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

Abstract

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.

Keywords

comparative effectiveness - explanatory trial - non-individualised homeopathic treatment - meta-analysis - pragmatic trial - randomised controlled trial - risk of bias - systematic review

Highlights

• This systematic review focuses on randomised controlled trials (RCTs) of non-individualised homeopathic treatment (NIHT) in which the control (comparator) group was other than placebo.

• For each eligible trial, risk of bias was assessed using Cochrane methods, and its relative pragmatic or explanatory attitude was approximated using the PRECIS tool.

• Seventeen RCTs, representing 15 different medical conditions, were eligible for inclusion.

• Fourteen RCTs were rated ‘high risk of bias’; the other three trials were rated ‘uncertain risk of bias’.

• Only three RCTs were judged to have clearly pragmatic study attitude.

• Quantitative data extraction did not yield a decisive conclusion about the comparative effectiveness of NIHT.

Authors' Contributions

RTM devised and led the study, developed the study protocol and contributed to all facets of the work. YYYF helped to develop the study protocol, co-assessed trials for risk of bias, co-assessed trials for pragmatic/explanatory study attitude, contributed to data interpretation and edited the manuscript. PV helped to develop the study protocol, co-assessed trials for pragmatic/explanatory study attitude, contributed to data interpretation and edited the manuscript. AKLT co-assessed trials for risk of bias and contributed to data interpretation. JRTD helped to develop the study protocol, contributed to data interpretation and edited the manuscript. All authors have approved the final manuscript.

Competing Interests

Authors RTM, YYYF, PV and AKLT are (or were) associated with a homeopathy organisation whose significant aim is to clarify and extend an evidence base in homeopathy. RTM holds an independent research consultancy contract with the Deutsche Homöopathie-Union, Karlsruhe, Germany. YYYF and AKLT belong to Living Homeopathy Ltd., which has contributed funding to some (but not this current) HRI project work. RTM and PV have no other relationships or activities that could appear to have influenced the submitted work. JRTD had no support from any organisation for the submitted work; in the last 3 years, and for activities outside the submitted study, he received personal fees, royalties or out-of-pocket expenses for advisory work, invitational lectures, use of rating scales, published book chapters or committee membership; he receives royalties from Springer Publishing Company for his book, A Century of Homeopaths: Their Influence on Medicine and Health. JTRD has no other relationships or activities that could appear to have influenced the submitted study.

• References

• 1 Swayne J. International Dictionary of Homeopathy. Edinburgh: Churchill Livingstone; 2000
• 2 Mathie RT, Ulbrich-Zürni S, Viksveen P. , et al. Systematic review and meta-analysis of randomised, other-than-placebo controlled, trials of individualised homeopathic treatment. Homeopathy 2018; 107: 229-243
• 3 Mathie RT, Lloyd SM, Legg LA. , et al. Randomised placebo-controlled trials of individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 2014; 3: 142
• 4 Mathie RT, Ramparsad N, Legg LA. , et al. Randomised, double-blind, placebo-controlled trials of non-individualised homeopathic treatment: systematic review and meta-analysis. Syst Rev 2017; 6: 63
• 5 Ernst E. Classical homeopathy versus conventional treatments: a systematic review. Perfusion (Nürnberg) 1999; 12: 13-15
• 6 Treweek S, Zwarenstein M. Making trials matter: pragmatic and explanatory trials and the problem of applicability. Trials 2009; 10: 37
• 7 Sedgwick P. External and internal validity in clinical trials. BMJ 2012; 344: e1004
• 8 Sedgwick P. Explanatory trials versus pragmatic trials. BMJ 2014; 349: g6694
• 9 Bornhöft G, Maxion-Bergemann S, Wolf U. , et al. Checklist for the qualitative evaluation of clinical studies with particular focus on external validity and model validity. BMC Med Res Methodol 2006; 6: 56
• 10 Thorpe KE, Zwarenstein M, Oxman AD. , et al. A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers. J Clin Epidemiol 2009; 62: 464-475
• 11 Mathie RT, Fok Y, Viksveen P. , et al. Systematic review and meta-analysis of randomised, other-than-placebo (OTP) controlled, trials of individualised homeopathic treatment (IHT): Study protocol. Version 1.2; 25 January 2018. Available at: https://www.hri-research.org/hri-research/learning-more-from-existing-evidence/systematic-review-programme/
• 12 Mathie RT, Hacke D, Clausen J, Nicolai T, Riley DS, Fisher P. Randomised controlled trials of homeopathy in humans: characterising the research journal literature for systematic review. Homeopathy 2013; 102: 3-24
• 13 Baker DG, Myers SP, Howden I, Brooks L. The effects of homeopathic Argentum nitricum on test anxiety. Complement Ther Med 2003; 11: 65-71
• 14 Higgins JPT, Altman DG. Assessing risk of bias in included studies. In: Higgins JPT, Green S. , eds. Cochrane Handbook for Systematic Reviews of Interventions; Version 5.1.0. The Cochrane Collaboration; 2011. . Chapter 8
• 15 Linde K, Clausius N, Ramirez G. , et al. Are the clinical effects of homeopathy placebo effects? A meta-analysis of placebo-controlled trials. Lancet 1997; 350: 834-843
• 16 Shang A, Huwiler-Müntener K, Nartey L. , et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet 2005; 366: 726-732
• 17 Hewitt CE, Torgerson DJ, Miles JNV. Is there another way to take account of non-compliance in randomized controlled trials?. Can Med Assoc J 2007; 175: 347-348
• 18 Higgins JPT, Deeks JJ, Altman DG. Special topics in statistics. In: Higgins JPT, Green S. , eds. Cochrane Handbook for Systematic Reviews of Interventions; Version 5.1.0. The Cochrane Collaboration: ; 2011. . Chapter 16
• 19 Sedgwick P. Equivalence trials. BMJ 2013; 346: f184
• 20 Sedgwick P. What is a non-inferiority trial?. BMJ 2013; 347: f6853
• 21 Deeks JJ, Higgins JPT, Altman DG. Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S. , eds. Cochrane Handbook for Systematic Reviews of Interventions; Version 5.1.0. The Cochrane Collaboration; 2011. . Chapter 9
• 22 Chinn S. A simple method for converting an odds ratio to effect size for use in meta-analysis. Stat Med 2000; 19: 3127-3131
• 23 Schünemann HJ, Oxman AD, Vist GE. , et al. Interpreting results and drawing conclusions. In: Higgins JPT, Green S. , eds. Cochrane Handbook for Systematic Reviews of Interventions; Version 5.1.0. The Cochrane Collaboration; 2011. . Chapter 12
• 24 Palm J, Kishchuk VV, Ulied À. , et al; TocTo Research Group. Effectiveness of an add-on treatment with the homeopathic medication SilAtro-5-90 in recurrent tonsillitis: An international, pragmatic, randomized, controlled clinical trial. Complement Ther Clin Pract 2017; 28: 181-191