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Model validity of randomised placebo-


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homeopathic treatment

Article in Homeopathy · September 2017


DOI: 10.1016/j.homp.2017.07.003

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Homeopathy (2017) 106, 194e202
Ó 2017 The Faculty of Homeopathy. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.homp.2017.07.003, available online at http://www.sciencedirect.com

ORIGINAL PAPER

Model validity of randomised


placebo-controlled trials of
non-individualised homeopathic
treatment
Robert T Mathie1,*, Michel Van Wassenhoven2, ALB (Lex) Rutten3, Christien T Klein-Laansma4, Jose Eizayaga5,
Anna Pla i Castellsague6, Miek C Jong4,7,8, Raj K Manchanda9, Flavio Dantas10, Menachem Oberbaum11,
Joyce Frye12, Helmut Roniger13, Stephan Baumgartner14, Robbert van Haselen15, Ton Nicolai3 and Peter Fisher13
1
Homeopathy Research Institute, 142 Cromwell Road, London SW7 4EF, UK
2
Belgian Homeopathic Medicines Registration Committee, FAMHP (Federal Agency for Medicines and Health Products),
Belgium
3
Independent Researcher
4
Department Nutrition & Health, Louis Bolk Institute, Driebergen, The Netherlands
5
Department of Homeopathy, Maimonides University, Buenos Aires, Argentina
6
Research Sub-committee, European Committee for Homeopathy, Belgium
7
Department of Health Sciences, Mid-Sweden University, Sundsvall, Sweden
8
National Information and Knowledge Centre for Integrative Medicine, The Netherlands
9
Central Council for Research in Homoeopathy, India
10
Faculty of Medicine, Federal University of Uberl^ andia, Uberl^andia, Brazil
11
Shaare Zedek Medical Center, Jerusalem, Israel
12
Center for Integrative Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
13
Royal London Hospital for Integrated Medicine, London, UK
14
Institute of Integrative Medicine, University of Witten-Herdecke, Germany
15
International Institute for Integrated Medicine, Kingston, UK

Background: The comprehensive systematic review of randomised placebo-controlled


trials (RCTs) in homeopathy requires examination of a study’s model validity of homeo-
pathic 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).

*Correspondence: Robert T Mathie, Homeopathy Research Institute, 124 Cromwell Road, London SW7 4ET, UK.
E-mail: robertmathie@hri-research.org, Michelvw@homeopathy.be, praktijk@dokterrutten.nl, ctlaansma@planet.nl, jose.eizayaga@
gmail.com, pla.c.anna@gmail.com, m.jong@louisbolk.nl, rkmanchanda@gmail.com, dantas@ufu.br, oberbaum@netvision.net.il,
joyce.frye@gmail.com, helmut.roniger@uclh.nhs.uk, stephan.baumgartner@uni-wh.de, vanhaselen@intmedi.com, tonnicolai@me.
com, peter.fisher@uclh.nhs.uk
Received 1 February 2017; revised 23 June 2017; accepted 31 July 2017
Model validity of randomised placebo-controlled trials
RT Mathie et al
195
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 un-
biased 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. Homeop-
athy (2017) 106, 194e202.

Keywords: Model validity; Non-individualised homeopathy; Randomised placebo-


controlled trials; Risk of bias; Systematic review

Background Objective: To appraise MVHT in the RCTs of non-


individualised homeopathy which, in an associated investi-
Our programme of systematic reviews and meta-analyses gation,9 were judged to be not at ‘high risk of bias’.
of randomised placebo-controlled trials (RCTs) in homeop- Through this approach, we aimed to identify the overall
athy includes examination of each eligible trial’s risk of bias high-, moderate- and low-quality evidence in RCTs of
as well as of its model validity (MV). The latter attribute re- non-individualised homeopathic treatment.
flects the concordance between the trial design and ideal
practice for the intervention under investigation, and is a
key facet of study quality in RCTs of complementary/alter- Methods
native medicine (CAM) therapies such as homeopathy.1e3
We have previously reported our evaluations of RCTs of Inclusion criteria for RCTs
individualised homeopathic treatment, presenting the We applied our MVHT assessment method (which was
findings in connected papers.4e6 We concluded that an designed to examine RCTs of either individualised or
individually prescribed homeopathic medicine may have non-individualised homeopathy) to peer-reviewed papers
a small treatment effect beyond that of placebo; however, reporting randomised, placebo-controlled trials of non-
decisive interpretation was undermined by the paucity of individualised homeopathic treatment, published up to
high-quality evidence.4,6 and including 2014. Through formal literature search
The present paper focuses on placebo-controlled RCTs methods, 110 records were identified as being potentially
of non-individualised homeopathic treatment. Trials of eligible for systematic review in this RCT category: after
this nature comprise the majority of the RCT literature application of pre-defined exclusion criteria, 72 records
in homeopathy.7 Akin to a conventional drug trial, these (reporting a total of 75 RCTs) remained eligible for sys-
are studies in which the same homeopathic medicine (or tematic review.9 Of those 75 RCTs, 49 were rated as
its corresponding placebo) has been given to each of ‘high’ risk of bias (relevant details in Appendix 1)9; the re-
the trial participants. The in-depth, individualised, ho- maining 26 RCTs (‘uncertain’ or ‘low’ risk of bias) were
meopathic prescribing approach is therefore not involved. therefore the material for the present study on MVHT (de-
Instead, non-individualised homeopathy trials have some tails, including reference citations,10e35 in Table 1).
basis in clinical homeopathy, in which a single medicine,
or combination of medicines, is prescribed to an individ-
ual patient on the basis of a specified somatic symptom or Assessment of model validity
set of symptoms.8 The medicine may be a single tradi- The development of our criteria-based method for
tional homeopathic remedy (e.g. Arnica), or a formulation MVHT has been described in detail elsewhere.3,5 The
of several remedies that is either a proprietary medicine assessment domains are as follows:
(‘complex medicinal product’) or a unique formulation Domain I (Rationale): Would a significant body of ac-
prepared for the purposes of the research. Alternatively, credited homeopaths support the rationale for the interven-
the single medicine may be a homeopathic nosode based tion used in the study?
on the principle of isopathy (‘the use of medicines Domain II (Principles): Is the specific intervention used
derived from a causative agent of the disease itself, or consistent with homeopathic principles?
from a product of the disease process, to treat the condi- Domain III (Practitioner): Does the study have suitably
tion’8). qualified and experienced homeopathic practitioner input?
The extent to which these several modes of homeopathy Domain IV (Outcome measure): Does the main
are successfully reflected in RCTs of non-individualised outcome measure reflect the main effect expected of the
treatment is the subject of the present paper. As previ- intervention used?
ously,5 we assess model validity of homeopathic treatment Domain V (Outcome sensitivity): Is the main outcome
(MVHT), defined as the extent to which a homeopathic measure capable of detecting change?
intervention and the main measure of its outcome, as im- Domain VI (Follow-up): Is the length of follow-up for
plemented in an RCT, reflect best clinical practice in home- the main outcome measure appropriate to detect the in-
opathy. tended effect of the intervention?

Homeopathy
Homeopathy

196
Table 1 The 26 trials that were assessed for model validity of homeopathic treatment (MVHT)

No. Author, date [Ref] Category Condition Main outcome measure Endpoint Hom. type

Model validity of randomised placebo-controlled trials


A47 Baker, 200310 Mental disorder Anxiety Revised test anxiety (RTA) scale 4d Single
A48 Balzarini, 200011 Dermatology Radiodermatitis Index of total severity during recovery (RTSI) (re: skin 7e8 wk Combination
colour, temp, oedema, pigmentation)
A272 Colau, 201212 Obstetrics & gynaecology Menopausal syndrome Hot flash score 12 wk OTC complex
A61 Cornu, 201013 Surgery & anaesthesiology Post-operative bleeding Cumulated blood loss at drain removal Up to 7 d Combination
A62 Diefenbach, 199714 Respiratory infection Bronchitis Treatment success (‘very good’ + ‘good’ results) e Up to 3 wk OTC complex
physician assessed
A64 Ferley, 198915 Respiratory infection Influenza Proportion of patients recovered (from 5 cardinal By 48 h Isopathy*
symptoms and from temp>37.5)
16
A67 Frass, 2005 Respiratory infection Tracheal secretions Total volume of tracheal secretions per day 2d Single
A75 GRECHO, 198917 Surgery & anaesthesiology Post-operative ileus Number of hours from operation until first stool Up to 100 h approx. Combination
A79 Hofmeyr, 199018 Obstetrics & gynaecology Postpartum pain Daily questionnaire responses: perineal pain 4d Single

RT Mathie et al
A83 Kaziro, 198419 Surgery & anaesthesiology Post-operative pain/swelling Pain score (VAS) 8d Single
A92 Leaman, 198920 Dermatology Minor burns Pain (0e10 VAS) e area under curve 6h Single
A93 Lewith, 200221 Allergy & asthma Allergic asthma Asthma VAS 16 wk Isopathy
A292 Malapane, 201422 Ear, nose & throat Tonsillitis Tonsillitis pain score (Wong-Baker FACES) 6d OTC complex
A290 Naidoo, 201323 Allergy & asthma Allergic skin reaction Wheal diameter 4 wk Combination
A100 Oberbaum, 200124 Oral/dental Stomatitis Area-under-curve (AUC) score for stomatitis 14 d minimum OTC complex
symptoms (severity and duration)
A103 Padilha, 201125 Toxicology Lead poisoning Proportion of workers with Pb decrease of at least 30 d Single
25%
26
A104 Papp, 1998 Respiratory infection Influenza Proportion of patients with physician-assessed By 48 h Isopathy*
recovery in health (i.e. ‘no symptoms’)
A105 Paris, 200827 Surgery & anaesthesiology Post-operative analgesic intake Cumulated consumption of morphine < 10 mg/day 24 h post-op Combination
A112 Reilly, 199428 Allergy & asthma Allergic asthma Proportion with improvement in daily overall VAS 4 wk Isopathy
score
A120 Singer, 201029 Surgery & anaesthesiology Post-operative pain Maximum daily pain at rest, using 11-point numerical 13 d OTC complex
rating scale (NRS-11)
A123 Taylor, 200030 Allergy & asthma Perennial allergic rhinitis Proportion with improvement in daily overall VAS 3e4 wk Isopathy
score
31
A125 Tveiten, 1991 Musculoskeletal Muscle soreness Muscle soreness (VAS) 3d Single
A126 Tveiten, 199832 Musculoskeletal Muscle soreness Muscle soreness (VAS) 3d Single
A128 Vickers, 199833 Musculoskeletal Muscle soreness Muscle soreness (VAS) 2d Single
A135 Wiesenauer, 199534 Allergy & asthma Seasonal allergic rhinitis Free of nasal symptoms 4 wk Single
A137 Zabolotnyi, 200735 Ear, nose & throat Sinusitis Sinusitis severity score (SSS) cf. Day 0 21 d OTC complex

VAS: visual analogue scale.


* Equivocal categorisation.
Model validity of randomised placebo-controlled trials
RT Mathie et al
197
For each paper, three members of our group were Merging MVHT and risk of bias into overall quality
randomly allocated to judge MVHT; no individual was designation
allocated to assess any of his/her own published papers, Risk of bias, including the description reliable evidence
thus removing any potential conflict of interest. The pa- as applicable, was attributed per trial as previously re-
pers’ authorship was not anonymised, and assessors were ported.4 In brief, a trial was designated ‘low’, ‘uncertain’
asked to read the Results and Discussion sections only if or ‘high’ risk of bias, based on the standard seven Cochrane
essential for clarifying relevant methodological details. assessment domains (Appendix 3): reliable evidence was
On a dedicated Excel spreadsheet, each assessor recorded attributed to a low risk-of-bias trial or to one whose uncer-
a judgment of ‘Yes’, ‘Unclear’ or ‘No’ to each domain’s tainty in risk of bias was restricted to a single pre-specified
question. For the domain III (Practitioner) criterion, we domain; all other trials were rated non-reliable evidence.9
added clarification that, for these non-individualised For each of the 26 trials, our separate ratings for risk of
RCTs, relevant details of the practitioners was neces- bias36 and for MVHT were merged to obtain a single over-
sarily stated in the paper only if focusing its MV assess- all quality designation (‘high’, ‘moderate’ or ‘low’ qual-
ment solely on homeopathic experience (i.e. if the ity), based on the GRADE principle of ‘downgrading’37
assessment was not being based, alternatively, on citation e Appendix 4. Thus, for example, a trial attained an overall
of a suitable literature source that informed the choice of designation of ‘high quality’ if it had no important defi-
the medicine(s) used) e see Appendix 2. The assessors ciency in either MVHT or risk of bias rating.
sent their independent reports, by e-mail, to the study
coordinator (RTM), who collected the findings and ana- Results
lysed the data.
In an RCT for which no domain was judged ‘No’ by any Assessment ratings per domain
independent assessor, and if no more than two domains Over all 26 trials (156 domains of assessment in total),
presented minor discrepancies per domain (e.g. two ‘Yes’ there were 78 domains (50% of the total number) that
and one ‘Unclear’ judgment), the recorded overall achieved unanimous votes (Table 2) during independent
MVHT was accepted by default, using the majority vote assessment; unanimity was least evident for domain II.
for the domains indicated. For an RCT in which there Consensus discussion took place for each of the remaining
were widely discrepant assessments in at least one domain 78 domains.
(e.g. two ‘Yes’ and one ‘No’ judgment), or in which there In some cases, application of the MVHT method was
were minor discrepancies in at least three domains, the distinctly challenging: this occurred notably for domain I
final assessment per domain was reached through in trials that involved the use of Arnica for running-
consensus discussion (via e-mail), arbitrated if necessary associated muscle soreness or for some complex medicinal
by the study coordinator. products such as Traumeel. Follow-up discussion on these
matters concluded that both categories typically comprised
Overall MVHT ratings and classifications acceptable MVHT, though consensus was not achieved for
We rated MVHT for each trial across all six domains and domain I in two of the trials that involved a complex medic-
using the following nomenclature7: inal product (A120 Singer29; A292 Malapane22): the ques-
tion was whether one or more of the homeopathic
A = ‘Yes’, as above, in all six domains. ingredients could reasonably be used for the treated condi-
Bx = ‘Unclear’, as above, in x domains; ‘Yes’ in all other tion or specified symptoms. It was agreed that ‘isopathy’
domains. was an equivocal categorisation for the two Oscillococci-
Cy.x = ‘No’, as above, in y domains; ‘Unclear’ in x do- num trials (A64 Ferley15; A104 Papp26).
mains; ‘Yes’ in all other domains.
As in the Cochrane approach to risk of bias,36 an overall MVHT rating and classification per trial
classification approach was used to ensure that the most Table 3 details the final MVHT assessments, by domain,
important aspects of study quality prevailed in assessment. per trial. For three of the trials, unanimity was achieved for
An ‘A’-rated trial was automatically designated ‘accept- all six domains without the need for consensus discussion
able MVHT’. A ‘B1’-rated trial was regarded as having (see Table 3). Overall, deficiencies of MVHT were most
acceptable MVHT if it was judged ‘Yes’ for each of do- frequently recorded for domains I (Rationale), II (Princi-
mains I, II, IV and V and ‘Unclear’ for domain III or ples), III (Practitioner) and V (Outcome sensitivity).
domain VI: in tabulations and text below, this rating is Seven trials were rated ‘A’, and were thus classified
shown as ‘B1*’. Other ‘B’-rated trials were designated ‘un- ‘acceptable MVHT’; two ‘B1*’ trials (i.e. ‘Unclear’
certain MVHT’. A ‘C’-rated trial was designated ‘inade- for domain III or domain VI only) were also classified
quate MVHT’. ‘acceptable MVHT’, giving a total of nine RCTs in this

Table 2 Frequency of unanimous assessments per domain in first (independent) round of assessment of 26 eligible trials

Domain I II III IV V VI Total


Rationale Principles Practitioner Outcome Sensitivity Follow-up
Frequency 10/26 7/26 11/26 18/26 13/26 19/26 78/156
(38.5%) (26.9%) (42.3%) (69.2%) (50.0%) (73.1%) (50.0%)

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Model validity of randomised placebo-controlled trials
RT Mathie et al
198
Table 3 Consensus assessments per domain, with overall MVHT rating and classification per trial

No. First author Domain of assessment No. of ‘Y’ No. of ‘U’ No. of ‘N’ MVHT rating Classification

I II III IV V VI

A272 Colau Y Y Y Y Y Y 6 0 0 A Acceptable MVHT


A67 Frass* Y Y Y Y Y Y 6 0 0 A
A93 Lewith Y Y Y Y Y Y 6 0 0 A
A112 Reilly Y Y Y Y Y Y 6 0 0 A
A123 Taylor Y Y Y Y Y Y 6 0 0 A
A126 Tveiten Y Y Y Y Y Y 6 0 0 A
A292 Malapane Yy Y Y Y Y Y 6 0 0 A
A48 Balzarini* Y Y U Y Y Y 5 1 0 B1*
A135 Wiesenauer Y Y U Y Y Y 5 1 0 B1*
A62 Diefenbach Y Y Y Y U Y 5 1 0 B1 Uncertain MVHT
A83 Kaziro* U Y Y Y Y Y 5 1 0 B1
A125 Tveiten Y Y Y Y U Y 5 1 0 B1
A128 Vickers Y Y Y Y U Y 5 1 0 B1
A290 Naidoo U Y Y Y Y Y 5 1 0 B1
A75 GRECHO U Y U Y Y Y 4 2 0 B2
A104 Papp U U Y Y Y Y 4 2 0 B2
A137 Zabolotnyi U U Y Y Y Y 4 2 0 B2
A64 Ferley U U U Y Y Y 3 3 0 B3
A79 Hofmeyr Y Y U Y U U 3 3 0 B3
A100 Oberbaum Y N Y Y Y Y 5 0 1 C1.0 Inadequate MVHT
A120 Singer Yy N U Y Y Y 4 1 1 C1.1
A61 Cornu U N Y Y U Y 3 2 1 C1.2
A105 Paris Y Y Y U N U 3 2 1 C1.2
A103 Padilha U U U Y U N 1 4 1 C1.4
A92 Leaman U N U N Y Y 2 2 2 C2.2
A47 Baker U U N U U N 0 4 2 C2.4
No. of ‘Y’ per domain 16 17 17 23 18 22
No. of ‘U’ per domain 10 5 8 2 7 2
No. of ‘N’ per domain 0 4 1 1 1 2

* Unanimity achieved for each domain without need for consensus discussion.
y
Majority vote: consensus not achieved among assessors.

classification. The remaining five ‘B1’ trials (with ‘Un- post-operative pain. The clinical category Obstetrics & Gy-
clear’ for domain I or domain V), together with five that naecology had the highest overall quality designation of
were rated ‘B2’ or lower, made a total of ten classified as ‘moderate’/‘high’, reflecting the sole high-quality trial’s
‘uncertain’ MVHT. Seven trials were rated ‘C’, and thus topic of menopausal syndrome. The overall quality was
classified ‘inadequate’ MVHT. There were no obvious dif- ‘moderate’ within four categories (Allergy & Asthma,
ferences in MVHT e either by domain or by overall Ear Nose & Throat, Musculoskeletal, Respiratory Infec-
rating e depending on the type of non-individualised tion), and in five categories it was ‘low’ or ‘moderate’/
homeopathy (single, combination or complex medicine, ‘low’.
or isopathy).
Discussion
Overall quality designation This study represents the second practical application of
Only one of the three trials previously rated as reliable our MVHT assessment method. We have reconfirmed that,
evidence had acceptable MVHT (A272 Colau12): this sin- in general, there is no ‘undue difficulty in the ability of
gle trial was therefore designated ‘high quality’ overall; three specialists to achieve a reasonable consensus agree-
the other two trials regarded as reliable evidence (A103 Pa- ment in judging the relevant issues’5: for 50% of the 156
dilha25; A120 Singer29) had inadequate MVHT, and so domains in total, independent assessment attained unanim-
were down-graded to ‘low quality’ overall (Table 4). Of ity without any need for consensus discussion. However,
the remaining 23 trials (i.e. those with non-reliable evi- these non-individualised trials did prove more challenging
dence), eight had acceptable MVHT, 10 had uncertain to assess for MVHT than their counterparts in individual-
MVHT, and five had unacceptable MVHT. The 26 trials ised homeopathy.5 Extra effort to reach consensus for
were thus designated overall as: ‘high quality’ (N = 1); domain I (rationale), for example, was sometimes needed
‘moderate quality’ (N = 18); ‘low quality’ (N = 7). for those trials that used a complex homeopathic prepara-
Table 5 lists the overall quality designation of each trial tion.
by the clinical condition it investigated (as previously char- In the current study, some assessors needed clarification
acterised7). For clinical conditions in which there have about the correct interpretation of the criteria for domain I,
been at least two RCTs without high risk of bias, the overall and specifically about the meaning of ‘Whether a substan-
quality designation was ‘moderate’ for allergic asthma, tial number of experienced homeopaths would support the
muscle soreness and influenza, and ‘moderate’/‘low’ in choice of this intervention for this type of patient’: ‘this

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Model validity of randomised placebo-controlled trials
RT Mathie et al
199
Table 4 Ordering of 26 trials by overall quality designation

Ref. First author MVHT Risk of bias9 Downgrading Overall designation

A272 Colau Acceptable Low risk* 0 High quality


A67 Frass Acceptable Uncertain risk 1 Moderate quality
A93 Lewith Acceptable Uncertain risk 1 Moderate quality
A112 Reilly Acceptable Uncertain risk 1 Moderate quality
A123 Taylor Acceptable Uncertain risk 1 Moderate quality
A126 Tveiten Acceptable Uncertain risk 1 Moderate quality
A292 Malapane Acceptable Uncertain risk 1 Moderate quality
A48 Balzarini Acceptable Uncertain risk 1 Moderate quality
A135 Wiesenauer Acceptable Uncertain risk 1 Moderate quality
A62 Diefenbach Uncertain Uncertain risk 1 Moderate quality
A83 Kaziro Uncertain Uncertain risk 1 Moderate quality
A125 Tveiten Uncertain Uncertain risk 1 Moderate quality
A128 Vickers Uncertain Uncertain risk 1 Moderate quality
A290 Naidoo Uncertain Uncertain risk 1 Moderate quality
A75 GRECHO Uncertain Uncertain risk 1 Moderate quality
A104 Papp Uncertain Uncertain risk 1 Moderate quality
A137 Zabolotnyi Uncertain Uncertain risk 1 Moderate quality
A64 Ferley Uncertain Uncertain risk 1 Moderate quality
A79 Hofmeyr Uncertain Uncertain risk 1 Moderate quality
A103 Padilha Inadequate Low risk* 2 Low quality
A120 Singer Inadequate Uncertain risk* 2 Low quality
A100 Oberbaum Inadequate Uncertain risk 2 Low quality
A61 Cornu Inadequate Uncertain risk 2 Low quality
A105 Paris Inadequate Uncertain risk 2 Low quality
A92 Leaman Inadequate Uncertain risk 2 Low quality
A47 Baker Inadequate Uncertain risk 2 Low quality

* Reliable evidence (regarding risk of bias).

intervention’ was agreed by all to mean ‘this specific kind Concern was expressed within our group about the po-
of homeopathy’, as was its original intention. Likewise, for tential redundancy of domain III in the context of these
domain III, it was initially unclear to some assessors that a non-individualised trials: domain I (rationale) and domain
paper’s citation of a suitable reference e e.g. materia II (principles) might be seen as sufficient, since practi-
medica or repertory e was in fact sufficient to accept there tioners are not directly involved in prescribing the homeo-
had been ‘experienced homeopathic input’ to the design of pathic treatment. However, assessment of each MV domain
a non-individualised trial. The descriptive details for is an independent task. Thus evidence of satisfactory ho-
domain III (Practitioner) were updated accordingly meopathic rationale and principles (domains I and II)
(Appendix 2). does not necessarily guarantee that a trial actually had

Table 5 Overall quality designation of trials by category of clinical condition

Category of clinical condition Clinical condition Ref. First author Year Overall quality designation

Allergy & asthma Allergic asthma A93 Lewith 2002 Moderate quality
Allergic asthma A112 Reilly 1994 Moderate quality
Allergic skin reaction A290 Naidoo 2013 Moderate quality
Perennial allergic rhinitis A123 Taylor 2000 Moderate quality
Seasonal allergic rhinitis A135 Wiesenauer 1995 Moderate quality
Dermatology Minor burns A92 Leaman 1989 Low quality
Radiodermatitis A48 Balzarini 2000 Moderate quality
Ear, nose & throat Sinusitis A137 Zabolotnyi 2007 Moderate quality
Tonsillitis A292 Malapane 2014 Moderate quality
Mental disorder Anxiety A47 Baker 2003 Low quality
Musculoskeletal Muscle soreness A125 Tveiten 1991 Moderate quality
Muscle soreness A126 Tveiten 1998 Moderate quality
Muscle soreness A128 Vickers 1998 Moderate quality
Obstetrics & gynaecology Menopausal syndrome A272 Colau 2012 High quality
Postpartum pain A79 Hofmeyr 1990 Moderate quality
Oral/dental Stomatitis A100 Oberbaum 2001 Low quality
Respiratory infection Bronchitis A62 Diefenbach 1997 Moderate quality
Influenza A64 Ferley 1989 Moderate quality
Influenza A104 Papp 1998 Moderate quality
Tracheal secretions A67 Frass 2005 Moderate quality
Surgery & anaesthesiology Post-operative analgesic intake A105 Paris 2008 Low quality
Post-operative bleeding A61 Cornu 2010 Low quality
Post-operative ileus A75 GRECHO 1989 Moderate quality
Post-operative pain A120 Singer 2010 Low quality
Post-operative pain/swelling A83 Kaziro 1984 Moderate quality
Toxicology Lead poisoning A103 Padilha 2011 Low quality

Homeopathy
Model validity of randomised placebo-controlled trials
RT Mathie et al
200
sufficient homeopathic input (domain III). In fact, only Although 19 trials were judged as not overtly deficient
three trials were judged ‘Yes’e‘Yes’e‘Unclear’ in the first (i.e. ‘acceptable’ or ‘uncertain’) in MVHT, just one of
three domains. One of those (A48 Balzarini11) did not those (A272 Colau12) has been identified ‘reliable evi-
require any consensus discussion: its deficiency was that dence’9 and thus able to be designated ‘high quality’ over-
treatment involved homeopathic Belladonna and X-ray, all. Two trials rated as ‘reliable evidence’ by risk-of-bias
which was not justified in the paper. In the other two papers assessment9 (A103 Padilha25; A120 Singer29) were down-
(A79 Hofmeyr18; A135 Wiesenauer34), there was insuffi- graded to ‘low quality’ overall due to inadequate MVHT,
cient information to permit judgment of ‘Yes’ or ‘No’ showing that the best conventionally viewed evidence is
for domain III: neither paper gave adequate references not necessarily also the best evidence from a homeopathy
to assure us that the authors or practitioners were aware perspective. The remaining 56 of the 75 trials that were
of a relevant literature to inform their selection of the eligible for the overarching systematic review (i.e. the
homeopathic treatment used. Explicit assurance on this seven clearly MV-deficient RCTs plus the 49 that were
point is the purpose of domain III. Importantly, this is ineligible for this MV assessment due to their high risk of
one of the two domains where an ‘Unclear’ vote does not bias) can, at best, be designated ‘low quality’ overall. Sig-
preclude ‘B1*’ classification (‘acceptable MVHT’).5,6 nificant quality issues also pervade the RCT literature in
The Balzarini and Wiesenauer papers are both in that conventional medicine,38 though, to our knowledge, MV
‘B1*’ category; the Hofmeyr paper included other has not been addressed in that research context.
concerns, leading to a lower MVHT classification. In relative terms, RCTs of individualised homeopathy
Perceived deficiencies in the current trials regarding seem to possess a somewhat higher standard of MVHT,
domains I (rationale) and II (principles) may be explained though only three such trials have been designated ‘high
by the nature of non-individualised homeopathy in the quality’ overall.6 In meta-analysis, data from these three
RCT context. Both for single and for combination/com- high-quality trials suggested that the medicines prescribed
plex medicines, two questions often arose: (a) Was/were in individualised homeopathy have small effects that are
the medicine/s used a reasonable choice for a given symp- greater than placebo effects. Our meta-analysis results for
tom or set of symptoms? (b) Was every trial participant the current non-individualised trials are reported in a sepa-
likely to manifest the symptom/s matched to those medi- rate communication9: the pooled data reported for ‘reliable
cine/s? The clinical approach in the current trials does not evidence’ should now be viewed from the perspective of
require accurate matching between the symptoms caused the present MVHT findings, in which a singular trial
by a homeopathic medicine and those displayed by a pa- (A272 Colau12) comprises the high-quality evidence over-
tient, as in individualised homeopathy; instead, a pre- all. The present paper also reveals the clinical research cat-
selected medicine is applied to the typical symptoms of egories that contain the least deficient quality of evidence:
a clinical condition. In the normal practice of ‘clinical ho- Allergy & Asthma; Ear Nose & Throat; Musculoskeletal;
meopathy’, a medicine is prescribed on the basis of a pa- Obstetrics & Gynaecology; Respiratory Infection.
tient’s manifest symptoms; the choice of a medicine
based on typical symptoms for an RCT of non-
individualised homeopathy may therefore not equate to
Conclusions
that normal practice. If a trial investigates a homeopathic Of the 26 RCTs of non-individualised homeopathic
product that does not match symptoms manifested by all treatment that were previously judged ‘not at high risk of
participants, it can be expected to produce sub-optimal re- bias’, nine have also now been rated as ‘acceptable
sults: it is important that this possibility is understood by MVHT’. One of those nine trials had been rated ‘reliable
consumers using such products in self-treatment and by evidence’ and is thus the sole trial that can be designated
medical practitioners not trained in homeopathy. The ‘high quality’ overall (‘acceptable MVHT’ and ‘reliable
problem of sub-optimal matching of the medicine to the evidence’). That singular paper, a study on menopausal
patient is more explicit in RCTs of non-individualised ho- syndrome, is currently the only reported RCT that repre-
meopathy than in those of individualised homeopathy. sents best therapeutic practice as well as unbiased evidence
Interestingly, the main outcome measure was typically in non-individualised homeopathy. Together with minimis-
deemed able to reflect the effect expected of the given ho- ing risk of bias, new placebo-controlled RCTs of non-
meopathic intervention (domain IV), as was the case also individualised homeopathy must aim to maximise
for the individualised trials.5 MVHT, and with sufficient clarity of reporting to assist
We classified just nine of the 26 eligible trials (34%) as its independent assessment in systematic review.
‘acceptable MVHT’ overall, a lesser proportion than in the
corresponding assessment of individualised homeopathy
trials (59%).5 Moreover, these 26 are the non-
Sources of funding
individualised trials (from 75 in total) judged to be without None.
overt risk of bias: the MVHT of the other 49 remains un-
known at present. The MVHT of 10 of the 26 trials was
classified as ‘uncertain’, again highlighting the need for
Declaration of interest
original authors to report sufficient details in their publica- Three of the authors provide, or have provided in recent
tions to enable a complete and unequivocal appraisal. years, consultancy services to Boiron (RvH, PF), Deutsche

Homeopathy
Model validity of randomised placebo-controlled trials
RT Mathie et al
201
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multicentrique [Evaluation of the effects of two homeopathic prep-
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