M
CED

December

2018

Volume 4-The Informed Prescriber

N 12

HECK

o

Dying Cochrane: Could it be resuscitated?
Herpes zoster subunit vaccine Shingrix:
Baloxavir (Xofluza®) for Influenza: No Value
No difference from Tamiflu in efficacy, and suppresses immunity

Cochrane review on HPV vaccine should be revised:
Due to missing trials, adjuvant toxicity, mortality and healthy user bias
CONTENTS （December 2018, Vol. 4, No. 12）

Editorial
Dying Cochrane: Could it be resuscitated?
New Products
Herpes zoster subunit vaccine Shingrix:Judgment Reserved
Baloxavir (Xofluza®) for Influenza: No Value

30
31
37

No difference from Tamiflu in efficacy, and suppresses immunity

Adverse Reactions
New evidence of severe abnormal behaviors/psychiatric reactions
to oseltamivir(Tamiflu)
Critical Review
Cochrane review on HPV vaccine should be revised:
News

40

41
50

MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 29

M
C

ED

-The Informed Prescriber

HECK

Editorial

Dying Cochrane: Could it be resuscitated?
Translated from the Editorial in Med Check-TIP (in Japanese) Nov 2018 ; 18 (127)

Cochrane's systematic reviews are an important

process, the board decided on the expulsion. Basedsource of information while fake information on

on the minimum number stipulated by the Articles ofdrugs and therapeutics is rampant. The recent

Association, six board members are enough to run theincident of expulsion of Dr. Peter Gøtzsche, one ofboard. However, if at least 13 members are needed

the cofounders of Cochrane is a critical issue thatas explained in Cochrane’s website (now it has beenhas shaken the credibility of the organization(see p41

changed), the current board is illegitimate. Moreover,and 50). It is an unprecedented event in the 25-year

the current governing board does not represent thehistory of Cochrane Collaboration.

opinions of the entire organization at first place.

Initially, Cochrane used to be "Cochrane Collaboration”,

Therefore, it should be dissolved and totally reelected.

but recently “Collaboration” was removed, and it

The direct reason why Dr. Gøtzsche had to be

is now registered as a Charity, a Limited Liability

expelled was that he has been criticizing CEO's top-

Company whose headquarter is based in the UK.

down approach and acceptance of distorted reviews

The organizational structure is complex. It includes

by researchers with conflict of interest. However,a Central Executive Team which is headed by a CEO.

there have been criticisms against CEO even before

Apart from them, Governing Board is responsible

the incident. Nine of the 12 Cochrane centers havefor overseeing the development and implementation

been raising concern over the management. The

of Cochrane’s strategic direction. The board also

US Cochrane Center closed down, and a director ofhas the right to decide on expulsion of its members.

Cochrane France resigned in frustration over lack of

The board (trustees of the charity and directors of thetransparency and poor leadership. German, Canadiancompany) is comprised of at least 13 members (butand Austrian centers expressed their opposition

according to the Articles of Association, the number ofby voting against the expulsion. In addition, all 31

the board members should not be less than three, andDirectors form the Iberoamerican Cochrane Network

this is largely inconsistent), and decisions are made byhave expressed their support for Dr. Gøtzsche.

majority vote. More than half of the board members

In 2016, ISDB (International Society of Drug Bulletins)are elected by Cochrane’s members; with the rest

adopted a policy that will be totally implemented inappointed by the board.

2019, in which members are not allowed to have

Before this incident, the governing board consisted

conflict of interest with the healthcare industry. Thoseof eight elected members and five appointed

who have not fulfilled the criteria will be removed

members. Among the eight elected members, four

from the full membership list. Med Check-TIP fulfills it.

remained in the board while three resigned in

Now it is clear that the information independent

protest. The remaining one is Dr. Gøtzsche. Amongof pharmaceutical companies is reliable. What is

the five appointed officers, two remained, and one

important is not simply the transparency, but the fact

resigned in protest followed by resignation of anotherthat conflict of interest distorts scientific information.

officer who opposed the decision. The other one

If conflict of interest is not eliminated, Cochraneabstained from voting, but later resigned so thatwill no longer be trusted by patients and medical

there would be less appointed members in the board.

professionals. We support the views of Dr. GøtzscheThis means that six members were in favor of theand the ISDB Committee that the current board should

expulsion while the other six, including Dr. Gøtzsche,

be dissolved and reelected. In addition, we believe thatwere against it. By excluding Dr. Gøtzsche from thethe Articles of Association should be amended as well.

Page 30 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

New Products
Herpes zoster subunit vaccine Shingrix:

Judgment Reserved

The effect is certain, but the evaluation of harm is flawed
Translated from Med Check-TIP in Japanese Nov 2018 ; 18 (80):128-131
MedCheck-TIP Editorial team

Summary● Relative preventive efficacy of a herpes zoster subunit vaccine (brand name: Shingrix, approved in March 2018) is

97% in people aged 50 and over and 90% in people aged 70 and over. There was no hospitalization nor death due
to herpes zoster, and the effect to prevent them was not proven. In order to prevent 1 postherpetic neuralgia, 1276
persons need to be vaccinated.
● When 1276 people are vaccinated, over 800 people would additionally experience local pain, and 171 people

would suffer from serious adverse reactions which lead to hospitalization or limit activity of daily living. Although
it was reported that there was no difference in serious adverse events, immunologic disorders and death between
the two groups, the report is not reliable. This is because in a phase II study, mortality rate increased by about sixfold in the second year after the vaccination as compared with that in other years. However, in subsequent pivotal
clinical trials, most serious adverse reactions were not followed after the first year. Moreover, since toxicity studies
are incomplete, safety is not guaranteed.
● Herpes zoster is a benign disease. If it is detected early, it can be cured by treatment with antivirals. Until harm isappropriately assessed, the judgement of Shingrix for preventing herpes zoster and postherpetic neuralgia in theelderly is reserved.
Conclusion: Judgment Reserved

Keywords:
herpes zoster subunit vaccine, Shingrix, HZ/su vaccine, relative prevention rate, local adverse reaction, systemic adverse
reaction, muscle pain, fatigue, fluctuation of mortality, adjuvant, AS01B

Introduction
An attenuated varicella vaccine, for which prevention

Shingrix® for intramuscular injection, Japan Vaccine Co.,Ltd.)This article summarizes its efficacy and harm.

of herpes zoster was approved as an additional indication

A novel adjuvant in this vaccine is called AS01B andin 2016, almost halves the incidence of herpes zoster incontains the main ingredient of the adjuvant in HPV

people aged 50 and over. However, the effect is reduced

vaccine. The toxicity studies for the adjuvant werein people aged 70 and over. Moreover, the preventive

incomplete (see the boxed column).

effect diminishes 5 years after the inoculation, and thebooster is ineffective. These facts raise concern over theeffectiveness in the elderly, the population which has
high need for the vaccination (MedCheck-TIP No.71).
Meanwhile, a new herpes zoster subunit vaccine (HZ/

Results of international joint clinical trials of Shingrix
Table 1 shows the results of randomized controlled
clinical trials that examined the preventive efficacy of
Shingrix on herpes zoster.

su vaccine) was approved on March 23, 2018 for the

The report no. 1 [1] is a summary of an international

prevention of herpes zoster (recombinant zoster vaccine:

joint phase III trial conducted by 18 countries, including
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 31

New Products
Table 1: Summary of preventive efficacy on herpes zoster [1, 2]* a: incidence rate (/1000 person-years)
NNTB: number needed to treat to benefit

ARR: absolute risk reduction

Japan, involving adults aged 50 years and older. The

report no. 1, and 6541 participants in the vaccine group

participants were randomly allocated and received 0.5

and 6622 participants in the control group remained.

mL of test vaccine or saline (control) intramuscularly

The median follow-up was 3.7 years. In the report no. 1

twice in total; at the beginning and the second[1], relative preventive effect was 97.2% (p <0.001), andmonth. Since both preparations were distinguishable

the number needed to treat to benefit (NNTB) was 114.

by appearance, investigators other than those who

In the report no. 2, the relative preventive effect was

had administered the substances were assigned for

89.8% (p <0.001), and NNTB was 120 [2].

assessment in order to ensure the blindness (so-called
PROBE method).

In 16,596 participants aged 50 years old in thereports no. 1 and 2 combined, the relative preventive

Total 7698 participants received at least one dose ineffect was 91.3% (p <0.001) [2]. In the both reports,

the vaccine group and 7713 in the control group. The

the preventive effect in each age group was almost thefollowing participants were excluded from the analysis;same. In addition, the result of subgroup analysis of

those who received only one dose, those who deviatedJapanese who were included in these clinical trials [3, 4]from the vaccination schedule and those who developed

was similar to the result of the whole study.

herpes zoster within 30 days after vaccination. After

Table 2 summarizes the preventive effect on

the exclusion, 7344 participants in the vaccine group

postherpetic neuralgia (sustained for 90 days or more)

and 7415 in the control group were subjected to the[2]. The median follow-up was 3.8 years, and theanalysis of the efficacy. The median follow-up was 3.1

relative preventive effect on neuralgia was 91.2% (pyears.

<0.001) in all age groups. Postherpetic neuralgia did not

The report no. 2 is the result of an international

occur in the vaccinated participants aged 70 years old

joint phase III clinical trial conducted by 18 countries

and below. Relative preventive effect of postherpetic

including Japan, for adults aged 70 years old and overneuralgia was 88.8% (95% CI: 68.7-97.1; p <0.001) when[2]. Total 6950 participants in the vaccine group andthe analysis was restricted to those aged 70 years old

6950 in the control group were analyzed. This study

and over. However, in those who had already developed

followed the same exclusion criteria as that of theherpes zoster, there was no difference in the incidence

Table 2: Preventive efficacy on postherpetic neuralgia (PHN) [2, 3]* a: incidence, NNTB, ARR: see the footnote for Table 1
PHN: postherpetic neuralgia was defined as a worst pain score of 3 or higher for pain (on a scale of 0 to 10, withhigher numbers indicating worse pain) that persisted or developed more than 90 days after the onset of herpes
zoster rash.
Person-years of observation: vaccine group: 53171.5 person-years, control group: 53545.0 person-years

Page 32 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

of neuralgia between the two

Figure 1: Annual variation of mortality in Phase II study (trial no.003)

groups (12.5% in the vaccine group
and 9.6% in the control group, p =0.54).

The absolute preventive effect
was 0.08% annually. This meansthat the vaccine can prevent
one postherpetic neuralgia by
inoculating 1276 people.
The rise of antibody titerpersisted at 3.8-fold to 7-fold
6 years after inoculation ascompared to the baseline [4].
Because there was no hospitalization nor death due to(odds ratio 6.3, p = 0.0001: Figure 1 ).

herpes zoster, reduction in such cases was not proven

If the vaccine is harmless and does not affect[4].However, reportedly, it was possible to use Shingrix

death, the mortality rate should remain constant fromfor recipients of autologous peripheral blood stem cell

beginning to the end. Therefore, the marked peak oftransplant and patients with HIV [5,6].

the mortality rate in the second year strongly suggests
the harmful effect of the vaccine. On the contrary, in

In phase II trials, mortality peaked in the second year

the third year, the number of death was 0 (mortality(Figure 1)

rate 0 ), and after that it stayed at the relatively low

Two phase II trials for dose finding were carriedlevel. Incidentally, the mortality rate in the secondout before the pivotal phase III trials [1, 2]. They wereyear, approximately 1700/100,000 person years, isnamely trial no. 003 for finding the dose of vaccine

at the same level as the mortality rate of the generalantigenic component (follow-up for 6 years) and trial no.

population which includes people with sickness. (Japan's

010 for finding the dose of adjuvant [4].

mortality rate among people aged 60 to 84 years old in

In trial no. 003, the antigenic component was used2008 was 1846/100,000 people). Considering that thein all 5 groups; 4 groups were treated with antigen +trial no. 003 was a clinical trial for healthy people, it

adjuvant twice (3 groups) or once (1 group), and thecan be said that the mortality rate in the second year isother group received antigen + saline twice. In a long-remarkably high.

term follow-up, all serious adverse events (serious AE)
and deaths were followed until the third year, after

Fatal flaw in reporting serious AEs after 14 months

which the vaccine adopted as a commercial product(Figure 2)

was followed until the sixth year.

In phase III trials [1, 2], serious AEs were collected up

There is no report on the number of nonfatal severe

to 1 year and 2 months after the inoculation, and afterAEs ( 238 persons, 328 events) and death ( 1st year: 1

that, only serious AEs that were considered to be relatedcase, 2nd year: 11 cases, 3rd year: 0 ) per each groupto study agents were collected. Moreover, in the phase

after 3 months from the first inoculation, but only

II trials, all serious AEs were considered “not related”.

on the number for all groups combined. The number

Even in the phase III trials, most serious AEs wereof deaths was reported by year. Based on this, theconsidered “not related”. Therefore, it is highly likely

annual mortality rate was calculated for each year afterthat serious AEs in the second year, when the incidence

inoculation. As a result, the mortality peaked in theis highest, were not collected. It is also unknown how

second year (after 1 year until the end of second year), anddeath was processed.

it was about 6 times higher than all other time periods

MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 33

New Products
Strong tissue toxicity is suggested in humans (Figure 3)
In phase III trials, local reaction and systemic reactions

more frequently in vaccine groups than in control groups[1-4] (Figure 3).

up to 7 days after the inoculation of Shingrix occurred

AEs that led to hospitalization or limited self care

Shingrix is not safe: Evidence from nonclinical studies
In accordance with GLP, only one dose level was

1. Components of Shingrix
Shingrix (HZ/su vaccine) is a subunit vaccine in whichinvestigated in the toxicity studies for Shingrix. The doses

glycoprotein component ( gE ) of varicella-zoster virus

tested were 0.1 mL in rat (400 g) and 0.5 mL in rabbit (about(HZV) is used as an antigen and a novel adjuvant is added.

4 kg); Human equivalent dose (HED) on the basis of body

Therefore, the advantage is claimed that it can be used forsurface area was only 4 times higher than human dose.

people with lowered immunity who cannot use attenuated●live varicella vaccines.

was observed: With saline control, inflammatory cell

In a single-dose toxicity study, extensive inflammation

The novel adjuvant is called AS01B. It is a substance ininfiltrations were observed locally in some rabbits, butwhich MPL ( MonoPhosphoryl-Lipid A), a derivative of theinflammatory cell infiltrations occurred extensively

lipid A, which is the main component of endotoxin ( orwith AS01B (up to moderate) and Shingrix (up to serious),

lipopolysaccharide), and a surfactant called purified Quillaja

respectively. Therefore, the tissue toxicity in order ofsaponin (QS-21) are bound to liposome. Both MPL and QS-21

severity is as follows; Shingrix > AS01B >> saline.

have cytotoxicity and stimulate/enhance natural immunity,●

which is essential for induction of acquired immunity. MPL

inflammation occurred in most animals: AS01B at the doseis also the main component of adjuvant AS04 in bivalent

4-time higher than the human dose was intramuscularly

HPV vaccine Cervarix.

administered to rats on the peroneal muscle for 7 times,

2. The purpose and method of general toxicity test

once every 2 week. No abnormal finding was observed

In repeated-dose AS01B toxicity studies with rats,

In order to predict possible toxicity in humans, usingwith saline control. With AS01B, swelling of the peroneala small number of animals, toxicity studies for medicines

muscle and up to “marked” inflammatory reactions

use markedly higher doses over a prolonged period. Moreoccurred extensively in most of the 10 animals.

specifically, the studies are conducted with at least four●

dose groups: 1) High-dose group to find out organs andwas administered subcutaneously and intramuscularly

lesions that may cause death, 2) the intermediate-doseto rabbits for 4 times, once every 2 weeks. Three days

group, 3) Low-dose group to find out NOAEL (No Observed

after the last dose, mild inflammatory reactions occurred

Adverse Effect Level) and 4) One control group. Animals in

extensively in all cases with Shingrix, and moderate

the control group are usually treated with vehicle (solvent)inflammatory reactions and extensive or multiple

alone. However, if the additive(s) such as adjuvants are toxic,

inflammatory reactions were observed in some animals

the studies should also have two control groups; one withtreated with AS01B. At days 28/29 after the final

saline and the other with the additive(s). Such studies should

administration, there was no histological changes caused

be conducted with 2 or more different animal species.

by Shingrix nor AS01B. However, it is not mentioned that

Adjuvants are toxic to tissues. Therefore, intrinsically, novel

all the findings resolved.

adjuvants and vaccines should be tested as new substances,

4. Summary of nonclinical findings

and the procedures for general toxicity studies should be

Extensive inflammation with vaccine/adjuvant: Shingrix

Since vaccines are basically administered to healthyfollowed.

people, higher safety is required for inoculation. However,

3. Toxicity studies of Shingrix

the standard imposed on toxicity study of vaccines andHowever, the EMEA's guidance and Good Laboratory

adjuvants is absolutely incomplete, compared to that for

Practice ( GLP) for vaccines and adjuvants do not follow

medicines in general. Even in such an incomplete toxicity

the standard methods of toxicity studies for new products.

study, Shingrix and the new adjuvant AS01B showed strong

EMEA's guidance and GLP only require one dose level in one

tissue toxicity. Therefore, it can be concluded that use ofanimal species even for new adjuvants and new vaccines

Shingrix is not clinically safe.

containing new adjuvants.

Page 34 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

Figure 2: Schedule for evaluation of harm: Phase III pivotal trials [1, 2]

control group while it was
78% in the vaccine group;
total 2 in 3 people additionally
suffered from local pain. The
incidences of redness andswelling were very high inthe vaccine group, as well.
Systemic symptoms within
30 days after the inoculation
included fatigue, muscle pain
and fever, as shown in Figure
3. In addition, headache, chills,
and gastrointestinal disorders

Solicited report of injection-site AE within 7 days: based on the daily record (pain, redness, swelling)and solicited report of systemic reactions within 7 days (fatigue, fever, gastrointestinal symptoms,

also occurred frequently.
It was reported that there

headache, myalgia, shivering) were collected.

was no difference between

All AE: all AEs observed for 30 days: no specification, but all AEs were collected for 30 days.

the two groups in theincidences of serious AEs andactivity of daily living (grade 3 and above) occurred in

immune-related disorders and the number of deaths.

16.5% of the participants in the vaccine group and 3.1%

However, it is highly likely that most of serious AEs inin the control group within 7 days after the inoculation.

the second year, when marked difference is expected,

This means that the vaccine may cause harm in 1 in 7.5

are not reported, and thus the report cannot be trusted.

people.

Furthermore, it is extremely unnatural that while non-

The incidence of pain at injection site which occurred

serious AEs were reported 2.3 time more frequently inwithin 7 days after receiving 2 doses was 11% in thethe vaccine group, no difference was found in serious
AEs (Figure 3, B).

Figure 3: Summary of vaccination and AEs [1-4]The incidence of AEs showed almost
similar trend in the study for Japanesewith that in the whole study.
Balance between harm/benefit and cost
In order to prevent postherpetic
neuralgia in 1 person, 1276 persons
had to be treated. Moreover, preventive
effect for hospitalization and death due
to herpes zoster was not proven.
On the other hand, as far as weknow, addit ional 2 in 3 persons
developed local pain and 1 in 7.5 people
experienced local reactions that required
hospitalization or disturbed their

Solicited AE: see the footnote for Figure 2

AE: Adverse event

NNTH: Number needed to treat to harm

activities of daily living as comparedwith the control group. In other words,

Grade 3 or more AE: hospitalization is required, daily living is disrupted or morein order to prevent postherpetic

serious cases (almost equivalent to serious AE)

neuralgia in 1 person, 833 people would
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 35

experience local pain, and 171 people would suffer fromvarious harms, such hospitalization or local reactions
that disrupt activity of daily living.

Conclusion
The relative preventive effect for postherpetic
neuralgia of two doses of Shingrix is 97% in people

Furthermore, in the phase II trials, death after

aged 50 years old and older and 90% in people aged 70

vaccination clearly increased in the second year, but

years and older. However, over 1200 persons must bein the phase III trials, even if any serious AEs occurredvaccinated in order to prevent potsherpetic neuralgia in

after the second year, most of them might not have been

one person. At the same time, additional 800 persons

included because they might have been considered “notwould develop local pain, and 171 persons would

related”. , Therefore, their conclusion that there was noexperience hospitalization or harm that disrupts theirdifference in serious AEs and death is not reliable.

activity of daily living. In the second year, mortality

QALYs (quality-adjusted life-year: 1 QALY corresponds

is suspected to increase, and safety studies, including

to 1 year in perfect health) is adopted as an indicator toanimal studies, are extremely insufficient. Herpes zoster

measure cost-effectiveness. The cost-effectiveness of

is a benign disease that can be cured by early detection

Shingrix was calculated as 50,000 USD (about 5.6 million

and swift antiviral treatment. Unless harm is assessedyen)/1QALY, and it was considered high [7]. However,more appropriately, the judgement on Shingrix should be

the computation is based on the assumption that there

reserved.

is no difference in adverse reactions between treatment
and control groups.
If the agent is marketed in Japan at the same priceas that in the U.S., 280 USD ( about 31,500 yen) for 2

References

doses, about 40 million yen would be required for the1) Lal H, et al. Efficacy of an adjuvanted Herpes Zoster subunit vaccine in older

pharmaceutical cost alone in order to prevent postherptic2) Cunningham AL, et al. Efficacy of the Herpes Zoster subunit vaccine in adults 70

neuralgia in one person. If the cost for inoculation

adults. N Engl J Med 2015; 372 (22): 2087-2096.
years of age or older. N Engl J Med 2016; 375 (11): 1019-1032.
3) PMDA, Shingrix. Examination report. 2018.2.13

is included, about 50 million yen would be needed.

4) Japan vaccine, Shingrix: Summary basis of approval

Adjuvant is indispensable because the immunogenicity of5) Stadtmauer EA et al. A phase 1/2 study of an adjuvanted Varicella-Zoster virus

Shingrix is significantly lowered without it [4]. The whole
picture should be clarified whether the adjuvant, whichitself is toxic, causes harm after the second year or not.
Herpes zoster is a benign disease that can be cured
without feeling much pain by early detection and swift
antiviral treatment. This also undermines the need fordeveloping new vaccines.

Page 36 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

http://www.pmda.go.jp/drugs/2018/P20180329002/index.html
subunit vaccine in autologous hematopoietic cell transplant recipients. Blood 2014;
124 (19): 2921-2929.
6) Berkowitz EM, et al. Safety and immunogenicity of an adjuvanted Herpes Zoster
subunit candidate vaccine in HIV-infected adults: a phase 1/2 a randomized,
placebo-controlled study. J Infect Dis 2015; 211 (8): 1279- 1287.
7) Le P, Rothberg MB. Cost-effectiveness of the adjuvanted Herpes Zoster subunit
vaccine in older adults. JAMA Intern Med 2018; 178 (2): 248-258.

New Products

Baloxavir (Xofluza®) for Influenza: No Value
No difference from Tamiflu in efficacy, and suppresses immunity
Translated from Med Check-TIP in Japanese Nov 2018 ; 18 (80):132-133
MedCheck-TIP Editorial team
Keywords:
Xofluza, baloxavir, influenza, CAP, high drug price, antibody, resistance, CYP3A

respectively for influenza virus to disappear. Therefore,

Introduction
Baloxavir marboxil ( “baloxavir” in short; brand name:viral load was reduced much faster with baloxavir.

Xofluza® ) is priced high as patients need to take thedrug only once, and viral shedding stops almost on

No difference in time to symptomatic improvement

the following day. The cost for one course of baloxavir

between oseltamivir and baloxavir

treatment is about 4800 yen (approximately 42 USD) in

However, time to flu-symptom disappearance was only

adults (body weight 40 kg-79 kg) while that for oseltamivir

one day earlier with baloxavir than with placebo. The(Tamiflu®), laninamivir (Inavir®) and zanamivir (Relenza®)

median time was 53.7 hours with baloxavir and 80.2

is 2720 yen (24 USD), 4280 yen (38 USD) and 2942 (26hours with placebo; there was only 26.5 hours difference

USD), respectively. During the influenza season of 2019,(Figure-a) [2,3,7]. Baloxavir and oseltamivir (Tamiflu) were

the drug is expected to be prescribed for 3.3 million

also compared (Figure-b). In the comparison between

patients with influenza

and the estimated sales is 14.1

subgroups aged 20 years old or over with baloxavir orbillion yen (124 million USD) in Japan[1]. Is baloxavir

oseltamivir, no difference was observed. The medianreally worth it?

time to symptomatic disappearance was 53.5 hours withbaloxavir and 53.8 hours with oseltamivir; difference isViral growth is suppressed

only 0.3 hours (Figure-b) [2, 3]. Although the difference

Baloxavir inhibits an enzyme called cap dependent

was not significant, there were more patients whoseendonuclease (CEN) [2-5]. It is reported that CEN is an

symptoms continued for 4 days or longer in baloxavir

enzyme unique to influenza virus and synthesizes mRNAgroup than in Tamiflu group. There was no difference in(messenger RNA), which is like a design drawing of eachthe proportion of patients who required hospitalization

part of the virus. Because of this characteristic, when thisor antibiotics [7].

enzyme is inhibited, synthesis of mRNA is disrupted, andAs we repeatedly mentioned in previous articles,

growth of influenza virus is suppressed. However, it doesapparent symptomatic improvement by oseltamivir andnot kill the influenza virus.

other neuraminidase inhibitors is not due to reduction

Oseltamivir ( Tamiflu ) and other neuraminidaseof the virus, but because the agents simply let patients

inhibitors do not inhibit viral growth, but simply prevent

abstain from fighting against the virus. Therefore, it does

the virus from leaving the surface of the epithelial cells

not really improve symptoms [6].

of the respiratory mucosa. Viral load is reduced in nasal
discharge, but not in the lung [6].

Although baloxavir has a mechanism of action different
from that of oseltamivir and other neuraminidase

However, baloxavir seems to suppress viral growth

inhibitors and strongly inhibits viral growth, the outcome

even in the lung of animals as well [2, 3]. Furthermore,is substantially the same with that of oseltamivir andin humans, no influenza virus was detected in the nasal

other neuraminidase inhibitors.

mucosa on the following day after taking baloxavir. Aftertaking placebo or oseltamivir, it took 4-5 days or 3 days,
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 37

New Products
Figure: Summary of Results: Phase III Trial of baloxavira) baloxavir versus placebob) baloxavir versus oseltamivir

Unknown effect on patients with severe influenza orthat by oseltamivir.

high-risk factors

Attenuation of secretory IgA (sIgA) by neuraminidase

In non-clinical studies, animals were infected with

inhibitors is more marked [6] Sawabuchi et al [8]lethal dose of influenza virus, and mortality was lower inreported that lower induction of sIgA against thebaloxavir group than in controlled group or oseltamivir

influenza A virus was observed in children treated withgroup. However, the effect of the agent in people with

oseltamivir in comparison with children treated without

severe influenza, diabetes or impaired immunity isoseltamivir. The odds of a child’s sIgA level increasing

unknown, as no study has been conducted to investigate

more than 10-fold were non-significantly lower init [2]. This is similar to the case of oseltamivir and otherchildren treated with oseltamivir (2/12) than in children

neuraminidase inhibitors [6].

without oseltamivir (3/3): odds ratio is 0.17 (95%CI: 0.01,
2.39, p=0.13) (calculated from the data shown in the Figure 1

Antibody production is reduced by 30%

of Ref [8])[6].

The problem is that antibody production might be

These findings are consistent with evidence frominsufficient, since the virus disappears quickly. No animal

animal tests using subclinical dose of oseltamivir instudy has confirmed that the agent does not interfere

influenza infected mice in which sIgA antibody decreased

with antibody production [2,3]. In clinical trials, theby 80 % ( 1/5 of control ) [6,9]. Indeed, re-infection iseffect on serum antibody level was investigated, but it isremarkable in the patients who were treated withnot mentioned in the documents for approval [2,3]. The

neuraminidase inhibitors including oseltamivir [6,8,10].

recently published study [7] is the only literature that

It is totally unknown about baloxavir whether thereported the results of the serum antibody production.

secretory IgA in respiratory mucosa is affected or

The main text of the study reported that there was

not and the risk of reinfection by baloxavir is greatly

no difference on antibody production compared withconcerned. If secretory IgA antibody production isplacebo. However, detailed analysis (meta-analysis) of

insufficient, patients might be easily re-infected in thethe appendix of the study revealed that odds of patientssame season or following years [6,8-10].

with a four-fold or more rise in serum antibody titre

Even if the virus disappears quickly, 10%-20% of thedecreased by 28% in baloxavir group compared to invirus remains as resistant (mutated) virus. In this case, theplacebo group (odds ratio 0.72, p=0.014).

virus regrows on around day 6, delaying overall recovery

Meta-analysis results on treatment trials of oseltamivir[2,3]. The median time to recovery was 43 hours without

showed that odds of those with a 4-fold or more rise inresistant virus and 80 hours with resistant virus (phase II

serum antibody decreased by 18% compared to placebo

study).

(odds ratio 0.82, p=0.004). Hence attenuation in serum
antibody production by baloxavir is rather greater than
Page 38 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

Further concern

influenza is a self-limiting infection or an infectious① Effect on human enzymes and their receptors

disease that can be cured naturally, no medication

CEN is believed to be a virus-specific enzyme. As far

is needed. Furthermore, much is still unknown with

as we have researched, it is unknown whether humans

baloxavir. If a serious harm occurs, even if it is rare,

have a similar enzyme. However, in toxicity studies, theit may be very difficult to save. The drug is not worth

liver and the coagulation system ( PT and APTT ) wereits high price, and various concerns remain. Baloxavir

affected. The possibility that coagulopathy was caused by(Xofluza) should not be used.

liver injury cannot be ruled out. In addition, “no observed
adverse effect level” (NOAEL) is only 2 to 3 times higher
than the human dose.
② Large individual difference in metabolism by CYP3A
Baloxavir is metabolized by a drug-metabolizing
enzyme CYP3A, which has a large individual difference.
If the drug is used by many patients, intense toxicity

References
1) M3.com News: https://www.m3.com/news/iryoishin/590171
2) Xofluza: Summary basis of approval3) Xofluza: Examination report by PMDA
4) Xofluza: Label

may be experienced by those with slow metabolism.

5) Xofluza: Interview form

Moreover, it interacts with many substances. When a

Infect Dis (Lond). 2016;48(9):651-60. https://www.tandfonline.com/doi/pdf/10.10

6) Hama R. The mechanisms of delayed-onset type adverse reactions to oseltamivir

serious adverse reaction occurs, harm is unavoidable as80/23744235.2016.1189592

the blood concentration remains high for a long time

Marboxil for Uncomplicated Influenza in Adults and Adolescents. N Engl J Med.

after taking just one dose.

8) Sawabuchi T, Suzuki S, Iwase K, et al. Boost of mucosal secretory immunoglobulin

7) Hayden FG et al (Baloxavir Marboxil Investigators Group). Baloxavir
2018;379(10):913-923. PMID: 30184455
A response by clarithromycin in paediatric influenza. Respirology. 2009;14:1173–
1179. PMID: 19909463

In practice (conclusion)
Baloxavir ( Xofluza ) demonstrated no difference in9) Shinahara W, Takahashi E, Sawabuchi T, et al. Immunomodulator clarithromycin
enhances mucosal and systemic immune responses and reduces re-infection rate inpediatric patients with influenza treated with antiviral neuraminidase inhibitors: asymptomatic improvement as compared with oseltamivir,

retrospective analysis. PLoS One. 2013;8:e70060. PMID:23875018

and shortened the time to symptom disappearance

immune responses by oseltamivir treatment in mice infected with influenza A virus.

by only one day as compared with placebo. Because

10) Takahashi E, Kataoka K, Fujii K, et al. Attenuation of inducible respiratory
Microbes Infect. 2010;12:778–783. PMID:20452454

MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 39

Adverse Reactions
New evidence of severe abnormal behaviors/
psychiatric reactions to oseltamivir(Tamiflu)
Translated from Med Check-TIP (in Japanese) Nov 2018 ; 18 (80):138
MedCheck-TIP Editorial team

Serious abnormal behaviors occurred 29 times more

Severe psychiatric reactions occurred 35 times more

frequently

frequently

From a prospective cohort study by Fujita et al. [1],In Cochrane's systematic review [1], the risk ofFukushima et al. (Hirota team) [2] extracted “abnormal

psychiatric symptoms increased dose-dependently

behavior A”, serious cases that could lead to accidents

in treatment trials of oseltamivir ( Tamiflu), and in the(24 persons in Tamiflu group and 4 persons in non-Tamiflu

prophylaxis trials it was significantly higher in thegroup ) to examine the risk of Tamiflu use by self-

Tamiflu group than in the placebo group. The review

controlled case series method.

reported that psychiatric symptoms were induced in

The risk ratios for Tamiflu use compared to non-use
were determined by adjusting various factors. They

about 1 person per 100 persons. However, the risk ratio
was 1.8 and not so high.

were between 1.9-fold and 29-fold ( 95%CI: 4.21-201 )Jones et al. used logistic regression method anddepending on the duration of Tamiflu use and non-use

analyzed psychiatric symptoms taking duration andthat was utilized in their analysis. The greatest risk ratio

intensity of symptoms into account. The odds ratio was

was yielded when the duration of about six hours after

3.46 (95% CI: 1.28 - 9.32) for overall intensities. Analysing

taking Tamiflu was utilized in the analysis. Fukushima

the intensity of the symptoms showed little difference

et al. concluded that they could not deny the possibility

between groups for mild ones ( OR 1.23, 95% CI: 0.30

that abnormal behavior was induced by influenza itself,- 5.04 ), but a statistically nonsignificant increase forsince the duration overlapped with the early period ofmoderate symptoms (OR 4.34, 95% CI: 0.79 - 24.0), and a

influenza where high fever was observed.

large, significant increase for severe psychiatric events

On the contrary, according to the data by Fujita et(OR 34.5, 95% CI: 3.66 - 325).

al. [1], the incidence rate of delirium per 1000 person-

Based on these results, Jones et al. stated that theirdays during high fever phase (until about 24 hours after

analysis shows evidence of a causal effect of oseltamivir

start of fever) was about 5 persons before Tamiflu use

on psychiatric symptoms.

while exceeding 30 persons at most after Tamiflu use.

There was little difference between both groups for

Therefore, it should be considered that Tamiflu causes

mild cases, even when symptom duration was taken“abnormal behavior A”.

into account. However, Tamiflu induced moderate andsevere psychiatric symptoms 1 per 210 persons and 1

References

per 230 persons, respectively which show that Tamiflu

1) Fujita Toshiharu et al., A Pharmacoepidemiologic Study on the Relationshipinduces moderate or severe psychiatric symptoms rather

between Neuropsychiatric Symptoms and Therapeutic Drugs after Influenza
Infection Pharmacoepidemiology 2010: 15 (2): 73-90.

frequently.

https://www.jstage.jst.go.jp/article/jjpe/15/2/15_2_73/_pdf/-char/ja
2) Fukushima W et al. Oseltamivir use and severe abnormal behavior in Japanesechildren and adolescents with infuenza: Is a self-controlled case series study
applicable? Vaccine 2017: 35: 4817-24

References
1) Jefferson T et al. Neuraminidase inhibitors for preventing and treating influenza in
adults and children Cochrane Database Syst Rev. 2014; 4: CD008965.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008965.
pub4/full?highlightAbstract=oseltamivir
2) Jones M et al. Psychiatric adverse events in oseltamivir prophylaxis trials:
Novel comparative analysis using data obtained from clinical study reports.
Pharmacoepidemiol Drug Saf. 2018 (Sep 12): 1-6.

Page 40 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

Critical Review
Cochrane review on HPV vaccine should be revised：
Due to missing trials, adjuvant toxicity, mortality and healthy user
bias in observational studies
HAMA, Rokuro M.D. NPO Japan Institute of Pharmacovigilance

Summary
Tovey’s comments on a paper by Jøorgensen et al. published in BMJ Evidence-Based Medicine related to therecently published Cochrane Review on HPV vaccines has many flows. The Cochrane review should be revised
by including all identified clinical trial data, considering adjuvant toxicity, significantly high mortality in midadult women and confounding bias with “healthy vaccinee effect” in observational studies. Before the revision iscompleted, I strongly recommend the Cochrane review should be suspended.
This is a revised article based on a letter as a rapid response [a] to Dr. David Tovey on a paper by Jørgensen et al [b]a) Hama R. https://ebm.bmj.com/content/23/5/165.responses#cochrane-review-should-be-revised-due-to-overlooked-trials-toxicity-of-adjuvantmortality-in-mid-adult-women-and-lack-of-discussion-on-observational-studies-with-serious-healthy-vaccinee-effectb) Jørgensen L, Gøtzsche PC, Jefferson T. The Cochrane HPV vaccine review was incomplete and ignored important evidence of bias. BMJ EvidenceBased Medicine 2018 July 27 https://doi.org/10.1136/bmjebm-2018-111012 2

Keywords:
Cochrane review, HPV vaccine, adjuvant, mortality, heaithy vaccinee effect,

Introduction
Tovey (Cochrane’s Editor in Chief) et al [1,2] commented

4. The review included published and unpublished dataon serious harms, and the findings on

on a paper by Jøorgensen et al. [3] published in BMJ

mortality were reported transparently and responsibly;

Evidence-Based Medicine related to the recently

5. The review was compliant with Cochrane’s current

published Cochrane Review on HPV vaccines [4]. I would

conflict of interest policy;

like to give my feedback on this issue. The key findings

6. Cochrane’s media coverage was cautious and balanced,of Tovey’s investigations are as follows:

but we recognize that there could be

1. The Cochrane Review did not miss "nearly half of the

improvements in relation to transparency where external

eligible trials". A small number of studies were missed

experts are quoted;

due to the primary focus on peer-reviewed reports in

7. The BMJ Evidence-Based Medicine article substantiallyscientific journals, but addition of these data makes little

overstated its criticisms.

or no difference to the results of the review for the main

I would like to comment on Tovey’s findings 1, 2, 4 andoutcomes;

lastly, I added comments as 8. Most observational studies

2. The trials comparators were unambiguously,

neglect “healthy vaccine effect/healthy user bias”.

transparently, and accurately described;
3. The selection of outcomes for benefits was appropriate

1. On “The Cochrane Review did not miss nearly

and was consistent with World Healthhalf of the eligible trials".

Organization guidance;

Tovey explained “A small number of studies were
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 41

missed due to the primary focus on peer-reviewed

toxicity of adjuvants.

reports in scientific journals.” However, the abstract of

It is true that the Cochrane review by Arbyn et al.

the Cochrane review reports: “We searched MEDLINE

described the comparators unambiguously, transparently,----- for reports on effects from trials.

and accurately. However, the problem is not the accuracy

We searched trial registries and company results’and transparency of the description of the comparators.

registers to identify unpublished data for mortality and

It is that adjuvants as the comparators conceal theserious adverse events.”

true harm of HPV vaccines because the safety of the

For the serious adverse events, the Cochran review

vaccine adjuvant has never been established clinicallydescribed in the sensitivity analysis as follows: “We[5] nor non-clinically. Instead, harm of adjuvant is rather

assessed the robustness of data collected for serious

unavoidable as indicated by laboratory tests and toxicity

adverse events, all-cause mortality and pregnancy

tests shown in the followings.

outcomes based on the source of data. The primary
analysis for these outcomes included data that we

2-2. Non-clinical tests strongly suggest the harm ofconsidered to represent the most complete follow-up.

adjuvant.

As a sensitivity analysis we used data for these same

It is revealed that true adjuvant is the DNA of theoutcomes that had only been reported in the publishedrecipient which is produced by tissue damage by thetrial reports.”

administered adjuvant, such as alum adjuvant. This

It is evident that the Cochrane review recognized thesuggests that the bigger the damage, the stronger theimportance of clinical study reports (CSRs) and partiallystimulation of innate immunity and work as adjuvant

gathered the unpublished data for mortality and serious[6,7], and autoimmune diseases [8], including those inadverse events.

the central nervous system [9] may be induced.

Jørgensen et al. pointed out that there were many

GlaxoSmithKline conducted several animal toxicity

missed trials which Cochrane review did not included

tests, although they did not fulfil the standard toxicity

because they were not published.

testing method for the ordinary pharmaceutical products.

As for the analysis of oseltamivir, we, the Cochrane

In the third toxicity test, single or repeated i.m.,

neuraminidase inhibitor team, used all CSRs and foundCervarix, and AS04 adjuvant induced item-related local

significantly increased psychiatric events in the 4 CSRs

degeneration, necrosis, and regeneration of muscle

for prophylaxis of influenza. However, if we restricted tofibers with hemorrhage and mild-to-moderate subacuteuse peer reviewed published journals, we would not haveinflammation at 4 days and 5 months after the firstdetected the psychiatric harm even if CSRs for publishedinoculation, unlike saline [10]. The extent and proportion

trials were used. This is the most important point thatof animals with these lesions were the same between

Jørgensen et al. emphasized.

Cervarix and AS04 group and immediately after the
single dose but more prominent in the Cervarix group

Summary of this section

than AS04 adjuvant group after 4 repeated doses [10].

The review should be revised by including all CSRs
identified and other points described in the following
sections. Before the revision is completed, theCochrane review should be suspended.

Summary of this section
In a randomized controlled trial, saline control isappropriate as the comparator for the analysis ofboth efficacy and harm. For efficacy analysis, active

2. Description of the comparators and thecontrol such as adjuvant or vaccines with/without

unavoidable toxicity of adjuvants

adjuvant may not be necessarily inappropriate as

2-1. The safety of adjuvants is not established.

the comparator. However, these active controls are

Tovey wrote “ The trials comparators were

definitely inappropriate for the harm analysis. The

unambiguously, transparently, and accurately described”.

other approach should be applied for the harm

However, the problem is not the descriptions but the real

analysis, if no saline control trials are available.

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4. On “The review included published

Figure 1: Mortality risk within 4 years after the first injection

and unpublished data on serious(Meta-analysis of 3 trials targeted mid-adult women)harms, and the findings on mortality
were reported transparently andresponsibly”;
4-1. Meta-analysis of mortality in the trials
targeting mid-adults women
You wrote “The review included publishedand unpublished data on serious harms,
and the findings on mortality were reported
transparently and responsibly.” According
to my meta-analysis using the extracted
data from the reference peer reviewed papers in which
subjects’ ages were 25 (or 26) to 45 year or older [11-14],

Risk of death in women aged 25 to 45 years may befurther robust by adding this trial.

the pooled odd ratio was 5.00 (95%CI: 1.71, 14.65), P =0.0022 (I2 = 0%) (Figure 1).
• For the VIVIANE trial [11,12], I used 13 deaths in

Summary of this section
Pooled odd ratio of death for mid-adult women

Cervarix group and 3 deaths in adjuvant group within

was 5.00 (95%CI: 1.71, 14.65), while no difference on

4 years, because after that period there was nomortality for younger women was observed. Serious

difference between these groups.

adverse event and mortality should be separately• For the FUTURE III trial [13], the numbers of deaths

analysed for different age groups: namely under thedescribed in the published paper were 7 in theage of 25 years and mid-adults (approximately 25 or

Gardasil group and 1 in the adjuvant group as shownolder) in addition to the analysis as the whole ages.

in its sensitivity analysis of death. However, in the
Cochrane review, the numbers are 8 and 4,
respectively, presumably based on the data including
after 4 years from unpublished CSR.
• For the Chinese trial [14], my extraction was HPV

4-2. Fluctuation of mortality and adverse events
If a vaccine does not cause harmful effects, theincidence rate of adverse events may stay at the baseline
or increase only slightly as age increases. However, if thevaccine 0 and adjuvant 0 while the Cochrane review

incidence rate of adverse events fluctuates substantially,

data were 1 and 0, respectively, also in the sensitivity

then it may be the result of the harmful effect of theanalysis.

vaccine. Several patterns of theoretical trend of incidence
rate are shown (Figure 2A).

Figure 1 indicates that HPV vaccines increase mortality

In the pivotal RCT of Cervarix (PATRICIA), no difference

in woman aged 25 or older by 5 times within 4 years

in the adverse events between Cervarix group andafter the first injection. Moreover, Tovey described thatadjuvanted HA vaccine group was observed. Hence, I

after adding the mortality data from newly included trial

calculated the overall (both groups) trend of incidence

NCT00834106 ( targeted 20 to 45 years of age ), RR ofrates of adverse events, including chronic diseases (CD),death increased from 1.54 (95% CI 0.73 to 3.23) to 1.65

autoimmune diseases ( AD ) and death ( D ) dividing 3(95% CI 0.80 to 3.38). It is highly probable that substantial

periods: 1: 0-1.2 year, 2: 1.2-3.4 year, 3:3.4-3.65 year.

difference of death risk may be reported in this added

Incidence rate (/100,000 person-year) of CD, AD and D

study. Tovey should clarify the number of deaths in bothfluctuate as follows: CD: 129-55-164, AD: 25-24-88,

groups (Data from Clinicaltrial.gov suggest that the number

D:22-30-135 respectively. These data show that theof deaths are estimated 2/1499 and 0/1498 for Gardasil andincidence rates or mortality rates greatly fluctuate

adjuvant group respectively).

and increase even after about 3.5 years from the first
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 43

Figure 2: Fluctuation of adverse events
A: Theoretical pattern

B. Cervarix trial (PATRICIA)

C. Gardasil (1) Autoimmune diseases

D. Gardasil (2) Specified autoimmune diseases■ Period 1: day 1 to 6 months,■ Period 2: 7 months to 2 years. Data were derived from Gardasil RCTs in the Japanese Summary Basis of Approval.

Grouped specified autoimmune diseases: Inflammatory bowel diseases (IBD: ulcerative colitis and Crohn’s disease), psoriasis/Stevens–Johnson syndrome(SJS), systemic lupus erythematosus (SLE)/rheumatoid arthritis (RA)/scleroderma, multiple sclerosis (MS)/optic neuritis.

inoculation (Figure 2B).

are greater in the HPV vaccine group.

For Gardasil studies, I calculated the incidence rates

If the numbers of deaths for FUTURE III trial are 8 for(/100,000 person-years) of various autoimmune-related

Gardasil group and 4 for adjuvant group, 1 and 3 deaths

adverse events ( AE ) among participants from both

may be observed after 4 years, respectively. Person-

Gardasil and control ( almost all received alum-adjuvant )years at risk is not estimated, but 7 in the first 4 years

groups ( Figure 2C and 2D ). Incidence rates ( /100,000

and 1 thereafter indicate similar fluctuation, and lessperson-years ) of total autoimmune related adverse

fluctuation is observed in the adjuvant group. This may

events are 2441 at the first period (day 1 to 6 months)

be a very similar phenomenon as shown in the VIVIANE

and 625 at the second period (7-24 months) and that oftrial.

inflammatory bowel disease are 77 and 28 respectively.
These also indicate that the incidence rates of various

Summary of this section

autoimmune diseases greatly fluctuate over time andFluctuation of serious adverse events including

suggest Gardasil affected these fluctuations (included

death should be considered in the RCTs using adjuvant

studies were all phase II and III trials targeted women aged 9

as comparator. Analysis of high risk and low risk

to 24).

periods together may conceal true harm of HPV

VIVIANE trial shows high mortality rate during thefirst 4 years and low mortality rate after 4 years in the
Cervarix group, but this was not evident in the control
adjuvant group (Figure 3). These data show fluctuations
Page 44 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

vaccines. Analysis should be conducted separately forthe different risk periods.

Figure 3 Fluctuation of mortality in Cervarix group in VIVIANE trial※ : A patient died from breast cancer at M52 is excluded in the first period (0-48 M) but included in
the second period (48-84 M). *:p=0.041, **:p=0.047, ***:p=0.013, NS: not significant.

4-3. Comparison of incidence rates of specificautoimmune diseases between RCT and general
population of women of similar age group
The incidences rates of some autoimmune diseases
examined, such as multiple sclerosis ( MS ), systemic
lupus
erythematosus (SLE), and inflammatory bowel diseases(IBD), calculated from the data in the “SBA” of Gardasil

Figure 4 ： Comparison of incidence rates of MS and IBD between
RCTs and general female population of similar age
A: Muitiple Sclerosis(MS)( age ranged 9–26 years, mainly 16–23 years ) were all
higher than those in the general female population ofsimilar age (15 to 25 years old).
For example, the incidence rate (per 100,000 personyear ) of MS in Gardasil RCTs ( 14.7 ) was about 3–15

times higher than that of general population in Italy(4.2–4.7), the United Kingdom (3.4), and France (1.0).
Notably, MS incidence reported in Gardasil RCTs waseven higher than the highest reported in the general
population, namely, in north Sweden (8.4) and Iceland

B: Inflammatory Bowel Disease(IBD)(12.5) (Figure 4A).
Incidence rates of IBD in the RCTs are also higher thanthat of the general female population of similar age,though the age range is a little broader (0 to 39 years
old) (Figure 4B).

Summary of this section
Annual incidence rates for typical adverse events
such as specific autoimmune diseases in the RCTs
should be compared with that of general population ofsimilar age.
In the discussion section, the Cochrane review
discussed the Adverse effects of HPV vaccines citing
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 45

8. Most observational studies neglect “healthyvaccine effect/healthy user bias”
many observational studies.

However, most observational studies have fundamental

Suzuki et al. [16] concluded “the results suggested nocausal association between the HPV vaccines and their
alleged harmful symptoms”.
However, according to my logistic regression analysis

flaws:

using the disclosed PDF data, odds ratios ( ORs ) of

• Negligence of healthy vaccine effect (healthy user bias),

positive symptoms before vaccination were significantly• Negligence of time dependent bias in the self-control(p<0.05) lower than 1.0 in 15 of 24 symptoms ranging

case-series method and• Confusion of incidence with prevalence.

from 0.16 ( Dependent on stick or wheel chair) to 0.86
(Irregular menstrual cycle). ORs for symptoms leading toHere I only discuss the Negligence of healthy vaccine

hospital visit were significantly lower than 1.0 in 7 ofeffect (healthy user bias) which most observational studies

24 symptoms, especially in severe symptoms, such as

neglected, affect the results seriously and sometimes“Unable to walk normally” (0.22), “Dependent on stick

reverse the association.

or wheel chair” (0.21), “Sudden loss of strength” (0.28)
and “Weak in the extremities” (0.30). OR for “Difficulties

Negligence of healthy vaccinee effect (healthy user bias)

in calculation” is not significant (P=0.148 ), but pointi) Theoretical basis

estimate of OR was very low (0.25, p=0.15).

It is important that confounding bias is avoided in

The trends of the proportion of the frail, by coverage

epidemiologic studies. In particular, confounding bias

both in the unvaccinated and the vaccinated groups fit

from “healthy vaccinee effect” always affects results inwell to the theoretical trends expected in each group.

favour of an intervention, leading to overestimation of its
effectiveness and safety.

On the other hand, odd ratios of positive symptoms
after vaccination leading to hospital visit were generally

People who have any diseases and/or are prone

higher than 1.0 ( no symptom was less than 1.0 ) andto have fever/infection tend to avoid vaccination.

significantly higher than 1.0 in 11 of 24 symptoms:

Autoimmune diseases often follow infection. Unlessfor example, “Weak in the extremities” (2.76, p=0.014)

unvaccinated people who are sicklier or frailer thanand “Difficult to remember Chinese characters” (8.46,

vaccinated people at baseline were not adequately

p=0.047). “Dependent on stick or wheel chair leading toadjusted, the results of the high incidence rate of

hospital visit” were reported in 13 girls in the vaccinatedautoimmune diseases in the vaccinated people may begroup, while none in the unvaccinated group: odds ratio

offset by the disease incidence in the sickly unvaccinated= 9.61 (95%CI: 1.21- infinity, p=0.027) by the exact-likepeople. This is “healthy-vaccinee effect,” “frailty selection

logistic regression using “R” software.

bias,” or “frailty exclusion confounding bias.” [15]Considering the low odds ratio of health status before

Bias from “healthy-vaccinee effect” becomes moreinoculation, each odds ratio after inoculation should

impactful as the coverage of vaccination becomes

be divided by the corresponding odds ratio before

higher, namely 80% or higher [15]. Theoretically ininoculation. Hence point odds ratio after vaccination

the unvaccinated, odds ratio for having symptoms at aof HPV vaccine for the symptoms leading to hospital

certain vaccine coverage (%) compared with the lowest

visit are estimated as follows (those above 5.0 are shown):

coverage group increases as the percent coverage

Dependent on stick or wheel chair: 46.7, Difficult

increases.

to remember Chinese character: 24.8, Difficult toii) Nagoya study

calculate: 15.5, Unable to walk normally: 11.0, Weak

Nagoya study is a questionnaire survey on symptoms
after HPV vaccination, involving about 70,000 girls (bornin the extremities: 9.2, Sudden loss of strength: 8.6 andInvoluntary movement: 5.7

between 2 April 1994 and 1 April 2001: approximately aged

Among many observational studies, French study is a

14 to 21 in September 2015) living in Nagoya City Japan.

study which apparently adjusted the health status prior

Of these, about 30,000 girls responded: 20,748 girls

to vaccination [17,18]. However, it has some limitations

were vaccinated and 9,098 girls were unvaccinated [16].

as follows:

Page 46 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

iii) French study: apparently incorporating prior healthstatus they adjusted included that after vaccination,

status but not actuallywhich may be affected by the HPV vaccination. They

1) The authors did not restrict the health status prior to

analysed without adjusting health status as sensitivity

vaccination as covariate for adjustment. They adjusted

analysis and did not show the results.

the health status after inclusion up to 3 months before

2) The health status they adjusted as that prior to

the event or censoring as covariate. Hence, the healthinclusion ( or vaccination) was at least one outpatient

French study [17,18] is a retrospective cohort study basedon national healthcare administrative databases. Total 2.25

visit during the year prior to inclusion and not prior
to vaccination. Vaccinated girls had more outpatient

million girls aged 13 to 16 years between 2008 and 2013

primary care than unvaccinated girls (94.2% vs 86.5%)

were included: 0.84 million (37.3%) were exposed to HPVand visited more specialists ( 75.9% vs 65.2% ). Thisvaccine and 1.41 million were not exposed. Proportion

phenomenon contradicts the common tendency thatof girls vaccinated was the highest in those included

unvaccinated people are usually sicklier or frailer

in 2008 ( 45.4% ) and subsequently decreased 43.3%,

than vaccinated people at baseline as explained in the

35.0%, 26.0% and 15.1% for 2009, 2010, 2011 andsection of “Theoretical basis of healthy vaccinee effect”.

2012 respectively. Outcome events were 14 autoimmune

Low proportion of outpatient visit in the unvaccinateddiseases ( AID ), including central nervous system ( CNS )may not indicate that unvaccinated girls are healthierdemyelinating diseases (MS: multiple sclerosis etc.), Guillain-

but may be related to their lower socioeconomic level.

Barres syndrome (GBS), and inflammatory bowel diseases

Hence, adjusting the status of outpatient visit could(IBD). Hazard ratios of any of the14 AIDs or of individual
AID were estimated by Cox regression analysis adjusting
age, year of vaccination as time dependent variable.
Vaccination other than HPV vaccine, hospitalisations,health-care seeking behaviour indicators, year of inclusion,
geographic area of residence and socioeconomic level werealso adjusted. “Health-care seeking behaviour indicators”
include all-causes hospitalizations, outpatient primary careand specialist visits. Hospitalizations were considered in
the model as a time-dependent binary variable, indicating

not adjust the true health status of the vaccinated andunvaccinated.
3) They also adjusted age, year of vaccination and yearof inclusion. Proportion of the vaccinated is closely
related to the year of inclusion. As shown in the section
of “Theoretical basis for healthy vaccinee effect (healthyuser bias)”, in the unvaccinated people, odds of having

illness prior to vaccination increases as the percent
coverage of vaccination increases.

if at least one hospitalisation occurred over the 12-month

As shown by Jackson et al. [19], risk of death forperiod running from 15 months to 3 months prior to eachvaccinated persons compared with unvaccinated persons

time point. Outpatient visits were considered as time-

was lower before influenza season than during and after

fixed variables: binary variables indicating the occurrence

influenza season. The reductions in risk before influenza

during the year prior inclusion, and quantitative variables

season indicate preferential receipt of vaccine byindicating the mean annual frequency of visits during

relatively healthy seniors, and adjustment of diagnosis

follow-up (ratio of the total number of visits after inclusion

code variables did not control this bias. Hence, unlessuntil 3 months before the event or censoring). A statisticallytrue health status prior to vaccination is adjusted, thesignificant association with HPV vaccine was shown in 2

adjustment is flawed in the French study.

autoimmune diseases: adjusted HR of inflammatory bowel
diseases ( IBD ) was 1.18 ( 95%CI: 1.01-1.38 ) and that ofGuillain-Barré syndrome (GBS) was 3.78 (95%CI: 1.79-7.98).
The sensitivity analysis showed that the association of bothautoimmune diseases were the strongest for the period
from 0 to 3 months and tended to decrease subsequently
without significance for IBD, but it remained significant for
GBS. Risk of GBS is robust as suggested by the sensitivity
and subgroup analysis.

In fact, crude rate ratios ( RRs ) calculated by the
number of patients with any autoimmune diseases (AIDs)
and 12 individual AIDs were higher than the adjusted
hazard ratios (HRs); for example, any AID: 1.14 (P<0.001)
vs 1.07 ( p=0.10 ), inflammatory bowel diseases (IBD ):1.54 (P<0.001) vs 1.18 (P=0.032) and CNS demyelinating
diseases: 1.28 (P=0.059) vs 1.06 (P=0.72).
Moreover, incidence rate (/105 py) of CNS
demyelinating diseases in the unvaccinated group (4.6
MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 47

or 5.9 ) is very high compared with that of multiple

comparator. However, these active controls are definitely

sclerosis ( 0.99 [95% CI: 0.94–1.04] ) in the general

inappropriate for the harm analysis. The other approach

female population of the same age group (aged 15 to 24

should be applied to the harm analysis, if no saline

years) in France between 2001 and 2007 [19]. Hencecontrol trials are available.

incidence rate (/105py) of CNS demyelinating diseases

3) Pooled odd ratio of death for mid-adult women

after HPV vaccine in the HPV vaccinated group in thewas 5.00 (95%CI: 1.71, 14.65), while no difference on

French pharmacovigilance study [17] is far higher thanmortality for younger women was observed. Seriousthat in the general population in France [19]. The highadverse event and mortality should be separately

incidence rate in the unvaccinated girls may be theanalysed for different age groups: namely under the age

result of healthy user bias and exclusion of frailty fromof 25 years and mid-adults (approximately 25 or older) in

vaccination due to the high vaccination coverage.

addition to the analysis as the whole ages.

These suggest that frail girls had been included in the4) Fluctuation of serious adverse events including deathunvaccinated group at the time of inclusion. Therefore,should be considered in the RCTs using adjuvant as

it should be considered that “healthy vaccinee effect” orcomparator. Analysis of high risk and low risk periods“frailty exclusion bias” may not have been completely

together may conceal true harm of HPV vaccines.

excluded even in this French pharmacovigilance study

Analysis should be conducted separately for the different[17,18].

risk periods.

Moreover, significantly high incidence of events

5) Annual incidence rate for typical adverse events suchafter inclusion such as frequent consultation ( ≧ 4/

as specific autoimmune diseases in the RCTs should beyear ): Odds ratio ( OR ) = 2.81 ( 2.80,2.83 ) and at least

compared with that of general population of similar age.

one hospitalization: OR = 3.54 ( 3.52, 3.56 ) ( based on

6) For the discussion of harm comparing the results

person-year ) should be taken into account. This iswith those from observational studies, it is essential

because high odds ratio needing frequent medical care

to consider the “healthy vaccinee effect”. Unless theand/or hospitalisation ( 9% of the girls per year needed

observational studies adjust the health status before

additional hospitalization compared with prior vaccination

vaccination ( pseudo vaccination date for unvaccinatedand unvaccinated girls) may be related to some adverse

group), the findings from such studies should not be usedoutcomes of HPV vaccination other than autoimmune

as evidence of safety.

diseases.
For the discussion of harm comparing the results

It is my sincere hope that Tovey et al. would consider
this feedback seriously in order to further improve thewith those from observational studies, it is essential toquality of the Cochrane review.

consider the “healthy vaccinee effect”. Unless the health

Rokuro Hama M.D.

status before vaccination (pseudo vaccination date for

Chairperson, NOP Japan Institute of Pharmacovigilance

unvaccinated group) is adjusted in observational studies,the findings should not be used as evidence of safety.

Conflict of interest
No conflict of interest with industries including

Conclusion

pharmaceutical companies.

1) The review should be revised by including all ASRs

Rokuro Hama (RH) has been a member of the Cochrane

identified and other points described below. Before

neuraminidase inhibitor team headed by Tom Jefferson

the revision is completed, I strongly recommend thesince January 2010. RH has met Dr. David Tovey (DT)

Cochrane review should be suspended.

and discussed the methods for conducting the systematic2) In a randomized controlled trial, saline control isreview of neuraminidase inhibitors [20] at the Oxford

appropriate as the comparator for the analysis of

meeting in April 2011. RH explained DT and otherboth efficacy and harm. For efficacy analysis, active

members of the Cochrane neuraminidase inhibitor

control such as adjuvant or vaccines with/without

team how Tamiflu lowered the antibody production

adjuvant may not be necessarily inappropriate as thein the treatment trial and that ITTI population wasPage 48 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

inappropriate for the assessment of efficacy. Instead, RH
proposed that ITT population should be used to assess
efficacy and harm of Tamiflu. The method using ITT
population was agreed by the Cochrane neuraminidase
inhibitor team at the meeting in April 2011.

References
1) Cochrane’s Editor in Chief responds to BMJ EBM article criticizing HPV review13) Castellsagué X, Munoz N, Pitisuttithum P, Ferris D, Monsonego J, Ault K. End-of-

https://www.cochrane.org/news/cochranes-editor-chief-responds-bmj-ebm-ar...

study safety, immunogenicity, and efficacy of quadrivalent HPV (types 6, 11, 16, 18)2) Tovey D and Soares-Weiser K. Cochrane’s Editor in Chief responds to a BMJ

recombinant vaccine in adult women 24 to 45 years of age. British Journal of Cancer

Evidence-Based Medicine article criticizing the Cochrane Review of HPV vaccines.

2011;105(1):28–37.

https://www.cochrane.org/sites/default/files/public/uploads/cochrane_hpv...

14) Zhu FC, Li CG, Pan HX, Zhang YJ, Bi D, Tang HW. Safety and immunogenicity of3) Jørgensen L, Gøtzsche PC, Jefferson T. The Cochrane HPV vaccine review washuman papillomavirus-16/ 18 AS04-adjuvanted vaccine in healthy Chinese females

incomplete and ignored important evidence of bias. BMJ Evidence-Based Medicine

aged 15 to 45 years: a phase I trial. Chinese Journal of Cancer 2011;30(8):559–64.

2018 July 27 https://doi.org/10.1136/bmjebm-2018-111012 2.

15) Hama R. Symptoms after HPV vaccine: typical "frailty exclusion bias" in Nagoya

4) Arbyn M, Xu L, Simoens C, Martin-Hirsch PPL. Prophylactic vaccination

City study.

against human papillomaviruses to prevent cervical cancer and its precursors.

MedCheckTIP 2016: 2(No5); 18-21 available at

Cochrane Database of Systematic Reviews 2018;(5): CD009069. https://doi.

https://npojip.org/english/MedCheck/Med% 20Check-TIP% 2005-08-08.pdf

org/10.1002/14651858.CD009069.pub3

16) Suzuki S, Hosono A. No Association between HPV Vaccine and Reported Post-

5) Jefferson T, Rudin M and Pietrantonj CD, Adverse events after immunization with

Vaccination Symptoms in Japanese Young Women: Results of the Nagoya Study.

aluminium-containing DTP vaccines: systematic review of the evidence, Lancet InfectPapillomavirus Res. 2018 Feb 23. pii: S2405-8521(17)30070-8

Dis 4, 2004, 84–90.

17) French National Agency for Medicines and Health Products Safety. Vaccins anti-

6) Marichal T, K. Ohata K, Bedoret D, Mesnil C, Sabatel C, Ishii KJ et al., DNA released

HPV et risque de maladies autoimmunes: étude pharmacoépidémiologique Rapport

from dying host cells mediates aluminum adjuvant activity, Nat Med 17, 2011, 996–

final Septembre 20151002.

http://ansm.sante.fr/content/download/80841/1023043/version/1/file/Ansm_...

7) Sloane JA, Blitz D, Margolin Z and Vartanian T, A clear and present danger:18) Miranda S, Chaignot C, Collin C, Dray-Spira R, Weill A, Zureik M. Human

endogenous ligands of Toll-like receptors, Neuromolecular Med 12, 2010, 149–163.

papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of8) Tsumiyama K, Miyazaki Y and Shiozawa S, Self-organized criticality theory ofover 2million young girls in France. Vaccine. 2017 Aug 24;35(36):4761-4768. PMID:

autoimmunity, PLoS One. 4, 2009, e8382.

28750853

9) Lampron A, Elali A and Rivest S, Innate immunity in the CNS: redefining the19) Jackson L.A., Jackson M.L., Nelson J.C., Neuzil K.M. and Weiss N.S., Evidence

relationship between the CNS and its environment, Neuron 24 (78), 2013, 214–232.

of bias in estimates of influenza vaccine effectiveness in seniors, Int J Epidemiol 35,10) GlaxoSmithKline Biologicals. Japanese Summary Basis of Approval of Cervarix.

2006, 337–344.

http://www.pmda.go.jp/drugs/2009/P200900052/index.html ; [accessed 18.9.4].

20) Fromont A, Binquet C, Sauleau E, Fournel I, Despalins R, Moreau T et al.

11) Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E,

National estimate of multiple sclerosis incidence in France (2001-2007). Mult Scler.

Salmeron J. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18

2012;18:1108-15.

AS04- adjuvanted vaccine in women older than 25 years: 4-year interim follow-

21) Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R et al. Neuraminidase

up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet

inhibitors for preventing and treating influenza in healthy adults and children.

2014;384(9961): 2213–27.

Cochrane Database Syst Rev. 2014;4:CD008965.

12) Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, Garland SM, Chatterjee

http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD008965.pub4/full

A, Lazcano-Ponce E, et al. Efficacy, safety, and immunogenicity of the humanpapillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years:
7-year interim follow-up of the phase 3, doubleblind, randomised controlled VIVIANE
study. Lancet Infectious Diseases 2016;16(10):1154-68.

MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 49

NEWS
Cochrane is a “sinking ship” [8, 11]. (Related articles: pages

Cochrane Out of Control: Expulsion of
the Prominent Member

30 and p41~)
References
1) BMJ. Https://www.bmj.com/content/362/bmj.k3945.full2) https://nordic.cochrane.org/news/prof-peter-c-g% C3% B8tzsche-becomes-

On September 13, 2018, Cochrane’s Governing Board
announced that it would expel Dr. Peter Gøtzsche, oneof its founders, from the organization. The decision wasmade with a slim margin; with six officers in favor, fivemembers against and one abstinence. Dr. Gøtzsche was
excluded from the discussion. Four officers resigned inprotest against the decision [1].
Dr. Peter Gøtzsche was the director of the Nordic
Cochrane Centre and one of the 13 board members.
He conducted 18 systematic reviews, and exposedthat breast cancer screening programs (see MedCheck-member-cochrane-governing-board3) Arbyn M et al https://doi.org/10.1002/14651858.CD009069.pub3
4) Jørgensen L et al https://doi.org/10.1136/bmjebm-2018-111012
5) Tovey D and Soares-Weiser K.
https://www.cochrane.org/sites/default/files/public/uploads/cochrane_hpv
6) Hama R.
https://ebm.bmj.com/content/early/2018/07/27/bmjebm-2018-111012.
responses#top7) Jørgensen L, Gøtzsche PC et alhttps://ebm.bmj.com/content/early/2018/07/27/bmjebm-2018-111012.
responses#top8) http://www.deadlymedicines.dk/9) https://docs.google.com/document/
d/1nCr402Kcnp5hx_5gr_aUT_zSItCN4XmddjS-1d7cPXY/edit?ts=5bdf0907Øt
10) https://www.rigshospitalet.dk/english/news-and-media/news/Pages/2018/
november/status-of-the-situation-at-the-nordic-cochrane-centre.aspx
11) Bijl D et al. Https://www.bmj.com/content/362/bmj.k3945/rr-0
See also: Editorial of this issue (p.30), Critical Review (p.41)

TIP No.63 and No.66 ) and comprehensive medical

examinations (MedCheck-TIP No.76) were ineffective. He
has made major contributions as a leader of Cochrane's
Methods Groups. His important achievements also

France has delisted anti-dementia agentsinclude research on overuse and harm of psychotropic
drugs [2].

From August 1, 2018, the French government has

Dr. Gøtzsche severely criticized Cochrane's systematic

decided to totally discontinue reimbursement of four

review on HPV vaccine published in May this year [3],drugs for dementia of the Alzheimer type (hereinafter anti-

indicating that the review had analyzed only about halfdementia agents), such as donepezil, by health insurance.

of the studies, and raising a question of conflicts ofAnti-dementia agents can be used only at patients’ owninterest with the manufacturers [4].

expense.

Cochrane's Editor in Chief and his Deputy refuted thecriticism [5], but their argument is flawed [6, 7].
Governing Board simply explained that Dr. Gøtzsche

The four drugs are, namely, donepezil ( Aricept® inJapan), galantamine (Reminyl®), rivastigmine (Rivastatch®
patch, Exelon® patch) and memantine (Memary®).

was expelled for causing “disrepute” to the organization,

The French Pharmacoeconomic Committee has been

but no concrete reason was provided. The board did notscientifically evaluating the benefit of the anti-dementia

allow him to defend himself in the discussion, and it even

agents, and the policies they introduced in the past 10

threatened to close the Nordic Cochrane Centre [8]. Dr.

years have prepared the ground for this decision [1].

Gøtzsche has been fired from his job as the director of
Nordic Cochrane Centre at Rigshospitalet [9,10].

First of all, in 2007, the committee stated thatagents for Alzheimer’s disease provide no “therapeutic

These events greatly undermined the founding spirit ofadvantage”, downgrading them from the level IV (minor)

the Cochrane Collaboration; that is to exclude influence

to the level V (no therapeutic advantage). This measurefrom the pharmaceutical industry and to build truly

was taken based on the committee’s judgement that there

reliable information about roles and benefits/harm of

was no evidence on the long-term benefit, but only on

therapeutic and diagnostic medicine by voluntary efforts

transient efficacy [1]. This coincides with the conclusionof researchers. However, now Cochrane itself has becomeof Med Check No. 27 published in July 2007; "there iscommercialized and influence from the pharmaceuticalno effective medicines for treatment of dementia”. This

industry is increasing. This seems to be the cause ofdecision was made four years before three anti-dementia

the crisis today. There is a growing concern now thatagents, except for donepezil, were approved in Japan.

Page 50 ・ MED CHECK - TIP Decembar 2018/ Vol.4 No.12

In September 2011, the committee recommended thatthe reimbursment rate for anti-dementia agents would
be lowered from the regular rate of 65% to 15% because
they were considered less useful.

Editor of Prescrire International, France, no other source
would cover the cost.
In Japan, over 150 billion yen is spent annually forthese ineffective drugs. Half of it is wastefully prescribed

In 2012, subscribing to this recommendation, the rates

for people aged 85 years or over, and three-fourth is forfor these agents were actually lowered. However, sincepeople aged 80 years or over [3]. This situation should

the expenses for donepezil and memantin were covered

be seriously reconsidered.

100 % by the other source, this measure was practically
References

ineffective.
However, on August 1, 2018, a new measure wasintroduced, which provides totally no reimbursement for
the agents. According to Dr. Christophe Kopp, Managing

MC1) MedCheck-TIP 2016: 16 (63): 7.
2) Kusuri-no-Check No. 27, 2007
3) Okamura et al. Int J Geriatr Psychiatry. 2018 May 20
Doi: 10.1002 / gps.4892

ED

HECK

The Informed Prescriber
2018

Vol.4

No.12

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD); TANIDA, Noritoshi (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); OHTSU,
Fumiko.(Pharmacist) ; TAKANO, Yoshihiko(MD[ pediatrician ]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
MUKAI, Junji (Pharmacist); SEGAWA,Yusuke; SUMIDA, Sachie(MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro(Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
Editorial Officers: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO,
Koji
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MED CHECK - TIP December 2018/ Vol.4 No.12 ・ Page 51