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2022

Volume 8

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Editorial
Crisis of scientific assessment of drugs
Review
Resuming HPV vaccination is dangerous
New Products
Doubt about efficacy of molnupiravir
CONTENTS（April 2022, Vol. 8, No. 23）

Editorial
Crisis of scientific assessment of pharmaceutical products

2

Review
Resuming HPV vaccination is very dangerous

3

New Products
Antivirals for COVID-19:molnupiravir (Lagevrio®)
Doubt about efficacy due to serious baseline imbalance

11

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Apr. 2022/ Vol.8 No.23 ・ Page 1

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Editorial

HECK

Crisis of scientific assessment ofpharmaceutical products
Translated from the Editorial in Med Check(in Japanese) Jan. 2022 ; 22 (99)：3

Amidst all the media coverage of development,competitive procurement, and inoculation

HPV vaccine is harmful with no proof of efficacy
for prevention of cervical cancer.

procedure of COVID-19 vaccines, scientific andcritical media report for the efficacy and safety

Globally, there is almost no critical appraisalof the vaccines is very rare, although it is theof epidemiological studies that take healthy-

most important issue.

vaccinee effects into account. For that reason,
it is difficult to resist the trend of active

What is worse, many countries, including

recommendation of HPV vaccine in Japan where

France, which is known for mature democracy

it is widely believed that the vaccine would

and high scientific standards, are now practically

prevent HPV infection.

in the process of introducing compulsory
vaccination. In Japan, policies in Europe andHowever, if you calmly and scientifically lookthe United States are generally highly respected.

at the data analyzed in detail in this issue, you

Therefore, they often serve as an effective means

will understand how harmful and useless theto hold back Japanese policy makers wheneverHPV vaccine is.

sloppy policies are about to be introduced inJapan. However, we cannot expect this to workin the case of COVID-19 vaccines.

The data from the clinical trial of molnupiravir, an antiviral agent for COVID-19, also
had a bias in baseline characteristics that raise

While “disaster capitalism” expands due tothe introduction of COVID-19 vaccines, theserious questions about randomisation andblinding in all pivotal RCTs of molnupiravir.

Ministry of Health, Labor and Welfare of Japan

There is a reality that even peer-reviewed

issued a notice on November 26, 2021 to resume

papers published in leading medical journals areactive recommendation of the HPV vaccine (so-not reliable.

called cervical cancer vaccine), saying that there
were no particular concerns about safety.

It is necessary to reexamine the methodsof drug evaluation once again, based on the

Regarding the HPV vaccine, Med Check has
repeatedly questioned its efficacy and safety:

Page 2 ・ MED CHECK

Apr. 2022/ Vol.8 No.23

discipline of science.

Review
Resuming HPV vaccination is very dangerous
Translated from Med Check (in Japanese) Jan. 2022 ; 22 (99):22-23
Med Check Editorial Team

Abstract● Active recommendation of HPV vaccine will be resumed in April 2022 in Japan after 8-year suspension.
● Pooled odds ratio for all-cause mortality of 3 RCTs involving women aged 25 to 40 years was 5.00 (95% CI:1.71,
14.65, p=0.002). This clearly indicates that HPV vaccine is highly toxic.

● The data in a report of health science research group indicate serious healthy vaccinee effect and large risk ratioof “extensive pain and/or movement disorders” after HPV vaccination.
● A large-scale questionnaire survey (Nagoya study) indicates that those who became dependent on a walking stickor wheel chair after vaccination was about 47-fold as compared with the unvaccinated, by adjusting the risk before
vaccination.
● In the three epidemiological studies reporting that HPV vaccine reduced cervical cancer, healthy vaccinee bias
was not adjusted. If the bias is adjusted, all these studies cannot conclude that HPV vaccine reduced HPV associatedcancer including cervical cancer.
Conclusion: It is dangerous to resume the active recommendation based on the results of observational
studies which ignore healthy vaccinee effect.

Keywords:
HPV vaccine, Healthy vaccinee effect, disability, bias adjustment, active recommendation, mortality

Introduction
On November 26th, 2021, Japan’s Ministry of Health,Labour and Welfare (MHLW) decided to resume active

evidence for harm and critically reviews the data which the
MHLW referred to [2,3]. The overview was also published in
Med Check No.99 in Japanese (Jan. 2022) [24].

recommendation of HPV (human papillomavirus) vaccine, or socalled “cervical cancer vaccine” in April 2022 after the council

Five-fold increase in mortality in women aged 25 andhad approved the resumption on November 12th [1].

overAs the main basis for this decision, the MHLW refers to the

In randomized controlled trials (RCTs) for HPV vaccine,following two findings obtained during the 8-year suspension

involving women under 25 years old, there was no differenceof the active recommendation. One is the results of a healthin the incidence of adverse events nor mortality, as comparedscience research group led by Sofue, which has concluded

with the control [4a,5a,5b].

that various symptoms were found also in the non-vaccinatedwith the young age of the participants as well as the adjuvants[2]. Another is the UK study, which has reported that theused in these trials as comparator: an alum adjuvant was usedvaccination has contributed to the reduction in cervical cancer

as a comparator for “placebo group” in an RCT for Gardasil

incidence [3].

(FUTURE II study) [25] and a hepatitis A vaccine containing

However, as have been examined in Med Check [4-19], The
Informed Prescriber (TIP) [20,21] and others [22,23] in detail,This result is largely associatedalum adjuvant as a comparator in an RCT for Cervarix(PATRICIA trial) [26-28].

HPV vaccine is very harmful while there is no robust evidence

However, according to the meta-analysis using the data fromindicating that it reduces cervical cancer. This paper explains

3 RCTs (4 reports) for HPV vaccine, involving women aged 25
MED CHECK

Apr. 2022/ Vol.8 No.23 ・ Page 3

Review
Figure1:Mortality risk within 4 years after the first injection (Meta-analysis of 3 RCTs targeted mid-adult women)

HPV vaccine increases mortality by 5-times in mid-adultwomen (aged 24 or 25 years and older t). This clearly
indicates no benefit, but harm.
*a: Alum adjuvant was used in the control in VIVIANE
study (Cervarix) [29,30] and FUTURE III study (Gardasil)[31], and hepatitis B vaccine that contained alum adjuvant
was used in the control in Chinese study (Cervarix) [32].
*b: The follow-up time was 1 year in Chinese study [32] and4 years in the other 2 studies [29-31].

to 40 years [29-32], pooled odds ratio for the risk of all-cause

women had had symptoms before vaccination (Figure 2) .

mortality was 5.00 (95% CI:1.71, 14.65, p=0.002) [22] (Figure 1).

This is merely one-twentieth of the proportion of those withThis clearly indicates that HPV vaccine is highly toxic.

symptoms in the unvaccinated (20.4/100,000 persons). As theduration of observation before/after vaccination and duration of

The results of the health science research group led

observation of the unvaccinated are unknown, the proportion

by Sofuecannot be accurately compared. However, the proportion ofThis paper examines the results of the health science researchthose with symptoms drastically increased from 1.0/100,000

group led by Sofue [2], which the MHLW considers as one

persons before vaccination to 27.8/100,000 persons afterof the crucial pieces of evidence for the resumption of active

vaccination.

recommendation.

Contrarily, in women with no history of vaccination, theThe results were published in March 2017 in the healthproportion of those with symptoms should be constant forscience research of the fiscal year 2016 titled “Epidemiologicala few years when they are young. Unlike in the vaccinatedstudy on the evaluation of efficacy and safety of cervical cancer

women, it is quite unlikely that the proportion would change

vaccine”, of which Tomotaka Sofue was a chief researcher.

markedly (although it might show slight increases by aging).

This study concluded “in those aged 12 to 18 years, theSuppose the proportion of those with symptoms remains thecomplaining proportion (proportion of those reporting symptoms)

same throughout the half of the time when they are 12 to 18of ‘various symptoms which are similar to those assumed toyears old, in the first half (equivalent of “before vaccination” inhave occurred after HPV vaccination’ was …40.3/100,000

the vaccinated), it would be 10.2/100,000 persons. Based on

persons in women and 20.4/100,000 in unvaccinated women.

this, the proportion of those with symptoms before vaccination

In other words, even among the young unvaccinated, ‘various

is only one-tenth in the vaccinated women.

symptoms’ were experienced by the certain number of them.”

There were 4.0/100,000 persons in whom it was“Various symptoms which are similar to those assumed to

unknown whether the time of symptom onset was before

have occurred after HPV vaccination” refer to “extensive pain

or after vaccination. Even if they all had symptoms before

and/or movement disorders”. Based on this report, the MHLW

vaccination, the proportion of those with symptoms would

announced that “various symptoms are also found in the

be only 5/100,000 persons, which is only one-fourth of thatunvaccinated population.”in the unvaccinated women (20.4/100,000 persons) . When

Among 1590 women who reportedly had various

4/100,000 persons is proportionally distributed to 27.8 persons

symptoms, vaccination status was unknown in 604 womenand 1 person, the proportion of the vaccinated women with(nearly 40%), and the proportion of those reporting symptoms

symptoms before vaccination would be 1.14/100,000 persons.

was 27.8/100,000 persons in women with clear history ofThis is about one-ninth of 10.2 persons, the proportion of thevaccination. Very important data, which the research group andunvaccinated women with symptoms in the first half of thethe MHLW did not mention, should be introduced here.

time.

Among women who received HPV vaccine, only 1.0/100,000
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Apr. 2022/ Vol.8 No.23

Figure2: HPV vaccination status and the proportion of women with any symptoms
Note that the proportion of women with any
symptoms is 20-fold in the unvaccinatedwomen and 27.8-fold in the vaccinated women
after vaccination as compared with that thevaccinated before vaccination.
※ Among 1590 women who had any symptoms,
vaccination status was unknown in 604 women(38%), which is more than the unvaccinated(477 women) and the vaccinated (525 women).
Therefore, the propor tion of those with any
symptoms in all 12-18 year-old women ishigher than that in the vaccinated women after
vaccination.

These suggest how much healthier the vaccinated women
were as compared with the unvaccinated. They also show

These results are similar to that of the Nagoya study, which is
discussed below.

how frequently symptoms occurred in women who avoided
vaccination and were classified as the unvaccinated.
Hence, the apparent or crude risk with one or more symptoms

Healthy vaccinee effect is evident in the Nagoya
study

after HPV vaccination (1.36) should be multiplied by 9.0 to

The Nagoya study is a large-scale questionnaire study,

adjust health condition before vaccination. Adjusted risk withinvolving about 70,000 women aged 15 to 21 years to

any symptom after HPV vaccination become 12-fold which isinvestigate symptoms before and after receiving HPV vaccines.

extremely high.

The results of this study have already been reported in backMoreover, the proportion above is that in women with atnumbers of MedCheck [18,19].

least one symptom. The risk ratio of HPV vaccine for at least

In this article, the risk after vaccination is adjusted by theone symptom is 27.8/20.4 = 1.36. However, this risk ratio

risk of symptoms before vaccination, and adjusted odds ratio

increases as the number of symptoms increases. The proportionand 95% confidence interval are calculated.

of those with 10 or more symptoms was 15.6/100,000 persons
in the vaccinated while it was 5.3/100,000 persons in the

Figure 3 shows the risk (odds ratio) computed by comparing

unvaccinated. The risk ratio was about 3-fold (15.6/5.3) .

the frequency of symptoms before vaccination in the

Figure3: Health condition of the HPV vaccinated women before vaccination (Nagoya study, odds ratio against the unvaccinated)

Almost all symptoms occurred less frequently in the vaccinated group than in the unvaccinated group. This implies that there were more healthy
women in the vaccinated group while there were more sickly women in the unvaccinated group.

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Apr. 2022/ Vol.8 No.23 ・ Page 5

Review
Figure4:Odds ratio of main symptoms that led to hospital visit before vaccination(HPV vaccinated v.s. unvaccinated)adjustment by the risk of symptoms before
vaccination is necessary.
Figure 4 shows the odds ratios of the main
symptoms which led to hospital visit before
vaccination in vaccinated to the unvaccinatedand 95% CI. Significantly less women had
hospital visit for the following symptoms
before vaccination in the vaccinated groupthan in the unvaccinated group: sudden vision
loss (OR 0.72) , skin problems (OR 0.75) ,hyperventilation (OR 0.49), loss of ability towalk in a normal way (OR 0.22), becoming

Logistic regression analysis was used to calculate age-adjusted odds ratios (ORs) and 95%

dependent on a walking stick or wheelchairCIs. Many symptoms, especially severe symptoms, led to hospital visit significantly lessfrequently in the vaccinated group than in the unvaccinated group before vaccination.

(OR 0.21), sudden loss of strength (OR 0.28),

and weakness in the hands and feet (OR 0.30).
It should be noted that those who had hospital

Figure5:Symptoms leading to hospital visit after vaccination(vaccinated v.s. unvaccinated):

visit for severe symptoms, such as loss ofability to walk in a normal way, becoming
dependent on a walking stick or wheelchair,sudden loss of strength and weakness inthe hands and feet, were found less in thevaccinated group and extremely more in theunvaccinated group; the difference was 3 to 5
fold.
“Symptoms leading to hospital visit”
occurred significantly more afterSome severe disorders that led to hospital visit were significantly higher after vaccination
without adjustment by the odds ratio before vaccination.

vaccination without adjustment
After vaccination, symptoms which led tohospital visit were observed more frequently

in the vaccinated group than in the unvaccinated group. Figure
vaccinated group and that in the unvaccinated during the same

5 shows the odds ratio of the vaccinated to the unvaccinated ofperiod, using logistic regression analysis. When odds ratio (■)

the main symptoms and 95%CI after receiving HPV vaccine

is smaller than 1 (vertical line), it indicates that there were lesswithout adjustment by the odds ratio before vaccination.

women with symptoms in the vaccinated group than in the

In particular, those who had hospital visit because they

unvaccinated group. When the right or left tip of the horizontal

become dependent on a walking stick or wheelchair, andline does not reach 1, the difference is considered statisticallybecause they experienced weakness in the hands and feetsignificant.

was 9.6-fold and 2.8-fold, respectively, as compared with the

In almost all symptoms, ■ is on the left side of 1 (smaller

unvaccinated group. For these severe symptoms, the difference

than 1), suggesting that less women in the vaccinated groupwas statistically significant. It is noteworthy that it was

had symptoms before vaccination as compared with thestatistically significant even without adjusting by the odds ratio

unvaccinated women. In other words, vaccinated womenof symptoms before vaccination.

were otherwise very healthy before receiving HPV vaccine.
Therefore, without adjusting by health condition at baseline,

Figure 6 shows odds ratios of the vaccinated against thethe new onset of harmful events after vaccination would not be

unvaccinated of the main symptoms which led to hospital visit

significant unless they occur at extreme frequency. This is why

after vaccination and 95%CI adjusted by the odds ratio ofPage 6 ・ MED CHECK

Apr. 2022/ Vol.8 No.23

Figure6: Symptoms that led to hospital visit after vaccination (HPV vaccinated v.s. unvaccinated) Age-adjusted logistic regression
analysis adjusted by symptoms before vaccination.

When adjusted by the odds ratio of symptoms before vaccination [33], OR becomes extremely high. ※ : 95% CI marked with ※ is calculated, assuming thatthe upper limit of 95% CI for OR is 100.

symptoms before vaccination.
When the risk after vaccination was adjusted by the risk
before vaccination, those who became dependent on a walking
stick or wheel chair after vaccination was about 47-fold ascompared with the unvaccinated.

rate of non-HPV associated cancers as a whole are compared,
it was 0.43-fold, showing a significant difference (OR 0.43,
95%CI:0.20-0.93, p=0.028).

HPV vaccine does not reduce the incidence of non-HPV
associated cancers, such as breast cancer and thyroid cancer.

It was also statistically significant in other symptoms, suchHence this reduction implies that the unvaccinated women

as loss of ability to remember fundamental Kanji (25-fold),

were originally “sickly” or had some kind of health problems,

loss of ability to perform simple calculations (16-fold), loss

which prevented them from receiving vaccination, and whichof ability to walk in a normal way (11-fold), weakness in thewere related to the increased risk of cancer.

hands and feet (9.2-fold), sudden loss of strength (8.6-fold), andinvoluntary uncontrollable body movements (5.8-fold) [23].

These health problems may also affect the incidence rate ofcervical cancer. If health condition in the unvaccinated women
was the same as in the vaccinated groups, the incidence rate ofApparent reduction of cervical cancer may be due tocervical cancer in the unvaccinated group (10/124,245py) should“healthy vacicnee effect”

be multiplied by 0.43 and would be 4.3/124,245py. When this

Next, this article examines the results of epidemiologicalincidence rate is compared with that in the HPV vaccinatedstudies which concluded that HPV vaccine reduced cervicalgroup (0/65,656), no significant difference is found (OR=0.13,

cancer, namely the UK study [3], which the MHLW considered

95%CI: 0.004, 4.13, p=0.3665) (Figure 7).

was important, the Finnish study [34], and the Swedish study[35].

Since vaccination coverage was as low as 35% in the Finnishcohort and incidence rate of non-HPV associated cancers

First of all, we show the examination results of the Finnish

was 0.43-fold in the vaccinated women as compared with thestudy [34], because it provides us a level of “healthy vaccinee

unvaccinated, it can be theoretically inferred that about a half

effect” in HPV vaccination.

of those who were prone to cancer avoided HPV vaccination

It reported that incidence rate of HPV associated invasive[12].

cancer was significantly lower in HPV vaccinated women thanin the unvaccinated, while incidence rates of other, non-HPV

The Swedish study [35] reported that the incidence rate

associated common cancers, such as breast cancer or thyroid

ratio for the comparison of the vaccinated population with thecancer did not differ between the two groups by comparing

unvaccinated population was 0.37 at all ages.

separately.

Figure 8 is based on the cumulative incidence curve of

However, these numbers of non-HPV associated cancers

cervical cancer among women who had been “vaccinatedwere too small for separate comparison. When incidences

before the age of 17, at the age of 17 to 30 years, and
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Apr. 2022/ Vol.8 No.23 ・ Page 7

Review
Figure7: Reality of Finnish study, which concluded the vaccination significantly
reduced HPV associated cancer

0.20-0.93), and is still poor as evidence

to support the preventive effect of HPV
vaccine against cervical cancer for thisage group.
The UK study: the cause of
reduction in women aged 12-13
years may be bias
In England, where the HPV
vaccination coverage is very high, acomparison was made between womenof generations before and after the
introduction of the HPV immunisation

HPV vaccine does not reduce the incidence of other cancers, thus this reduction implies that theunvaccinated women were originally “sickly”. If health condition in the unvaccinated women was
the same as in the vaccinated groups, the number of patients with HPV associated cancers in theunvaccinated group would be 10×0.43=4.3. When 0/65,656 and 4.3/124,245 are compared, thedifference is not significant (p=0.3665).

program. The incidence rate ratio ofcervical cancer is 0.66 (95%CI: 0.59-0.75)
in women vaccinated at the age of 16
to 17, 0.38 (95%CI: 0.29-0.48) in thosevaccinated at the age of 14 to 15, andunvaccinated women” which was shown in the study [35].

0.13 (95%CI: 0.06-0.28) in those vaccinated at the age of 12 to

We added the adjusted cumulative incidence curve of the13, as compared with the women at the same age of the older

unvaccinated group calculated by the methods below.

generation: they all showed significant difference. In other

Based on the data of this study [35], the HPV vaccination
coverage is estimated as 35%, similar to that in Finland.
Therefore, just like in the Finnish study, the incidence rate ofcervical cancer in the unvaccinated group should be multipliedwords, in women who had been vaccinated at the age of 16 to
17 years, 14 to 15 years and 12 to 13 years, the incidence rateof cervical cancer was reduced by 66% (about two-thirds), 38%,
and 13%, respectively.

by 0.43 for fair comparison to adjust the healthy vaccinee bias.

Although details are not explained here, based on the result

Based on this, the risk in the vaccinated group is 0.86-fold asof the Finnish study, it can be inferred that about a half ofcompared with that in the unvaccinated group, and the risk for

women who were sickly have avoided HPV vaccination.

cervical cancer in the vaccinated is
not significantly different.
The red bold line in Figure 8 isthe curve calculated by multiplying
the curve for the unvaccinated groupby 0.43. The cumulative incidence
rate in women who were vaccinatedat the age of 17 to 30 years tended
to be higher than this.
There were only two cases ofcervical cancer reported in women
who were vaccinated before the ageof 17. The adjusted risk ratio is 0.12
and the upper limit of 95% CI is
0.34. This does not differ much fromthe risk ratio of non-HPV associatedcancers in Finland (0.43, 95%CI:
Page 8 ・ MED CHECK

Apr. 2022/ Vol.8 No.23

Figure8: Results of Swedish study and adjusting healthy vaccinee bias

Avoidance of vaccination by a half of sickly women affects
the proportion of sick persons in the unvaccinated populationcompared with simultaneously vaccinated population, but it
does not affect those of women of the previous generation who
did not receive vaccination.
However, the proportion of sickly women who were
vaccinated may be reduced, since certain proportion of women
may avoid vaccination due to health problems. Therefore, even
if female population of the previous generation was chosen asa control, this bias “healthy vaccinee effect” would remain andcould also be applied to the UK study.
Then, the incidence rates ratio (0.66) of those who were
vaccinated at the age of 16 to 17 is higher than 0.5, showing
no difference with that of the unvaccinated group (previous
generation). Moreover, in women who were vaccinated at theage of 14 to 15, the upper limit of 95% CI of incidence rate
ratio is 0.48. It is close to 0.5 and suggests no difference withthat of the unvaccinated (previous generation).
In women who were vaccinated at the age of 12 to 13, theupper limit of 95% CI of incidence rate ratio is 0.28. Suppose
70% of them, which is the upper limit of proportion of
women who were excluded from vaccination, have avoided
vaccination, the risk in the vaccinated group is 0.3-fold of thatin the unvaccinated. This is not very different from 0.28, theupper limit of 95% CI of the incidence rate ratio in women who
were vaccinated at the age of 12-13. Therefore, if adjustment
is made accurately with health condition before vaccination,
it is uncertain whether there would be significant difference ascompared with the unvaccinated (previous generation).
The authors of this study [3] wrote that vaccination at the ageof 12 to 13 is markedly effective because 12 to 13 year-old girls
have not yet been exposed to HPV. If so, by the time they reachthe age of 14, many of them have already experienced sexualintercourse and have been exposed to HPV. However, this isquestionable.
It is rather suspected that apparent preventive effect against
cervical cancer is simply because healthy vaccinee effect also
has strong impact on this age group. Furthermore, womenin this age group might have stronger tendency to avoid
vaccination when they have any health problems. It should be
carefully examined whether such a tendency is also related.
Conclusion
It is dangerous to resume the active recommendation
based on the results of observational studies which ignore
healthy vaccinee effect.
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Apr. 2022/ Vol.8 No.23 ・ Page 9

Review
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28) Lehtinen M, Paavonen J, Wheeler CM, HPV PATRICIA Study Group, et al.,Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 orgreater cervical intraepithelial neoplasia: 4-year end-of-study analysis of therandomised double-blind PATRICIA trial, Lancet Oncol 13, 2012, 89–99.
29) Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E,

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2737390031) Castellsagué X, Munoz N, Pitisuttithum P et al. End-of-study safety,

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34）Luostarien T, Apter D, Dillner J, et al. Vaccination protects against invasive
HPV-associated cancers. Int J. Cancer 2018;142:2186-2187. PMID: 29280138
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Cervical Cancer. N Engl J Med. 2020 Oct 1;383(14):1340-1348. PMID:
32997908

New Products

Antivirals for COVID-19:molnupiravir (Lagevrio®)
Doubt about efficacy due to serious baseline imbalance
Translated and revised from Med Check (in Japanese) Mar. 2022 ; 22 (100):46-48
Med Check Editorial Team

Abstract● Molnupiravir (Lagevrio®), an oral antiviral agent for COVID-19 is used in many countries by emergency use
authorisation including Japan. It is based on a interim analysis of clinical trial (MOVe-Out trial) which showed that it
halved hospitalisation or death (hospitalisation/death) in mild to moderate COVID-19 patients.
● However, sex adjusted hazard ratio in all-randomised population was not significant and the baseline imbalanceof the risk factors makes the results doubtful. In the interim analysis population, patients with COPD was assigned
less than one third in the molnupiravir group. The sum of the proportion of important four risk factors was
significantly lower in the molnupiravir group (19.4%) than in the placebo group (28.4%) (odds ratio 0.61, p=0.003).
●In the MOVe-IN trial which targeted hospitalised COVID-19 patients, score 6 COVID-19 patiens who needed noninvasive ventilation or high flow oxygen were significantly 0.27 fold less assigned in molnupiravir group than theplacebo group, but mortality rate increased in the molnupiravir group non-significantly. If the baseline imbalance
was adjusted, mortality rate might increase significantly.
● Molnupiravir mutates viral genes and prevents them from replication, but at the same time it suppresses cell
division in mammals. Irreversible myelosuppression (whole blood cell damage) was observed in dogs given 0.4 times
the human equivalent dose for 22 days. Was it really safe in humans?,● There are too many inconsistencies in clinical trials of antiviral agents. It is necessary to re-analyse the disclosed
clinical trial reports and re-examine whether it is really effective or safe.
Conclusion: The efficacy of molnupiravir on COVId-19 has not been proven. There is also a risk ofmutation of virus and of toxicity to the bone marrow (blood cells) in humans. Don't use molnupiravir.

Keywords:
molnupiravir, baseline imbalance, hospitalisation, death, MOVe-Out, MOVe-IN, randomisation, myelotoxicity

Did regulators examine the full clinical study reports?
On November 4, 2021, the UK’s medicines regulator
has issued temporary authorisation of the antiviral drug®

a decision by national authorities for the possible early use ofmolnupiravir based on the interim analysis results [5].
On December 23, 2021 US Food and Drug Agency (FDA)

molnupiravir (Lagevrio MSD) for the treatment of mild togave an emergency use authorisation (EUA) [6] and on the next

moderate COVID-19 in adults with at least one risk factor

day, Japanese regulatory authorities [7,8] gave a "provisional

for severe illness [1,2]. At that moment, scarce evidence forauthorisation" to the molnupiravir. Authorisation was issued

efficacy and safety of the agent was open to the public: onlyin the US and Japan after the publication (December 16,

the press released data by MSD were available saying that2021) of peer reviewed paper (MOVe-Out trial) on the phasemolnupiravir reduced the risk of hospitalisation or deaths by

3 randomised controlled trial (RCT) including not only theapproximately 50 percent compared to placebo for patients

interim analysis (N=775) , but also the full analysis of allwith mild or moderate COVID-19 at risk in interim analysis ofrandomised sample (N=1433) [9].

phase 3 study [3,4].

France canceled the order of molnupiravir [10] and EMA

On November 21, 2021 the European Medicines Agency

did not give formal authorisation to molnupiravir by the(EMA) has also issued emergency use advice (EUA) supportingend of January 2020 [11], because it was significantly less
MED CHECK

Apr. 2022/ Vol.8 No.23 ・ Page 11

New Products
Figure1:Proportion of Hospitalisation or death by time of analysis

narrowed to -3.0 % (95%CI, -5.9 to -0.1): 6.8% (48 of 709
participants) in the molnupiravir group as compared with

9.7% (68 of 699 participants) in the placebo group [9].
(Figure 1).

By a time-to-event analysis, the rate of hospitalisation/
death through day 29 was approximately 31% lower
with molnupiravir than with placebo (hazard ratio, 0.69;
95% CI, 0.48 to 1.01). The risk of hospitalisation/death

was reduced about 31 % and was not halved. The risk
difference was barely significant, and was not significant
by the time-to-event analysis [9].

Interim analysis (IA): OR (odds ratio) is 0.48 (95%CI: 0.30-0.78, p=0.0023)
according to the calculation by MedCheck [17]. All randomised analysis:
Hazard ratio was 0.69 (0.48-1.01) reported by Jayk Bernal et al. [3]. Afterinterim analysis (AIA) : OR is 1.35 (0.68-2.68, p=0.395) comparing bothgroups and 3.35 (1.85-6.06, p<0.0001) comparing IA and AIA populationsof placebo groups according to the calculation by MedCheck.

Molnupiravir may worsen COVID-19 after interim
analysis
When calculating simply the proportion of
hospitalisation/death among population who were notincluded in the interim analysis but included in the final
analysis, the molnupiravir group had a higher risk (6.2 %effective than previously thought [10,11]. This is consideredor 20 of 324 participants) than the placebo group (4.7% or 15 of

to indicate the followings: the risk reduction of hospitalisation/

322 participants), although the difference was not significant.

death by day 29 of molnupiravir group fell from about 50 %in the interim analysis to about 30 % in the full analysis of

Significant imbalance in proportion of risk factors

all randomised samples [9]. The editorials of British Medical

In the phase 3 RCT [9], participants were selected as eligible

Journal entitled “Molnupiravir’s authorisation was premature”

if they had one of the seven risk factors for severe illness[12] emphasised the dangers of making decisions based on afrom COVID-19: obesity (BMI ≧ 30), age > 60 year (old age),

single prematurely terminated trial.

diabetes mellitus (DM), chronic kidney disease (CKD), chronic

This paper discusses the other serious problems which
reduce the value of molnupiravir especially the imbalance ofobstructive pulmonary disease (COPD), serious heart disease,and active cancer.

important risk factors not found in the approval documents for

Jayk Bernal et al [9] describe that with the exception of anmolnupiravir by regulators of UK [1,13], US [14] and Japan

imbalance in sex, baseline characteristics were similar in the[15,16].

two groups including the above risk factors. However, in theinterim analysis population, proportion of participants with

Sex-adjusted hazard ratio was not
Figure2:Comparison of baseline characteristics (interim analysis population)

significant
In the interim analysis of MOVe-Out trial,
participants receiving molnupiravir had alower risk of hospitalisation/death throughday 29: 7.3% (28 of 385 participants) inthe molnupiravir group as compared with
14.1% (53 of 377 participants) in the placebogroup and. Risk difference was reported as-6.8% (one-sided p = 0.0012). Odds ratio was
0.48 (two-sided p = 0.0024) according to thecalculation by Med Check [17].
In the all-randomised modified intentionto-treat population, risk difference wasPage 12 ・ MED CHECK

Apr. 2022/ Vol.8 No.23

COPD was significantly less assigned in the molnupiravir

analysis were adjusted by the baseline characteristics, it maygroup: odds ratio is 0.31 (95% CI: 0.13 to 0.73, p=0.0043) andbecome non-significant at all. For example, the ratio of hazard

those with obesity was marginally significantly more assigned

ratio for hospitalisation/death (0.69) to odds ratio of sum ofin the molnupiravir group (odds ratio 1.33, 95% CI: 0.95 to1.86,

baseline risk factors except obesity (0.79) was 0.87 (95%CI:

p=0.094) by MedCheck’s analysis [17].

0.57-1.33) according the methods described by Kalossa [18].

Among the 7 risk factors, more patients with 2 risk factors(obesity and serious heart diseases) were assigned to molnupiravir

Doubt about the randomisationgroup, while less patients with the other 5 risk factors (old age,

Significantly lower sum of proportion of participants with

DM, CKD, COPD and active cancer) were less assigned to therisk factors in the analysis of all-randomised population

molnupiravir group.

raises doubt as to whether the randomisation has been fairly

The sum of the percentages of the participants who haveconducted in the trial.

risk factors other than obesity (group 10 in the Figure 2) was

A further significant imbalance in the above risk factors insignificantly lower in the molnupiravir group (43.4%) than in

the interim analysis, and a great difference in the proportion

the placebo group (51.8 %). Odds ratio is 0.71 (95%CI: 0.54

of participants with COPD alone (odds ratio 0.31, p=0.0043)

to 0.95, p=0.019). If the sum of the percentages of risk factors

suggests the possibility that before the interim analysis,

was restricted to the 4 risk factors (DM, CKD, COPD and active

blinding might have been broken. Is there any possibility ofcancer), odds of participants with important risk factors was

selections of patients for interim analysis?

almost 40 % lower in the molnupiravir group: Odds ratio is0.61, 95%CI: 0.43 to 0.85 p = 0.0043 (Figure 2) [17].

Subgroup analysis may not support the efficacy
In a subgroup analysis, it was reported that molnupiravir

Significant imbalances also in all-randomized

showed no efficacy for those with diabetes nor with severe

population

heart disease, although it showed apparent efficacy for obese

Similarly, the sum of the percentages of the patients who

participants [9] (Figure 4A). No data for efficacy have been

have risk factors other than obesity in the all-randomised

reported for those with CKD, COPD nor active cancer. In

population was also significantly lower in the molnupiravir

addition, it cannot be denied that the result of apparent effect ongroup (53.8%) than in the placebo group (59.4%). Odds ratio isobese people and females may be affected by the bias of other0.79 (95%CI: 0.64 - 0.98, p=0.031). If the sum of the percentages

risk factors. Hence, it may be hard to say that it is effective forof risk factors were restricted to the 4 risk factors (DM, CKD,

these subgroups.

COPD and active cancer), odds ratio was 0.77 (95%CI: 0.61 - 0.97,
p = 0.026) which shows the significant imbalance of risk factors

Two RCTs for moderate COVID-19 were terminatedin the both groups (Figure 3) [17].

due to futility

If the hazard ratio of hospitalisation/death by a time-to-event

According to the document submitted to the UK regulator
by Merck Sharp & Dohme (UK) Ltd [13],Figure3:Comparison of baseline characteristics (all-randomised population)

hospitalisation/death was significantly reducedin the subgroup of moderate COVID-19 and theeffect size was greater in the moderate patients(Risk difference=-8.0, 95%CI: -15.5, -0.5) than in

the mild patients (-4.9, 95%CI:-10.5, 0.2) [13](Figure 4B).

However, two RCTs for moderate COVID-19
have been terminated due to futility by theinterim analysis [19].
MOVe-IN trial also has serious imbalance inbaseline severity
In the MOVe-IN trial [3], participants with
MED CHECK

Apr. 2022/ Vol.8 No.23 ・ Page 13

New Products
Figure4:Absolute risk reduction by SubgroupsA) all randomised population

B) Interim Analysis population

Excerpt from Figure 3 of reference [9]Excerpt from Figure in p30 of reference [13]a: Positive antibody against SARS-CoV-2 nucleocapsid. In other words, it is not an “antibody against spike protein” that is produced by a vaccine. It meansthat positive person has a history of COVID-19.
* b: Subgroup analysis results for chronic kidney disease, COPD, and active cancer have not been reported in the text and Supplementary appendix.

score 6 COVID-19 (hospitalized and administered oxygen by

Beware of DNA damage, bone marrow toxicity andnon-invasive ventilation or high flow) were significantly lessmutationsassigned in molnupiravir groups (5/218=2.3%) than the placebo

Molnupiravir is a substance similar to some antivirals

group (6/75=8.0%) : OR=0.27 (95%CI:0.08-0.91, p=0.025) .

including favipiravir or ribavirin, which causes mutations not

Despite this serious bias favouring molnupiravir group, non-only in viral genes to prevent proliferation but also which may

significant increase of death was reported in molnupiravir

suppress human cell division [20-23]. Especially, bone marrowgroup (13/218=6.0%) compared with placebo group (2/75=2.7%):

toxicity is the most serious concern, because irreversible

OR=4.69 (95%CI: 0.60-36.50, p=0.105). If the baseline imbalance

myelosuppression (total blood cell damage) was observed infavouring molnupiravir group is adjusted, OR for all-cause

dogs that were treated with 0.4-fold the human equivalent dose

mortality may be statistically significant. For example, the ratio

according to the area under the curve (AUC) level of activeof mortality odds ratio to odds ratio of baseline score 6 wasform of molnupiravir at the 800 mg q 12 h human dose for 22

17.38 (95%CI:1.60-188.84) according the methods described bydays and no observable adverse effect level (NOAEL) is only

Kalossa [18].

0.13-fold the human dose [13].

Reanalysis is needed and the reasons of serious

Full clinical study reports should be disclosed andimbalance should be verified.

reanalysis is needed

It is necessary to reanalyse acurate incidence ofAs was warned by Sidebottom et al in the editorial of BMJ,

hospitalisation or death (MOVe-Out trial) and mortality ratein the absence of sufficient evidence of safety and efficacy(MOVe-IN trial) by adjusting baseline risk factors (MOVe-Out

raises serious concerns about further mistakes being madetrial) and baseline severity especially of score 6 (MOVe-IN trial).

[24]. It seems that the warning has come true. The RCTs of

It is necessary to verify why the completely opposite orantiviral agents for SARS-CoV-2, such as remdesivir [25,26]

highly contradictory results were observed among RCTs

and baricitinib [27], which are authorized for emergency use intargeted at moderate COVID-19.

various countries also have contradictions.

Page 14 ・ MED CHECK

Apr. 2022/ Vol.8 No.23

In order to resolve these situations, as was conducted in the

References

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1) Regulatory approval of Lagevrio (molnupiravir). https://www.gov.uk/

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Conclusion
The efficacy of molnupiravir on COVId-19 has not been
proven. There is also a risk of mutation of virus and of
toxicity to the bone marrow (blood cells) in humans. Don't use
molnupiravir.

n2422 pmid:34607801FREE Full Text
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Competing interests: None

November 22, 2021
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M
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HECK

2022

Vol.8

No.23

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); TAKANO, Yoshihiko(MD[pediatrician]/Pharmacist) ; UMEDA, Tadahito (MD[psychiatrist]) ;YANAGI,
Motokazu (MD); YASUDA, Yoshinobu (Pharmacist)
Translators: NAKAMURA, Akari

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Apr. 2022/ Vol.8 No.23

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