EMA), and academia discussed the current state, challenges, opportunities, and future direction of utilizing model-based approaches to inform dosing recommendations in specific populations.

Assessment of serum 25-hydroxyvitamin D concentrations of beef cows and calves across seasons and geographical locations.

Vitamin D is critical for the growth and development of calves and positively contributes to immune function of cattle. Serum 25-hydroxyvitamin D (25(OH)D) concentrations above 20 ng/mL have traditionally been considered adequate for growth and development of cattle, but recent evidence has indicated that concentrations below 30 ng/mL are insufficient for immunity. Because little information is available regarding vitamin D status of beef cattle, the objective of this study was to evaluate vitamin D status of beef cow-calf herds on pasture as affected by season and location. Serum samples were collected from 43 cow-calf pairs plus an additional 54 calves in herds located in Florida, Idaho, and Minnesota in the spring calving season. Samples were collected again over the summer months from animals in the Florida and Minnesota herds. Effects of subcutaneous injection of vitamins A, D, and E also were investigated in a subset of calves from the Idaho herd. All cows sampled had serum 25(OH)D concentrations above 30 ng/mL at the time of calving in the spring. The average serum 25(OH)D concentrations of cows rose from near 60 ng/mL in the spring to 75 ng/mL in the summer ( < 0.001). Most calves, on the other hand, had serum 25(OH)D concentrations below 20 ng/mL. The calves in the Florida and Minnesota herds similarly rose from averages of 10 to 15 ng/mL at birth to near 50 ng/mL by the end of summer. Serum 25(OH)D of severely deficient calves increased from 3 ng/mL in nonsupplemented calves to 11 ng/mL at 48 h after birth if given a bolus supplementation of 40,000 IU of vitamin D via subcutaneous injection of a vitamin A, D, and E supplement at birth ( < 0.001). Vitamin D supplementation of cows late in pregnancy has been shown to increase serum 25(OH)D of calves; however, beef cattle generally receive very little supplemental vitamin D, as was the case for the cows studied here. The lower serum 25(OH)D of cows in spring compared with summer and the prevalence of vitamin D deficiency of calves observed here indicate that increased vitamin D supplementation of cows over the winter months or vitamin D supplementation of newborn calves would be beneficial.

Developments in life cycle assessment applied to evaluate the environmental performance of construction and demolition wastes.

This paper provides a review of the literature that applies the life cycle assessment (LCA) methodology to the assessment of the environmental performance of the life cycle of construction and demolition waste (CDW) management systems. This article is focused on generating a general mapping of the literature and on identifying the best practices in compliance with LCA framework and proposing directions for future LCA studies in this field. The temporal evolution of the research in this field and the aim of the studies have grown in parallel with the legal framework related to waste and energy efficiency of buildings. Most studies have been published in Europe, followed by USA. Asia and Australia, being at an incipient application stage to the rest of the world. Topics related to "LCA of buildings, including their EoL" and "LCA of general CDW management strategies" are the most frequently analysed, followed by "LCA of EoL of construction elements" and "LCA of natural material vs recycled material". Regarding the strategies, recycling off-site and incineration, both combined with landfill for the rejected fractions, are the most commonly applied. Re-use or recycling on-site is the strategy least applied. The key aspect when LCA is applied to evaluate CDW management systems is the need to normalise which processes to include in the system boundary and the functional unit, the use of inventory data adapted to the context of the case study and the definition of a common set of appropriate impact assessment categories. Also, it is important to obtain results disaggregated by unit processes. This will allow the comparison between case studies.

Factors influencing the adoption of self-management solutions: an interpretive synthesis of the literature on stakeholder experiences.

BACKGROUND: In a research context, self-management solutions, which may range from simple book diaries to complex telehealth packages, designed to facilitate patients in managing their long-term conditions, have often shown cost-effectiveness, but their implementation in practice has frequently been challenging. METHODS: We conducted an interpretive qualitative synthesis of relevant articles identified through systematic searches of bibliographic databases in July 2014. We searched PubMed (Medline/NLM), Web of Science, LISTA (EBSCO), CINAHL, Embase and PsycINFO. Coding and analysis was inductive, using the framework method to code and to categorise themes. We took a sensemaking approach to the interpretation of findings. RESULTS: Fifty-eight articles were selected for synthesis. Results showed that during adoption, factors identified as facilitators by some were experienced as barriers by others, and facilitators could change to barriers for the same adopter, depending on how adopters rationalise the solutions within their context when making decisions about (retaining) adoption. Sometimes, when adopters saw and experienced benefits of a solution, they continued using the solution but changed their minds when they could no longer see the benefits. Thus, adopters placed a positive value on the solution if they could constructively rationalise it (which increased adoption) and attached a negative rationale (decreasing adoption) if the solution did not meet their expectations. Key factors that influenced the way adopters rationalised the solutions consisted of costs and the added value of the solution to them and moral, social, motivational and cultural factors. CONCLUSIONS: Considering 'barriers' and 'facilitators' for implementation may be too simplistic. Implementers could instead iteratively re-evaluate how potential facilitators and barriers are being experienced by adopters throughout the implementation process, to help adopters to retain constructive evaluations of the solution. Implementers need to pay attention to factors including (a) cost: how much resource will the intervention cost the patient or professional; (b) moral: to what extent will people adhere because they want to be 'good' patients and professionals; (c) social: the expectations of patients and professionals regarding the interactive support they will receive; (d) motivational: motivations to engage with the intervention and (e) cultural: how patients and professionals learn and integrate new skills into their daily routines, practices and cultures.

Incidence, management and outcomes of the first cfr-mediated linezolid-resistant Staphylococcus epidermidis outbreak in a tertiary referral centre in the Republic of Ireland.

AIM: To report the first Irish outbreak of cfr-mediated linezolid-resistant Staphylococcus epidermidis. METHODS: Linezolid-resistant S. epidermidis isolated at University Hospital Limerick from four blood cultures, one wound and four screening swabs (from nine patients) between April and June 2013 were characterized by pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing. Antibiotic susceptibilities were determined according to the guidelines of the British Society for Antimicrobial Chemotherapy. The outbreak was controlled through prohibiting prescription and use of linezolid, adherence to infection prevention and control practices, enhanced environmental cleaning, isolation of affected patients, and hospital-wide education programmes. FINDINGS: PFGE showed that all nine isolates represented a single clonal strain. MLST showed that they belonged to ST2, and SCCmec typing showed that they encoded a variant of SCCmecIII. All nine isolates were cfr positive, and eight isolates were positive for the G2576T 23S rRNA mutation commonly associated with linezolid resistance. Isolates exhibited multiple antibiotic resistances (i.e. linezolid, gentamicin, methicillin, clindamycin, ciprofloxacin, fusidic acid and rifampicin). The adopted infection prevention intervention was effective, and the outbreak was limited to the affected intensive care unit. CONCLUSIONS: This is the first documented outbreak of cfr-mediated linezolid-resistant S. epidermidis in the Republic of Ireland. Despite this, and due to existing outbreak management protocols, the responsible micro-organism and source were identified efficiently. However, it became apparent that staff knowledge of antimicrobial susceptibilities and appropriate hygiene practices were suboptimal at the time of the outbreak, and that educational interventions (and re-inforcement) are necessary to avoid occurrence of antimicrobial resistance and outbreaks such as reported here.

Long-term cost-effectiveness analysis of endovascular versus open repair for abdominal aortic aneurysm based on four randomized clinical trials.

BACKGROUND: A number of published economic evaluations of elective endovascular aneurysm repair (EVAR) versus open repair for abdominal aortic aneurysm (AAA) have come to differing conclusions about whether EVAR is cost-effective. This paper reviews the current evidence base and presents up-to-date cost-effectiveness analyses in the light of results of four randomized clinical trials: EVAR-1, DREAM, OVER and ACE. METHODS: Markov models were used to estimate lifetime costs from a UK perspective and quality-adjusted life-years (QALYs) based on the results of each of the four trials. The outcomes included in the model were: procedure costs, surveillance costs, reintervention costs, health-related quality of life, aneurysm-related mortality and other-cause mortality. Alternative scenarios about complications, reinterventions and deaths beyond the trial were explored. RESULTS: Models based on the results of the EVAR-1, DREAM or ACE trials did not find EVAR to be cost-effective at thresholds used in the UK (up to £30,000 per QALY). EVAR seemed cost-effective according to models based on the OVER trial. These results seemed robust to alternative model scenarios about events beyond the trial intervals. CONCLUSION: These analyses did not find that EVAR is cost-effective compared with open repair in the long term in trials conducted in European centres. EVAR did appear to be cost-effective based on the OVER trial, conducted in the USA. Caution must be exercised when transferring the results of economic evaluations from one country to another.

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness.

BACKGROUND: Small abdominal aortic aneurysms (AAAs; 3.0-5.4 cm in diameter) are usually asymptomatic and managed by regular ultrasound surveillance until they grow to a diameter threshold (commonly 5.5 cm) at which surgical intervention is considered. The choice of appropriate surveillance intervals is governed by the growth and rupture rates of small AAAs, as well as their relative cost-effectiveness. OBJECTIVES: The aim of this series of studies was to inform the evidence base for small AAA surveillance strategies. This was achieved by literature review, collation and analysis of individual patient data, a focus group and health economic modelling. DATA SOURCES: We undertook systematic literature reviews of growth rates and rupture rates of small AAAs. The databases MEDLINE, EMBASE on OvidSP, Cochrane Central Register of Controlled Trials 2009 Issue 4, ClinicalTrials.gov, and controlled-trials.com were searched from inception up until the end of 2009. We also obtained individual data on 15,475 patients from 18 surveillance studies. REVIEW METHODS: Systematic reviews of publications identified 15 studies providing small AAA growth rates, and 14 studies with small AAA rupture rates, up to December 2009 (later updated to September 2012). We developed statistical methods to analyse individual surveillance data, including the effects of patient characteristics, to inform the choice of surveillance intervals and provide inputs for health economic modelling. We updated an existing health economic model of AAA screening to address the cost-effectiveness of different surveillance intervals. RESULTS: In the literature reviews, the mean growth rate was 2.3 mm/year and the reported rupture rates varied between 0 and 1.6 ruptures per 100 person-years. Growth rates increased markedly with aneurysm diameter, but insufficient detail was available to guide surveillance intervals. Based on individual surveillance data, for each 0.5-cm increase in AAA diameter, growth rates increased by about 0.5 mm/year and rupture rates doubled. To control the risk of exceeding 5.5 cm to below 10% in men, on average a 7-year surveillance interval is sufficient for a 3.0-cm aneurysm, whereas an 8-month interval is necessary for a 5.0-cm aneurysm. To control the risk of rupture to below 1%, the corresponding estimated surveillance intervals are 9 years and 17 months. Average growth rates were higher in smokers (by 0.35 mm/year) and lower in patients with diabetes (by 0.51 mm/year). Rupture rates were almost fourfold higher in women than men, doubled in current smokers and increased with higher blood pressure. Increasing the surveillance interval from 1 to 2 years for the smallest aneurysms (3.0-4.4 cm) decreased costs and led to a positive net benefit. For the larger aneurysms (4.5-5.4 cm), increasing surveillance intervals from 3 to 6 months led to equivalent cost-effectiveness. LIMITATIONS: There were no clear reasons why the growth rates varied substantially between studies. Uniform diagnostic criteria for rupture were not available. The long-term cost-effectiveness results may be susceptible to the modelling assumptions made. CONCLUSIONS: Surveillance intervals of several years are clinically acceptable for men with AAAs in the range 3.0-4.0 cm. Intervals of around 1 year are suitable for 4.0-4.9-cm AAAs, whereas intervals of 6 months would be acceptable for 5.0-5.4-cm AAAs. These intervals are longer than those currently employed in the UK AAA screening programmes. Lengthening surveillance intervals for the smallest aneurysms was also shown to be cost-effective. Future work should focus on optimising surveillance intervals for women, studying whether or not the threshold for surgery should depend on patient characteristics, evaluating the usefulness of surveillance for those with aortic diameters of 2.5-2.9 cm, and developing interventions that may reduce the growth or rupture rates of small AAAs. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The UK EndoVascular Aneurysm Repair (EVAR) trials: randomised trials of EVAR versus standard therapy.

OBJECTIVE: To assess the efficacy of endovascular aneurysm repair (EVAR) against standard alternative management in patients with large abdominal aortic aneurysm (AAA). DESIGN: Two national, multicentre randomised trials - EVAR trials 1 and 2. SETTING: Patients were recruited from 38 out of 41 eligible UK hospitals. PARTICIPANTS: Men and women aged at least 60 years, with an AAA measuring at least 5.5 cm on a computerised tomography scan that was regarded as anatomically suitable for EVAR, were assessed for fitness for open repair. Patients considered fit were randomised to EVAR or open repair in EVAR trial 1 and patients considered unfit were randomised to EVAR or no intervention in EVAR trial 2. INTERVENTIONS: EVAR, open repair or no intervention. MAIN OUTCOME MEASURES: The primary outcome was mortality (operative, all-cause and AAA related). Patients were flagged at the UK Office for National Statistics with centrally coded death certificates assessed by an Endpoints Committee. Power calculations based upon mortality indicated that 900 and 280 patients were required for EVAR trials 1 and 2, respectively. Secondary outcomes were graft-related complications and reinterventions, adverse events, renal function, health-related quality of life and costs. Cost-effectiveness analyses were performed for both trials. RESULTS: Recruitment occurred between 1 September 1999 and 31 August 2004, with targets exceeded in both trials: 1252 randomised into EVAR trial 1 (626 to EVAR) and 404 randomised into EVAR trial 2 (197 to EVAR). Follow-up closed in December 2009 with very little loss to follow-up (1%). In EVAR trial 1, 30-day operative mortalities were 1.8% and 4.3% in the EVAR and open-repair groups, respectively: adjusted odds ratio 0.39 [95% confidence interval (CI) 0.18 to 0.87], p = 0.02. During a total of 6904 person-years of follow-up, 524 deaths occurred (76 AAA related). Overall, there was no significant difference between the groups in terms of all-cause mortality: adjusted hazard ratio (HR) 1.03 (95% CI 0.86 to 1.23), p = 0.72. The EVAR group did demonstrate an early advantage in terms of AAA-related mortality, which was sustained for the first few years, but lost by the end of the study, primarily due to fatal endograft ruptures: adjusted HR 0.92 (95% CI 0.57 to 1.49), p = 0.73. The EVAR procedure was more expensive than open repair (mean difference £1177) and not found to be cost-effective, but the model was sensitive to alternative assumptions. In EVAR trial 2, during a total of 1413 person-years of follow-up, a total of 305 deaths occurred (78 AAA related). The 30-day operative mortality was 7.3% in the EVAR group. However, this group later demonstrated a significant advantage in terms of AAA-related mortality, but this became apparent only after 4 years: overall adjusted HR 0.53 (95% CI 0.32 to 0.89), p = 0.02. Sadly, this advantage did not result in any benefit in terms of all-cause mortality: adjusted HR 0.99 (95% CI 0.78 to 1.27), p = 0.97. Overall, EVAR was more expensive than no intervention (mean difference £10,222) and not found to be cost-effective. CONCLUSIONS: EVAR offers a clear operative mortality benefit over open repair in patients fit for both procedures, but this early benefit is not translated into a long-term survival advantage. Among patients unfit for open repair, EVAR is associated with a significant long-term reduction in AAA-related mortality but this does not appear to influence all-cause mortality. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 55703451. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 9. See the HTA programme website for further project information.

The management of ruptured abdominal aortic aneurysms: screening for abdominal aortic aneurysm and incidence of rupture.

Twenty-five years have passed since the first randomised controlled trial began its recruitment for screening for abdominal aortic aneurysm (AAA) in men aged 65 and above. Since this and other randomised trials, all launched in the late 80s and 90s of the last century, the epidemiologic profile of abdominal aortic aneurysm may have changed. The trials reported an AAA prevalence in the range of 4-7% for men aged 65 years or more. AAA-related mortality was significantly improved by screening, and after 13 years, the largest trial showed a benefit for all-cause mortality. Screening also was shown to be cost-effective. Today, there are studies showing a substantial decrease of AAA prevalence to sometimes less than 2% in men aged ≥ 65 years and there is evidence that the incidence of ruptured aneurysm and mortality from AAA is also declining. This decline preceded the implementation of screening programmes but may be due to a change in risk factor management. The prevalence of smoking has decreased and there has been improvement in the control of hypertension and a rising use of statins for cardiovascular risk prevention. Additionally, there is a shift of the burden to the older age group of ≥ 75 years. Such radical changes may influence screening policy and it is worth reflecting on the optimum age of screening - it might be better to screen at ages >65 years - or rescreening 5 to 10 years after the first screen.

Media coverage and public reaction to a celebrity cancer diagnosis.

BACKGROUND: Celebrity diagnoses can have important effects on public behaviour. UK television celebrity Jade Goody died from cervical cancer in 2009. We investigated the impact of her illness on media coverage of cervical cancer prevention, health information seeking behaviour and cervical screening coverage. METHODS: National UK newspaper articles containing the words 'Jade Goody' and 'cancer' were examined for public health messages. Google Insights for Search was used to quantify Internet searches as a measure of public health information seeking. Cervical screening coverage data were examined for temporal associations with this story. RESULTS: Of 1203 articles, 116 (9.6%) included a clear public health message. The majority highlighted screening (8.2%). Fewer articles provided advice about vaccination (3.0%), number of sexual partners (1.4%), smoking (0.6%) and condom use (0.4%). Key events were associated with increased Internet searches for 'cervical cancer' and 'smear test', although only weakly with searches for 'HPV'. Cervical screening coverage increased during this period. CONCLUSION: Increased public interest in disease prevention can follow a celebrity diagnosis. Although media coverage sometimes included public health information, articles typically focused on secondary instead of primary prevention. There is further potential to maximize the public health benefit of future celebrity diagnoses.

Fatal and non-fatal fire injuries in England 1995-2004: time trends and inequalities by age, sex and area deprivation.

AIM: To examine time trends and deprivation gradients in fire-related deaths and injuries. METHODS: A cross-sectional study and time trend analysis using data on fire casualties in England between 1995 and 2004 obtained from the Department for Communities and Local Government. Injury rates were calculated assuming a Poisson distribution. Incidence rate ratios (IRRs) were calculated to compare changes in deprivation gradients over time. RESULTS: There were significant reductions in fatal and non-fatal fire injuries in children (fatal injuries IRR chi(2)(1) = 11.18, P < 0.001; non-fatal injuries IRR chi(2)(2) = 61.44, P < 0.001), adults (fatal injuries IRR chi(2)(1) = 15.99, P < 0.001; non-fatal injuries IRR chi(2)(2) = 183.25, P < 0.001) and older people (fatal injuries IRR chi(2)(1) = 56.88, P < 0.001; non-fatal injuries IRR chi(2)(2) = 54.09, P < 0.001) between 1995 and 2004. Adult and child fire deaths were most commonly caused by smokers' materials (e.g. cigarettes, cigars and tobacco), and cigarette lighters and matches, respectively. Cooking appliances caused most non-fatal fire injuries. Injury rates increased with increasing levels of deprivation and deprivation gradients did not change over 10 years. CONCLUSIONS: Fire prevention interventions should promote the safe use of cooking and heating appliances and the responsible use of smokers' materials, lighters and matches, and should target those at greater risk of fire, including the socially disadvantaged.

Antibiotic options for treating community-acquired MRSA.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections are developing as a prominent public-health threat. While minor CA-MRSA infections are treatable in an out-patient setting, the pharmacotherapeutic options for oral therapies are dwindling as resistance continues to rise in general and levels of susceptibility vary geographically. In many instances, fluoroquinolones and clindamycin are not reasonable empiric treatment choices, leaving physicians with trimethoprim-sulfamethoxazole, doxycycline or linezolid as viable options, depending on patient-specific circumstances and the impact of potential adverse effects. Resistance to intravenous options remains low and attention should be focused on the site and severity of infection when choosing antibiotic/intravenous immunoglobulin treatment. Clinical trials directly comparing antibiotic options in both out-patient and in-patient settings are needed to enhance recommendations for empiric therapy algorithms.

Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

OBJECTIVES: To review UK guidelines regarding the use of financial incentives for healthcare professionals to become involved in clinical trials, and to survey perceptions and current practice. DATA SOURCES: Electronic databases were searched from inception to June 2006. Interviews were held with NHS healthcare professionals, research managers from the pharmaceutical industry and members of the public. REVIEW METHODS: From the searches, 634 identified studies were assessed for inclusion in the systematic review, but only three met the criteria for data extraction. Fifty-eight individuals were interviewed: 38 chief investigators, six non-research active clinicians, eight public and six pharmaceutical managers. Investigators were selected from those funded by the HTA Programme, the other by 'snowballing' and personal contact. RESULTS: The evidence from the literature was limited and inconclusive. In UK guidelines, the issues around payments to clinicians or patients were implied rather than stated, usually linked to discussion of conflict of interest and disclosure of any such conflicts. Developments in NHS research governance had led to increased transparency in all payments for research participation and for payments to be made to NHS Trusts rather than individual clinicians. While reimbursement of costs incurred by research was strongly supported by the interviewees, payments to incentivise recruitment were not. A code of practice was suggested for payments in publicly funded trials, which was closely linked to the principles of Good Clinical Practice in research. Factors such as interest in the topic, scope for patient benefit and good communication were considered more important than payment. Interviews with the general public indicated low levels of awareness of the existence of payments to clinicians linked to patient recruitment in trials, and unanimous support for full disclosure. Interviews with managers in the pharmaceutical industry showed greater familiarity with payments for research involvement. GPs were seen as the only group for whom scope existed for individual payments. Concerns were expressed by the pharmaceutical company interviewees at the rising cost of research and unnecessary bureaucracy. CONCLUSIONS: The ethical stances outlined in Good Clinical Practice in research were widely endorsed by the three groups interviewed. These allow reasonable payments to clinicians, subject to disclosure of any possible conflicts of interest. The potential for incentivising clinicians to recruit was limited as any payments should be based on the cost of inputs and should not be made to individuals but to their host organisation. NHS professionals were concerned that payments could damage the quality of research and also considered full disclosure to patients as challenging. Patients and members of the public favoured full disclosure and payment of expenses to patients involved in research. Pharmaceutical company interviewees viewed payment to the NHS for all research activities as normal and highly regulated. They complained that the prices charged were high and so variable that they required benchmarking. Considerable scope exists for compiling data on the factors that help and hinder the progress of clinical trials and also for experimenting with different incentives to encourage involvement in clinical research. Further research should focus on improved reporting of those organisational aspects of trials that are known to affect recruitment; retrospective analysis of the factors associated with different levels of recruitment to RCTs; prospective comparative research on trial recruitment; qualitative research on participants' experiences of being involved in different kinds of trials, and proposals to include within trials experiments with payments methods.

Leveraging prior quantitative knowledge to guide drug development decisions and regulatory science recommendations: impact of FDA pharmacometrics during 2004-2006.

The End-of-Phase 2A meetings are proposed to identify opportunities to make innovative medical products available sooner and to increase the quality of drug applications through early meetings between sponsors and the FDA. This article summarizes the overall experience across 11 pilot End-of-Phase 2A meetings since 2004. Four case studies are presented in more detail to demonstrate the various issues and methods encountered at these meetings. Overall, industry and FDA scientists ranked these meetings to be "very helpful" (average score of 4 on a scale of 1 to 5). In almost all the instances the sponsors changed their drug development plans subsequent to these extensive quantitative analyses-based meetings. A draft Guidance is being developed to be issued in 2008, and we hope this initiative will be resourced by then.

Modelling the long-term cost-effectiveness of endovascular or open repair for abdominal aortic aneurysm.

BACKGROUND: Recent randomized trials have shown that endovascular abdominal aortic aneurysm repair (EVAR) has a 3 per cent aneurysm-related survival benefit in patients fit for open surgery, but it also has uncertain long-term outcomes and higher costs. This study assessed the cost-effectiveness of EVAR. METHODS: A decision model was constructed to estimate the lifetime costs and quality-adjusted life years (QALYs) with EVAR and open repair in men aged 74 years. The model includes the risks of death from aneurysm, other cardiovascular and non-cardiovascular causes, secondary reinterventions and non-fatal cardiovascular events. Data were taken largely from the EVAR trial 1 and supplemented from other sources. RESULTS: Under the base-case (primary) assumptions, EVAR cost 3800 pounds sterling (95 per cent confidence interval (c.i.) 2400 pounds sterling to 5200 pounds sterling) more per patient than open repair but produced fewer lifetime QALYs (mean -0.020 (95 per cent c.i. -0.189 to 0.165)). These results were sensitive to alternative model assumptions. CONCLUSION: EVAR is unlikely to be cost-effective on the basis of existing devices, costs and evidence, but there remains considerable uncertainty.