Principles for the Evaluation of Vaccines Against the Novel Coronavirus SARS-CoV-2

September 2, 2020
Office of Vaccines and Blood Products,
Pharmaceuticals and Medical Devices Agency

1. INTRODUCTION
 Infectious disease preventive vaccine is a medical product to activate the immune system against specific
antigen. For general considerations regarding nonclinical and clinical evaluations of investigational
preventive vaccines for infectious diseases, Guidelines for Nonclinical Studies of Preventive Vaccines
for Infectious Diseases (PFSB/ELD Notification No. 0527-1, dated May 27, 2010)1) and Guidelines for
Clinical Studies of Preventive Vaccines for Infectious Diseases (PFSB/ELD Notification No. 0527-5,
dated May 27, 2010)2) can be used for reference.
 As a result of the recent pandemic of SARS-CoV-2 infectious disease (COVID-19), more than 20 million
people have been affected to date worldwide. Vaccines to prevent SARS-CoV-2 infectious disease
(SARS-CoV-2 vaccines) are being developed using various modalities such as inactivated virus vaccine,
recombinant protein vaccine, mRNA vaccine that uses lipid nanoparticles (LNPs) as a carrier (LNP-
mRNA vaccine), DNA vaccine, and recombinant virus vaccine with a recombinant virus vector and so
on.
 This document presents basic principles concerning the efficacy and safety evaluation to develop a
SARS-CoV-2 vaccine in Japan, based on the situation as of August 2020. It should be noted, however,
that although the principles presented in this document are based on our knowledge at present and have
been developed after discussions with experts on infectious diseases and vaccines, they may change in
accordance with new findings and the status of SARS-CoV-2 vaccine development in Japan and overseas.
Also this document shows one of examples concerning the benefit/risk evaluation of SARS-CoV-2
investigational vaccines and at the time of the regulatory review approval for each investigational vaccine,
its benefit/risk will be reviewed taking into account its characteristics.
 For principles concerning the quality of a SARS-CoV-2 vaccine, the ICH guidelines regarding the quality
of drugs and biological medicines, and existing guidelines in Japan and overseas can be used,3)-10)
depending on the modality of the investigational SARS-CoV-2 vaccine. Investigational products used in
clinical trial must be controlled in accordance with Good Manufacturing Practice for Investigational
Drugs (GMP-ID).11)

2. NONCLINICAL STUDY
 Development of SARS-CoV-2 vaccine candidates has been needed to rapidly move forward to clinical
trials. Principles for SARS-CoV-2 vaccine candidates to support proceeding to a first-in-human clinical
trials and Phase III trials are presented in the summary reports of the workshops organized by the
International Coalition of Medicines Regulatory Authorities (ICMRA), Global Regulatory Workshops
on COVID-19 Vaccine Development (March 18, 2020 and June 22, 2020).12), 13)

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2.1. Pharmacological study
 The following nonclinical pharmacology assessments are generally required to support clinical trials:
 Assessment of immunogenicity
 To confirm production of SARS-CoV-2 antigen-specific antibodies
 To confirm production of neutralizing antibodies to SARS-CoV-2
 To analyze characteristics of the immune response induced by SARS-CoV-2 (e.g., SARS-
CoV-2 antigen-specific antibody titer, neutralizing antibody titer, characterization of IgG
subclass, and cytokine production)
 To confirm induction of cell-mediated immunity to SARS-CoV-2
 Assessment of anti-infective/disease-preventive effect
 The anti-infective/disease-preventive effect against SARS-CoV-2 should be assessed in an
animal model(s) of the infection.
 The correlation with immune responses such as the SARS-CoV-2 antigen-specific antibody
titer, the neutralizing antibody titer, and cell-mediated immunity should be assessed in an
animal model(s) of infection
Each assessment should be validated to ensure appropriate assessment.
 Any SARS-CoV-2 vaccine candidate should be required to confirm function as an infectious disease
preventive vaccines and to assess immunogenicity of the vaccine candidate before starting clinical trials
since nonclinical safety assessment to support human safety should be conducted in relevant animals,
which show immune response against the vaccine candidate. In addition, in order to estimate the potential
risk of disease enhancement that can be elicited by administration of the SARS-CoV-2 vaccine (see
Section 2.4), the immune response induced by administration of the vaccine candidate must also be
characterized prior to the initiation of the clinical trials.
 The assessments of anti-infective/disease-preventive effect of infectious disease in animal model(s)
should be conducted as early as possible, although they can be done in parallel with early phase of
clinical trials.

2.2. Nonclinical Safety study

 For the nonclinical safety studies to support the clinical trials, Guidelines for Nonclinical Studies of
Preventive Vaccines for Infectious Diseases and the summary reports of ICMRA Workshops on COVID-
19 Vaccine Development can be useful as reference.
 To develop the SARS-CoV-2 vaccine, the nonclinical safety should be assessed. Conducting nonclinical
safety studies of the SARS-CoV-2 vaccine candidate in parallel with the clinical trials can be accepted if
the SARS-CoV-2 investigational vaccine is a LNP-mRNA vaccine, DNA vaccine, or recombinant virus
vaccine, and the nonclinical safety can be explained by using the results of nonclinical safety studies and
clinical studies of other LNP, DNA plasmid vector, or recombinant vector virus.
 Nonclinical safety of a SARS-CoV-2 vaccine candidates should be conducted according to Good
Laboratory Practice (GLP) regulation.14) To support clinical trials, assessment of safety pharmacology,
general toxicity (multiple dose toxicity), and topical irritation are usually required.

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 The test substance used for nonclinical safety studies should be a formulation that properly reflects the
characteristics (composition, formulation, manufacturing process and control, etc.) of the product used
for clinical trials.
 The dose in preclinical safety studies should be the maximum human dose in the clinical trials. If it is
not feasible, administrating at multiple sites should be considered, taking into account animal welfare
(3Rs principles).15)
 In nonclinical safety studies, it is preferable to use animal species susceptible to the SARS-CoV-2 vaccine
candidate. At least one animal species in which the vaccine candidate can induce immune response
should be used.
 Stand-alone nonclinical studies to assess safety pharmacology and local tolerance are not recommended
if they can be assessed in repeated-dose toxicity studies.
 Repeated-dose toxicity should be assessed considering the followings:
 Number of doses should be equal or exceed the number of doses proposed in humans.
 Systemic toxicity can be assessed even if the route of administration is different from that
intended for use in the clinical trials as long as an adequate immune response is induced, while
local tolerance should be assessed by the intended therapeutic route .
 Reproductive and developmental toxicity should be assessed considering the followings:
 Fertility can be assessed as part of repeated-dose toxicity studies by through standard
histopathological examination on reproductive organs.
 Given that women of childbearing potential can be a recipient of the SARS-CoV-2 vaccine,
assessment of embryo-fetal development, pre-postnatal development including maternal
function should be conducted.
 Generally, reproductive and developmental toxicity studies can be conducted by the time of
marketing application. If, however, there is any concern regarding the reproductive and
developmental toxicity based on the characteristics of the SARS-CoV-2 vaccine candidate,
reproductive and developmental toxicity studies should be conducted and completed prior to
the initiation of a large-scale clinical trial.
 In general, study endpoints covering the period from the reproductive/developmental stage C
(implantation to closure of the hard palate) through stage E (birth to weaning) should be
assessed, in accordance with the WHO guidelines 16) and the ICH S5 Guideline 17).
 If a novel adjuvant is used for the SARS-CoV-2 vaccine candidate, safety assessments are required for
the adjuvant. Repeated-dose toxicity and reproductive and developmental toxicity of the adjuvant can be
assessed as part of the studies with the SARS-CoV-2 vaccine candidate. For genotoxicity, safety
evaluation of the novel adjuvant itself should be considered.

2.3. Pharmacokinetics study

 Pharmacokinetic studies are usually not required for infection prophylaxis vaccines. If, however, the
vaccine contains a novel substance such as a novel adjuvant, pharmacokinetic studies of the substance
may be required.

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 For an LNP-mRNA vaccine, DNA vaccine, or recombinant virus vaccine, its postdose biodistribution
needs to be assessed. This assessment must be completed prior to the initiation of the first clinical trial
in Japan for DNA vaccines and recombinant virus vaccines, or prior to the initiation of a large-scale
clinical trial in Japan for LNP-mRNA vaccines.
 For an LNP-mRNA vaccine, DNA vaccine, or recombinant virus vaccine, a biodistribution study with
the SARS-CoV-2 vaccine candidate is generally needed. The need for this biodistribution study with the
SARS-CoV-2 vaccine candidate may, however, be obviated if the biodistribution of the vaccine candidate
can be explained on the basis of the results of biodistribution and clinical studies of another vaccine with
the same LNP, DNA plasmid vector, or recombinant virus vector as the SARS-CoV-2 vaccine candidate.

2.4. Disease Enhancement Caused by Administration of SARS-CoV-2 Vaccine

 The disease enhancement possibly caused by administration of SARS-CoV-2 vaccine is referred to as an
antibody-dependent enhancement (ADE) or enhanced respiratory disease (ERD). Disease enhancement
is believed to be a phenomenon in which antibodies (and/or other substances) produced by administration
of vaccine enhance infections or infection-induced inflammation. At present, however, its mechanism of
development has not been elucidated. In the development of coronavirus vaccines, animal studies of
vaccines against severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome
(MERS) viruses suggest a possibility of these vaccines causing disease enhancement.18), 19)
As for
preventive vaccines other than coronavirus vaccines, clinical studies of vaccines against RS (respiratory
syncytial) virus and dengue virus report fatal and worsened cases to which disease enhancement may
have contributed.20), 21)
 Prior to clinical trials, it is necessary to estimate the risk of disease enhancement based on the results of
the immunogenic characterization such as the Th1/Th2 balance, SARS-CoV-2 antigen-specific antibody
titer and neutralizing antibody titer in the nonclinical pharmacology studies .
 Essentially, a test system with a relevant animal infection model should be introduced to assess the risk
of disease enhancement prior to the clinical trials. Considering the current status of COVID-19, however,
conducting early phase clinical trials in parallel with the development of the animal model of infection
is unavoidable if the risk of disease enhancement has been estimated to be low in the nonclinical
pharmacology studies. Even in such a case, the results of the animal study should be reported to the
Pharmaceuticals and Medical Devices Agency (PMDA) as soon as possible.
 If a relevant animal infection model becomes available, it is important to assess the risk of disease
enhancement by through histopathological examination on the target organ (e.g. lung) in challenge test.
It is recommended to assess the risk of disease enhancement using the animal infection model, prior to a
large-scale clinical trials.
 If new knowledge regarding how to assess the risk of disease enhancement is obtained in the future, an
additional risk assessment by means of the new method should be considered.

2.5. Actions to the Cartagena Act

 To comply with the Act on the Conservation and Sustainable Use of Biological Diversity through

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 Regulations on the Use of Living Modified Organisms (Act No. 97 of 2003; Cartagena Act), some actions
are needed depending on the type or manufacturing method of the SARS-CoV-2 vaccine candidate.
 To conduct a clinical study of a SARS-CoV-2 vaccine candidate that uses a recombinant virus (including
replication-incompetent virus) as an active ingredient in Japan, Cartagena type 1 use codes must be laid
down and approved in accordance with the Cartagena Act. To manufacture a protein, plasmid DNA, or
recombinant virus that is produced with a gene recombination technique in Japan, the manufacturing
facility at which a living modified organism(s) is processed must undergo a verification concerning the
Cartagena type 2 use.
 When applying for approval of the type 1 use codes, not only meeting the above-mentioned conditions
concerning Sections 2.1 to 2.3 of the Cartagena Act, but submission of test results concerning
environmental assessment is also required.
 Regarding the actions to the Cartagena Act, scientific advice by PMDA is recommended as early as
possible because additional studies might be required to comply with the Act and a certain length of time
is required for the reviewing process of the type 1 use codes or the verification procedure concerning the
type 2 use.

3. CLINICAL TRIALS IN JAPAN

 The benefit-risk judgement of any SARS-CoV-2 vaccines can differ depending on the situation of each
country/region given that the degree of the COVID-19 epidemic, that the virus may undergo mutation
according to the geographic/passage conditions, and that the percentage of severe patients with worsened
COVID-19 and the background of the worsening is being investigated in various ways. In addition, ethnic
differences might affect the efficacy and safety of the SARS-CoV-2 vaccine. There may therefore be a
high need of evaluating the efficacy and safety of the vaccine in Japanese subjects by conducting a
clinical trial(s) in Japan, even if a large-scale confirmatory trial is conducted overseas to evaluate the
disease-preventive effect.
 SARS-CoV-2 vaccine candidates for which pivotal clinical trials are conducted in Japan (vaccine
candidates firstly developed in Japan) and those for which pivotal trials are conducted overseas prior to
clinical trial in Japan (vaccine candidates that are ahead of development overseas) can differ with respect
to the requirements for clinical trials in Japan. In this section, therefore, principles for the two types of
vaccine candidate are described separately.
 For principles concerning the evaluation in clinical trials, the summary reports of ICMRA Workshops on
COVID-19 Vaccine Development as well as WHO and FDA guidance documents can be used for
reference.22)-24)

3.1. Vaccine Candidates Firstly Developed in Japan

3.1.1. Selection of Dosage
 Multiple dosages should be considered to conduct a clinical trial in Japan, taking into account the routes
and schedule of administration, dosages, investigated in nonclinical studies.
 In the present situation in which the relationship between the efficacy of vaccine against COVID-19 and

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 the antibody titer has not been established, the route of administration, dose and schedule should be
determined so that a higher immune response is induced.
 We must assume that in the future a situation in which limited productions of SARS-CoV-2 vaccines
must be administered widely to the public can be realized. It is therefore preferable to have a smaller
vaccination dose and a fewer administration, and if multiple doses need to be administered, it is
preferable to have a shorter dosing interval for rapid acquisition of immunity. Thus, development
considering these factors from an early stage is recommended.

3.1.2. Evaluation of Immunogenicity

 Collection data on the SARS-CoV-2 antigen-specifi
 c antibody titer, neutralizing antibody titer, cytokine productions, and others should be considered to
evaluate the immunogenicity of the SARS-CoV-2 vaccine candidate. The geometric mean concentration
(GMC) and geometric mean titer (GMT) of antibodies should be assessed. In late phase clinical trials, it
should be considered to, if possible, assess the seroconversion rate or the seroprotection rate of antibodies
after a standard value of the antibody concentration or antibody titer is established on the basis of the
immunoreactivity results (SARS-CoV-2 antigen-specific antibody titer, neutralizing antibody titer, etc.)
from completed clinical trials.
 If a possible disease-preventive marker has been determined from the nonclinical data using animal
models in challenge test, it will be useful to perform assessments with the marker when conducting
clinical trials in Japan.
 In clinical trials to assess the immunogenicity, information about the incidence of COVID-19 during the
observation period should also be collected in an appropriate manner by assuming symptoms possibly
related to COVID-19 beforehand, considering the possibility of being able to evaluate the efficacy and
safety of the vaccine candidate exploratorily.
 For a recombinant virus vaccine, the immune response to the recombinant virus vector and its effects
should be assessed.

3.1.3. Evaluation of Efficacy

 The efficacy of infectious disease preventive vaccines is in principle evaluated using the disease-
preventive effect as the primary endpoint. In the current situation in which no surrogate marker for the
disease-preventive effect against COVID-19 is known, in principle, clinical trials to assess the preventive
effect against COVID-19 must be conducted to evaluate the efficacy of the SARS-CoV-2 vaccine
candidate. Other possible key endpoints may include SARS-CoV-2 infection confirmed by a virological
or serological method, as well as endpoints concerning the severity of COVID-19 such as arterial oxygen
saturation (SpO2), requirement of oxygen therapy, management with ventilator or ECMO, and death.
 If another SARS-CoV-2 vaccine of which the disease-preventive effect is demonstrated overseas
becomes available in Japan, a SARS-CoV-2 vaccine candidate clinically evaluated thereafter may be
evaluated for its efficacy in a controlled clinical trial using the efficacy-demonstrated SARS-CoV-2
vaccine as a comparator. In this case, study endpoints should be determined on the basis of the scientific

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 understanding at that point concerning the mechanism of the disease-preventive effect of SARS-CoV-2
vaccines.
 If in the future the disease-preventive effect of other SARS-CoV-2 vaccines is proved in a clinical trial
and an immunogenic marker associated with the disease-preventive effect is confirmed, immunogenicity
of the vaccine may be used for reference. For example, efficacy of a SARS-CoV-2 vaccine candidate
intended to be developed might be evaluated by confirming its disease-preventive effect in nonclinical
studies and its immunogenicity in a Japanese clinical trial.

3.1.4. Evaluation of Safety

 It is required to collect adverse events (AEs) of solicited local reactions (swelling, redness, induration,
pain, etc.) and solicited systemic reactions (pyrexia, headache, malaise, myalgia, etc.) observed during
the first at least 7 days after administration of the SARS-CoV-2 vaccine candidate as well as all AEs
observed during the first at least 28 days after administration; longer periods may however be required
depending on the characteristics of the vaccine candidate.
 Adverse events may be collected for at least 7 days after administration of the SARS-CoV-2 vaccine
candidate using a method such as (1) calling each subject and hearing the AEs recorded in their Subject
Diary or (2) collecting the Subject Diary when the subject visits the study site. The collection of AEs
from Day 8 onward must be planned so that information is properly collected; for example, AEs may be
collected by calling each subject every week or inputted AE data by each subject on an electronic device.
 Disease enhancement risk should be assessed in clinical trials based on the immunogenic characterization
such as the Th1/Th2 balance, SARS-CoV-2 antigen-specific antibody titer, neutralizing antibody titer.
When a clinical trial is conducted, it is required to implement an appropriate procedure of informed
consent in which subjects have knowledge of the theoretical risk of disease enhancement, perform careful
safety follow-up of subjects, and prepare a management system for possible cases of disease
enhancement.

3.1.5. Follow-up during the Clinical Trial

 To collect information about the long-term efficacy and safety after administration of the SARS-CoV-2
vaccine candidate, subjects should be followed up at least one year in a clinical trial. A follow-up period
longer than one year may be required depending on the characteristics of the SARS-CoV-2 vaccine
candidate.
 During the follow-up period, collection of information about the persistence of antibody titer as well as
incidence of COVID-19 and AEs including assessment of the disease enhancement risk are required.
 It is preferable to perform the safety follow-up during the clinical trial period also for subjects
withdrawing from the trial after vaccination, considering the disease enhancement risk.

3.1.6. Procedure of Clinical Trial

 Clinical trials must be properly conducted in compliance with Good Clinical Practice (GCP).25)
 In a first-in-human study, appropriate measures to ensure subjects' safety must be planned and

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 implemented referring the guidance document, Notification on Revision of Guidance for Safety
Assurance in First-in-Human Studies of Drug Development (PSEHB/PED Notification No. 1225-1,
dated December 25, 2019)26). In particular, note the following:
 In a first-in-human study, for risk reduction, it is more appropriate, for example, to evaluate
the safety in one or a few subject(s) when administering the vaccine candidate for the first
time or administering each stepped-up dose for the first time and then, proceed (i.e., not
administering the vaccine candidate to the next subject or at the next dose level until the safety
evaluation in one or a few subject(s) is completed). In such a case, prior to administration to
subsequent subjects, it is necessary to assess the reactions and AEs experienced by the
previous subjects.
 In the protocol, criteria for step-ups within the clinical trial (regarding, e.g., dose escalation
and extension to wider age group) and for suspension/termination of the trial, as well as the
procedures, management systems, and responsibilities for these decisions should be
predefined.
 When the sponsor of a clinical study chooses study sites, it should make sure:
 That each site has facilities that make it possible to respond to emergencies (such as
cardiopulmonary arrest, anaphylaxis, cytokine release syndrome, loss of consciousness,
seizure and shock) and in the site, physicians who can appropriately respond to those
emergencies are deployed, and
 That in case of the occurrence of AE(s) that cannot be managed in the site, it is defined the procedure
for transferring the subject to an appropriate external emergency medical institute and for referring the
subject to another medical institute or another department in the study site that can manage the
AE(s).Actions to take when any signs or symptoms suggestive of COVID-19 is found during the study
period should be predefined in the study protocol. Subjects should be given an explanation about those
actions.

3.1.7. Necessity of Other Endpoints

 If the vaccine contains novel adjuvant(s) and/or novel excipients, their pharmacokinetics may need to be
evaluated.
 For a recombinant virus vaccine or live attenuated vaccine, whether the vaccine strain is shedded from
the subject and how to manage the risk of transmission to others should be determined. If the vaccine
strain is found to be shedded from the subject, the SARS-CoV-2 vaccine candidate also should be
assessed regarding the possibility of transmission to those who have contacted the subject, the genetic
stability of the vaccine strain, and the possibility of mutation to a highly virulent strain. In addition, the
possibility of shedding and the risk of transmission to others should be explained to subjects and
appropriate actions should be taken.

3.1.8. Clinical Trial Design

 The sample size for a clinical trial should be determined to evaluate efficacy and safety of the SARS-

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 CoV-2 vaccine candidate appropriately, considering the characteristic of the endpoints.
 For a SARS-CoV-2 vaccine candidate produced using innovative technology such as an LNP-mRNA
vaccine, DNA vaccine, or recombinant virus vaccine, or for a SARS-CoV-2 vaccine candidate with a
novel adjuvant, particularly careful evaluation of its safety is required in clinical trials.
 In principle, any SARS-CoV-2 vaccine candidate should be evaluated in randomized, double-blind, (e.g.,
placebo-)controlled trials to assess the effect of antibody titer increased by a natural infection of SARS-
CoV-2 on postvaccination, to evaluate the safety concerning vaccination, and to assess the incidence of
COVID-19 and the risk of disease enhancement.

3.1.9. Evaluation in the Geriatrics, Pregnant Women/Nursing Mothers, and Children

 Considering the high risk of severe COVID-19 in the geriatrics,27) it is recommended to conduct a clinical
trial in the geriatrics as early as possible after the vaccination experience in adults (except the geriatrics)
has reached a certain level. In late phase of clinical trials, it is recommended to consider inclusion of
subjects whose risk of severe COVID-19 may be high (e.g., those who have an underlying disease).
 For infectious disease preventive vaccines, it is possible to initiate clinical trials enrolling women of
childbearing potential even if any developmental and reproductive toxicity study has not been conducted;
in this case, however, adequate measures to avoid pregnancy need to be implemented with an informed
consent about the embryo-fetal risk being uncertain.
 Whether pregnant women/nursing mothers can be enrolled in clinical trials should be determined after
the risk of reproductive and developmental toxicity is assessed according to the type of the SARS-CoV-
2 vaccine candidate, available nonclinical and clinical study data.
 For children, it is recommended to plan and conduct an appropriate clinical trial after information about
the efficacy and safety in adults is obtained.

3.2. Vaccine Candidates that are ahead of Development Overseas

 Even if development precedes overseas and large-scale clinical trials are being conducted to evaluate
efficacy and safety overseas, the basic principles concerning their evaluation are the same as those for
vaccine candidates first developed in Japan, although in principle, clinical trial must be conducted also
in Japan to confirm the efficacy and safety in Japanese subjects. For the clinical trial in Japan, it is
recommended to ask scientific advice to the PMDA as early as possible.

3.2.1. Selection of Dosage

 When the clinical development of a SARS-CoV-2 vaccine candidate is further along overseas than in
Japan and it can be concluded that the dosage determined overseas are appropriate for the use in clinical
trials in Japan, the dosage determined overseas can be used in Japanese clinical trials without conducting
a clinical trial in Japan for the selection of the dosage.

3.2.2. Evaluation of Immunogenicity

 Measuring the SARS-CoV-2 antigen-specific antibody titer, neutralizing antibody titer, cytokine

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 productions, and others should be collected. The (GMC) and (GMT) of antibodies should be also
evaluated. It should be considered to, if possible, assess the seroconversion rate or the seroprotection rate
of antibodies after a standard value of the antibody concentration or antibody titer is established on the
basis of the immunoreactive results (SARS-CoV-2 antigen-specific antibody titer, neutralizing antibody
titer, etc.) from overseas trials.
 In clinical trials to assess the immunogenicity, information about the incidence of COVID-19 during the
observation period should also be collected in an appropriate manner by assuming symptoms possibly
related to COVID-19 beforehand, considering the possibility of being able to evaluate the efficacy and
safety of the vaccine candidate exploratorily.
 If the SARS-CoV-2 vaccine candidate has been evaluated in clinical trials overseas, it will be useful to
examine the immunoreactive results from a Japanese clinical trial in comparison with the results from
overseas trials.
 For a recombinant virus vaccine, the immune response to the recombinant virus vector and its effects
should be assessed.

3.2.3. Evaluation of Efficacy

 When a large-scale confirmatory clinical trial of the vaccine candidate is conducted overseas using the
disease-preventive effect as the primary endpoint, it may be sufficient to conduct a Japanese clinical trial
to confirm the immunogenicity and safety in Japanese subjects without conducting a confirmatory
clinical trial in Japan to evaluate the disease-preventive effect in Japanese subjects. When a global
development program (multi-regional clinical trial(s)) to evaluate the disease-preventive effect is planned,
the efficacy of the vaccine candidate in the Japanese population may be evaluated by participating in the
program from Japan.
 If in the future the disease-preventive effect of other SARS-CoV-2 vaccines is proved in a clinical trial
and an immunogenic marker associated with the disease-preventive effect is confirmed in multiple trial
s, immunoreactive results of the vaccine may be used for reference. For example, efficacy of a SARS-
CoV-2 vaccine candidate intended to be developed might be evaluated by confirming its disease-
preventive protective effect in nonclinical studies and its immunogenicity in a Japanese clinical trial.

3.2.4. Evaluation of Safety

 See Section 3.1.4.

3.2.5. Follow-up during the Clinical Trial

 See Section 3.1.5.

3.2.6. Procedure of Clinical Trial

 When a vaccine candidate is clinically developed in Japan at the same time as overseas, it is necessary
to implement a system that makes it possible to obtain safety information from the overseas clinical trials
and reflect them to the Japanese clinical trial.

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 See Section 3.1.6.

3.2.7. Necessity of Other Endpoints

 See Section 3.1.7.

3.2.8. Clinical Trial Design

 See Section 3.1.8.

3.2.9. Evaluation in the Geriatrics, Pregnant Women/Nursing Mothers, and Children

 See Section 3.1.9.

4. POST-MARKETING ACTIONS
 If a SARS-CoV-2 vaccine has been given marketing approval based on the results of the clinical trials
conducted, the marketing authorization holder must take appropriate post-marketing actions for safety
based on the safety information obtained from the clinical studies. For example, for the SARS-CoV-2
vaccine candidates currently developing because certain local and systematic AEs have been reported,
safety measures at the time of administration and information provision based on these reports are
absolutely needed.
 Because the safety information from the clinical studies conducted by the time of approval may be
limited, whether the vaccine can be administered widely to the public will be carefully reviewed.
 Following approval, the marketing authorization holder needs to organize a system that makes it possible
to properly and rapidly collect the safety information in Japan and overseas and promptly provide it to
all medical and other institutions concerned.
 Long-term follow-up results of a large-scale clinical studies can become available after approval. The
manufacturer must promptly report those results to PMDA, and publicize them and take necessary
actions.

5. ACKNOWLEDGEMENTS
 This document has been prepared after hearing from the following experts, and we would like to express
our sincere thanks to them:
IWATA Satoshi, Director, Infection Division, National Cancer Center Hospital
OUCHI Kazunobu, Professor, Department of Pediatrics, Kawasaki Medical School
OISHI Kazunori, Director General, Toyama Institute of Health
OBA Koji, Associate Professor, Interfaculty Initiative in Information Studies and Department of
Biostatistics, Graduate School of Medicine, The University of Tokyo
OKADA Kenji, Professor, Division of Basic Medical Science and Fundamental Nursing, Fukuoka
Nursing College
OKABE Nobuhiko, Director General, Kawasaki City Institute for Public Health
TAKAHASHI Yoshimasa, Director, Department of Immunology, National Institute of Infectious

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 Diseases
TAKEDA Makoto, Director, Department of Virology 3, National Institute of Infectious Diseases
HAMADA Atsuo, Professor, Travellers' Medical Center, Tokyo Medical University Hospital
HAYASHI Kunihiko, Professor, Gunma University Graduate School of Health Sciences
HIRABAYASHI Yoko, Director, Biological Safety Research Center, National Institute of Health
Sciences
YAMAGUCHI Teruhide, Visiting Professor, Department of Pharmacy, Nihon Pharmaceutical
University

6. REFERENCES
1) Guidelines for Nonclinical Studies of Preventive Vaccines for Infectious Diseases (PFSB/ELD
Notification No. 0527-1 issued by the Director of the Evaluation and Licensing Division, Pharmaceutical
and Food Safety Bureau, Ministry of Health, Labour and Welfare, dated May 27, 2010) (in Japanese)
2) Guidelines for Clinical Studies of Preventive Vaccine for Infectious Diseases (PFSB/ELD Notification
No.0527-5 issued by the Director of the Evaluation and Licensing Division, Pharmaceutical and Food
Safety Bureau, Ministry of Health, Labour and Welfare, dated May 27, 2010) (in Japanese)
3) Considerations Concerning the Assurance and Evaluation of the Quality of Nucleic Acid Drugs
(PSEHB/PED Notification No. 0927-3 issued by the Director of the Pharmaceutical Evaluation Division,
Pharmaceutical Safety and Environmental Health Bureau, Ministry of Health, Labour and Welfare, dated
September 27, 2018) (in Japanese)
4) Quality and Safety Assurance of Gene Therapy Products (PSEHB/MDED Notification No. 0709-2 issued
by the Director of Medical Device Evaluation Division, Pharmaceutical Safety and Environmental
Health Bureau, Ministry of Health, Labour and Welfare, dated July 9, 2019) (in Japanese)
5) Guidelines for the Development of Liposomal Drugs (PSEHB/ELD Notification No. 0328-19 issued by
the Director of Evaluation and Licensing Division, Pharmaceutical Safety and Environmental Health
Bureau, Ministry of Health, Labour and Welfare, dated March 28, 2016) (in Japanese)
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