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Supplementary
memorandum submitted by Edzard Ernst (HO 16a)
In the document submitted on 5 November
2009, I stated that "systematic reviews or meta-analyses of the totality of the
clinical trial data fail to show that homeopathic remedies generate clinical
effects beyond those of placebo". This is an appendix substantiating this claim
which I ask to be attached to my previously submitted evidence.
1. Systematic reviews of homeopathy
In 2002, I published a summary 1 of all systematic reviews that emerged after Linde's positive Lancet
meta-analysis (first row in Table 1). Six re-analyses of Linde's data -
including two by Linde himself [never cited by homeopaths!] - arrived at a less
than positive conclusion (Table 1). Furthermore, 11 new and independent
systematic reviews published after Linde's article also fail to conclude that
homeopathy is effective (Table 2). Since the publication of my article 1, further negative systematic reviews have appeared, e.g. the
well-known one by Shang et al in the Lancet 2 and our review of homeopathy for childhood conditions 3.
2. Shang et al
Probably, the review by Shang et al [2] has
been criticised by homeopaths. While no review can ever be without limitations,
these criticisms have been refuted. If needed, I can provide further written
evidence on this issue.
3. The
evidence is getting weaker
We published a further analysis testing
whether the evidence for or against homeopathy is getting stronger. 4 It compares the old 5 with the
new edition 6 of one of our books. Both are based on systematic
reviews employing virtually the same methodology5, 6. The indications included in our
books are those which are common in primary care, frequently treated with CAM and for which clinical trials are available. The
literature was searched up to March 2000 for the first 5 and up to May 2005 for the second
edition 6. To evaluate the data, we created
a parameter which we called the "weight of the evidence". This was a compound
variable consisting of the level of evidence (e.g. whether there was a single
trial or a meta-analysis), the quality of the primary studies and the volume (i.e.
total number of trials and their total sample size) 7. The weight was graded in 3
categories: low, moderate and high. We graded the direction of the evidence in
5 categories: clearly positive, tentatively positive, uncertain, tentatively
negative and clearly negative. In Table 3, we compared the weight and direction
of the evidence of homeopathy for treating those conditions which were included
in our book: AIDS, anxiety, asthma, cancer, chronic fatigue syndrome,
fibromyalgia, hay fever, headache, hypertension, labour induction, migraine, osteoarthritis, overweight, premenstrual syndrome,
rheumatoid arthritis, stroke, tinnitus and upper respiratory tract infection. Our comparison suggests that, as more clinical trials of homeopathy
become available, the overall evidence gets not stronger but weaker. For 4
conditions for which no trial evidence had been available in 2000, new evidence
had emerged in 2005. In three cases, this was clearly negative, and in one it
was rated as uncertain. Changes in either the weight or the direction of the
evidence were observed in 4 of the 18 homeopathy-related indications (Table 3). By definition, the weight could
only grow between 2000 and 2005. For one condition, namely chronic fatigue
syndrome, the direction of evidence changed in a "positive" sense. For three
indications, the evidence had altered in the opposite sense: anxiety, asthma,
rheumatoid arthritis. (Table 3)
4.
Other evidence
Homeopaths
often argue that there are further systematic reviews which allegedly do show
that homeopathy works. Examples are a recent Swiss Health Technology Assessment
or the review by Mathie 8. The problem is that these
articles do not fulfil the formal criteria for a systematic review, originate
from homeopaths, are open to bias and can be criticised on important
methodological grounds 9.
5. Conclusion
Systematic
reviews of rigorous trials of homeopathy fail to demonstrate that homeopathic
remedies have effects beyond those of placebo. Monitoring the development of
the evidence over time we find that the overall evidence-base of homeopathy is
becoming more and more negative. Confronted with such data, homeopaths tend to
counter that the method of testing homeopathy in clinical trials is flawed and
the hierarchy of evidence is of disputed value. Nowadays they frequently cite
Sir Michael Rawlins (NICE) in support of this view who recently gave a lecture
discussing that the evidence from randomised clinical trials should not be seen
in isolation. Homeopaths fail to mention, however, that Sir Michael also made the
following statement about homeopathy: "As far as homeopathy is concerned it breaks
every rule in the evidential base! It is biologically implausible; it is almost
always used to treat conditions where the natural history is unpredictable; and
the signal to noise ratio is close to one!". 10
Table 1
The systematic review by Linde et al 11 and its subsequent
re-analyses
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Reference
|
Included trials (number)
|
Total patient number
|
Assessment of
methodological quality
|
Meta-analysis
|
Overall conclusion*
|
Comment
|
|
Linde
(1997)
11
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all double-blind and/or randomized
placebo-controlled trials of any clinical condition
(n=186)
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2588
|
yes
|
of 89 trials which could be submitted to
meta-analysis: OR = 2.45;of 26 "good quality trials": OR = 1.66 (both in
favour of homeopathy)
|
clinical effects of homeopathy are not
completely due to placebo
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review was criticised for
1)including different remedies
2) including different conditions
3) including non-randomized trials
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Ernst
(1998)
12
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all studies from Linde et al 11 which received 90 (of 100) points
in at least 1 of the 2 quality ratings, using highly dilute remedies,
following the principles of "classical"* homeopathy
(n=5)
|
587
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yes
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OR=1.0
(no evidence in favour of homeopathy)
|
homeopathic remedies are associated with
the same clinical effects as placebo
|
this analysis specifically tested the
efficacy of highly diluted remedies (other remedies could still work via
conventional pharmaceutical effects)
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|
Linde
(1998)
13
|
all trials from Linde et al 11 which tested "classical"*
homeopathic remedies against placebo, no treatment or another treatment
(n=32)
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1778
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yes
|
19 placebo-controlled trials were
submitted to meta-analysis; OR = 1.62; however, when this analysis was
restricted to the methodologically best trials the effect was no longer
significant
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individualised homeopathy has an effect
over placebo; the evidence, however, is not convincing
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not all of the included trials were
randomized and many had other serious methodological weaknesses
|
|
Linde
(1999)
14
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all trials from Linde et al 11 which could be submitted to meta-analysis
(n=89)
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n.d.p.
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yes
|
the
mean OR of the best studies was not in favour of homeopathy
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there was clear evidence that studies
with better methodological quality tended to yield less positive results
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the authors felt that these results
"weaken the findings of [their] original
meta-analysis"
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Morrison
(2000)
15
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26 trials classified by Linde et al 11 as high quality
(n=26)
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n.d.p.
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yes
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none
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no significant trend was seen when
correlating security of randomisation and trial result
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large multicenter trials were recommended
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Ernst
(2000)
16
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all trials from Linde et al 11 that received quality ratings
between 1-4 on the Jadad score
(n=77)
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n.d.p.
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yes
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none
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there is a...strong linear correlation
between OR and Jadad score (n=0.97, p<0.05); homeopathic remedies are, in
fact, placebos
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extrapolation from this correlation
implies that the most rigorous studies yield an effect size of zero
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Sterne
(2000)
17
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89 trials of Linde et al 11 review compared to 89 trials of allopathic medicines
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n.d.p.
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yes
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strong evidence for publication bias
causing a false positive result in favour of homeopathy
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when adjusting high quality trials [of
homeopathy] for publication bias, the OR changed from 0.52 to 1.19 but
remained unchanged for allopathy
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paper probably not peer-reviewed,
adjusting for bias nullified the effect of homeopathy but not for allopathy
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RCT
= randomized clinical trial, OR = odds ratio, * = verbatim quotes, n.d.p. = no details provided.
° classical homeopathy = approach where
remedies are individualised according to patient characteristics deemed
important by homeopaths.
Table 2
Independent systematic reviews of homeopathy
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Reference
|
Included trials (number)
|
Total patient number
|
Assessment of
methodological quality
|
Meta-analysis
|
Overall conclusion
|
Comment
|
|
Barnes
(1997)
18
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all placebo-controlled trials of
homeopathy for post-operative ileus
(n=6)
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776
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yes
|
weighted mean difference to time until
first sign of peristalsis was in favour of homeopathy (-7.4 hours)
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homeopathic treatment can reduce the
duration of post-operative ileus, however, several caveats preclude a
definitive judgement
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the methodologically best trial was
convincingly negative
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Ernst
(1998)
19
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all placebo-controlled trials of
homeopathy for delayed onset muscle soreness (DOMS)
(n=8)
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311
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yes
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no meta analysis possible, all randomized
trials were negative
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the evidence does not support he
hypothesis that homeopathic remedies are more efficacious than placebo for
DOMS
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DOMS was chosen because it was submitted
to clinical trials more often than any other condition
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Ernst
(1998)
20
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all placebo-controlled trials of
homeopathic arnica
(n=8)
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338
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yes
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no meta-analysis possible, no clear trend
in favour of homeopathy
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the claim that homeopathic arnica is
efficacious beyond a placebo effect is not supported by rigorous clinical
trials
|
this analysis set out to test the remedy
that had been most frequently submitted to clinical trials, i.e. arnica (see
also Lüdtke below)
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Ernst
(1999)
21
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all RCTs of homeopathy for migraine
prophylaxis (n=4)
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284
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yes
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no meta-analysis possible; 3 of 4 trials
were negative (including the methodologically best)
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the trial data...do not suggest that
homeopathy is effective in the prophylaxis of migraine or headache beyond a
placebo effect
|
this analysis tested the efficacy for a
condition that homeopaths often treat in clinical practice
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Ernst
(1999)
22
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all controlled clinical trials of
"classical"* homeopathy versus conventional treatments (n=6)
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605
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no
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no meta-analysis possible
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no clear trend in favour of homeopathy
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non-randomized studies were also included
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|
Lüdtke
(1999)
23
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all controlled clinical trials of
homeopathic arnica
(n=37)
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n.d.p.
|
yes
|
no meta-analysis possible
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no clear evidence in favour of
homeopathic arnica was found
|
paper probably not peer-reviewed, trials
that used arnica in combination with other remedies and those which were not
placebo controlled were also included
|
|
Cucherat
(2000)
24
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all RCTs of homeopathy vs placebo with
clinical or surrogate endpoints (n=16)
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2617
|
yes
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combined 2-tailed p value was highly
significant (p=0.000056) in favour of homeopathy
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there is some evidence that homeopathic
treatments are more effective than placebo
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strength of evidence was estimated to be
low by the authors
|
|
Vickers
(2000)
25
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all RCTs of homeopathic oscillococcinum
vs placebo for influenza (n=7)
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3459
|
yes
|
RR=0.64 for influenza prevention;RR=0, 28
for influenza treatment
|
treatment reduced length of illness
significantly by 0.28 days
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the authors stated that "the data are not
strong enough to make a general recommendation"
|
|
Linde
(2000)
26
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all RCTs of homeopathy vs placebo for
chronic asthma
(n=3)
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154
|
yes
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no meta-analysis possible
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no clear tread in favour of homeopathy
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not enough evidence for reliable
assessment
|
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Jonas
(2000)
27
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all controlled clinical trials of
homeopathy for rheumatic conditions (n=6)
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392
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yes
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combined OR = 2.19
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homeopathic remedies work better than
placebo
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not enough trials for any specific
condition to allow reliable assessment
|
|
Long
(2001)
28
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all RCTs of homeopathy for osteoarthritis
(n=4)
|
406
|
yes
|
no meta-analysis possible
|
no clear trend in favour of homeopathy
|
not enough evidence for reliable
assessment
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RCT
= randomized clinical trial, OR = odds ratio, RR = relative risk
* classical homeopathy = approach where
remedies are individualised according to patient characteristics deemed
important by homeopaths.
Table 3
Summary of clinical evidence for homeopathic medicines
(comparison of old and new editions of 'The Desktop Guide to Complementary and
Alternative Medicine')
|
Condition
|
Weight of Evidence
|
Direction of evidence
|
|
|
2000
|
2005
|
2000
|
2005
|
|
AIDS/HIV
infection
|
O
|
O
|
ö
|
ö
|
|
anxiety
|
O
|
OO
|
ö
|
ø
|
|
asthma
|
OO
|
OO
|
ð
|
ø
|
|
cancer palliation
|
no entry
|
O
|
no entry
|
ò
|
|
chronic fatigue syndrome*
|
O
|
OO
|
ö
|
ñ
|
|
fibromyalgia
|
O
|
O
|
ö
|
ö
|
|
hay fever*
|
OO
|
OO
|
ñ
|
ñ
|
|
headache
|
O
|
O
|
ò
|
ò
|
|
hypertension
|
no entry
|
O
|
no entry
|
ò
|
|
labour induction
|
no entry
|
OO
|
no entry
|
ò
|
|
migraine
|
OO
|
OO
|
ø
|
ø
|
|
osteoarthritis
|
O
|
O
|
ö
|
ö
|
|
overweight/obesity
|
no entry
|
O
|
no entry
|
ð
|
|
premenstrual
syndrome
|
O
|
O
|
ñ
|
ñ
|
|
rheumatoid
arthritis
|
OO
|
OO
|
ö
|
ð
|
|
stroke
|
O
|
O
|
ò
|
ò
|
|
tinnitus
|
O
|
O
|
ò
|
ò
|
|
upper
respiratory tract infection
|
OO
|
OO
|
ð
|
ð
|
* For two
conditions, the direction of the evidence is positive but the weight of the evidence
is not sufficient to justify positive recommendations
Legend
OOO high weight
of evidence
OO moderate weight of
evidence
O low
weight of evidence
ñ clearly positive
evidence
ö tentatively positive
evidence
ð uncertain
evidence
ø tentatively
negative evidence
ò clearly
negative evidence
Reference List
(1) Ernst E. A systematic review of systematic
reviews of homeopathy. Br J Clin Pharmacol 2002; 54:577-582.
(2) Shang A, Huwiler-Müntener K, Nartey L, Jüni P,
Sterne JAC, Pewsner D 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.
(3) Altunc U, Pittler MH, Ernst E. Homeopathy for
childhood and adolescence ailments: systematic review of randomized clinical
trials. Mayo Clin Proc 2007; 82(1):69-75.
(4) Ernst E, Pittler MH, Wider B, Boddy K.
Homeopathy: is the evidence-base changing? Perfusion 2006; 19:1-3.
(5) Ernst E, Pittler MH, Stevinson C, White AR.
The Desktop Guide to Complementary and Alternative Medicine. 1st Edition.
Edinburgh: Mosby. 2001.
(6) Ernst E, Pittler MH, Wider B, Boddy K. The
Desktop Guide to Complementary and Alternative Medicine. 2nd edition.
Edinburgh: Elsevier Mosby. 2006.
(7) Jadad AR, Moore RA, Carrol D, Jenkinson C,
Reynolds DJM, Gavaghan DJ et al. Assessing the quality of reports of randomized
clinical trials - is blinding necessary?
Contr Clin Trials 1996; 17:1-12.
(8) Mathie RT. The research base for homeopathy: a
fresh assessment of the literature. Homeopathy 2003; 92:80-87.
(9) Ernst E. Weighing the homeopathic evidence.
Homeopathy 2003; 92:67-68.
(10) Rawlins M. As cited in Rose L, BMJ Rapid Response. BMJ Rapid
Response 2009; 14 July.
(11) Linde K, Clausius N, Ramirez G, Melchart D, Eitel F, Hedges LV et
al. Are the clinical effects of homoeopathy placebo effects? A meta-analysis of
placebo-controlled trials. Lancet 1997; 350:834-843.
(12) Ernst E. Are highly dilute homoeopathic remedies placebos? Perfusion
1998; 11:291-292.
(13) Linde K, Melchart D. Randomized controlled trials of individualized
homeopathy: a state-of-the-art review. J Alt Complementar Med 1998; 4(371):388.
(14) Linde K, Scholz M, Ramirez G, Clausius N, Melchart D, Jonas WB.
Impact of study quality on outcome in placebo controlled trials of homoeopathy.
J Clin Epidemiol 1999; 52:631-636.
(15) Morrison B, Lilford RJ, Ernst E. Methodological rigour and results
of clinical trials of homoeopathic remedies. Perfusion 2000; 13:132-138.
(16) Ernst E, Pittler MH. Re-analysis of previous meta-analysis of
clinical trials of homeopathy. J Clin Epidemiol 2000; 53:1188.
(17) Sterne J, Egger M, Smith GD. Investigating the dealing with
publication and other biases. In: Systmeatic reviews in healthcare:
meta-analysis in context. In: Egger M, Smith GD, Altman DG, editors. London:
2001. 189-208.
(18) Barnes J, Resch KL, Ernst E. Homeopathy for Postoperative Ileus. J
Clin Gastroenterol 1997; 25:628-633.
(19) Ernst E, Barnes J. Are homoeopathic remedies effective for
delayed-onset muscle soreness? A systematic review of placebo-controlled
trials. Perfusion 1998; 11:4-8.
(20) Ernst E, Pittler MH. Efficacy of homeopathic arnica. A systematic review of
placebo-controlled clinical trials. Arch Surg 1998; 133:1187-1190.
(21) Ernst E. Homoeopathic prophylaxis of headaches and migraine? A
systematic review. J Pain Sympt Managem 1999; 18:353-357.
(22) Ernst E. Classical homoeopathy versus conventional treatments: a
systematic review. Perfusion 1999; 12:13-15.
(23) Ludtke R, Wilkens J. Klinische Wirksambeitsstudien zu Arnica in
homoeopathischen Zubereitungen. In: Company Report, Carstents Stiftung. Essen,
German: 1999.
(24) Cucherat M, Haugh MC, Gooch M, Boissel J-P. Evidence of clinical
efficacy of homeopathy. A meta-analysis of clinical trials. Eur J Clin
Pharmacol 2000; 56:27-33.
(25) Vickers AJ, Smith C. Homeopathic oscillococcinum for preventing and
treating influenza and influenza-like syndromes. The Cochrane Library 2001;
1:1-10.
(26) Linde K, Jobst KA. Homeopathy for chronic asthma. The Cochrane
Library 1998; 1:1-7.
(27) Jonas WB, Linde K, Ramirez G. Homeopathy and rheumatic disease.
Rheum Dis Clin North Am 2000; 26:117-123.
(28)
Long L, Ernst E. Homeopathic remedies
for the treatment of osteoarthritis: a systematic review. Br Homeopath J 2001;
90:37-43.
Edzard
Ernst MD, PhD, FMedSci, FSB, FRCP, FRCPEd
Complementary Medicine, Peninsula Medical
School, Universities of Exeter & Plymouth
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