<The Fifth Recommendation>
Recommendation on the Reporting System of Adverse Reactions to Vaccines andthe Development of Infrastructure related to Vaccine Risk Management in Japan
Introduction
The vaccination policy is a key to the primary prevention of infection-relateddiseases in Japan. However, the approach to vaccination in Japan has long beenconservative since the 1990s. During that period, various novel vaccines have beendeveloped in foreign countries, and the vaccine gap between Japan and foreigncountries has become a problem. In recent years, however, vaccines introduced on
the market in foreign countries have at last come to be approved in Japan, andsince the revision of the Vaccinations Act in 2013, vaccines that are used for regularvaccination in foreign countries have also come to be used for the same purpose inJapan.
However, although the “types” and the “product lineup” of vaccines have been
improved to nearly the same level with that of foreign countries, the environment
relating to the risk management of vaccination has hardly been established. Thereis still room for improvement in establishing a mechanism for efficient collection,
evaluation, and provision of immunization-related information, and thus we arestill experiencing unnecessary confusion. With regard to the handling of
spontaneous reports and the framework of safety evaluation in particular, during
the period when Japan’ attitude toward vaccination was still conservative, foreigncountries have established various environments and infrastructures in accordancewith the changes in the social landscape and the development of information
technology. Thus, compared to foreign countries, Japan still has a lot of unsolved
problems.
It is extremely important that robust infrastructures related to risk management
are established when introducing new vaccines. Therefore, we would like to makethe following recommendations to citizens in general including healthcare
providers, vaccine specialists, administrative authorities and healthcare educators.

September 24, 2015
Tadao Terao, Chairman
Pharmaceutical and Medical Device
Regulatory Science Society of Japan

Recommendation on the Reporting System of Adverse Reactions to Vaccines andthe Development of Infrastructure related to Vaccine Risk Management in Japan<Recommendation Excerpt>
１．Legal matters
1-1 Use of correct terms
As our Foundation described in the Fourth Recommendation (Aiming at More
Scientific Drug Risk Management in Japan—A Recommendation to theRegulatory Authority and Industry), the definition of “adverse drug reactions” inJapan and that stipulated in the ICH E2D are different, and by definition, thecase reports made spontaneously to the industry or the regulatory authority
actually refer to “suspected adverse drug reactions.” Similarly, the term “adverse
reactions to vaccines” when reported in the case reports in accordance with the
Vaccinations Act means “suspected adverse reactions to vaccines.”
The evaluation of safety information regarding vaccines is discussed, inprinciple, publicly at the Adverse Reactions to Vaccines Reviewing Committee ofthe Ministry of Health, Labour and Welfare. However, although what are
reviewed here are actually not “adverse reactions to vaccines” but are “suspected
adverse drug reactions” stipulated in the Pharmaceuticals and Medical Devices
Act, and “adverse events” according to the Vaccinations Act, they are treated as“adverse reactions to vaccines” in the publicly available documents. Whenreported by the media etc., however, all the cases reviewed by the committee aretreated and communicated as “adverse reactions to vaccines,” causing
unnecessary anxiety and misunderstanding to the general public and also
confusion regarding risk management activities.
It is important to prevent confusion related to risk management activities byconsidering again appropriate wordings including descriptions in public
documents and the naming of the Committee itself, and thereby to help
healthcare providers and the general public understand the information correctly.
1-2 Clarification of the objective of the reporting systems
Currently, the criteria for unsolicited reporting are different between Preventive
Vaccinations Act and Pharmaceuticals and Medical Devices Act. The Preventive
Vaccinations Act requires that all cases of specific events associated with regularly
inoculated vaccines that occur during the risk period be reported irrespective ofseriousness or the assessment of causal relationship by physicians; thus, thesereports are actually the reports of adverse events. In addition, the definition of theevents concerned is given in the report form; thus, the reporting system for
spontaneous reports (which should be “unsolicited” reports by nature) can be1interpreted as the reporting system for solicited reports rather than unsolicitedreports. On the other hand, with regard to the adverse drug reaction reports byphysicians etc. in accordance with the Pharmaceuticals and Medical Devices Act,the objects to be reported are the events for which causal relationships are
suspected and for which reporting was considered necessary by the reporter inorder to prevent the occurrence or escalation of harm to public health. Thus, thenature of information obtained from these two reporting systems is naturally very
different.
With regard to regular vaccinations (including those changed from voluntary
vaccinations), case reports based on two different systems are accumulated; thus,
the integration and comparison of the data are impossible, and the possibility ofoverlapped cases cannot be ruled out. Actually, reported data to the Adverse
Reactions to Vaccines Reviewing Committee cannot be integrated, and thus bynecessity individual data are aggregated and presented. This kind of data
presentation is hard to understand for the general public. Therefore, due to various
misunderstandings, multiple and different numerical data are reported throughthe media; thus, the general public cannot know the true figures. This situation has
caused unnecessary confusion, doubts, and anxiety.
If unification of the two systems with two different data collection objectives isdifficult, then evaluations according to the objectives should be made individually
after explicitly explaining the objectives of the two systems. Regarding the regularvaccination, one of the objectives of the “report of suspected adverse reactions tovaccines” under the Vaccinations Act would be to comprehensively grasp thesymptoms beforehand that are concerned about. The data from the spontaneous(unsolicited) report system based on the Pharmaceuticals and Medical Devices Act
are the key to safety monitoring in that the data broadly reflect safety signals.
Thus, the conduct of more scientific and appropriate monitoring is considered
critical in the risk management of vaccination. In order to disseminate information
which is medically clear and easy to understand for healthcare providers and thegeneral public, it is essential that the objectives of these two systems are explicitly
explained.
1-3 Construction of the system for managing vaccination history
The efficiency of preventing the epidemic of infectious diseases by vaccination isclosely associated with the vaccination rates; therefore, in view of public health, thevaccination coverage and the vaccination history are important information. In
addition, although vaccination is conducted by local governments, theresponsibilities of risk management of vaccination should mainly be borne by theinstitutions of the central government and not by the local governments. Thus, the2vaccination rate of residents in Japan is important information for the central
government institutions. The information of vaccination rate and vaccination
history is also important for medical institutions etc.; in addition, this information
should also be provided to the general public in a timely manner.
However, currently, no appropriate database of the records of vaccination has
been developed. Although the ledgers of the preventive vaccination which is
subsidized publicly are managed by individual local governments, their formalities,
media, etc. are varied. In order for the central government to know the vaccination
rate, it needs to be provided with the data by the local governments etc., and thus itis difficult for the central government to grasp the nationwide vaccination rate
automatically and in a timely manner.
To grasp and manage the vaccination records in an integrated fashion and for along time, the central government should develop a “Registry of Vaccination
Records” which manages the electronic vaccination records collectively, by using
the national identity number (nicknamed “MY NUMBER”) system note, for example.
Even under the current design, usefulness, such as (a) the coverage of regularvaccination of individual age groups in individual local governments can be grasped
real time through the linkage with the information of the resident card etc., and (b)vaccinated individuals can confirm the information by themselves, are conceivable.
The personal-level vaccination history management such as this can be thebackground information of adverse reactions to preventive vaccination; in addition,
it will make the long-term post-vaccination follow-up outcomes available. Thus, itwill also play an important role in the comparison of the frequencies of theoccurrences of adverse reactions to vaccines etc. before and after the
implementation of the policy. On the other hand, under the current design, theinformation of voluntary vaccination and the information of adverse events cannot
be managed. Therefore, taking into consideration the linkage with otherinformation, such as making it possible to link with clinical records by using the
My Number system, the value of the Registry of Vaccination Records should be
maximized as an infrastructure that is involved in scientific risk management.
Note) This is planned to be introduced in October 2015. It is the number assigned toeach person holding a resident card and tie personal information owned by different
organizations.

1-4 Enrichment and effective use of health survey following vaccination (omitted)
1-5 Enrichment of relief service system for adverse health effects
Enrichment and operation of the safety net are important for “peace of mind” ofthe people. The relief system for sufferers from adverse drug reactions serves as asafety net for voluntary vaccination, and the relief system for adverse health effects3following vaccination serves as a safety net for regular vaccination. However, it ishard to say that these systems are used to their full capacity and are satisfactory
for the general public. One of the reasons for this is their low degree of recognition,
and another reason may be that it takes a long time from the application for relief
to the decision of provision of benefits.
In addition, currently, the amount and the range of benefits to be provided are
different between the two relief systems. Therefore, even if the same vaccine isused, the amount and the range of benefits to be provided are different dependingon whether their national positioning is voluntary vaccination or regularvaccination. That the amount and the range of benefits to be provided are different
depending on whether or not there is an obligation to make efforts to receive
certain vaccinations as a national policy, even if the vaccines are the same, may beunderstandable to persons who know that there are two different relief systems inaccordance with two different acts. However, it may be difficult for the generalpublic who receive vaccination. In view of the understanding of the general public,
it may be desirable to eventually unify the two systems; however, if it is difficult,information provision activities should be performed before vaccination so that theindividuals receiving vaccination and their guardians are fully explained about therelief systems to gain their understanding.
2．Enrichment of information provided by the central government
2-1 More flexible operation of the Adverse Reactions to Vaccines Reviewing
Committee
Accumulated data are mainly explained at Adverse Reactions to Vaccines
Reviewing Committee meetings, with the Ministry of Health, Labour and Welfare
serving as the secretariat; however, because the amount of the data dealt with at
the committee meeting is large, there seems to be room for improvement withregard to time allocated to the explanation of data and actual discussion. Whendetails of some data are asked, it happens that the secretariat has to ask a relevant
company for confirmation, and thus the matter is postponed until the next meeting.
This kind of things decreases the efficiency of the committee meeting, leading todelayed decision making. Thus, it may be said that the maximum safety of thepeople is hardly secured.
The secretariat should consider more efficient operation of the meeting. It would
be possible to operate the Adverse Reactions to Vaccines Reviewing Committee,
which is open to the public, as a place for substantial discussion by, for example,
disclosing the data of a briefing session and explaining the data to the members of
the committee meeting beforehand, and then encouraging them to ask questions
about the data, if there are any, before the meeting. In addition, rapidity would be4

secured by taking measures, such as inviting relevant companies to the Adverse
Reactions to Vaccines Reviewing Committee meeting as references and have them
respond to questions on the spot or before the next committee meeting at the latest,
as necessary.
Furthermore, it should be noted that the data for deliberation at this committee
meeting are public information. For example, when risks are deliberated at an
Advisory Committee on Immunization Practices (ACIP) meeting in the U.S., theinformation regarding benefits are also publicly presented. Thus, the data of theresults of benefit-risk comparison, which can be easily understood by even a third
party, are often used. However, in the case of the Adverse Reactions to Vaccines
Reviewing Committee meeting in Japan, only the information of risks is recorded
as data, and only the data that do not contain clear conclusion of the committee
meeting are presented to the public. Part of the conclusion may be supplemented byreading the minutes of the meeting; however, the information regarding thecommittee meetings reported by the media etc. include contents which more or lessgenerate misunderstanding.
2-2 Provision of appropriate information
In Japan, people are required to make an effort to receive vaccination, butultimately, the decision is up to vaccinees. However, it is hard to say that the
government is making sufficient effort to provide information which is necessary
for the general public to make judgement and the validity of which is guaranteedby the government through multiple and various media in a clear andeasy-to-understand way.
To prevent information lacking sufficient evidence from spreading, thegovernment should quickly and timely issue clear information, the validity of which
is sufficiently guaranteed. With regard to the validity of scientific data related tosafety and efficacy, it is important that the government provides neutral andeasy-to-understand information quickly.
For example, the Centers for Disease Control and Prevention (CDC) of the U.S. ispresenting on its website an easy-to-understand and concise explanation of thebenefits and risks of vaccines for vaccinees and their parents. In addition, if
information with insufficient evidence is reported by the media etc., the CDC issues
an information article with clear evidence to raise awareness as necessary. It isvery important in Japan as well that, following this example, the National Instituteof Infectious Diseases and other public institutions take the lead to create a sitethrough which the general public can acquire and understand information about
the efficacy and safety of vaccines at one stop. At the same time, it is also important
for risk communication that the media, which play an important role in5communicating information, understand the information provided by these public
institutions scientifically and appropriately. It is desirable that the National
Institute of Infectious Diseases as a leading organization appointing a
spokesperson and actively “provide appropriate information, including backgroundinformation” to the media so that correct information is provided to the generalpublic.
In addition, it will be one of the important responsibilities of the Japanese
regulatory authorities, as one of the trilateral members of the International
Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH), to issue and globally disseminate on the
web “information with clear evidence” from the summary of the material of theAdverse Reactions to Vaccines Reviewing Committee meetings in English, acommon language of the world.
3．Improvement of education
3-1 Ensuring that healthcare providers are fully aware of Preventive Vaccinations
Act and Pharmaceuticals and Medical Devices Act
Reporting of suspected adverse reactions to vaccines is essential for improving
healthcare and is an important responsibility of healthcare providers.
It is important to have healthcare providers to recognize that they are playing animportant role in gathering information of adverse reactions to vaccines and thatthey are also responsible for providing the information. In the case of regularvaccination, in particular, reporting is clearly described as an “obligation;” however,in view of the fact that provision of information is sometimes refused by healthcare
providers on the ground that they are too busy, it has to be said that practicing
healthcare providers are not well informed about the obligation.
Whether or not healthcare providers have had sufficient opportunities to receive
education about Preventive Vaccinations Act and Pharmaceuticals and Medical
Devices Act should be reviewed. Knowledge about these Acts is important for quick
reporting of safety information and for making use of the accumulated data of theinformation. In this respect, it is necessary to construct a framework which ensuresthat practicing healthcare providers be given education at least at the timing oflegal revisions, for example, as part of career-long education and that they are wellinformed about the reporting system and its significance.
3-2 Cultivation of experts on evaluation of adverse reactions to vaccines and theiruse
Different skills are needed for evaluating individual cases and accumulated data.
When investigating whether or not a certain event is an adverse reaction to6

vaccines, medical, chronological, and geographic validities need to be considered.
Both the main effects and adverse reactions to vaccines occur via immune
response; therefore, molecular biological and physiological knowledge about thesereactions is necessary for evaluating the medical validity of adverse reactions tovaccines.
It is hard to say that there is sufficient number of experts in the field of
epidemiology in Japan. The government should not only cultivate experts in thefield of epidemiology but also positively foster “epidemiologists well versed in
vaccinology with knowledge of immunology, molecular biology, and physiology” asspecialists of “the study of adverse reactions to vaccines” with a long-term
perspective.
3-3 Enriching vaccine education at school
By enriching the education of vaccines in compulsory education for the generalpublic and specialized education for healthcare providers, the general public will beable to correctly understand the “information regarding the benefits and risks ofvaccines” issued by the government.
Provision of solid basic knowledge necessary for judging the benefits and risks ofvaccines (personal and societal significance of preventive vaccination, risks
associated with vaccination, and the fact that drugs or vaccines are not free fromrisks) should be one of the policies that the government needs to implement.
Particularly, establishing a system in which this basic education is firmly provided
in the compulsory education at elementary schools and junior high schools should
be an important policy to implement.
In addition, whether or not vaccine education is sufficiently provided tohealthcare providers should be once again reviewed. Healthcare providers need todeeply understand the information about personal and societal significance ofpreventive vaccination, basic action mechanisms of vaccines, preventive
vaccination systems, and the mechanisms and frequencies of occurrences ofadverse reactions to vaccines, bearing in mind that these items are inter-related.
The Ministry of Education, Culture, Sports, Science and Technology and theMinistry of Health, Labour and Welfare are encouraged to collaborate in thisendeavor.

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