Systematic Review and Meta-Analysis of Randomised, Other-than-Placebo Controlled, Trials of Non-Individualised Homeopathic Treatment.

INTRODUCTION: This study focuses on randomised controlled trials (RCTs) of non-individualised homeopathic treatment (NIHT) in which the control (comparator) group was other than placebo (OTP). OBJECTIVES: To determine the comparative effectiveness of NIHT on health-related outcomes in adults and children for any given condition that has been the subject of at least one OTP-controlled trial. For each study, to assess its risk of bias and to determine whether its study attitude was predominantly 'pragmatic' or 'explanatory'. METHODS: Systematic review. For each eligible trial, published in the peer-reviewed literature up to the end of 2016, we assessed its risk of bias (internal validity) using the seven-domain Cochrane tool, and its relative pragmatic or explanatory attitude (external validity) using the 10-domain PRECIS tool. We grouped RCTs by whether these examined IHT as alternative treatment (study design 1a), adjunctively with another intervention (design 1b), or compared with no intervention (design 2). RCTs were sub-categorised as superiority trials or equivalence/non-inferiority trials. For each RCT, we designated a single 'main outcome measure' to use in meta-analysis: 'effect size' was reported as odds ratio (OR; values > 1 favouring homeopathy) or standardised mean difference (SMD; values < 0 favouring homeopathy). RESULTS: Seventeen RCTs, representing 15 different medical conditions, were eligible for study. Three of the trials were more pragmatic than explanatory, two were more explanatory than pragmatic, and 12 were equally pragmatic and explanatory. Fourteen trials were rated 'high risk of bias' overall; the other three trials were rated 'uncertain risk of bias' overall. Ten trials had data that were extractable for analysis. Significant heterogeneity undermined the planned meta-analyses or their meaningful interpretation. For the three equivalence or non-inferiority trials with extractable data, the small, non-significant, pooled effect size (SMD = 0.08; p = 0.46) was consistent with a conclusion that NIHT did not differ from treatment by a comparator (Ginkgo biloba or betahistine) for vertigo or (cromolyn sodium) for seasonal allergic rhinitis. CONCLUSIONS: The current data preclude a decisive conclusion about the comparative effectiveness of NIHT. Generalisability of findings is restricted by the limited external validity identified overall. The highest intrinsic quality was observed in the equivalence and non-inferiority trials of NIHT.

The N-of-1 Clinical Trial: A Timely Research Opportunity in Homeopathy.

BACKGROUND: The randomised controlled trial (RCT) is considered the 'gold standard' for establishing treatment efficacy or effectiveness of an intervention, but its data do not infer response in an individual patient. Individualised clinical care, a fundamental principle in complementary and alternative medicine (CAM), including homeopathy, seems well disposed in principle to being researched by single-patient (N-of-1) study design. Guidelines for reporting N-of-1 trials have recently been developed. OBJECTIVE: To overview the current status in the literature of the N-of-1 method and its application in medicine, including CAM. To consider whether the N-of-1 trial design offers an opportunity for novel research in homeopathy. N-OF-1 TRIAL DESIGN: The N-of-1 trial applies the principles of the conventional crossover, blinded, RCT design. The treatment under study and the comparator are repeated in a randomised order, and with suitable washout time, over a defined period. N-of-1 design is constrained for use in chronic stable conditions, and for interventions that have quick onset and cessation of effect, with modest or negligible carryover. Outcome data can be aggregated and interpreted for the individual subject; they can also be pooled with data from several similar N-of-1 trials, enabling more generalisable conclusions. THE N-OF-1 TRIAL IN CAM: The typical individualisation of patient care can be accommodated in N-of-1 study design if the patient and the specific therapeutic intervention are selected within the constraints of the method. Application of the N-of-1 method in CAM has been advocated but has been mainly limited, in practice, to a small number of studies in herbal and traditional Chinese medicine. THE N-OF-1 TRIAL IN HOMEOPATHY: Individualised homeopathy can be accommodated for investigation within the same methodological constraints; less in-depth homeopathic approaches to prescribing are also amendable to investigation using the N-of-1 method. No such studies have been published. We identify three main targets in its ready applicability to homeopathy: (1) to optimise clinical care in an individual patient; (2) to investigate whether the outcomes of treatment using homeopathy differ from those of placebo; (3) to aggregate data from a series of N-of-1 trials to enable broader conclusions about a group of patients or intervention. CONCLUSION: The N-of-1 trial design offers important new investigative possibilities in homeopathy and should be explored as a means to optimise individualised health care or investigate effectiveness of the homeopathic intervention compared with placebo in individual subjects.

Systematic Review and Meta-Analysis of Randomised, Other-than-Placebo Controlled, Trials of Individualised Homeopathic Treatment.

BACKGROUND: This study focuses on randomised controlled trials (RCTs) of individualised homeopathic treatment (IHT) in which the control (comparator) group was other than placebo (OTP). AIMS: To determine the comparative effectiveness of IHT on health-related outcomes in adults and children for any clinical condition that has been the subject of at least one OTP-controlled trial. For each study, to assess the risk of bias and to determine whether its study attitude was predominantly 'pragmatic' or 'explanatory'. METHODS: Systematic review. For each eligible trial, published in the peer-reviewed literature up to the end of 2015, we assessed its risk of bias (internal validity) using the seven-domain Cochrane tool, and its relative pragmatic or explanatory attitude (external validity) using the 10-domain PRECIS tool. We grouped RCTs by whether they examined IHT as an alternative treatment (study design Ia), adjunctively with another intervention (design Ib), or compared with a no-intervention group (design II). For each RCT, we identified a 'main outcome measure' to use in meta-analysis: 'relative effect size' was reported as odds ratio (OR; values >1 favouring homeopathy) or standardised mean difference (SMD; values < 0 favouring homeopathy). RESULTS: Eleven RCTs, representing 11 different medical conditions, were eligible for study. Five of the RCTs (four of which in design Ib) were judged to have pragmatic study attitude, two were explanatory, and four were equally pragmatic and explanatory. Ten trials were rated 'high risk of bias' overall: one of these, a pragmatic study with design Ib, had high risk of bias solely regarding participant blinding (a bias that is intrinsic to such trials); the other trial was rated 'uncertain risk of bias' overall. Eight trials had data that were extractable for analysis: for four heterogeneous trials with design Ia, the pooled OR was statistically non-significant; collectively for three clinically heterogeneous trials with design Ib, there was a statistically significant SMD favouring adjunctive IHT; in the remaining trial of design 1a, IHT was non-inferior to fluoxetine in the treatment of depression. CONCLUSIONS: Due to the low quality, the small number and the heterogeneity of studies, the current data preclude a decisive conclusion about the comparative effectiveness of IHT. Generalisability of findings is limited by the variable external validity identified overall; the most pragmatic study attitude was associated with RCTs of adjunctive IHT. Future OTP-controlled trials in homeopathy should aim, as far as possible, to promote both internal validity and external validity.

HRI Malta 2017-Cutting Edge Research in Homeopathy: HRI's Third International Research Conference in Malta.

The third international conference on "Cutting Edge Research in Homeopathy" organised by the Homeopathy Research Institute (HRI) was held on the inspiring and historic island of Malta from 9th to 11th of June, 2017. One hundred and two abstracts underwent peer review by the HRI Scientific Advisory Committee and external experts to produce the programme of 36 oral presentations and 37 posters, presented by researchers from 19 countries. The 2.5-day programme covered a diverse range of topics, including quantitative and qualitative clinical research, basic research, veterinary research, and provings. These intensive plenary and parallel sessions were interspersed with multiple opportunities for delegates to discuss and exchange ideas, in particular through interactive panel discussions and a pre-conference workshop. The continuing commitment of the homeopathy research community to generate high-quality studies in this rapidly evolving field was clear. In this conference report, we present highlights from this memorable event.

Model validity of randomised placebo-controlled trials of non-individualised homeopathic treatment.

BACKGROUND: The comprehensive systematic review of randomised placebo-controlled trials (RCTs) in homeopathy requires examination of a study's model validity of homeopathic treatment (MVHT) as well as its risk of bias (extent of reliable evidence). OBJECTIVE: To appraise MVHT in those RCTs of non-individualised homeopathy that an associated investigation had judged as 'not at high risk of bias'. DESIGN: Systematic review. METHODS: An assessment of MVHT was ascribed to each of 26 eligible RCTs. Another 49 RCTs were ineligible due to their high risk of bias. MAIN OUTCOME MEASURES: MVHT and the prior risk of bias rating per trial were merged to obtain a single overall quality designation ('high', 'moderate', 'low'), based on the GRADE principle of downgrading. RESULTS: The trials were rated as 'acceptable MVHT' (N = 9), 'uncertain MVHT' (N = 10) and 'inadequate MVHT' (N = 7); and, previously, as 'reliable evidence' (N = 3) and 'non-reliable evidence' (N = 23). The 26 trials were designated overall as: 'high quality' (N = 1); 'moderate quality' (N = 18); 'low quality' (N = 7). CONCLUSION: Of the 26 RCTs of non-individualised homeopathy that were judged 'not at high risk of bias', nine have been rated 'acceptable MVHT'. One of those nine studies was designated 'high quality' overall ('acceptable MVHT' and 'reliable evidence'), and is thus currently the only reported RCT that represents best therapeutic practice as well as unbiased evidence in non-individualised homeopathy. As well as minimising risk of bias, new RCTs in this area must aim to maximise MVHT and clarity of reporting.

Veterinary homeopathy: systematic review of medical conditions studied by randomised trials controlled by other than placebo.

BACKGROUND: No systematic review has previously been carried out on randomised controlled trials (RCTs) of veterinary homeopathy in which the control group was an intervention other than placebo (OTP). For eligible peer-reviewed RCTs, the objectives of this study were to assess the risk of bias (RoB) and to quantify the effect size of homeopathic intervention compared with an active comparator or with no treatment. METHODS: Our systematic review approach complied fully with the PRISMA 2009 Checklist. Cochrane methods were applied to assess RoB and to derive effect size using standard meta-analysis methods. Based on a thorough and systematic literature search, the following key attributes of the published research were distinguished: individualised homeopathy (n = 1 RCT)/non-individualised homeopathy (n = 19); treatment (n = 14)/prophylaxis (n = 6); active controls (n = 18)/untreated controls (n = 2). The trials were highly diverse, representing 12 different medical conditions in 6 different species. RESULTS: No trial had sufficiently low RoB to be judged as reliable evidence: 16 of the 20 RCTs had high RoB; the remaining four had uncertain RoB in several domains of assessment. For three trials with uncertain RoB and without overt vested interest, it was inconclusive whether homeopathy combined with conventional intervention was more or was less effective than conventional intervention alone for modulation of immune response in calves, or in the prophylaxis of cattle tick or of diarrhoea in piglets. CONCLUSION: Due to the poor reliability of their data, OTP-controlled trials do not currently provide useful insight into the effectiveness of homeopathy in animals.

Homeopathic Oscillococcinum® for preventing and treating influenza and influenza-like illness.

BACKGROUND: Influenza is a highly infectious viral disease that is particularly common in the winter months. Oscillococcinum® is a patented homeopathic medicine that is made from a 1% solution of wild duck heart and liver extract, which is then serially diluted 200 times with water and alcohol. OBJECTIVES: To determine whether homeopathic Oscillococcinum® is more effective than placebo in the prevention and/or treatment of influenza and influenza-like illness in adults or children. SEARCH METHODS: We searched CENTRAL (2014, Issue 8), MEDLINE (1966 to August week 4, 2014), MEDLINE In-Process & Other Non-Indexed Citations (4 September 2014), AMED (2006 to September 2014), Web of Science (1985 to September 2014), LILACS (1985 to September 2014) and EMBASE (1980 to September 2014). We contacted the manufacturers of Oscillococcinum® for information on further trials. SELECTION CRITERIA: Randomised, placebo-controlled trials of Oscillococcinum® in the prevention and/or treatment of influenza and influenza-like illness in adults or children. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data and assessed risk of bias in the eligible trials. MAIN RESULTS: No new trials were included in this 2014 update. We included six studies: two prophylaxis trials (327 young to middle-aged adults in Russia) and four treatment trials (1196 teenagers and adults in France and Germany). The overall standard of trial reporting was poor and hence many important methodological aspects of the trials had unclear risk of bias. There was no statistically significant difference between the effects of Oscillococcinum® and placebo in the prevention of influenza-like illness: risk ratio (RR) 0.48, 95% confidence interval (CI) 0.17 to 1.34, P value = 0.16. Two treatment trials (judged as 'low quality') reported sufficient information to allow full data extraction: 48 hours after commencing treatment, there was an absolute risk reduction of 7.7% in the frequency of symptom relief with Oscillococcinum® compared with that of placebo (risk difference (RD) 0.077, 95% CI 0.03 to 0.12); the RR was 1.86 (95% CI 1.27 to 2.73; P value = 0.001). A significant but lesser effect was observed at three days (RR 1.27, 95% CI 1.03 to 1.56; P value = 0.03), and no significant difference between the groups was noted at four days (RR 1.11, 95% CI 0.98 to 1.27; P value = 0.10) or at five days (RR 1.06, 95% CI 0.96 to 1.16; P value = 0.25). One of the six studies reported one patient who suffered an adverse effect (headache) from taking Oscillococcinum®. AUTHORS' CONCLUSIONS: There is insufficient good evidence to enable robust conclusions to be made about Oscillococcinum® in the prevention or treatment of influenza and influenza-like illness. Our findings do not rule out the possibility that Oscillococcinum® could have a clinically useful treatment effect but, given the low quality of the eligible studies, the evidence is not compelling. There was no evidence of clinically important harms due to Oscillococcinum®.