Economic evaluations of homeopathy: a review

Transcription

1 Eur J Health Econ DOI /s ORIGINAL PAPER Economic evaluations of : a review Petter Viksveen Zofia Dymitr Steven Simoens Received: 2 July 2012 / Accepted: 28 January 2013 Ó Springer-Verlag Berlin Heidelberg 2013 Abstract Context Economic evaluations of commonly used complementary and alternative medicine (CAM) therapies such as are needed to contribute to the evidence base on which policy makers, clinicians, health-care payers, as well as patients base their health-care decisions in an era of constrained resources. Objectives To review and assess existing economic evaluations of. Methods Literature search was made to retrieve relevant publications using AMED, the Cochrane Library, CRD (DARE, NHS EED, HTA), EMBASE, MEDLINE, and the journal Homeopathy (former British Homoeopathic Journal). A hand search of relevant publications was carried out. Homeopathy researchers were contacted. Identified publications were independently assessed by two authors. Results Fifteen relevant articles reported on 14 economic evaluations of. Thirteen studies reported numbers of patients: a total of 3,500 patients received homeopathic treatment (median 97, interquartile range ), and 10 studies reported on control group participants (median 57, IQR ). Eight out of 14 studies P. Viksveen School of Health and Related Research, University of Sheffield, Sheffield, UK P. Viksveen (&) Lindeveien 55, 4314 Sandnes, Norway p.viksveen@sheffield.ac.uk; homeopat@ .com Z. Dymitr 2 St Helen s Road, Dorchester, UK S. Simoens Research Centre for Pharmaceutical Care and Pharmaco-economics, KU Leuven, Leuven, Belgium found improvements in patients health together with cost savings. Four studies found that improvements in patients were at least as good as in control group patients, at comparable costs. Two studies found improvements similar to conventional treatment, but at higher costs. Studies were highly heterogeneous and had several methodological weaknesses. Conclusions Although the identified evidence of the costs and potential benefits of seemed promising, studies were highly heterogeneous and had several methodological weaknesses. It is therefore not possible to draw firm conclusions based on existing economic evaluations of. Recommendations for future research are presented. Keywords Complementary and alternative medicine Economic evaluations Homeopathy Cost-effectiveness JEL Classification C18 Methodological Issues: General I10 General I11 Analysis of Health Care Markets I12 Health Production I13 Health Insurance, Public and Private I15 Health and Economic Development Introduction The use of complementary and alternative medicine (CAM) in the general population varies from 5 to 75 % (median 23 %), according to a recently published systematic review including ten countries (Austria, Denmark, Germany, Italy, Switzerland, United Kingdom, Canada, United States, Australia and South Korea) [1]. A uniform, internationally agreed definition of CAM is lacking [1]. However, the World Health Organization (WHO) has

2 P. Viksveen et al. defined CAM as: a broad set of health care practices that are not part of a country s own tradition, or not integrated into its dominant health care system (p. 7) [2]. Homeopathy was found to be one of the most commonly used CAM therapies, particularly in Europe. Homeopathy is based on the principle of similars, where a range of low to highly diluted substances that are known to cause certain symptoms in healthy individuals are used to treat the same symptoms in persons who are ill [3]. So-called classical or individualised involves the use of a single homeopathic remedy adapted to each individual person. Non-classical forms of include the use of either several homeopathically prepared products at the same time, the same single homeopathic remedy for all patients, or so-called complex remedies where a product consists of a combination of various substances. A number of systematic reviews have tried to summarise either the evidence base of overall or in a particular area. Three reviews of systematic reviews have been published [4 6]. The first review identified positive but not convincing evidence of the effectiveness of in most trials [4]. A second review [5] concluded that collectively the identified studies: failed to provide strong evidence in favor of (p. 577). The authors of the third review [6] stated: Taking internal and external validity criteria into account, effectiveness of can be supported by clinical evidence and professional and adequate application be regarded as safe and Reliable statements of cost-effectiveness are not available at the moment (p. 19). In summary, the overall evidence for the effectiveness and cost-effectiveness of seems uncertain. The main cost involved in homeopathic treatment is the cost of the consultation with the homeopath, with a first consultation often lasting at least 1 h and a follow-up consultation lasting 20 min or more. Costs of homeopathic medicinal products are lower than those of most conventional drugs. The costs that can be considered when evaluating homeopathic treatment include direct costs (e.g. practitioner fees and costs of homeopathic medicines), nonmedical costs (e.g. transportation) and indirect costs (e.g. productivity loss associated with work absence or reduced productivity at work). Cost-effectiveness in health care is of major concern to individuals, employers, national governments and society at large in an era of constrained resources. Claims have been made stating that complementary and alternative medicine (CAM) in general and in particular are cost-effective treatment modalities [7, 8]. The aim of this publication is to assess economic evaluations of homeopathic treatment by reviewing the results and methodological quality of economic evaluations of published to date. The authors of a health technology assessment published in 2006 identified only three studies assessing costs in combination with quality of life measures and concluded that reliable documentation of the cost-effectiveness was not currently available [6]. We add to the existing literature by providing a more complete review including a larger number of identified studies and offering a more thorough description of existing research evidence. The relevance of the findings is discussed and gaps in the evidence base are identified. Methodology A literature search was carried out in February 2011 and updated in April 2012, identified through AMED, the Cochrane Library, EMBASE and MEDLINE databases, as well as a search of one of the major research journals, Homeopathy (former British Homeopathic Journal). Moreover, a search of the Centre for Reviews and Dissemination databases (DARE, NHR EED, HTA) was carried out in July 2011 and updated in April Database searches were made for variations of the words and cost, using the Boolean operator AND and wildcard symbols as appropriate for each database. The journal Homeopathy was searched for the word cost. All identified titles were considered and all articles considered relevant were included in the. No time or language limitations were set. The following inclusion/exclusion criteria were used: reports of economic evaluations of used in treatment of humans. An economic evaluation was defined as a study contrasting an intervention with a comparator in terms of both costs and consequences [9]. The intervention was homeopathic treatment. Studies assessing CAM treatment but not specifying results for were excluded. The comparator could range from do nothing or placebo, to conventional drug treatment or other health intervention. Studies assessing results from before to after homeopathic treatment were also included, using data from before treatment start as a comparator. Inclusion was restricted to articles published in peer-reviewed journals. Congress abstracts were not considered because they do not provide sufficient details of methodology and results. Articles were excluded if studies analysed a single intervention without a comparator and if data on either costs or consequences were absent. The quality of economic evaluations was assessed by using the most relevant parts of the Cochrane Consumers and Communication Review Group s data extraction template [10], perspective (i.e. society or third-party payer), study design (i.e. research design and type of economic evaluation); source of clinical and economic data; cost and consequence measures; time horizon; allowance for

3 Economic evaluations of uncertainty (i.e. sensitivity ); and incremental of costs and consequences (i.e. calculation of ICER). Risk of bias was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions [11]. Studies were assessed by one reviewer and interpretations were checked by a second. An inclusion/exclusion and data extraction form was completed for each study. Economic evaluations were summarised by focussing on the study country, type of study and type of economic evaluation (i.e. cost-effectiveness, cost-minimisation, cost-utility, cost-benefit ), sample, intervention, comparator, costs and consequences results. Any disagreements between the two reviewers were resolved by a third reviewer and, if there was still no consensus, this was cleared through discussion within the research team. In practice, this was not required. Due to the heterogeneity of the primary studies, a descriptive synthesis of the extracted data was made. The characteristics and the results of the included studies were summarised via tabulation. To compare costs between studies, costs were actualised to 2012 values using a rate of annual average inflation based on the evolution of the Consumer Price Index. Costs were converted using US dollar exchange rates. Results Search results A literature search resulted in a total of 868 titles (including duplicates) (Fig. 1). After removal of duplicates, 496 titles remained. Each individual title was considered for relevance, and when there was doubt the abstract or full article was considered. The assessment process helped to identify 15 relevant articles reporting on 14 studies, which were included in this review [12 26]. Three titles were found in one source only, including the AMED (1 title) and through a hand search (2 titles). The remaining articles were identified through more than one source. The studies included economic evaluations based on clinical trials, observational studies, case and insurance company reports including various ways of presenting costs and consequences of homeopathic treatment. Results of studies Numbers of studies and types of methodologies The 14 studies (16 articles) (Table 1) included in this review considered various aspects of the costs and consequences of homeopathic treatment [12 26]. Twelve studies (13 articles) compared the results of homeopathic treatment with other treatment or placebo [12 14, 16 19, 21 26]. Comparators were mainly conventional treatment, with one study also comparing results with acupuncture [17] and another with placebo [15]. Two studies used a before-toafter treatment design for comparison of results [19, 20]. Thirteen articles reported on 12 cost-effectiveness analyses [13, 14, 16 26], and the remaining two were a cost-minimization [12] and a cost-utility [15]. This included three randomised controlled trials [15, 17, 21], four articles reporting on three cohort studies [16, 22, 23, 25], two case series [19, 20], two uncontrolled parallelgroup studies [18, 26] and two other uncontrolled studies Records identified through database searches n=868 Additional records identified through other sources n=2 Records after duplicates (n=374 ) removed n=496 Records assessed n=496 Studies included n=15 Records excluded, with reasons n=481 Animal & plant studies n=19 Congress abstracts n=20 No costs or consequences n=113 Not n=79 Not research n=156 Planned study n=3 Reviews n=89 Single cases n=2 Fig. 1 Flow of information in the review

4 P. Viksveen et al. Table 1 Studies considering economic evaluations of Author, year Study sample Intervention N = 3,512 Comparator N = 151,955 Economic evaluation and study type Bachinger et al. [12], Germany Osteoarthritis of the knee Injections of Zeel comp. (combination product) (n = 57) Hyaluronic acid injections (n = 57) Cost-minimisation (noninferiority design) based on model calculation (methodology unclear) Perspective of economic evaluation and time horizon societal 12 months Results a Comments strengths Comments weaknesses Zeel comp. USD 950/patient. Success in 26 of 57 patients. Qualityadjusted cost USD 2,084 per successfully treated patient (pain reduction min. 30 %) Hyaluronic acid USD 1,934/patient. Success in 34 of 57 patients. Quality-adjusted cost USD 3,242 per successfully treated patient Zeel comp. costs 50.9 % lower than hyaluronic acid costs. Qualityadjusted cost difference: Zeel comp % lower costs than hyaluronic acid costs per successfully treated patient (costs of all patients divided amongst successfully treated patients) Reported: direct health-care costs: medication (main cause of difference in costs); appropriate time horizon Comparison with existing treatment Direct nonhealth-care costs: travel expenses mentioned, but figures not reported; Indirect costs: work disability mentioned, but figures not reported No baseline data; Details of study methodology insufficiently reported; No blinding mentioned; Insufficient information on assessment method and time of assessment; No sensitivity

5 Economic evaluations of Table 1 continued Author, year Study sample Intervention N = 3,512 Feldhaus [13], Germany Dental surgery, patients with compulsory health insurance, single dental practice Arnica montana D12 (single remedy) for 3 days prior to and 7 days after surgical treatment (n not reported) Frei and Thurneysen [14], Switzerland Acute otitis media in patients aged 0 16 years, single pediatric practice Individualised (n = 230) Comparator N = 151,955 Other dental practices, statistics provided by dental association (n not reported) Comparison with other studies (n not reported) Economic evaluation and study type Cost-effectiveness based on data in a single practice with all consecutive patients collected and compared to figures provided by dental association for all dental practices Cost-effectiveness based on an unontrolled clinical trial (particpiants given conventional treatment in case of non-response to homeopathic treatment) Perspective of economic evaluation and time horizon insurance companies unknown. Data collection period: 7 years unclear 12 h Results a Comments strengths 55 % reduction in postoperative treatments from before to after introduction of Arnica in surgery Costs 40 % lower compared to other dental practices. Insurance companies costs for postoperative treatments reduced by USD 1,267 annually. 37 % sick-leave reduction, 40 % below other dental practices Reported: direct health-care costs: postoperative treatment costs Some comparison of results with figures for other practices presented by dental association 39 % free of pain within 6 h, 72 % within 12 h. Resolution of pain 2.4 times faster than placebo. No complications Homeopathic treatment 14 % cheaper than conventional treatment: USD 114, conventional USD 132 per patient Reported: direct health-care costs: medication and consultations Comments weaknesses Indirect costs: sick-leave mentioned, but figures not presented; Direct non-health care costs not reported Single practice; Not RCT; Unclear whether this practice is otherwise comparable to other practices; horizon not reported; Unclear if other practices offered same treatment; No sensitivity Costs other than medication and consultations not reported Single practice; Not RCT; Comparison with control group from another study considerably reduces validity of results; Very short time horizon; No sensitivity

6 P. Viksveen et al. Table 1 continued Author, year Study sample Intervention N = 3,512 Kneis et al. [15], Germany Acute maxillary sinusitis in consecutive patients in a single GP practice Complex HMP b (sinfrontal) (n = 57) Kooreman and Baars [16], The Netherlands Various patients, 28 GPs compared to other GPs Health insurance data Homeopathy (approach not reported) (n = 1,182) Comparator N = 151,955 Placebo (n = 56) Conventional treatment (n not reported) Conventional treatment (n = 151,955) Economic evaluation and study type Cost-utility based on RCT Cost-effectiveness based on a cohort study (data from a single health insurance company) Perspective of economic evaluation and time horizon societal 11 weeks insurance company 4 years Results a Comments strengths Comments weaknesses Compared to antibacterials Sinfrontal cure rate 59 versus 11 % for antibacterials (p \ 0.001) at similar or lower costs (22-day period) Over 22 days Incremental savings USD 404 (95 % CI ) per patient compared to placebo, primarily due to work absenteeism (7.83 vs workdays) Incremental utility QALYs (95 % CI ) or 3.2 QALDs Over 11 weeks (8 weeks post-treatment observation): Sinfrontal: incremental cost savings of USD 751, utility gains of QALY or 5.4 QALDs compared to placebo Homeopathy GP patients had reduced mortality (p \ 0.05) Substantially lower health-care costs (15 %) for all age groups below 75 (p \ 0.05). Lower costs resulted from reduced prescription drug costs and fewer hospital stays. Differences unrelated to socioeconomic status Reported: direct health-care costs: medication; Indirect costs: work absenteeism Results robust to sensitivity analyses Reported: direct health-care costs: GP care, hospital care, pharmaceutical care, paramedic care (e.g. physical therapy); horizon allows for long-term assessment Relatively large sample size, in particular for comparator; Several practitioners included; Reported on mortality; Linear and loglinear regression included Apart from medication costs and work absenteeism, no other costs reported Single practice; No long-term assessment Non-direct healthcare costs and non-health-care costs not reported No RCT; limited data set (only one health insurer); Potential selfselection bias (more healthconscious patients choose / CAM); Not assessed: morbidity, subjective health

7 Economic evaluations of Table 1 continued Author, year Study sample Intervention N = 3,512 Paterson et al. [17], UK Dyspepsia, single clinic Individualised (n = 21) Pomposelli et al. [18], Italy Diabetic neuropathy, single clinic with 4 MDs Individualised (n = 32) Sevar [19], UK Various chronic complaints, single clinic Individualised (n = 455) Comparator N = 151,955 Conventional treatment (n = 19) Acupuncture (n = 20) Conventional treatment (n = 29) Before to after treatment (n N/A) Economic evaluation and study type Cost-effectiveness based on pragmatic RCT Cost-effectiveness based on uncontrolled parallel-group study Cost-effectiveness based on prospective case series Perspective of economic evaluation and time horizon societal 6 months (some data 12 months after treatment end, at 18 months) societal 12 months patient 11 months (mean) Results a Comments strengths Symptom improvement (MYMOP) in all three groups at 6 weeks, 3 and 6 months. No further change from 6 to 12 months. No between-group differences Wide variations, but no statistically significant differences in consultation and prescription costs. Costs per patient over 6 months (mean/sd): USD 216 (68), acupuncture USD 360 (107), GP consultations USD 16 (37) and prescriptions USD 132 (150) Reported: direct health-care costs: medication and consultation costs; Appropriate time horizon Pragmatic RCT Diabetic neuropathy symptoms and quality of life improved significantly only in the group (p = 0.016). Objective measures were stable in both groups First 6 months costs for conventional drugs reduced by USD 181 (USD 30/month) in the group (p = 0.078) compared to a USD 89 (USD 15/month) increase in a control group (p = 0.139), a difference of USD 270 (USD 45/month) (p = 0.071) For the 12-month period: USD 66 (USD 5.5/month) (p = 0.432) reduction for and USD 161 increase for the control group (USD 13/month) (p = 0.074), a difference of USD 227 (19/month) (p = 0.089) 67 % improved, 61 % improved to such a degree that it affected their daily living (9-point self-report numerical rating scale) Total cost savings per year USD 11,295 (USD 77 per patient). Previously prescribed conventional drugs were discontinued in 33 % Reported: direct health-care costs: medication; Appropriate time horizon; Blinded assessment Reported: direct health-care costs: medication; Appropriate time horizon Larger sample size; Similar to regular practice (higher external validity) Comments weaknesses Other than medication and consultation costs, no other costs reported Single practice; Small sample size; Heterogeneity of study sample, low intensity and high variability of symptoms; High degree of comorbidities with a variety of medications Costs other than for medication not reported No RCT; Small sample size; Potential patient selfselection bias; Baseline drugconsumption differences (higher for ) (p = 0.007) Costs other than for medication not reported No RCT; No control group; No sensitivity

8 P. Viksveen et al. Table 1 continued Author, year Study sample Intervention N = 3,512 Slade [20], UK Various complaints (mainly arthritis, depression, anxiety, skin complaints), single GP practice with patients referred from 8 GP practices Homeopathy (approach not reported) (n = 97) Thompson et al. [21], UK Children with severe asthma, single doctor in hospital outpatient department, recruited from two secondary care respiratory hospital clinics Individualised (with some isopathy) in addition to usual care (n = 18) Comparator N = 151,955 Before to after treatment (n N/A) Usual care (conventional treatment in respiratory hospital clinics) (n = 21) Economic evaluation and study type Costeffectiveness based on prospective case series Costeffectiveness based on pragmatic RCT Perspective of economic evaluation and time horizon societal time 12 months societal and patient 4 months Results a Comments strengths Comments weaknesses Significant improvement in primary and secondary symptoms, ability to undertake activities and well-being measured with MYMOP c at mean follow-up of 134 days (p \ ). Improvement in complaints was reported by 80 % of patients and well-being by 76 % Costs of conventional drugs: 71 of 97 patients were taking conventional drugs at trial start, 57 % (n = 28 of 49 who provided information on costs) stopped or reduced conventional medication. Cost savings USD 5,519 (n = 22 patients, savings USD 252 per patient per year) No between-group differences, except better morning and afternoon peak flow in favour of usual care, with patients taking more and higher doses of conventional medication NHS costs significantly higher in group, mainly because of consultations, mean difference USD 1,129 (95 % CI 257 2,001). Nonsignificantly higher costs in personal (patient) costs, mean difference USD 156 (95 % CI ) Reported: direct health-care costs: medication; appropriate time horizon Several practitioners; similar to regular practice (higher external validity) Reported several aspects allowing for cost-effectiveness : direct health-care costs: medication, consultations, secondary hospital care, ambulance services; indirect costs: work absenteeism; Direct non-health care: patients travel expenses; Pragmatic RCT; Higher model validity because of practitioner with high competence in homeopathic treatment of this patient group Costs other than for medication not reported; Medication cost calculation based on 1 year of consumption (might not have been the case for some) No RCT; No control group; Single practice; No sensitivity Small sample size (pilot study); Single practitioners; No long-term assessment; Lower external validity due to pathology more severe than in regular practice)

9 Economic evaluations of Table 1 continued Author, year Study sample Intervention N = 3,512 Trichard et al. [22, 23], France Children with ear, nose and throat infections, 135 GP practices Homeopathy (approach not reported), 73 GPs (n = 268) van Wassenhoven and Ives [24], Belgium Various compaints (most common CNS and respiratory complaints, 78 % with severity affecting daily living), 80 GP practices Individualised (mostly) (n = 782) (10 consecutive patients in each practice) Comparator N = 151,955 Conventional 62 GPs (n = 231) Conventional treatment, data obtained from national statistics on 14,000 GP pactices Economic evaluation and study type Costeffectiveness based on cohort study Costeffectiveness based on crosssectional survey Perspective of economic evaluation and time horizon societal and patient unknown Data collection period: 6 months patient 9 years (mean treatment period) Results a Comments strengths Homeopathy resulted in a lower number of episodes of rhinopharyngitis and complications compared to conventional treatment (p \ 0.001) Overall direct costs were the same in the (USD 276) and antibiotics groups (USD 272) (p [ 0.05), with lower costs to social security for (USD 139) compared to antibiotics (USD 157) (p \ 0.05), but higher costs to patients for (USD 136) compared to antibiotics (USD 115) (p \ 0.05). Differences in costs were due to consultations, and not drugs and tests Indirect costs: number of parents who missed days of work was lower in the group (13 %) than in the control group (27 %) (p = 0.001). Homeopathic GPs initiated preventive treatment in 82 % and antibacterials in 21 %; non-homeopathic GPs preventive 43 %, antibacterials in 90 % Physical complaint better 89 %, moderately or much better 57 %, psychological better 78 %, moderately or much better 48 %, satisfaction 95 % Costs were significantly lower than for conventional treatment: consultation costs were reduced by 22 % and prescriptions costs (including conventional medication) were 1/3 of GP average (subset of data from 47 GPs). Previously prescribed conventional drugs were discontinued in 52 % Reported: direct healthcare costs: medication, tests, consultations; Indirect costs: work absenteeism mentioned Higher external validity due to large number of practitioners Reported: direct healthcare costs: medication, consultation; horizon allows for long-term assessment Higher external validity due to larger number of practitioners; Comparison with large number of other practices Comments weaknesses No costs reported for work absenteeism; Direct non-health-care costs not reported; Unknown time horizon No RCT; Potential selection bias: patients less likely to be exposed to passive smoking (p \ 0.001), less likely to be at home daytime (p = 0.02), more likely to be from blue/white-collar employment families (p \ 0.001); Homeopathy vs. antibiotics: risk of unequal distribution of confounding factors (both groups received other drugs) No sensitivity Costs other than for medication and consultation not reported No RCT; potential selection bias; Insufficient inter-rater reliability (patients and practitioners ratings); No sensitivity

10 P. Viksveen et al. Table 1 continued Author, year Study sample Intervention N = 3,512 Witt et al. [25], Germany Patients suffering from various chronic complaints (headache, lower back pain, depression, insomnia, sinusitis, asthma, atopic dermatitis, allergic rhinitis), 160 physicians Individualised d, 101 GPs (n = 265) Comparator N = 151,955 Conventional treatment, 59 GPs (n = 228) Economic evaluation and study type Costeffectiveness based on comparative parallelgroup cohortstudy Perspective of economic evaluation and time horizon insurance company 12 months Results a Comments strengths Comments weaknesses Symptom severity (patient assessed): significantly better than conventional treatment for adults (p = 0.002) and children (p = 0.029) Symptom severity (physician assessed): improvement in both groups (p \ 0.001), but no between-group difference in adults (p = 0.251), but significant between-group differences in favour of in children (p \ 0.001) No between-group differences in physicians overall assessed therapeutic success or satisfaction Quality of life (physical): significant improvement first 6-month period and better compared to conventional (p = 0.016), not the second 6-month period (p = 0.649), conventional no change. Quality of life (mental): no changes/differences No significant difference in treatment costs between homeopathic and conventional treatment groups, except for adults whose medication costs were higher for conventional compared to homeopathic treatment. Overall costs for USD 3,359, conventional USD 3,138 (p = 0.856) for adults, and USD 2,293, conventional USD 1,225 (p = 0.137) for children Reported several types of costs including: direct health-care costs: medication, consultations, hospital care, physiotherapy care Indirect costs: work absenteeism; Appropriate time horizon Higher external validity due to the large number of practitioners and patients with a variety of complaints representative of general practice; Adjusted to reduce bias due to between-group differences Direct nonhealth-care costs not reported No RCT; Potential selection bias (but adjusted ); Small sample size for costeffectiveness (cost analyses Only for subgroup); Potential detection bias (non-blinded severity rating)

11 Economic evaluations of Table 1 continued Author, year Study sample Intervention N = 3,512 Comparator N = 151,955 Economic evaluation and study type Perspective of economic evaluation and time horizon Results a Comments strengths Comments weaknesses Witt et al. [26], Germany Atopic eczema in children (1 14 years), 26 physicians Individualised by 10 physicians (n = 48) Conventional treatment by 16 physicians (n = 87) Cost-effectiveness based on uncontrolled multicentre parallel group prospective study societal 12 months No significant between-group differences in atopic dermatitis score (SCORAD) (p = 0.290/0.974 at 6 and 12 months), QoL similar Significantly reduced use of conventional drugs in group (similar at baseline) Adjusted costs higher in homeopathic than conventional group: First 6 months: Homeopathy USD 1,335, Conventional USD 734 (p = 0.026) 12 months: Homeopathy USD 2,176 (95 % CI 1,711 2,642) Conventional USD 1,030 (95 % CI 607 1,454) (p = 0.001) Differences were due to higher costs of consultations (p \ 0.001), medical aids and adjuvant therapies (p = 0.004). Differences in indirect costs were nonsignificant (p = 0.652) Reported several types of costs including: direct health-care costs: medication, consultations, hospital care; indirect costs: work absenteeism; Higher external validity due to large number of practitioners and complaint commonly treated in practice; Blinding of assessors; Adjusted to reduce bias in between-group baseline differences Not reported direct non-health-care costs No RCT; Potential selfselection bias: between-group baseline differences (but adjusted ); Small sample size (underpowered, recruited 56 %); Potential recall bias (patients recall complemented by physicians data) Main findings are here not necessarily what was defined as the main findings by the authors of the publications, but the main findings that are of relevance to this review. Results adjusted for inflation rates from publication date to 2012 level Change from German mark to euro on 1 January 1999 (1 EUR = DM) Currency conversion rates on 13 March 2012 (1 CHF = USD, 1 EUR = USD, 1 GBP = USD) a HMP homeopathic medicinal product b MYMOP measure yourself medical outcome profile c Personal communication d

12 P. Viksveen et al. [13, 14], a cross-sectional study [24] and one study not specifying the used methodology [12]. Overall results and methodological quality of studies Out of a total of 14 identified studies, 8 reported improvements in patients complaints and/or state of health, together with some sort of cost savings [12 16, 19, 20, 24]. In four studies (5 articles) clinical outcomes for were either better than [18, 25] or as good as those in controls [17, 22, 23, 25], at similar costs. In the last two studies, clinical results were similar to those in controls, but at higher cost in the group [21, 26]. The time horizon varied considerably, from only 12 h to several years, with most studies being assessed over at least 6 months. Even though the overall results of this review of economic evaluations of may seem promising, studies were highly heterogeneous and mostly of low methodological quality, preventing any firm conclusions from being drawn. It is, from a theoretical perspective, not possible to determine a priori whether methodological issues/limitations will under- or overestimate differences in costs and outcomes. Although case series were mostly prospective and included consecutive patients, this methodological approach serves as weak evidence, as there are considerable risks of results being influenced by confounding factors and improvements may (at least in part) be the result of fluctuations in patients state of health and regression to the mean effects. This is also true for any other non-randomised methodological approach. Another question is whether patients are different from the general population, e.g. in terms of having less serious disease. This is however unlikely, as patients more often consult with a homeopath after having suffered from chronic disease for a longer period of time and often first tried conventional care. For comparison of results with data from other studies or other practices, results were in most cases not adjusted for participants characteristics [13, 14, 24]. An exception was a cohort study where results were compared to a large comparison group [16]. In this study linear and log linear regression showed that age (which was higher in the group) and socioeconomic status (which was lower in the group) affected the results. However, it is still possible that factors other than homeopathic treatment may have influenced results. Examples could be participants health consciousness, and thereby their lifestyle, or practitioners tendency to give advice on prevention of disease. Moreover, results of this study were from a single insurance company and results in half of the identified studies were from a single practice, which raises the question of generalisability to the wider population. Overall, transferability of results to other settings was uncommon, and discussion of transferability to other countries was not found. A variety of outcome measures were used in the identified studies. Many outcome measures are related to intermediate outcomes (e.g. reduction in diabetic neuropathy symptoms) rather than final outcomes (e.g. health status or quality of life). The impact of homeopathic treatment on quality of life was only assessed in a limited number of studies [18, 25, 26]. With one exception that reported on treatment [13], all studies reported specifically on costs of medication, with four studies solely reporting on costs of medication [12, 18 20]. Costs of consultations, which commonly are higher than costs of medication in homeopathic treatment, were included in 8 out of 14 studies [14, 16, 17, 21 26]. Only four studies included hospital [16, 21, 25, 26] or other [16, 25] care costs. Only two studies considered direct non-health care costs (transportation to consultations) [12, 21], one of which did not specify these costs [12], and another that did not find significant differences in costs between and conventional care for costs of travel to primary and secondary care visits [21]. Other non-health care costs included work absenteeism, which was mentioned in seven studies (8 articles) [12, 13, 15, 21 23, 25, 26]. Out of these, three reported reduced sick leave, but no financial consequences of it [13, 15, 22, 23]; one stated that these costs were low compared to direct costs [12]; one registered sick-pay, but did not report results of this separately [25]; and two did not find that the number of sick-leave days or costs of workabsenteeism were significantly different from conventional treatment [21, 26]. No other non-health-care costs were considered. Because studies employed multiple outcome measures and did not combine them into a single index, in most cases, it was not possible to get an idea of the overall costeffectiveness of homeopathic treatment. It was not relevant to present incremental cost-effectiveness ratios or incremental cost-benefit ratios, as no study reported greater improvement at higher costs compared to comparators. Few studies allowed for uncertainty, with only four studies [15, 16, 25, 26] conducting sensitivity analyses to account for uncertainty around key estimates and assumptions made during the identification, measurement and valuation of costs and outcomes. Other quality problems included insufficient information on research methodology and/or methodology used for economic evaluation, potential selection and recall bias, small sample sizes or lack of sample size calculation, lack of or differences in baseline data with heterogeneity of study samples, insufficient information on assessment methods and lack of blinding of assessors.

13 Economic evaluations of Numbers of participants and types of complaints In 13 out of the 14 studies, homeopathic treatment was given to a total of 3,512 patients, with a median number of 97 participants (interquartile range , range 18 1,182) [due to skewed data the median and interquartile range (IQR) are presented]. One study did not report the number of participants [13]. The median number of patients in control groups was 57 (IQR , total 151,955) in the nine studies (10 articles) where this was reported [11, 15 18, 21 23, 25, 26]. Five studies [16, 19, 20, 24, 25] considered costs and consequences for a total of 2,781 patients suffering from various complaints (comparison group total over 152,000) [17, 27] and four (5 articles) [14, 15, 21 23] in respiratory and ear complaints for a total of 573 patients (comparison 287) [15, 21 23]. The five remaining studies considered for patients suffering from atopic dermatitis ( 48/comparison 87) [26], diabetic neuropathy (32/29) [18], dyspepsia (21/39) [17], osteoarthritis of the knee (57/57) [12], and dental complaints (numbers not reported) [13]. horizon The time horizon was 11 or 12 months for six studies [12, 18 20, 25, 26], about 3 6 months for three studies [15, 17, 21], only 12 h in one study [14], and 4 [16] and 9 years [24] for the longest studies. The time horizon was unknown in two studies, but data collection was carried out over 6 months in one of them [22, 23] and 7 years in another [13]. Most studies took the societal perspective (details in Table 1). Numbers of practitioners and countries In six of the studies treatment was provided by a single practitioner or clinic [13 15, 17, 19, 21]. The remaining studies included from 4 to 101 homeopaths or clinics [16, 18, 20, 22 26], and one study did not report the number of practitioners [12]. Only four studies (5 articles) reported on the number of practitioners in comparison groups, ranging from 16 to 14,000 [22 26]. Five studies were carried out in Germany [12, 13, 15, 25, 26], four in the UK [17, 19, 21], and one in each of the following countries: Belgium [24], France [22, 23], Italy [18], the Netherlands [16] and Switzerland [14]. Types of Eight studies involved mainly classical, with a total of 1,851 patients (median 139, IQR ) [14, 17 19, 21, 24 26], three studies applied non-classical methods where all participants were prescribed the same product (two complex, n = 114) [12, 15] (one single HMP, n not reported) [13]. The remaining three studies (4 articles), with a total of 1,547 participants, did not specify the homeopathic approach [15, 20, 22, 23]. Studies assessing homeopaths treatments of patients with various complaints Five studies reporting on patients with various complaints included cost-effectiveness analyses based on two case series [19, 20], two cohort studies [16, 25] and a crosssectional survey [24]. Two case-series were carried out in single practices with a total of 552 patients assessed over an month period [19, 20]. Patient self-reported improvements were found in 67 % [19] and 80 % [20] of patients from before to after treatment, with improvements in 61 % [19] affecting daily living and 76 % [20] experiencing improved well-being. In one of these studies [20], patients self-reported MYMOP scores [27] showed significant improvements in primary and secondary symptoms, ability to undertake activities and well-being at a mean follow-up period of 134 days (p \ ). The other study used a 9-point numerical rating scale [19]. Based on reduction in consumption of conventional drugs, annual savings were calculated to $ 78 or $ 252 per patient [19, 20]. No other costs were reported. An economic evaluation by Van Wassenhoven and Ives [24] was based on a cross-sectional survey including 782 consecutive patients suffering from various complaints who had received mostly classical homeopathic treatment provided by 80 general practitioners (GPs) for an average period of 9 years. Results showed improvement in physical complaints in 89 % of patients (57 % moderately/much better) and in 78 % for psychological complaints (48 % moderately/much better), with 95 % saying they were satisfied with the treatment. Costs were significantly lower as compared to 14,000 conventional GP practices (consultation costs 22 % lower, prescription costs 1/3 of conventional GPs). No other costs were reported. Witt et al. [25] carried out an economic evaluation based on a parallel-group cohort study of 265 patients suffering from various complaints who received classical homeopathic treatment from 101 GPs compared to results in 228 patients receiving conventional treatment from 59 GPs over a 12-month period. Patient-assessed improvement was significantly better for compared to conventional treatment for both adults (p = 0.002) and children (p = 0.029). Physicians assessment of symptoms was better for children in the group (p \ 0.001), and both the and the conventional adult group s symptoms improved (p \ 0.001), but without between-group differences (p = 0.251). There was no

14 P. Viksveen et al. between-group difference in physician overall assessed therapeutic success or satisfaction. Physical quality of life improved significantly for the group over the first 6 months (p = 0.016), but not for the next six (p = 0.649), and no changes were found for mental quality of life. Adults medication costs were higher in the conventional compared to the homeopathic group, but overall treatment costs were similar for the two groups (p = for adults, p = for children). The scope of the cost included medication, consultations, hospital care, physiotherapy care and work absenteeism. An economic evaluation by Kooreman and Baars [16] was based on a cohort study comparing results for 1,182 patients treated with for various complaints in 28 GP practices with over 150,000 patients in regular GP practices over a 4-year period. Results showed reduced mortality in patients (p \ 0.05) and 15 % lower health-care costs (p \ 0.05) resulting from reduced drug prescriptions and hospital expenses. Direct healthcare costs included GP, hospital, pharmaceutical and paramedic care. Studies assessing homeopaths treatment of patients with respiratory tract and ear complaints Four studies (5 articles) [14, 15, 21 23] in respiratory tract and ear complaints included cost-effectiveness analyses based on an uncontrolled clinical trial [14] and a cohort study [22, 23], and a cost-effectiveness [21] and a cost-utility [15] based on randomised controlled trials. The shortest study (assessed at 12 h) found 2.4 times faster resolution of pain in acute otitis media in 230 children treated with classical compared to conventionally treated children in other studies [14]. Costs of consultations and medication were 14 % lower in the group ( $ 114 and conventional $ 132 per patient). No other costs and no long-term results were reported. An economic evaluation by Kneis and Gandjour [15] was based on a randomised placebo-controlled trial of acute maxillary sinus infections treated with a standardised complex homeopathic medicinal product (n = 57) or placebo (n = 56). Homeopathy patients had a cure rate of 59 % compared to 11 % for anti-bacterials (n not reported) (p \ 0.001) at similar or lower costs over a 22-day period. Incremental savings were $ 404 (95 % CI ) per patient compared to placebo, primarily because of the difference in work absenteeism (7.83 vs workdays). The incremental consequence was QALYs (95 % CI ) or 3.2 QALDs. Eight weeks after treatment, incremental cost savings of the homeopathic product was $ 751, with consequence gains of QALY or 5.4 QALDs compared to placebo. The economic evaluation included costs of medication and work absenteeism. Thompson et al. [21] published a cost-effectiveness based on a pragmatic randomised controlled trial comparing classical in 18 patients suffering from severe asthma treated by a single homeopath in a hospital outpatient department with results for 21 patients receiving usual care in a respiratory hospital clinic over a 4-month period. No differences were found, except better morning and afternoon peak flow in favour of usual care, but with patients taking more and higher doses of conventional medication. NHS costs were significantly higher in the group, primarily because of consultation costs, with a mean difference of $ 1,129 (95 % CI 257 2,001). No significant between-group differences were found in patient costs. An economic evaluation by Trichard et al. [22, 23] based on a cohort study of 268 patients suffering from ear, nose and throat infections treated homeopathically by 73 GPs compared results to 231 patients treated conventionally by 62 GPs. Data collected over a 6-month period showed that patients had significantly fewer episodes of rhino-pharyngitis and complications compared to conventional treatment (p \ 0.001). Overall direct costs were similar in the two groups, with lower costs to social security for patients, but higher costs to patients (details in Table 1). Costs included consultations, medication and tests. Differences originated from consultations, and not from drugs or tests. Parents work absenteeism was reported to be lower in the group (13 %) than in the control group (27 %) (p = 0.001), but resulting costs were not reported. The homeopathic approach and direct non-health care costs were not reported. Studies assessing homeopaths treatment of patients with eczema, diabetic neuropathy, dyspepsia, osteoarthritis and dental surgery The cost-effectiveness of classical was assessed in two 12-month uncontrolled parallel group studies of eczema [26] and diabetic neuropathy [18] and a 6-month pragmatic randomised controlled trial in dyspepsia [17]. No significance between-group differences were found by Witt et al. [26] in atopic dermatitis scores or quality of life for 48 children with eczema treated by 10 physicians compared to 87 children treated by 16 conventional physicians. Homeopathy patients significantly reduced the use of conventional drugs. However, costs were higher for the than the conventional group, with $ 1,335 compared to $ 734 for the first 6 months (p = 0.026) and $ 2,176 compared to $ 1,030

15 Economic evaluations of over the entire 12-month period (p = 0.001). Costs included consultations, medication, hospital care and work absenteeism. Pomposelli et al. [18] found that symptoms of diabetic neuropathy and quality of life improved significantly in 32 patients treated homeopathically by 4 doctors in a single clinic compared to 29 patients treated conventionally (p = 0.016). No significant between-group differences were found in costs of conventional drugs (details in Table 1). No other costs were reported. Dyspepsia symptoms improved significantly in a study by Paterson et al. [17] at 6, 12 and 24 weeks in all three groups (, acupuncture and conventional treatment) in a study including a total of 60 patients, with no statistically significant between-group differences in symptoms or costs of consultations and prescriptions. A non-inferiority cost-minimisation by Bachinger et al. [12] of 114 patients suffering from osteoarthritis of the knee assessed over a 1-year period showed that costs of injections of a homeopathic standardised combination product were 36 % lower than injections of hyaluronic acid. Costs per successfully treated patient were $ 2,084 in the group compared to $ 3,242 in the hyaluronic acid group (costs of all patients divided among successfully treated patients). Indirect costs (work disability) and direct non-health-care costs were not reported. A cost-effectiveness published by Feldhaus [13] reported on a single dental practice using the homeopathic remedy Arnica montana D12 prior to and after surgical treatment. The author found 55 % reduction in postoperative treatments with insurance company costs reduced by $ 1,267 annually and 37 % reduction in sick-leave rates from before to after treatment. Costs were 40 % lower compared to other dental practices in the country. The time horizon was not reported, but consecutive patient data were collected over a 7-year period. Data other than postoperative treatment costs were not reported. Discussion Our literature search identified 14 studies (in 15 articles) assessing various aspects of economic evaluations of. Our use of only a limited number of databases and other sources does not rule out that additional health economic evaluations of exist. However, to our knowledge, no previous reviews have reported a higher number of studies or greater detail in reported data and of evaluations including both changes in results and costs during and after homeopathic treatment. Eight out of 14 identified studies reported on improvements in patients health after homeopathic treatment combined with some sort of cost savings. Four studies found that patients improved more than or at least as much as patients in control groups, at comparable costs. Only two studies found similar results when comparing and control groups, but at higher costs. Results seem promising, but limitations of existing evidence reduce the reliability of results and of the possibility to generalise to other populations. Studies were highly heterogeneous, with considerable variation in the applied research methodology and type of economic evaluation, numbers and types of participants, outcome measures, time horizon, completeness in reported results, and statistical and economic analyses. In many cases applied methodologies had limitations or information on used methodologies was insufficient, reducing the reliability of results, increasing the risk of bias and resulting in difficulties in summarising results and generalising results to other populations. The majority of studies did not involve random selection of participants, resulting in risk of selection bias. Lack of randomisation and limited reporting of potential confounding factors adds to the risk of bias. Moreover, most studies did not involve blinding of participants, practitioners or assessors, thereby resulting in the risk of performance bias. Sample sizes varied considerably, ranging from 18 to over 1,180 patients and 21 to over 150,000 control group participants. The median number of participants was fairly low for both groups ( n = 97, control groups n = 57). Comparability of and control groups was considered in the majority of the 12 studies that included control groups. Although some of these reported baseline differences, most had comparable groups or used adjusted analyses to control for betweengroup baseline differences. Only a few studies carried out sensitivity analyses in order to assess the impact of variations in input parameters on the cost-effectiveness of. Due to limitations in the study design, it was difficult to determine whether improvements in patients symptoms and state of health were the result of treatment, variations in their condition or regression to the mean effects. The time horizon varied considerably, but was at least 12 months in half of the studies. It has previously been pointed out that the cost-effectiveness of CAM therapies should be assessed only after a sufficiently long period of time [6, 28, 29], with some suggesting a minimum of 6 months of treatment [30]. Results in the studies we identified were not less promising after longer than shorter time periods. The majority of economic evaluations were based on observational clinical studies (e.g. cohort study, case control study). Such economic evaluations reflect the use of in daily practice, but may have a limited internal validity because of inherent weaknesses in the