What is the quality of economic evaluations of non-drug therapies? A systematic review and critical appraisal of economic evaluations of radiotherapy for cancer.

BACKGROUND: Breast, cervical and colorectal cancers are the three most frequent cancers in women, while lung, prostate and colorectal cancers are the most frequent in men. Much attention has been given to the economic evaluation of pharmaceuticals for treatment of cancer by the National Institute for Health and Care Excellence (NICE) in the UK and similar authorities internationally, while economic analysis developed for other types of anti-cancer interventions, including radiotherapy and surgery, are less common. OBJECTIVES: Our objective was to review methods used in published cost-effectiveness studies evaluating radiotherapy for breast, cervical, colorectal, head and neck and prostate cancer, and to compare the economic evaluation methods applied with those defined in the guidelines used by the NICE technology appraisal programme. METHODS: A systematic search of seven databases (MEDLINE, EMBASE, CDSR, NHSEED, HTA, DARE, EconLit) as well as research registers, the NICE website and conference proceedings was conducted in July 2012. Only economic evaluations of radiotherapy interventions in individuals diagnosed with cancer that included quality-adjusted life-years (QALYs) or life-years (LYs) were included. Included studies were appraised on the basis of satisfying essential, preferred and UK-specific methods requirements, building on the NICE Reference Case for economic evaluations and on other methods guidelines. RESULTS: A total of 29 studies satisfied the inclusion criteria (breast 14, colorectal 2, prostate 10, cervical 0, head and neck 3). Only two studies were conducted in the UK (13 in the USA). Among essential methods criteria, the main issue was that only three (10%) of the studies used clinical-effectiveness estimates identified through systematic review of the literature. Similarly, only eight (28%) studies sourced health-related quality-of-life data directly from patients with the condition of interest. Other essential criteria (e.g. clear description of comparators, patient group indication and appropriate time horizon) were generally fulfilled, while most of the UK-specific requirements were not met. CONCLUSION: Based on this review there is a dearth of up-to-date, robust evidence on the cost effectiveness of radiotherapy in cancer suitable to support decision making in the UK. Studies selected did not fully satisfy essential method standards currently recommended by NICE.

Prioritizing investment in public health and health equity: what can commissioners do?

OBJECTIVES: To explore commissioners' views on prioritizing for investment in health. This study reviewed: methods for decision support; their relevance for prioritizing health and health equity in principle; and their adoption by decision makers in practice. METHODS: Decision makers' views were sought through semi-structured interviews and an online survey, and prioritization tools were reviewed. Interviews were held in 2008-2009 with a subsample followed up in 2009-2010. In late 2009, a national online survey was sent to 508 individuals across 146 primary care trusts (PCTs). The two phases of the interviews comprised 52 and 17 participants, respectively. Responses to the national survey were received from 138 decision makers in 95 (65%) PCTs. Prioritization tools were identified through interviews and the survey as above, a rapid review of literature and in consultation with health economists. A grounded theory approach was adopted for the qualitative interview analysis. RESULTS: Although most PCTs used a prioritization framework, few of the tools identified in this review were used by public health commissioners. This was partly a consequence of limitations of priority-setting tools in the context of public health investment, and partly a lack of relevant skills and data. Tensions in relation to developing strategies for disinvestment and in prioritizing a long-term public health agenda in a context of economic austerity were evident. CONCLUSIONS: The context for decision making appears to be more important than the deployment of specific tools and techniques. Commissioners need to recognize the limitations of priority-setting tools, but also know how to apply them to help maximize health gain and health equity over the longer term. Decision-support tools should be developed in collaboration with public health commissioners to ensure relevance and practicality of use.

Stapled haemorrhoidopexy for the treatment of haemorrhoids: a systematic review.

OBJECTIVE: This systematic review aimed to evaluate the short- and long-term safety, efficacy and costs of stapled haemorrhoidopexy (SH) compared with conventional haemorrhoidectomy. METHOD: We searched 26 electronic databases and websites for studies in any language up to July 2006. Inclusion criteria were predefined, and each stage of the review process was conducted in duplicate. RESULTS: Twenty-seven randomized controlled trials were included (n = 2279). All had some methodological flaws. Postoperatively, 19 trials (95%) reported less pain, 17 (89%) reported a shorter operating time, 14 (88%) a shorter hospital stay, and 14 (93%) a shorter convalescence time following SH. However, prolapse was significantly more common after SH (OR 3.38; 95% CI: 1.00, 11.47). In the longer term, prolapse was significantly more common after SH (OR 4.34; 95% CI: 1.67, 11.28) as was reintervention for prolapse (OR 6.78; 95% CI: 2.00, 23.00). There were no differences in the rate or type of complications. Conventional haemorrhoidectomy and SH had similar costs during the initial admission. CONCLUSION: Compared with conventional haemorrhoidectomy, SH resulted in less postoperative pain, shorter operating time, a shorter hospital stay, and a shorter convalescence, but a higher rate of prolapse and reintervention for prolapse.

Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea-hypopnoea syndrome: a systematic review and economic analysis.

OBJECTIVES: To determine the clinical effectiveness, safety and cost-effectiveness of continuous positive airway pressure (CPAP) devices for the treatment of obstructive apnoea-hypopnoea syndrome (OSAHS), compared with the best supportive care, placebo and dental devices. DATA SOURCES: The main search was of fifteen electronic databases, including MEDLINE, EMBASE and the Cochrane Library, up to November 2006. REVIEW METHODS: Randomised controlled trials (RCTs) comparing CPAP with best supportive/usual care, placebo, and dental devices in adults with a diagnosis of OSAHS were included. The primary outcomes of interest were subjective daytime sleepiness assessed by the Epworth Sleepiness Scale (ESS) and objective sleepiness assessed by the Maintenance of Wakefulness Test (MWT) and the Multiple Sleep Latency Test (MSLT). A new economic model was developed to assess incremental cost per quality-adjusted life-year (QALY). The cost-effectiveness of CPAP was compared with that of the use of dental devices and conservative management. The costs and QALYs were compared over a lifetime time horizon. Effectiveness was based on the RCT evidence on sleepiness symptoms (ESS), which was 'mapped' to utilities using individual patient data from a subset of studies. Utilities were expressed on the basis of generic HRQoL instruments [the EQ-5D (EuroQoL-5 Dimensions) in the base-case analysis]. The base-case analysis focused on a male aged 50. A series of subgroup and scenario analyses were also undertaken. RESULTS: The searches yielded 6325 citations, from which 48 relevant clinical effectiveness studies were identified, 29 of these providing data on daytime sleepiness. The majority of the included RCTs did not report using an adequate method of allocation concealment or use an intention-to-treat analysis. Only the studies using a sham CPAP comparator were double blinded. There was a statistically significant benefit with CPAP compared with control (placebo and conservative treatment/usual care) on the ESS [mean difference (MD) -2.7 points, 95% CI -3.45 to -1.96]. However, there was statistical heterogeneity, which was reduced when trials were subgrouped by severity of disease. There was also a significant benefit with CPAP compared with usual care on the MWT. There was a non-statistically significant difference between CPAP and dental devices (six trials) in the impact on daytime sleepiness (ESS) among a population with moderate symptom severity at baseline (MD -0.9, 95% CI -2.1 to 0.4). A review of five studies evaluating the cost-effectiveness of CPAP was undertaken. All existing cost-effectiveness studies had limitations; therefore a new economic model was developed, based on which it was found that, on average, CPAP was associated with higher costs and benefits than dental devices or conservative management. The incremental cost per QALY gained of CPAP was below 20,000 pounds in the base-case analysis and most alternative scenarios. There was a high probability of CPAP being more cost-effective than dental devices and conservative management for a cost-effectiveness threshold of 20,000 pounds per QALY gained. CONCLUSIONS: CPAP is an effective and cost-effective treatment for OSAHS compared with conservative/usual care and placebo in populations with moderate to severe daytime sleepiness, and there may be benefits when the disease is mild. Dental devices may be a treatment option in moderate disease but some uncertainty remains. Further research would be potentially valuable, particularly investigation of the effectiveness of CPAP for populations with mild sleepiness and further trials comparing CPAP with dental devices.

Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

OBJECTIVES: To determine the safety, clinical effectiveness and cost-effectiveness of circular stapled haemorrhoidopexy (SH) for the treatment of haemorrhoids. DATA SOURCES: Main electronic databases were searched up to July 2006. REVIEW METHODS: Randomised controlled trials (RCTs) with 20 or more participants that compared SH with any conventional haemorrhoidectomy (CH) technique in people of any age with prolapsing haemorrhoids for whom surgery is considered a relevant option, were used to evaluate clinical effectiveness. An economic model of the surgical treatment of haemorrhoids was developed. RESULTS: The clinical effectiveness review included 27 RCTs (n = 2279; 1137 SH; 1142 CH). All had some methodological flaws; only two reported recruiting patients with second, third and fourth degree haemorrhoids, and 37% reported using an appropriate method of randomisation and/or allocation concealment. In the early postoperative period 95% of trials reported less pain following SH; by day 21 the pain reported following SH and CH was minimal, with little difference between the two techniques. Significantly fewer patients had unhealed wounds at 6 weeks following SH [odds ratio (OR) 0.08, 95% confidence interval (CI) 0.03 to 0.19, p < 0.001]. Residual prolapse was more common after SH (OR 3.38, 95% CI 1.00 to 11.47, p = 0.05, nine RCTs, results of a sensitivity analysis). There was no difference between SH and CH in the incidence of bleeding or postoperative complications. SH resulted in shorter operating times, hospital stay, time to first bowel movement and return to normal activity. In the short term (between 6 weeks and a year) prolapse was more common after SH (OR 4.68, 95% CI 1.11 to 19.71, p = 0.04, six RCTs). There was no difference in the number of patients complaining of pain between SH and CH. In the long term (1 year and over), there was a significantly higher rate of prolapse after SH (OR 4.34, 95% CI 1.67 to 11.28, p = 0.003, 12 RCTs). There was no difference in the number of patients experiencing pain, or the incidence of bleeding, between SH and CH. There was no difference in the total number of reinterventions, or reinterventions for pain, bleeding or complications, between SH and CH. Significantly more reinterventions were undertaken after SH for prolapse at 12 months or longer (OR 6.78, 95% CI 2.00 to 23.00, p = 0.002, six RCTs). Overall, there was no statistically significant difference in the rate of complications between SH and CH. In the economic assessment it was found that, on average, CH dominated SH. However, CH and SH had very similar costs and quality-adjusted life-years (QALYs). On average, the difference in costs between the procedures was 19 pounds and the difference in QALY was -0.001, favouring CH, over 3 years. In terms of QALYs, the superior quality of life due to lower pain levels in the early postoperative period with SH was offset by the higher rate of symptoms over the follow-up period, compared with CH. The results are very sensitive to modelling assumptions, particularly the valuation of utility in the early postoperative period. The probabilistic sensitivity analysis showed that, at a threshold incremental cost-effectiveness ratio of 20,000-30,000 pounds per QALY, SH had a 45% probability of being cost-effective. CONCLUSIONS: SH was associated with less pain in the immediate postoperative period, but a higher rate of residual prolapse, prolapse in the longer term and reintervention for prolapse. There was no clear difference in the rate or type of complications associated with the two techniques and the absolute and relative rates of recurrence and reintervention for both are still uncertain. CH and SH had very similar costs and QALYs, the cost of the staple gun being offset by savings in hospital stay. Should the price of the gun change, the conclusions of the economic analysis may also change. Some training may be required in the use of the staple gun; this is not expected to have major resource implications. Given the currently available clinical evidence and the results of the economic analysis, the decision as to whether SH or CH is conducted could primarily be based on the priorities and preferences of the patient and surgeon. An adequately powered, good-quality RCT is required, comparing SH with CH, recruiting patients with second, third and fourth degree haemorrhoids, and having a minimum follow-up period of 5 years to ensure an adequate evaluation of the reintervention rate. Other areas for research are the effectiveness of SH in patients with fourth degree haemorrhoids and patients with co-morbid conditions, the reintervention rates for all treatments for haemorrhoids, utilities of patients up to 6 months postoperatively, the trade-offs of patients for short-term pain versus long-term outcomes, and the ability of SH to reduce hospital stays in a real practice setting.

A systematic review and economic model of switching from non-glycopeptide to glycopeptide antibiotic prophylaxis for surgery.

OBJECTIVES: To determine whether there is a level of methicillin-resistant Staphylococcus aureus (MRSA) prevalence at which a switch from non-glycopeptide to glycopeptide antibiotics for routine prophylaxis is indicated in surgical environments with a high risk of MRSA infection. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: The effectiveness review included controlled clinical trials comparing a glycopeptide with an alternative antibiotic regimen that reported effectiveness and/or adverse events. Controlled observational studies were also included for adverse events. The cost-effectiveness review included economic evaluations comparing glycopeptide prophylaxis with any alternative comparator. Study validity was assessed using standard checklists. The supplementary economic reviews assessed evaluations of non-glycopeptide antibiotic prophylaxis; evaluations where antibiotic resistance is a problem; methods of modelling resistance in infectious diseases; and developing a conceptual framework. An indicative decision analytic model was developed to compare vancomycin with a cephalosporin and with a combination of vancomycin and cephalosporin, using hip arthroplasty as an exemplar. Available data on, for example, surgical site infection (SSI) rates, MRSA rates, effectiveness of the antibiotics, were incorporated into the model. Costs were estimated from the perspective of the NHS. RESULTS: The effectiveness review included 16 randomised controlled trials, with a further three studies included for adverse events only. There was no evidence that glycopeptides were more effective than non-glycopeptides in preventing SSIs. Most of the trials did not report either the baseline prevalence of MRSA at the participating surgical units or MRSA infections as an outcome. The cost-effectiveness review included five economic evaluations of glycopeptide prophylaxis. Only one study incorporated health-related quality of life and undertook a cost-utility analysis. None of the studies was undertaken in the UK and none explicitly modelled antibiotic resistance. The supplementary reviews provided few insights into how to assess cost-effectiveness in the context of resistance. No studies modelled cost-effectiveness alongside epidemiological models of resistance. There was little information regarding the impact of surgical infections on costs post-discharge and patient quality of life. The lack of available clinical evidence limited the development of the cost-effectiveness model and meant that the modelling could only be indicative in nature. The model can be used to show the threshold baseline risk at which the use of vancomycin as prophylaxis might be cost-effective (the model did not include teicoplanin). The indicative model suggests that the baseline risk of MRSA can be fairly modest at below the national average and it would still appear cost-effective to use glycopeptide prophylaxis. The model indicates that the use of glycopeptides as a form of prophylaxis in addition to a treatment for MRSA infections is unlikely to decrease the total usage and hence reduce the risk of future problems with glycopeptide-resistant bacteria. CONCLUSIONS: There is insufficient evidence to determine whether there is a threshold prevalence of MRSA at which switching from non-glycopeptide to glycopeptide antibiotic prophylaxis might be clinically effective and cost-effective. Future research needs to address the complexities of decision-making relating to the prevention of MRSA and infection control in general. Research including evidence synthesis and decision modelling comparing a full range of interventions for infection control, which extends to other infections, not just MRSA, is needed. A long-term research programme to predict the pattern of drug resistance and its implications for future costs and health is also needed.

A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

OBJECTIVES: To review the evidence for different models of community-based respite care for frail older people and their carers, where the participant group included older people with frailty, disability, cancer or dementia. Where data permitted, subgroups of carers and care recipients, for whom respite care is particularly effective or cost-effective, were to be identified. DATA SOURCES: Major databases were searched from 1980 to March 2005. Ongoing and recently completed research databases were searched in July 2005. REVIEW METHODS: Data from relevant studies were extracted and quality assessed. The possible effects of study quality on the effectiveness data and review findings were discussed. Where sufficient clinically and statistically similar data were available, data were pooled using appropriate statistical techniques. RESULTS: Twenty-two primary studies were included. Most of the evidence came from North America, with a minority of effectiveness and economic studies based in the UK. Types of service studied included day care, host family, in-home, institutional and video respite. Effectiveness evidence suggests that the consequences of respite upon carers and care recipients are generally small, with better controlled studies finding modest benefits only for certain subgroups. However, many studies report high levels of carer satisfaction. No reliable evidence was found that respite can delay entry to residential care or that respite adversely affects care recipients. Randomisation validity in the included randomised studies was sometimes unclear. Studies reported many different outcome measures, and all of the quasi-experimental and uncontrolled studies had methodological weaknesses. The descriptions of the studies did not provide sufficient detail of the methods of data collection or analysis, and the studies failed to describe adequately the groups of study participants. In some studies, only evidence to support respite care services was presented, rather than a balanced view of the services. Only five economic evaluations of respite care services were found, all of which compared day care with usual care and only one study was undertaken in the UK. Day care tended to be associated with higher costs and either similar or a slight increase in benefits, relative to usual care. The economic evaluations were based on two randomised and three quasi-experimental studies, all of which were included in the effectiveness analysis. The majority of studies assessed health and social service use and cost, but inadequate reporting limits the potential for exploring applicability to the UK setting. No study included generic health-related quality of life measures, making cost-effectiveness comparisons with other healthcare programmes difficult. One study used sensitivity analysis to explore the robustness of the findings. CONCLUSIONS: The literature review provides some evidence that respite for carers of frail elderly people may have a small positive effect upon carers in terms of burden and mental or physical health. Carers were generally very satisfied with respite. No reliable evidence was found that respite either benefits or adversely affects care recipients, or that it delays entry to residential care. Economic evidence suggests that day care is at least as costly as usual care. Pilot studies are needed to inform full-scale studies of respite in the UK.

A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

OBJECTIVES: To assess the clinical and cost-effectiveness of oral methylphenidate hydrochloride (MPH), dexamfetaminesulphate (DEX) and atomoxetine (ATX) in children and adolescents (<18 years of age) diagnosed with attention deficit hyperactivity disorder (ADHD) (including hyperkinetic disorder). DATA SOURCES: Electronic databases covering 1999--July 2004 for MPH, 1997--July 2004 for DEX and 1981--July 2004 for ATX. REVIEW METHODS: Selected studies were assessed using modified criteria based on CRD Report No. 4. Clinical effectiveness data were reported separately for each drug and by the type of comparison. Data for MPH were also analysed separately based on whether it was administered as an immediate release (IR) or extended release (ER) formulation. For all drugs, the data were examined by dose. Data for the core outcomes of hyperactivity (using any scale), Clinical Global Impression [as a proxy of quality of life (QoL)] and adverse events were reported. For crossover studies, the mean and standard deviation (SD) for each outcome were data extracted for end of trial data (i.e. baseline data were not considered). For parallel studies, change scores were reported where given, otherwise means and SDs were presented for end of trial data. In addition, mean differences with 95% confidence intervals were calculated for each study. For adverse events, self-ratings were reported when used, otherwise, parent reports were utilised. Percentages of participants reporting adverse events were used to calculate numbers of events in each treatment arm. All the clinical effectiveness data and economic evaluations (including accompanying models) included in the company submissions were assessed. A new model was developed to assess the cost-effectiveness of the alternative treatments in terms of cost per quality-adjusted life-year. To achieve this, a mixed treatment comparison model was used to estimate the differential mean response rates. Monte Carlo simulation was used to reflect uncertainty in the cost-effectiveness results. RESULTS: In total, 65 papers met the inclusion criteria. The results suggest that MPH and DEX are effective at reducing hyperactivity and improving QoL (as determined by Clinical Global Impression) in children, although the reliability of the MPH study results is not known and there were only a small number of DEX studies. There was consistent evidence that ATX was superior to placebo for hyperactivity and Clinical Global Impression. Studies on ATX more often reported the study methodology well, and the results were likely to be reliable. Very few studies made direct head-to-head comparisons between the drugs or examined a non-drug intervention in combination with MPH, DEX or ATX. Adequate and informative data regarding the potential adverse effects of the drugs were also lacking. The results of the economic evaluation clearly identified an optimal treatment strategy of DEX first-line, followed by IR-MPH for treatment failures, followed by ATX for repeat treatment failures. Where DEX is unsuitable as a first-line therapy, the optimal strategy is IR-MPH first-line, followed by DEX and then ATX. For patients contraindicated to stimulants, ATX is preferred to no treatment. For patients in whom a midday dose of medication is unworkable, ER-MPH is preferred to ATX, and ER-MPH12 appears more cost-effective than ER-MPH8. As identified in the clinical effectiveness review, the reporting of studies was poor, therefore this should be borne in mind when interpreting the model results. CONCLUSIONS: Drug therapy seems to be superior to no drug therapy, no significant differences between the various drugs in terms of efficacy or side effects were found, mainly owing to lack of evidence, and the additional benefits from behavioural therapy (in combination with drug therapy) are uncertain. Given the lack of evidence for any differences in effectiveness between the drugs, the economic model tended to be driven by drug costs, which differed considerably. Future trials examining MPH, DEX and ATX should include the assessment of tolerability and safety as a priority. Longer term follow-up of individuals participating in trials could further inform policy makers and health professionals. Such data could potentially distinguish between these drugs in a clinically useful way. In addition, research examining whether somatic complaints are actually related to drug treatment or to the disorder itself would be informative.

Implementing the findings of health technology assessments. If the CAT got out of the bag, can the TAIL wag the dog?

OBJECTIVE: To explore whether more could be done to increase the implementation of health technology assessment (HTA) findings. METHODS: A literature review was undertaken to identify the main barriers to implementation, the mechanisms that influence the diffusion and use of health technologies, and evidence of the successful implementation of findings. RESULTS: Numerous barriers to the implementation of HTA findings exist at the public policy, healthcare professional, and general public levels. Several mechanisms for influencing the use of health technologies exist, and there are some examples of findings being implemented through these mechanisms. However, there are also concerns about the aggressive implementation of findings. A balanced approach to the implementation of HTAs is required. CONCLUSION: The main elements of a successful implementation strategy are: a) defining a clear policy question; b) defining a clear research question; c) making recommendations commensurate with the evidence; d) identifying the implementation mechanism; e) paying attention to incentives and disincentives; and f) clarifying the roles and responsibilities of the various parties. Further research is also required into several aspects of implementation.

A peptidergic circuit for reproductive behavior.

A projection from the medial amygdaloid nucleus to the hippocampus and septum probably uses vasopressin as a transmitter. The nucleus synthesizes vasopressin and activation of the nucleus has a hippocampal effect that is completely blocked by a vasopressin antagonist. The afferent and efferent projections of this peptidergic nucleus suggest a possible role for the system in sexual behavior. Stimulation of the nucleus inhibits the output of the hippocampus in both genders and reorganizes behavior for a period of 15-20 min. In males, the effect of peptidergic activation is to produce a behavior that resembles the post-ejaculatory interval in coitus. This state is characterized by an EEG that resembles slow-wave sleep and by ultrasonic vocalizations at a characteristic frequency of 22 kHz. Castration in either gender causes depletion of the peptide from the target fields and eliminates the peptidergic signal in the hippocampus after about 15 weeks. The effects of castration in males can be reversed by testosterone replacement. The fluctuation of estrogen levels in rat plasma during the estrus cycle happens too quickly to impact the peptidergic system, and thus there is no significant change in the strength of the peptidergic signal among the proestrus, estrus, metestrus and diestrus stages. This fact permits study of the physiology of the system without concern for stage of estrus but does not permit conclusions regarding its function in females.