British Ivermectin Recommendation Development Panel –

Response to EMA Statement on Ivermectin for Covid-19

On 22 March, the European Medicines Agency (EMA) issued a statement [0] that, after reviewing
the evidence, they recommend against the use of ivermectin for the prevention and treatment of
covid-19, outside of ‘well-designed’ clinical trials. The EMA claims evidence from laboratory
studies, clinical trials, observational studies, and meta-analysis, but provides no sources, specifics
or citations. We fill these omissions below.

The British Ivermectin Recommendation Development (BIRD) panel was set up in January 2021
by Dr Tess Lawrie of the Evidence-Based Medicine Consultancy Ltd (E-BMC), an independent
medical research company based in Bath, UK. A systematic review and meta-analysis of
ivermectin for covid-19 was recently conducted by Dr Lawrie, the director, with a team of expert
systematic reviewers. A preliminary report was released in the public domain on 3 January [1]. A
comprehensive paper including 21 RCTs has been submitted to a peer-reviewed journal, and
meanwhile is available on two pre-print servers [2 ,3]. Moreover, on 20 February 2021, a panel of
65 clinicians, researchers and patient representatives from 16 countries attended the BIRD panel
meeting, convened by Dr. Lawrie and her team, to evaluate the evidence on ivermectin for covid-
19.

Following the standard “DECIDE” Evidence-to-Decision framework [4] for clinical

recommendations, BIRD concluded that there was enough evidence to recommend the rapid
implementation of ivermectin for covid-19 [5, 6]. This recommendation is by implication global
and not restricted to the UK or the EU. Indeed, the low cost and widespread use make ivermectin
uniquely placed to tackle covid-19 worldwide, including very low income countries.

BIRD provides a detailed response to the EMA statement, with citations to the evidence.

EMA advice against ivermectin for the prevention or treatment of COVID-19:

1. Review of the evidence

EMA has reviewed the latest evidence on the use of ivermectin for the prevention and treatment of
COVID-19 and concluded that the available data do not support its use for COVID-19 outside well-
designed clinical trials. … Results from clinical studies were varied, with some studies showing no
benefit and others reporting a potential benefit. Most studies EMA reviewed were small and had
additional limitations, including different dosing regimens and use of concomitant medications. EMA
therefore concluded that the currently available evidence is not sufficient to support the use of
ivermectin in COVID-19 outside clinical trials.

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 Ivermectin's potential therapeutic utility has expanded over the last decade as broad-spectrum
anti-viral and even anti-neoplastic properties have been discovered [7, 8]. Since April 2020, the
evidence base of observational and randomised trials of ivermectin for covid-19 has accumulated.
A review [9, 10] by the Front Line Covid-19 Critical Care Alliance (FLCCC) summarised findings from
27 randomised controlled trials (RCTs) and 16 observational studies on ivermectin both for
prevention and treatment of covid-19. They conclude that ivermectin “demonstrates a strong
signal of therapeutic efficacy.” Moreover, ivermectin is the sole therapeutic so far to have
demonstrated efficacy at all stages of the very complex clinical course of the covid-19 disease,
from prophylaxis through to critical care.

A systematic review and meta-analysis [2, 3] was subsequently conducted by Dr Lawrie and a
team of experts. Twenty-one RCTs involving 2741 participants met review inclusion, according to
strict criteria, and subsequent meta-analysis of 13 trials found that ivermectin reduced risk of
death (compared to no ivermectin) with an average Risk Ratio 0.32 [ 95% confidence interval (CI)
0.14 to 0.72; n=1892; I2=57% ] with “low to moderate-certainty.” Low certainty evidence found
ivermectin prophylaxis reduced the risk of covid-19 infection by an average of 86% [95% CI 79% to
91%]. Adverse events were rare and usually attributable to other adjunct medications.

In practical terms this means that ivermectin reduces the risk of death from covid-19 to about
one-third of the risk of death without using this medication. In the long run, of every nine patients
who would otherwise die from covid-19, six can now be saved by using ivermectin. Similarly the
risk of contracting covid-19 is reduced to one-seventh of the risk faced by other healthy people
with similar exposure, when using ivermectin as prophylaxis. For every seven people who would
catch covid-19 from an infected person, only one is likely to catch the illness, when using
ivermectin.

To our knowledge, in addition to the narrative review of Kory et al. [9, 10] and the rigorous
meta-analysis of Bryant et al [2,3] , three1 other systematic reviews have so far been conducted
viz.: Hill et al [11] (commissioned by the WHO); Castañeda-Sabogal et al [12]; and Nardelli et al
[13]. That of Nardelli is brief, but consistent with our own 2. Hence, of the five reviews to date, only
Castañeda-Sabogal is negative, and in methodological assessment against the AMSTAR 2 criteria
[15] scores very poorly, as does that of Hill [11, 2, 3]. Hill et al nevertheless report a 75% reduction
in mortality, whilst inconsistently opining that the “results are insufficient for review by regulatory
authorities.” This is not a conclusion that follows from the evidence.

1
A fourth review (Cobos-Campos et al. [14]) is available at https://t.co/EDRx8vyqoe but its DOI reference
10.15761/CRT.1000333 has been over-ridden, contrary to the principles of the Digital Object Identifier system.
2
Though reporting an Odds Ratio rather than Risk Ratio. The difference is merely the choice of a different metric.

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 It is significant that the review by Bryant et al [2, 3] (on which the recommendation of BIRD is
based) is the most up-to-date systematic review and meta-analysis. It is also the first, and to date
the only one, to use the strict Cochrane systematic review methodology [16]. These review
procedures interpret findings in light of risk of bias in individual trials and thereby derive a
“certainty of the evidence” for each of the clinical outcomes for which data exists. “Low Certainty”
in this context has a technical meaning: that further research is “likely” to change the quantitative
estimate of the effect and “very likely” to change our confidence in it. “Moderate” certainty
means that further research “may” change the estimate, and is “likely” to change our confidence
in it. The low-to-moderate certainties reported do not mean that the therapeutic effect is weak:
on the contrary, the observed effect is strong and consistent for all of the clinical “outcomes” for
which evidence is available.

The evidence base does not end with the trials covered by Bryant et al [2, 3] which deliberately
restricted itself to reports from Randomised Controlled Trials (RCTs). These are considered the
highest quality of evidence by regulators, but other high-quality observational trials (OCTs) are
available, covering many more patients, and which endorse the findings of the RCTs. Comparisons
between the reliability of RCTs versus OCTs (such comparisons being themselves reviewed by strict
Cochrane methods [17]) show that high-quality OCTs are as reliable as RCTs in their findings. It is
illogical not to consider them in addition.
Finally ‘real world’ whole-country case studies, of which the most completely described is that
of Peru [18], show striking reductions of covid-related deaths and infections as soon as ivermectin
distribution is implemented on a wide scale. 25 countries are now using ivermectin against covid-
19, 15 of them country-wide with official endorsement [19]. Several Indian States have adopted
ivermectin as official policy, serving a total population of around 400 million. Within the EU itself,
ivermectin has already been adopted by three countries (Bulgaria, Czech Republic, Slovakia).
In summary: The EMA’s position is inconsistent with the findings of 4/5 reviews, the fifth being
methodologically poor. It is inconsistent with policy already adopted in 25 countries, including
three Member States of the EU itself.

2. Dosage and Safety

Although ivermectin is generally well tolerated at doses authorised for other indications, side effects
could increase with the much higher doses that would be needed to obtain concentrations of
ivermectin in the lungs that are effective against the virus. Toxicity when ivermectin is used at higher
than approved doses therefore cannot be excluded.

Two distinct claims are implied: (i) That efficacy against covid-19 requires higher concentrations
than in the anti-parasitic indications; (ii) That safety in those higher concentrations is not
established. Neither assumption is borne out by the evidence.

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(i) That adequate lung or serum concentrations (derived from initial in vitro EC50 values reported
by Caly et al [20]) may not be achievable in vivo is a well-known controversy in the literature
(e.g. [21]). It is however already refuted by the clinical trials showing a consistent therapeutic
effect in dosages either no higher, or up to double, the standard dose of 200g/kg
recommended for strongyloidiasis [22]. Schedules [5] do not exceed 5 doses, and in most
protocols just 2 or 3 are recommended. Many protocols standardize on a fixed 12 mg dose,
corresponding to 200g/kg only at a body weight of 60 kg, light-weight for many adults.
(ii) The safety of ivermectin is better-established than almost any other medicine in the
pharmacopaeia, having been distributed worldwide in “Mass Drug Administration” (MDA)
campaigns for the control and elimination of tropical parasites [23]. The cumulative number of
doses now exceeds 3.8 billion [24], approximately half of the world’s population. Moreover
detailed safety studies [25] show that ivermectin is well-tolerated in doses up to 10  the FDA
maximum indicated for strongyloidiasis, giving a more than adequate therapeutic range.

Several other safety studies are available. An expert review report of over 500 studies assessed
reported adverse events associated with the use of ivermectin, and found that adverse events
were rare, and mostly mild to moderate [26]. Many of the adverse reactions relate to the
treatment of parasitic infections with inflammation and irritation caused by the decay of dead or
dying internal parasites; these are of course completely irrelevant to the treatment of covid-19.
An extreme example of continuous administration of ivermectin is its use in treatment of
childhood leukaemia, where daily doses of 1 mg/kg or 60 mg (5 x the strongyloidiasis dose,
repeated daily) were continued for six months. The 13-yr old patient’s only complaint related to
the smell of ivermectin [27] (dispensed as an oral solution in some countries, rather than a tablet).
A Phase 1 clinical trial validating the safety of continuous administration of ivermectin,
authorised by the Medicines & Healthcare products Regulatory Agency (MHRA, the UK regulator),
found no side effects with the first two doses administered [28].

Records [29] show only 16 deaths from ivermectin ingestion since 1992. This drug that has
been used for 30 years, for a range of indications, in colossal quantities, with adverse reaction
reports that are either at a very low rate, or mild to trivial (e.g. headache).
In summary: (i) High doses are plainly not essential (though dose-optimising trials should
certainly be welcomed. Current covid-19 protocol doses are well within previously established safe
ranges. (ii) Likewise, whilst further pharmacovigilance is always welcome, ivermectin is an
exceptionally safe drug, with negligible rates of serious adverse events, and only trivial common
side effects, which must of course be compared to the symptoms and risks of the disease itself.

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3. Recommendation that Ivermectin be restricted to clinical trials

EMA therefore concluded that use of ivermectin for prevention or treatment of COVID-19 cannot
currently be recommended outside controlled clinical trials.

As discussed above, this recommendation is based upon a review of the evidence that is
inconsistent with five of out of six positive reviews of ivermectin already available, and consistent
only with a single review that is methodologically poor. It is a recommendation in defiance of
decisions in 25 countries, including three Member States of the EU itself.
A restriction to clinical trials supposes that the effect of ivermectin remains unknown. This is
simply not so. Many important clinical trials have already been done. The reported effects are
strong, and overwhelmingly in the beneficial direction. Whilst the “certainty” of the evidence is
low, or “low to moderate” (as reported in the review [2, 3] on which the BIRD recommendation is
based) this does not mean the effect is weak. It means that further and better-quality evidence
may change either the quantitative measure of benefit, or our confidence in it. The evidence that
some positive benefit exists is already clear.
When a treatment has been found to be effective, it is unethical to perform further controlled
clinical trials for a potentially life-threatening illness using a placebo arm. They would also violate
international law protocols such as the Helsinki Protocols for clinical trials [30]. Further clinical
trials should be restricted to (i) dose-optimising trials, (ii) trials comparing the effect of various
adjunct medications commonly used at various disease stages (antibiotics, other anti-virals,
vitamins and minerals, anti-inflammatories and anti-coagulants) and (iii) contact trials quantifying
reduction of contagion when used as a prophylactic.
Emergency authorization has been granted for therapeutics (e.g. remedesivir) with less
positive evidence and more negative safety profiles than we currently have for ivermectin.
Ivermectin itself has been approved by the WHO in the scabies indication, and added to the
Essential Medicines list (including the Children’s list) in that indication, on an evidence base plainly
weaker than the systematic reviews already available for covid-19 [31].
In summary: It is time for regulatory authorities to recognize that ivermectin’s effectiveness in
covid-19 has already been demonstrated, and that its general safety profile is extremely well-
known. In a pandemic situation, regulators should approve this very safe medicine for routine use,
at the clinical discretion of any licensed medical practitioner. Further delay can lead only to further
unnecessary loss of life.
The Evidence-Based Medicine Consultancy Ltd, Bath, England 26 March 2021

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References

[0] European Medicines Agency. EMA advises against use of ivermectin for the prevention or
treatment of COVID-19 outside randomised clinical trials. Statement 22 March 2021.
https://www.ema.europa.eu/en/news/ema-advises-against-use-ivermectin-prevention-treatment-covid-
19-outside-randomised-clinical-trials

[1] Lawrie, T. (2021). Ivermectin reduces the risk of death from Covid-19 – a rapid review and
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E-BMC Ltd report, 3 January, at www.e-bmc.co.uk
[2] Bryant, A., Lawrie, T.A., Dowswell, T., Fordham, E.J., Mitchell, S., Hill, S.R. & Tham, T.C. (2021).
Ivermectin for prevention and treatment of COVID-19 infection: a systematic review and meta-
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