The working group on “Future Postmarketing Surveillance (PMS) in Japan” was established by theboard of JSPE in May, 2002.
The working group have had meetings on a monthly basis to discuss issues on “Future PMS in
Japan”. The working group worked out the task and prepared a report on this subject.
The report was approved by JSPE, published in the journal of JSPE, “Pharmacoepidemiology 2003;
8: 1-36, and presented in other pages of this website in Japanese.
The following is a provisional translation into English.
Provisional translation of the report of the working group on “Future PMS in Japan”
Translated by Yuka Ohgaki (AstraZeneca Japan),Fumiko Miyaji and Mikihito Kosuge (Eli Lilly Japan)
Chair of the working group : Yasuo Ohashi (Professor of University of Tokyo)
Members of the working group
Yasuo Arima (RAD-AR Council)
Shigeru Kageyama (Jikei University School of Medicine)
Akira Kamiya (Yamaguchi University)
Shikifumi Kitazawa (Nihon University)
Akira Kokan (RAD-AR Council)
Kiyoshi Kubota (University of Tokyo)
Takeshi Mayama (RAD-AR Council)
Mayumi Mochizuki (Kitasato University)
Takeshi Nakamura (Nihon University)
Toshimichi Nishi (JPMA)
Yutaka Nojima (RAD-AR Council)
Takao Orii (NTT Higashi Nihon Kanto Hospital)
Hironori Sakai (Mitsubishi Pharma Corporation)
Akira Sakuma (The Organization for Pharmaceutical Safety and Research)
Naokata Shimizu (The Organization for Pharmaceutical Safety and Research)
Takashi Shirai (RAD-AR Council)
Hideaki Suzuki (JPMA)
Hiroyuki Usuki (JPMA)
Motoko Watanabe (Pfizer Pharmaceuticals Inc.)
Secretariat: Tadashi Kusunoki (Japanese Society for Pharmacoepidemiology)-1-TABLE OF CONTENTSPREFACEPage･･････ 1

OVERVIEW(1) Common recognition on necessity of PMS among various sectors(2) Initiatives of PMS(3) Attitudes of companies(4) Regulatory systems and organizations(5) Recognition by health care providers and issues of education(6) Practical use of pharmacoepidemiology(7) Spontaneous reporting and safety surveillance(8) Risk / benefit balance and overall evaluation(9) Ethical principles･･････ 2･･････ 2･･････ 2･･････ 2･･････ 2･･････ 3･･････ 3･･････ 3･･････ 4･･････ 4

PROPOSALS AND REQUEST
1. Initiatives of PMS
2. Attitudes of companies
3. Regulatory systems and organizations
4. Recognition by health care providers and issues of education
5. Practical use of pharmacoepidemiology
6. Spontaneous reporting of ADR safety surveillance
7. Ethical principles in PMS･･････ 5･･････ 5･･････ 5･･････ 6･･････ 6･･････ 6･･････ 7･･････ 8

SECTIONS OF DETAILED DISCUSSIONS
1. Issues on investigator initiated and public PMS
2. Issues on companies
3. Issues on regulatory system and organizations
4. Issues to increase interests of medical professionals in PMS
5. Practical use of pharmacoepidemiology
6. Issues on spontaneous reporting
7. Issues on signal detection and case control study
8. Issues on cohort study
9. Issues on establishment of database
10. Issues on clinical trials
11. Issues on meta-analysis
12. Issues on ethical principles･･････ 9･･････ 9･･････ 11･･････ 12･･････ 14･･････ 15･･････ 18･･････ 20･･････ 22･･････ 24･･････ 26･･････ 28･･････ 30-2-

Report from the Working Group on“Future Postmarketing Surveillance（PMS）in Japan”
Preface
Clinical trials for drugs before marketing are studied in the subjects of selected patients, i.e., thoseclinical trials are conducted in the “ideal world”, whereas post-marketing drugs are used in the “realworld” and “medical practice”, therefore unexpected adverse events and interactions may occur.
There have been cases such as SMON due to enteobioform where unexpected adverse drug reaction
became social issue. However, as seen in the case of haemorrhagic cerebral stroke with PPA(phenylpropanolamine)1), there is a case where causal relationship between an adverse event and adrug was detected3), leading to adequate post-marketing studies which contributed to establishment ofappropriate use of the drug.
On the other hand, the effect of aspirin on prevention of relapse of cardiac accidents such as
myocardial infarction was revealed almost one century after its launch2), and the primary effect ofdiuretics and beta blockers on prevention of cebrovascular/cardiovascular accidents was discoveredby post-marketing studies.
All of these facts were found after launch and the importance of post-marketing studies for medical
community should be recognized. In order to establish further appropriate drug use, close observation
by a physician and well organized post-marketing studies are crucial, while studies by medical
institutes and public entities are necessary as well as PMS conducted by pharmaceutical companies.
Recently, there have been initiatives to put more emphasis on the post marketing such as introductionof Early Post-marketing Phase Vigilance (EPPV), revision of Pharmaceutical Affairs Law (PAL)
including a change from manufacturing to manufacturing marketing approval, PMS as a new theme at
ICH. Assuming that the era of new medicine started in the mid 20th century, it seems that interest in
the post marketing has eventually begun to increase in the 21st century.
Under the circumstances, JSPE organized ‘Working Group on ‘Future Post-marketing Surveillance inJapan’ where “PMS as it should be in future” has been discussed and compiled into this report. The
report reviewed proposals to make PMS further developed and recommendations toward relevant
entities. It is hoped that those who are involved in the post marketing vigilance and studies would
review and refer to following comments, and would also make feedback.

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OVERVIEW
It is possible that PMS (Post-marketing surveillance) has been interpreted as post-marketingsurveillance conducted by companies, however, broader concept including post-marketing studies
initiated by organizations of researchers and public institutions is adopted here. PMS is necessary forsafety surveillance of marketed (ethical) drugs and to add evidence of efficacy. It should be continued
as far as the drugs are marketed. Scientific aspects of PMS are mainly discussed but issues
concerning its system are also reviewed. In this statement, general issues are discussed while current
issues are examined and proposals of measures to resolve/improve are listed in Sections of Detailed
Discussion.
(1) Common recognition on necessity of PMS among various sectors
The objective of PMS is to establish appropriate use of drugs. Pharmacotherapy should be selectedaccording to evidence of efficacy/safety indicating whether the drug is appropriate to the target
disease and to the target patient, i.e., evidence based medicine (EBM). Because many evidences are
obtained after a drug is marketed, PMS is necessary for vigilance of marketed drugs, to foster them tobetter products, and to establish their appropriate use. There are opportunities for improvement inJapan, considering the current situation as discussed below. It is important, for the issues which are
difficult to improve in short term, to make directions for improvement in long term by establishing theideal situation in the future. As prerequisite for every improvement, companies, health care providers
and regulatory authorities should commonly recognize the necessity of PMS and give mutual
cooperation.
(2) Initiatives of PMS
The word “PMS” used to mean post-marketing surveillance conducted by companies in compliancewith the pharmaceutical regulatory systems. However, many drugs may be compared each other inmedical practice and efficacy studies to evaluate concomitant use may be conducted outside of theframework of company, and safety issues common to a therapeutic class may be significantly
important in the light of public health. Therefore, PMS initiated not only by companies but also by
researchers and public organizations are necessary.
Since such PMS is not adequately carried out under the current condition, it is recommended toenhance support for PMS conducted by organizations outside of companies. It is essential for
regulatory authorities, public organizations and companies to provide financial and other supports todevelop non-company PMS.
(3) Attitudes of companies
Some companies consider that PMS may be conducted only within the regulatory requirements, andsignificance of PMS has been neglected compared to the studies before approval.
Under the concept of bringing up better drugs throughout their lifecycle from development tomarketing, PMS should be considered more importantly with consistent study objective and personnel
training and organization should be improved. Systems to appropriately handle issues after marketing,to support studies conducted outside of companies such as investigator initiated studies, and todisseminate information on appropriate use of drugs to health care providers should be further
promoted. Mechanism to assess such activities internally and externally from company should be
defined.
(4) Regulatory systems and organizations
ADR/infection reporting, re-examination and re-evaluation are the major regulatory requirements formarketed drugs in Japan. Some revisions have been made including cooperation of ADR reporting
not only from designated institutions but also from all institutions, abolishment of 3000 cases ofClinical Experience Investigation (CEI), and establishment of EPPV. While ADR reporting system issimilar to that in foreign countries, re-examination and re-evaluation systems do not exist in Westerncountries. Classification of the investigations such as CEI, Special Investigation (SI) and postmarketing clinical studies conducted by companies are not based on the scientific methodology.
-4-In conformity with ideal PMS in future, it is requested to review the current regulations andorganizations and systems to apply the regulations, in consideration of its purpose/function,international harmonization, and distinction between methodology and regulations.
(5) Recognition by health care providers and issues of education
Health care providers not only “provide” but “use” evidences. Appropriate PMS cannot be conductedwhen health care providers do not consider PMS important, because all PMS data are generated byhealth care providers. However, health care professionals are less concerned with PMS, and they do
not fully understand that Article 77-3 of PAL requires their cooperation. The background to this isthat pharmacotherapy has not been considered important in the process of medical/pharmaceuticaleducation. Even if financial support to PMS is increased as stated in (2) above, PMS would not be
improved unless people who wish to conduct studies to make evidence increase.
To enhance attention to PMS and to bring up personnel who would achieve improvement ofpharmacotherapies, it is requested to further improve education/training/practice of pharmacotherapy
during education of health care professionals including physicians, pharmacists, and nurses.
(6) Practical use of pharmacoepidemiology
Evaluation of drugs in medical practice is feasible only with PMS. Clinical studies before marketingare intervention studies with experimental elements. Intervention of patient treatment should be
limited as much as possible in PMS and evaluation should be as close as actual medical practice.
Studies, in which drug users and patient populations are subjects as they are, are called observational
studies. PMS should be based on the pharmacoepidemiology which is epidemiology concerning
drugs.
In Section 5 of Detailed Discussion, scientific principle of PMS was examined to determine whichstudy method should be chosen according to the research objective. Methods to verify causal
relationship between a drug and an adverse event, methodology of observational studies, anddifference between pre-marketing clinical studies and PMS are not adequately understood, andexperience of PMS using correct methodology is insufficient. Current issues and measures toimprove them are reviewed in Section 5 through 11 of Detailed Discussion. The ideal PMS in the
future is recommended with summary of these items as follows:
According to the methodologies compiled in Section 5 of Detailed Discussion, it is desirable to draftin cooperation with related societies “Scientific guideline of PMS” which is common to all types of
PMS conducted by companies and organizations outside companies. Followings are considerednecessary: system and methodology of PMS should be distinguished, and the method which was
designated as CEI should be positioned as one of the methods of observational studies. Data inmedical institutions should be archived for research purpose, and observational studies using databaseshould be developed as one of significant PMS methods. Long term and large scale clinical studies toobtain evidence of long term use in Japanese population should be planned and implemented
appropriately in accordance with “simple and large” principle. Maintenance of investigation sites ingood environment should be facilitated.
(7) Spontaneous reporting and safety surveillance
Important role of PMS is to detect unexpected serious adverse drug reactions (ADRs). It is essential
to obtain reports of adverse event (AE) cases or suspected ADR cases. Reports from health careproviders include spontaneous reports and solicited reports relating to studies and investigations.
They are separated between direct reporting to authorities, and indirect reporting via companies whichis called company reporting. All of them are referred to as “spontaneous reports” here in after, but the
number of reports has not increased as expected. (See appendix to Section 6 of Detailed Discussion).
Causal relationship with drugs has been evaluated in each case, but currently, studies of statistic
methods using large accumulated data from spontaneous reports have been initiated globally, and it iscalled signal detection4).

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Safety issues are increasing, and it is necessary to promote both quality and quantity of spontaneous
reports of ADRs, etc. PMS should not only request companies to enhance AE reporting but also call
health care providers’ interest. As for signal detection which has significant meaning in safetysurveillance, it is proposed to advance methodological studies to utilize data accumulated inregulatory authorities and to create concepts of systems mainly operated by regulatory authorities ortheir related organizations and systems in which companies and other organizations can share theaccumulated data.
(8) Risk/benefit balance and overall evaluation
PMS gradually increases information on the appropriate use of drugs, and balance of safety andefficacy, and economic efficiency are important factors for the evidence of EBM and appropriate useof drugs. Evidence of long term prognosis may affect selection of pharmacotherapy, and safety issues
may affect not only life cycle of drugs but life of patients exposed. While it is the most important taskof PMS to secure safety, overseas data should be utilized more frequently for the drugs used globally,and safety measures should not be determined only with safety data. Views from patients exposureand from society should become more important for the future since users of the drugs and patientsare the ones who suffer from health hazard affecting people around them such as relatives, and it issociety that should take risks. When decision on appropriate use of a drug is made, balance of risk andbenefit should always be evaluated fairly and objectively and a comprehensive decision byconsidering type of diseases, necessity in medical practice, estimated patient exposure, similar drugs,
economic efficiency and view points from patients and society should be sought. Regulatory
authorities and companies must make decision by fulfilling their accountability to their decisions, andmust take necessary countermeasures.
(9) Ethical principles
It is obvious that conduct of PMS must be scientifically and ethically appropriate. “Ethical guideline
for epidemiological studies” has already been implemented by Ministry of Education, Culture, Sports,
Science and Technology (MECSST) and Ministry of Health, Labor and Welfare (MHLW). It has
become more important to plan PMS appropriately and to conduct it with thorough consideration ofhuman rights of subjects/patients.
It is recommended to specify ethical principles of PMS in compliance with “Ethical guideline for
epidemiological studies” and to prepare “PMS Guideline” according to the scientific principles in (6)above.

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Proposals and Requests
The issues discussed in the previous chapter of over view were assessed for current situation,
obstructive factors, and direction of improvement, and measures for improvements were reviewed. In
this chapter, proposals and requests reached through each section of Detailed Discussion aresummarized. In the following chapter discussions on each issue are described.
1. Initiatives of PMS: Overview (2)There are issues for which non-company organizations should have initiative in research for safetythat has social impact and research for efficacy in which series of drugs and drug classes are studied,however, PMS conducted outside of companies has not been implemented adequately.
Measures to increase investigator initiated PMS and public PMS: from Section 1 of Detailed
Discussion.
(1) Increase financial support from public organization, companies and other groups to PMS
organizations independently of companies, and newly created individual research or researchorganization. Pooled funds by contribution from companies according to their sales could also be
used for this support.
(2) It is desired to support not only R&D but also PMS of drugs with the independent administrative
institution to be established by combining the Evaluation Center and the Organization of
Pharmaceutical Safety and Research to establish a system to operationally support PMS and toprovide PMS with financial support.
(3) It is requested to establish public organization with functions such as selecting research subject for
PMS conducted outside of companies, supporting organization and implementation of research, andarrangement of outsourcing and an organization which actually conducts research is included in the
future. When possible, it is preferable to incorporate such organization in the independentadministrative institution described in (2) above.
(4) It is requested to establish pharmacoepidemiology course to develop human resources such as
PMS researcher, PMS coordinator, and research manager in curriculum of National Institute of Public
Health, and a one-year postgraduate school of vocational training to be newly established, etc(5) Orphan diseases and pediatrics are the examples of the area where indications of drugs are
expected to be expanded. For such issues, it is requested to establish systems to conduct publicresearch with support from companies as a prerequisite and to aid to research with public funds.
(6) It is desirable that result of investigator initiated PMS is allowed to be a part of re-examination
application data and that companies could provide financial support to such PMS by keeping
transparency and independence from companies.
(7) Methods, such as revision of health care system, to reflect the evidence of off-label use to medical
practice should be sought.
2. Attitudes of Companies: Overview (3)Pharmaceutical companies must attach importance to PMS by keeping consistency with research
projects from development phase to post-marketing phase and take appropriate measures to issues
occurring after marketing.
Attitudes required to companies in the future: from Section 2 of Detailed Discussion(1) PMS should be conducted adequately and issues should be managed in timely manner by stopping
conservative attitude of just complying with regulations but assuming constructive approach topromote drugs consistently from pre-marketing to post-marketing to be valuable.
(2) Safety information should be transparent and scientific. Safety issues should be managed
promptly with sufficient accountability.
(3) Organization for PMS should be expanded by increasing awareness of importance and necessity of
Pharmacoepidemiology, developing human resources and allocating sufficient personnel. There is a
proposal to consider establishment of an official certification system by the JSPE for persons incharge of product safety in companies as one of eligibilities for Manufacturing Marketing Supervisor
General and Safety Control Manager under the revised PAL.
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(4) Assuming PMS conducted outside of company advances as described in Section 1 of Detailed
Discussion, companies should contribute fund to supporting organization according to their sales,
provide researches independent of companies with drugs and information and provide fair funds.
3. Regulatory systems and organizations: Overviews (4)It is requested to review regulatory systems and organizations in which the regulations are operated inaccordance with the recommendations for future PMS.
Direction of the review: from Section 3 of Detailed Discussion(1) Systems should be reviewed by considering objective and function, international harmonizationand distinction between methodology and regulation.
(2) Consistency between organization and its operational purpose and simplicity of organization
should be considered.
(3) Development of people with expertise and neutrality who could permanently be assigned to PMS,and establishment of organization specialized in PMS is desired. Research organization for safetysurveillance should also be included in the future.
(4) It is requested that the data at regulatory authority on spontaneous reports including adverse
reactions, periodic safety reports, clinical experience investigations and special investigations should
be compiled to database in timely manner which is available to companies and other researchorganizations under certain condition.
4. Recognition by health care providers and issues of education: Overview (5)Further fulfillment of education and training for pharmacotherapy for physicians, pharmacists andnurses to increase awareness in PMS and to develop people who achieve improvement ofpharmacotherapies is required.
Request to bring up talented people: from Section 4 of Detailed Discussion(1) Not only pharmacological actions of drugs on organs but also drug development process and PMS
which is conducted to establish appropriate use should be further incorporated to the undergraduate
education for medical students.
(2) The state examination for medical doctor includes only about 30 questions on pharmacotherapies.
The answers to most of the questions are to select an appropriate drug according to its
pharmacological action. It is recommended to increase questions regarding comprehensive
pharmacotherapies including efficacy and safety.
(3) Training and practice for medical school graduates should aim at accumulation of practicalexperience including methodology for interventional studies and observational studies, EBM,
development of pharmaceutical products, and method for assessment of post-marketing efficacy andsafety (adverse reaction) with clinical pharmacology, clinical epidemiology andpharmacoepidemiology as major theme.
(4) Concepts in the model curriculum for pharmacy education proposed by the PharmaceuticalSociety of Japan in the light of shift to 6-year system should be implemented at early opportunity, andprofessional education should be enhanced to include pharmacotherapy, methods of clinical researchand PMS regulations.
5. Practical use of pharmacoepidemiology: Overview (6)PMS evaluates drugs in actual practice and it should be based on pharmacoepidemiologicalmethodology.
Observational study or interventional study should be selected according to the research subject
illustrated in Fig. 2: from Section 5 of Detailed Discussion(1) It is recommended to prepare “PMS Guideline” common to PMS conducted by companies and byoutside of companies with cooperation from various groups by adding ethical principles in Section 12
of Detailed Discussion to scientific rules in Fig.2 of Section .5 of Detailed Discussion.
It may be difficult to apply Fig 2 in practice, however, effort is necessary to gradually approach toideal situation in the guideline without compromising with the current condition as much as possible.
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The internationally valid term for observational study, “cohort study”, should be applied to CEI. It
should be included in the guideline to be developed as useful method of PMS: from Section 8 of
Detailed Discussion.
(1) Guideline should stipulate that intervention and selective bias should be avoided in cohort studies,and that control group should be established in the study when possible.
(2) When a company plans a study in which users of other drugs in actual practice are sampled andcompared with comparator group, contacting with third party, etc. should be used to establish themechanism to avoid bias.
Data at medical practice should be compiled into database for utilization for observational studies in
PMS: from Section 9 of Detailed Discussion9(1) Leading body should be established at regulatory authority or related organization, and databaseshould be developed, with financial support, through cooperative system with regulatory authority,
health care providers, insured by health insurance, academics and companies.
(2) Maintenance and improvement of database should be conducted by a non-profitable neutral
organization with public funds. It should be managed to accept request for access to the databasefrom outside organization including companies.
Following measures other than 1-4 in Section 1 of Detailed Discussion are necessary to develop
clinical studies necessary for PMS: from Section 10 of Detailed Discussion(1) A job position (Clinical study coordinator) which includes management of studies and assuranceof data quality should be established. Enhancement of education and development of people should
be adequately implemented and qualified people should be assigned to medical institutions to gain
their experience.
(2) For long-term and large-scale studies, principle of “simple large” should be applied in plan,
implementation, management and analysis. Operation should be standardized especially for quality
assurance and audit by taking balance of cost into consideration and by putting emphasis on primary
endpoints, important baseline parameters and mandatory data relating to serious adverse reactions, etc.
6. Spontaneous reporting of ADR and safety surveillance: Overview (7)Issues concerning safety have been increasing, and safety surveillance system should be reviewed bypromoting quality and quantity of spontaneous reporting of ADR and by evaluating international
trends.
Measures to promote quality and quantity of spontaneous reports: from Section 6 of Detailed
Discussion(1) The Pharmaceutical Affairs Law revised in 2002 obligates health care professionals to conduct
spontaneous reporting according to Article 77-4-2, Item 2. This should be communicated inorder to promote understanding of the requirement by the relevant people.
(2) Reporting formats for direct reporting from health care professionals and for company reporting
should be standardized and simplified. Health care professionals and company personnel shouldbe educated on what and how to report. Importance of reporting of serious cases and unexpected
adverse reactions should be emphasized.
(3) Direct reporting usually comes from physicians, dentists and pharmacists, however, cooperationfrom nurses should be sought.
(4) Under the current situation companies submit reports to the regulatory authority while reports
from direct reporting are not transferred to companies. This should be improved to have mutual
recognition of cases. All reporting should be centralized to the regulatory authority and its
related organizations and comprehensive scheme which enables information exchange with
WHO and signal detection as in Section 7 of Detailed Discussion should be reviewed. Actions
including protection of privacy information could be necessary.

-9-(5) The time frame of 6 months for EPPV is not considered long enough. The system and period of
EPPV should be reviewed not only by requesting intensified reporting to companies but also byimplementing measures to increase direct reporting.
To promote researches for signal detection and hypothesis strengthening / testing studies : from
Section 7 of Detailed Discussion(1) Regulatory authorities should recognize statistical significance of the signal detection, consider the
introduction of signal index, and sponsor / support researches to utilize signal detection.
(2) Observational studies to strengthen / test hypothesis, especially case control studies should be
developed. “Public organization” in Section 1 of Detailed Discussion should select and organize thistype of safety studies as research project of non-company PMS.
(3) Signal detection and case control studies should be included in (3) and (4) of Section 4 of Detailed
Discussion.
7. Ethical principles in PMS: Overview (9)Ethical principles should be established in line with “Ethical guidelines for epidemiological studies”:
from Section 12 of Detailed Discussion(1) Consent from individuals is required in case control studies with control arm of general population,
however, individual consent is not necessary in spontaneous reporting, activities and research forsafety surveillance such as signal detection, prospective cohort studies, and studies utilizing database.
(2) Ethical committee is necessary in principle, however, it should not be required for studies
conducted with different drugs in similar system.
(3) It is requested to review “ethical guidelines for epidemiological studies” by taking 1 and 2 above
into consideration. It is necessary to take similar consideration as excluding cancer in disease specificsystem or to add descriptions to keep consistency in the whole guideline.
(4) “PMS guideline” should be prepared in conformity with the ethical principles and scientific rules
in Section 5 of Detailed Discussion.

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Sections of Detailed Discussions
1. Issues on investigator initiated and public PMS
When a drug is started to be used in medical practice, it is appropriate to plan and implement PMS not
only by the company which supplies the drug but also by health care medical professionals andregulatory authorities considering a study subject necessary in each party’s point of view.
(1) Necessity and significanceIn addition to the evidence for individual drugs collected by companies, results of studies clarifying
characteristics in comparison among drugs in the same class or drugs of similar effects, and effects ofconcomitant use are requested in actual medical practice. PMS mainly conducted by investigators andpublic bodies is called as “PMS outside companies” in the following description.
(2) Required characteristics
Research subjects which should be conducted in PMS outside companies include:a) Safety issues common to drugs in the same class or drugs of similar effects: Safety issues havingsocial significance such as MHLW scientific studies evaluating causality between influenza
encephalitis /encephalopathy and NSAIDs.
b) Subjects on efficacy common to drugs in the same class or drugs of similar effects: Efficacy issues
not requiring evaluation of surrogate endpoint such as hypotensive effects but of true endpointsuch as inhibition of development of cerebrovascular/cardiovascular accidents.
c) Subjects on concomitant pharmacotherapy or addition of pharmacotherapy to other therapy: Issuesof studies evaluating development of new treatment or overseas standard therapies, such as
studies on concomitant chemotherapies and adjuvant therapies.
d) Issues requiring evidence of off-label use
The studies which have public interest and may affect public health a), long-term large scale studies
which are difficult for companies to conduct b), and studies in which multiple drugs from more than
one companies are investigated c) are suitable as PMS outside companies, however, companies
conduct studies for their own drugs d). d) is usually the issue of companies, but it is difficult forcompanies to conduct such studies when the issue considers orphan disease or pediatric use even if it
is considered significant in medical practice.
(3) Relationship with companies
Investigators may receive drugs, drug related information, financial support, and sponsorship fromcompanies, but operation of a study from its plan to its completion should be independent fromcompanies and the operations should be fair and transparent. Publication should be actively sought,
and conflict of interest with companies should be clearly specified. On the other hand, compensation
is difficult when an accident occur in PMS of off-label use.
(4) Current issues
Many PMS studies have been conducted for drugs by company, however, PMS outside companies has
not yet been carried out adequately. “Expert committee for clinical study guideline” and “Conferenceof large-scale clinical study network” have been started, but their systems are not yet available todetermine, organize, support and implement appropriate PMS study subjects in timely manner.
Insufficient funds due to inadequate financial support cannot be used appropriately and sufficientresults have not been obtained. A number of long-term large scale clinical studies carried out inWestern countries have provided basic information to guidelines such as treatment for hypertension as
evidence of appropriate use, but there is less experience of such studies in Japan.
(5) Utilization of study outcome
It has been suggested as an issue by some medical investigators that even though valuable evidence isobtained in difficult situations, it is sometimes not utilized for appropriate use. Since companies haveobligations to observe global safety studies, outcome of safety studies should be utilized forappropriate use regardless of type of the organisations which conduct the studies. Results of efficacy- 11 -

study may be used within approved indication of a drug, but results on off-label use can be used only
after a change in indication and dosage/administration is approved. When a company submits
application using data of PMS outside the company, quality assurance of the data is necessary. It is
discussed in Section 10 of Detailed Discussion concerning clinical trials. When a company does not
submit application, it is difficult to utilize such data. Some measures are required for their utilization.
(6) Direction of improvement
PMS outside companies would not be developed until following improvements are initiated towards
the current condition: investigators should recognize necessity of PMS and make efforts to conduct it,
qualified personnel such as administrators, coordinators and researchers who plan and organize PMS
should be developed, and environment to implement studies and financial foundation should beestablished.
(7) Recommendation: Measures to promote investigator initiated and public PMSa) Financial support from public organizations, companies and other groups provided to PMS
organizations having activities independent of companies and newly started individual research or
research organization should be increased. It is also possible that support is to be given by poolingfunds by contribution from companies according to their sales.
b) It is requested to establish mechanism to support and give financial assistance not only R&D but
also PMS of drugs in the independent administrative institution to be established by integrating
Pharmaceuticals and Medical Devices Evaluation Center (EC) and Organization for Pharmaceutical
Safety and Research (OPSR).
c) It is requested to establish public organization with functions of selecting research subject of PMS
outside companies, supporting organization and implementation of studies, and management ofoutsourcing, etc. and an organization which actually conducts studies should be included in the future.
It is preferable to include such organization in the independent administrative institution in b) above
when possible.
d) It is requested to establish Pharmacoepidemiology course to develop PMS investigators,
coordinators and research managers at national health medical institute and one-year graduate schoolfor development of workers to be newly founded.
e) It is recommended to establish a system of public studies premised on cooperation from companies,
and a supporting system with public funds for issues such as orphan disease and pediatrics in whichsocial interest is high and expansion of indication of drugs are desired.
f) It is requested to allow results of investigator initiated PMS to be utilized as re-examination
application document and companies to provide transparent funds on the assumption that such PMS
studies are independent of companies.
g) Methods to utilize evidence of off-label use to medical practice should be investigated, for example,
revision of health insurance system.

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2. Issues on companies
Almost all PMS studies have been carried out by companies in the past. In the future, PMS studies
should share its roles with PMS outside companies according to their issues. However, responsibility
to products ultimately lies with companies, and especially the responsibility to secure safety issignificant.
(1) Issues in attitude of companies
In the past, some companies put emphasis only on development of products and negative attitude ofjust complying with regulations in post-marketing after obtains approval was seen. PMS has been
considered less significant than product development. Number of patients in pre-marketing studies isfew, it is obvious that conditions of pre-marketing studies such as targeted patients, method andperiod of administration, and concomitant drugs are different from those of post-marketing medical
practice.
In order to establish appropriate use of drugs in medical practice, PMS should be planned andimplemented with a view consistent from development to post-marketing, however, there werecompanies which did not have positive attitude to develop their drugs better through PMS.
While consistent planning from pre-marketing to post-marketing is required, appropriate measures for
issues which occur post-marketing are also necessary. However, experience and knowledge of
Pharmacoepidemiology are not adequate. Safety issues are increasing, and it is required to take rapid
actions against unexpected issues, however, regulatory reporting and explanation to outside ofcompanies may be delayed. Safety information should be highly transparent and scientific. Attitude
of companies toward adequate explanation and appropriate measures for issues should be sought.
(2) Future direction
As for significant safety issues, it is desirable to cooperate with public entities as explained in Section
1 of Detailed Discussion. With regard to efficacy, issues on new indication which are difficult forcompanies or necessary for medical practice should be managed by cooperation with PMS outside ofcompanies including investigator initiated studies to submit additional application as much as possible.
Personnel should be educated and developed by attaching importance to PMS and efforts should bemade to expand organization by securing adequate people. It is not considered appropriate to abolish
CEI with 3,000 cases as it is no longer a mandatory requirement. Making plans by returning to thefundamentals to seek methodology for research subject, adaptation of new methodology and effort toimprove quality of PMS are also necessary.
(3) Recommendation: Position of companies in futurea) PMS should be adequately conducted with positive attitude of developing good drugs from premarketing to post-marketing and measures should be taken for issues timely. Negative attitude of justfollowing the regulatory system should be abolished.
b) Safety information should be transparent and scientific. Safety issues should be managed promptly
by achieving sufficient accountability for explanation.
c) Organization for PMS should be expanded by increasing awareness of importance and necessity of
Pharmacoepidemiology, developing people and securing adequate personnel.
Qualification system for safety persons in companies by JSPE as one of the requirements for
Manufacturing Marketing Supervisor-general or Safety Supervisor as described under the revisedPAL.
d) If PMS outside companies advances as described in Section 1 of Detailed Discussion, companies
should contribute to the funds to supporting groups according to their sales, supply drugs andinformation and provide transparent funds to studies independent of companies.

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3. Issues on regulatory system and organizations
Japanese system started as ADR monitoring system in 1967 are complicated having been added newelements and revisions. While international harmonization of drug regulations are being achieved,
the system including organizations to operate the regulations should now be reviewed.
(1) Systems in Japan and in foreign countries
Western system has mainly been aimed at safety surveillance. The major source of the system in the
US has been reports of adverse reactions from companies, however, reports from patients andconsumers were added through MEDWatch and reports from pharmacists are increasing. In UK,
adverse reaction reporting to CSM (Committee on Safety of Medicines) from physicians using yellow
cards is the major source of the system. For the drugs marketed with a black triangle in the Data
Sheet, all suspected adverse reactions are to be reported in the intensifying period of approximately 2
years after launch (after the period, unexpected/serious adverse reactions are to be reported.) In
France, pharmacovigilance system is characterized by the process where adverse reaction reports fromhealth care professionals collected in about 30 regional centers in the country are gathered to anational center for evaluation.
PMS system in Japan requires companies to conduct adverse reaction/infection reporting, early phasepost-marketing vigilance, CEI, SI and post-marketing clinical studies and submit documents for earlyphase post-marketing vigilance, periodic safety reports, re-examination and re-evaluation.
(2) Issues on systems and organizations
Fig 1 shows outline of Japanese systems. Relationship of each system, studies and reports is socomplicated that it is difficult to describe it accurately. For example, EPPV is explained as intensified
evaluation and reporting of adverse reactions immediately after launch, but it has other aspects suchas dissemination of information and calling attention to medical institutions. Although safetysurveillance is important, repeated submission of reports for EPPV, PSR and re-examination would beburden to both companies and regulators. Idea to unify them to a single periodic report should be
reviewed.
Fig 1: PMS reporting system between regulatory authority and companies
approval

Reexamination

Reevaluation

EPPV, PSUR

Reevaluation: Report submission: Case reports of adverse reactions,

ADR/infection reportetc.
CEI, SI, Post-marketing clinical study (PMS guideline, GPMSP, GCP)

Centralization of ADR reporting to regulatory authorities in Fig 1 is also common in foreign countries.
Direct reports from medical institutions are also centralized to regulatory authorities. WHO Uppsala
Monitoring Center, UK MCA (Medicines Control Agency) and US FDA (Food and Drug
Administration) have started to make signal detection (See Section 7 of Detailed Discussion) whichuses collected data mandatory. Such operations related to safety surveillance should be conducted byregulatory authorities or their subsidiaries where data are centralized. FDA is conducting
observational studies under contract with owners of database as explained in Section 9 of Detailed
Discussion, and the UK database, GPRD, is managed by MCA.
Re-examination and re-evaluation are the systems which are not implemented in Western countries,
but in some countries re-application is required for approval. Efficacy may be evaluated under reapplication. As explained in Section 1 of Detailed Discussion, in long term large scale studies
conducted by groups outside of companies, and in studies which evaluate efficacy of concomitant
pharmacotherapies, the issue that evidence obtained as the study outcome may not be utilized as
information on the appropriate use is due to the current systems.

- 14 -

While companies have conducted PMS with the methods specified in the guideline for re-examination
and re-evaluation of the products, CEI and SI specified in the regulation are Japan specific terms andnot globally valid. As explained in Section 5 of Detailed Discussion, study methods should beselected according to pharmacoepidemiological methodology, and it is not necessary for regulatory
system to regulate methodology. It is useful for regulatory authorities and companies to discuss PMS
plans and agree study methods, but methodology should be independent from regulations.
In terms of organization, it should be reviewed by considering Future PMS in Japan, since PMS isconsidered less important than review of NDA. Contact points of PMS are divided into two parts,
Evaluation and Licensing Division for re-examination and re-evaluation which have nature of reconfirmation of approved items, and Safety Division for safety management such as ADR/infection
reports and revision of “Precautions for Use”. It may be a tactic to unify all operations related to PMS
into a single organization. Since continuous management of safety information from development
through marketing is also considered applicable, it is desirable to establish a system to reflect suchdata into draft package insert. Operations related to evaluation including re-evaluation and reexamination are outsourced to EC and OPSR, and there are inconsistencies between theseorganizations due to complicated operation system.
(3) Make use of data retained by authorities
Many data such as ADR, CEI, SI, Post Marketing CT, etc. are centralized and kept at authorities
as figure 1 shows. Data that is useful as appropriate use information should be made into public
and it is considered most of data are useful for PMS as later in Section 6 & 8 explained. PSR
should be used to detect signals, while data of CEI/SI should be, after evaluation, sorted out andretained for the use in the next PMS since these data are seen as the result of observational
studies and can be comparable.
(4) Recommendation: It is requested that regulations systems and organizations should be reviewed
by considering following items.
a) Objectives and functions, international consistency and separation between methodology andsystems should be considered.
b) Consistency of organization and operational purposes, and simplification of organization should beconsidered.
c) It is requested to develop experts having neutral position who can conduct PMS permanently and toestablish organization specialized for PMS. It is preferable to include pharmacovigilance study
organization in future.
d) It is requested to make database of the data of spontaneous reports of ADR, PSR, CEI and SI
accumulated in regulatory authorities, and to make them available for use by companies, research
institutes, etc., under certain condition.

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4. Issues to increase interests of medical professionals in PMS
Interests in PMS could not be increased only by emphasizing the significance of PMS to health care
professionals. Back ground issues are not limited to PMS, but there are issues of researches andeducations common to all clinical studies. Historical consideration about actions toward improvement
and making efforts in long range will bring develop of PMS.
(1) Background issues
Based on the idea that treatment cannot be initiated without diagnosis, therapeutics have been
considered less significant than diagnostics in clinical medicine. Basic researches have been
traditionally considered significant and clinical studies with patients less significant. In
pharmacological field, studies on pharmacotherapies have been considered less significant than basic
researches, and there have been issues that pharmacists have insufficient knowledge and experienceon pharmacotherapies. Researches on pharmacotherapies have double handicap: therapeutics against
diagnostics and clinical researches against basic researches. PMS was less interested especiallycompared with pre-marketing research. These issues have affected education and medical students
have not been able to spend much time for therapeutics, because they are busy in understanding
symptoms, pathology and diagnosis. Pharmacotherapeutic education has also been insufficient topharmacological students.
(2) Current status
EBM has been emphasized in recent years, and significance of clinical studies with patients has beenrecognized. Concerning pharmacotherapies, opportunities may increase for health care professionals
to voluntarily conduct or participate in researches to seek evidence, and to critically examine studies
conducted by others. In 2002, PAL revision made reporting of diseases/deaths of possible ADRs
from medical professionals mandatory. In 2004, two-year post-graduate training will become
mandatory for clinicians. These current changes may enhance increase of health care professionals
who have interests in pharmacotherapy, and also intensify development of personnel who want to be apharmacotherapy researcher. Such trends may enhance interests in PMS and it will make PMS
advanced.
Since pharmaceutical medicine is being established, and interest of hospital pharmacists is increasing,roles of pharmacists in medical practice will become more important according to progress of
separation of dispensing/prescription, and education period of qualification for national examination
for pharmacists is to be extended to six years.
(3) Recommendation: Request to increase interest to PMS and to educate qualified persons
who will achieve improvement of pharmacotherapiesa) Not only pharmacological actions of drugs to organs but also PMS which is conducted to establish
appropriate use during development phase and post-marketing phase of drugs should be emphasizedin the undergraduate education of medical students.
b) National examination for medical practitioners includes only about 30 questions onpharmacotherapies. In most of the questions, selection of an appropriate drug is asked according to its
pharmacological actions. It is recommended to increase questions requiring overview ofpharmacotherapies, including efficacy and safety.
c) Post-graduate training of medical doctors should include practical experiences such as
methodology of intervention studies and observation studies, EBM, development course of drugs,
evaluation methods of efficacy and safety in development and post-marketing phases as well as
clinical pharmacology, clinical epidemiology and pharmacoepidemiology.
e) Concerning education for pharmacy students, concepts of the model course defined by the
Pharmaceutical Society of Japan in view of increase of the years for education of pharmacy students
to six from four should be realized, and the professional course should include pharmacotherapies,
methods of clinical studies, and PMS systems.

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5. Practical use of pharmacoepidemiology
In PMS, observational studies and clinical trials (intervention studies) should be properly utilized inaccordance with pharmacoepidemiological methodology. Scientific principles common to all PMS
investigations will be discussed below. Although research objectives vary, when they are classified as
1-11 below, methods/designs corresponding to research objectives are summarized as Fig 2.
Fig 2: PMS research objectives and corresponding study method
1. Detection of unexpected serious AE/ADR cases
Research objectives
2. Generation of hypothesis concerning causal relationship3. Hypothesis strengthening/testing concerning causal relationship
4. AE/ADR profile - frequencies and sequential change
5. Efficacy/usefulness in medical practice (QOL, etc)
6. Long term prognosis
7. Discovery of new efficacy
8. Hypothesis strengthening/testing
concerning efficacy
9. Efficacy and safety in patients withspecial backgrounds
10. Concomitant therapy efficacy and safety includinginteraction
11. Understanding of use ofdrugs in actual practice andevaluation of
Method and design
appropriateness~
Spontaneous reporting{: method which{ ~{~Case series
should be selected~
Signal detection~: method considered{ { ~Analysis of secular trend
as the first choice{{{~
Drug utilization study~{{
Case control study~ ~ ~ ~ { { ~ ~ {Cohort study
{
~
~ { ~
Clinical trial
{
{ { {
{
Meta-analysis(1) Objective and method of safety study
Serious and less frequent adverse reactions are often unknown, when drugs are launched. Detectionof such ADRs is important objective of PMS. It starts after such cases are detected in 1. Whilespontaneous reporting is not a study method, it is included in above list, because data of AE reports
regardless of causality are essential for objective 1.
When cases are accumulated, causal relationship with the drug used would be suspected. 2.
Generation of hypothesis concerning causal relationship implies it, and when it is proceeded tostatistical hypothesis strengthening and testing, unknown ADRs could be detected. The objectives 1-3
are continuous, and the following method which belongs to descriptive study is used for generationand strengthening of hypothesis:
Case series is the study method to indicate cases in specific area or medical institutions in a table ofcase chart. Studies on statistic method have been started globally to search relationship between an
AE and a drug by using case series and accumulated data of spontaneous reports concurrently. In Fig
2, it is described as “signal detection”. Analysis of secular trend is a method to examine correlationby collecting frequency of an AE and manufacturing volume/patient exposure of a drug. The study is
year-to-year secular trend, if annual data are used as unit, and ecologic study, if local population is- 17 -

used as unit. The method does not require data of individual case, but can use populational data.
Analysis of year-to-year secular trend is applicable to the research objective 4., sequential change of
AEs/ADRs.
Method of analytic study, which is one of observational studies, can be applied to estimate causal
relationship between a drug and an AE statistically and to quantify risks as below.
Cohort study is a method to investigate the occurrence of AE by following up a group of users of the
drug and a group of non-users of the drug in medical practice. There are prospective studies in whichinvestigations are toward the future from the beginning of the study, and retrospective studies inwhich groups are made according to the past medical records and the data are examined sequentiallytowards the present. Control of no-treatment group is placed to evaluate effects of drug use. Several
groups are made according to drugs and dosages in consideration of the study objective, or control
group of standard drugs or low dose groups instead of non-treatment group can be applied.
Case control study is a method to analyze relationship between AE and drug by investigating andcomparing drug use and other risk factors between risk factors between a case group of patients who
experienced the AE and control group of patients who did not. It is always conducted retrospectively.
Cross sectional study investigates factors such as drugs and outcomes simultaneously, and it isdistinguished from longitudinal study which cohort study conducted along lapse of time, and casecontrol study conducted retrospectively.
While in observational study, external validity which can grasp the population without bias isimportant, treatment/non-treatment groups and case/control groups may have bias such as age and risk
factors including concurrent disease, and results may be distorted. On the other hands, an intervention
study in which subjects are allocated randomly is controlled not to cause bias between groups. It has
internal validity, but sometimes lacks external validity. It cannot be determined which one issuperior: observational study or intervention study. The method should be used after characteristics
of each study are fully understand and the results should be interpreted accordingly. In order toimprove the quality of observational study, it is required to secure external validity, organize groups
by selecting subjects from population to avoid biases among groups, collect accurate data on cause
and result by through follow-up on drug use and occurrence of AE, and utilize analysis method toadjust effects from bias. Because it runs a risk to make conclusions with a single study, analysis
should be conducted carefully. Quality of the intervention study is to be discussed in Section 10 of
Detailed Discussion.
(2) Objective and method of efficacy studies
Possible on efficacy objectives are 5, 6, 7 & 8 in Fig 2. Evaluations such as QOL are done not only
by changes in symptom but also by outcome in 5 and long-term prognosis in 6. Detection of
unexpected ADRs as well as 7 and 8 concerning unknown efficacy are also objectives of the studies.
Case series may induce detection of new efficacy.
In safety study section, cohort study was explained as investigation of occurrence of AE, however,result of therapy and final results such as cure and QOL may be investigated instead of AEs such as
occurrence of concurrent disease or death, and thus cohort study is also widely applicable to efficacy
objectives. Even in the studies with parameters of AEs such as occurrence of concurrent disease anddeath, detection of increase trend of them due to the drug is a safety study, but a study to expect
decreased trend is an efficacy study. Not only cohort study but also case control study are applicablefor studies with objective of efficacy.
Concerning objective 8 to test hypothesis developed in observational study, clinical trial withintervention, especially randomized controlled trial (RTC), is the first choice. In “6. Long-term
prognosis study”, decrease of rare diseases such as cerebro/cardio-vascular diseases (efficacy), or
increase (safety) is evaluated. Therefore, parameter of evaluation is true endpoint but not surrogate- 18 -

endpoint. In a safety study in which intervention should be avoided, the observational study should
be selected and measures should be taken according to its result.
(3) Other research objectives and methods
Other objectives include 9 for patients with special background such as pediatrics, elderly andconcurrent disease, 10 for patients using concomitant drugs, and 11 for information of drug use.
Observation study or RCT may be selected for 9 and 10.
Target of PMS is to add evidence to objectives in 1 to 10 and to take measures when there is a issue
concerning appropriate use.
As for the objective to understand the drug use in actual practice (11), drug utilization (DU) study isnecessary. Researches to investigate information on subjects such as age, disease, concurrent
condition, drugs in use, dosage, dosing period according to drug class or by product are classified as
drug utilization (DU), researches to evaluate appropriateness by making comparison to the appropriate
use condition obtained from 1 – 10 are called drug utilization review/evaluation (DUR or DUE). The
methodology for DU corresponds to cross sectional study.
Evaluation of appropriateness links to package insert in terms of individual product and to revision oftherapeutic guidelines in terms of target disease or drug class. It is possible that a severe issue may
link to product lifecycle. Comprehensive evaluation of risk and benefit is necessary, and comparison
with similar drugs is required. Therefore all results of PMS should be disclosed to the public.
Results from multiple researches would not always coincide and meta-analysis is used to intensify
evidence by evaluating multiple researches comprehensively.
(4) Current situation and issue of PMS in terms of methodology
PMS should be conducted under pharmacoepidemiological methodology, however, CEI, SI and postmarketing study by companies are classification by the regulatory system and only a few
considerations have been given to methodology.
Although CEI and SI correspond to cohort study, principles of observational study and characteristics
of clinical trials in PMS are not understood enough and case control studies which are indispensable
to safety research have not been conducted as expected.
These issues and measures for improvement are discussed at each discussion section. Fig 2
comprehensively summarize post-marketing research objectives and methodologies to be selected forcorresponding objectives.
Regulatory system is necessary, however, companies are expected to conduct PMS because ofobjectives, not due to regulatory system.
As discussed in Section 1 of Detailed Discussion, groups outside of companies should conduct PMS
for the issue difficult for companies to conduct. Although the current PMS guidelines are guidancefrom regulatory authority, scientific guidelines which would be applicable to all PMS is required to
improve the current situation.
(5) Proposal: To utilize Pharmacoepidemiological methodology in PMS
By combining scientific principles in Fig.2 and ethical principle in Section 12 of Detailed Discussion,“PMS Guidelines” which are applicable to both PMS by companies and PMS outside of companies
should be prepared in cooperation with relevant parties.
It may be difficult to apply Fig.2 to actual issues, however, efforts are necessary in the Guidelines toapproach to the ideal principle without compromising with the current situation..

- 19 -

6. Issues on spontaneous reporting
A case report from an individual physician was the start of the thalidomide issue, and safetysurveillance system with spontaneous reporting was established. Safety surveillance is the starting
point of PMS. Collection and evaluation of spontaneous reports, as well as countermeasures are
significant. In Japan, reporting numbers are not many and issues of spontaneous reporting is
discussed in this section.
Reports include spontaneous reporting from physicians and pharmacists, and solicited reporting
related to studies and investigations. All of such reports are defined here as “spontaneous reports”,
and among them, reports from medical institutions to companies are called company report andreports from medical institutions directly to regulatory authorities are called direct reports.
(1) Necessity, significance and limitation
ADRs of incidence less than 1/1000 include serious ones, and such ADRs cannot be detected before
launch in many occasions. Spontaneous reports are essential not to overlook unexpected ADRs oflower incidence. If detection of a serious ADR delayed, it may cause social issue due to loss of many
lives affecting the product’s life cycle. Safety surveillance with spontaneous reports is, therefore, themost significant objective of PMS. Spontaneous reports are also necessary to understand situation of
occurrence and change of expected ADRs. The issues to detect unexpected ADRs are discussed
below.
It is difficult to identify causal relationship with a drug used to a patient in individual cases unlessrechallenge test is conducted. Many cases require statistic inference from observational studies.
Limitation of spontaneous reports is that individual case reports only indicates “suspected ADR”. In
urgent safety issue, it is required to evaluate causality in individual cases. In observational study,
however, analysis of causal relationship is required based on reports on AE, as in Section 7 of
Detailed Discussion.
Even if spontaneous reports are accumulated, it is impossible to determine incidence of ADR/AE,
when extent of patient exposure is not available. It requires cohort study explained in Section 8 of
Detailed Discussion. However, if patient exposure can be calculated according to production/delivery
amount, estimation according to descriptive epidemiology is possible (please see Section 5 of
Detailed Discussion).
(2) Current issues and actions toward improvement
Changes in number of reports in Japan and the result of comparison between Japan and
US/UK/France using number of reports per 1 million population were described in Appendix (notshown).
Increase of reporting numbers since 1995 was probably due to implementation of GPMSP, revision ofsafety information reporting system, and so on. The number is leveling off recently. Simple
comparison of data among each country is difficult due to differences in regulations. Though the dataof 1995 are rather old, it seems that reporting number is fewer in Japan than other countries.
Underreporting is a global issue. Its factors include legal issues which is difficult to be solved, but
the number will not increase unless health care professionals are aware of the issue discussed in
Section 4 of Detailed Discussion. Health care professionals may raise questions as to what should bereported. It is important to seek their understandings by explaining them in activities to promote theirknowledge. Cases should be reported if they are possibly caused by a drug, serious, “I have neverseen”, unusual, etc. It is one technique to shown medical institutions which report many AE/ADR
cases as the collaborative institutions of appropriate use of drugs.
Determination of causal relationship requires data understandable to the third parties who conduct
evaluation in terms of patient information, sequential change of the event, diagnosis and temporal
relationship with drugs including concomitant drugs. Not only number of reports but also their highquality are required. It may take time to follow up and actions may delay. For both company reports- 20 -

and direct reports, case report form should be standardized, and it is preferable to add special items for
key ADRs specific to a product.
Follow-ups and evaluation require expertise. Workload increases with increase of reporting numbers.
System to intensify resources on important issues is necessary. Grading of significance is determinedby factors such as expectedness and seriousness of the AE/ADR. Standard5) of follow-up
investigation posed by CIOMS V is considered effective for efficiency.
Causal relationship becomes an issue when cases are accumulated. Judgment should be made byusing all the accumulated reports. In the future, mutual alignment system with data from company
reports, direct reports and overseas reports collected in WHO is ideal. Study to approach to the ideal
situation has been started in the world.
When the data can be linked with other data such as medical records, death registration andprescription data, serious ADRs of lower incidence are considered detectable. It is the method which
can be available after database is fully equipped. This topic will be discussed at Section 9 of Detailed
Discussion. Spontaneous reports of AE/ADRs of considerably lower incidence should be continued
as far as possible. Future safety vigilance model would be the combined methods indicated inAppendix(not shown).
(3) Recommendation: It is proposed to intensify spontaneous reports as described below tomeet increasing safety issuesa) After PAL revision in 2002, it should be known to related persons without exception thatspontaneous reports became obligation for health care professionals (Article 77-4-2 Item 2 of
PAL). This should be informed to promote their awareness to understand the revision thoroughly.
b) Forms of the direct report from health care professionals and company report should bestandardized and simplified. Reporting items and methods should be well educated to health care
professionals and company personnel, and it should be stressed that reports of serious cases andunexpected ADR cases are specially important.
c) While the reporters of direct reports are specified as physicians, dentists and pharmacists, it
should be examined6) to request assistance from nurses.
d) Company reports are submitted to regulatory authorities, but direct reports are not transferred tocompanies. Such practice should be revised and mutual cooperation should be examined.
Regulatory authorities and its related organizations where all reports are collected should play as
a leading roles in future plans to establish general systems including information exchange with
WHO and signal detection described in Section 7 of Detailed Discussion. However, measures toprotect privacy should be necessary.
e) Six months of EPPV period is considered not long enough. Intensification of reports should not
be required only to companies, but measures should be taken to increase direct report inconsideration of a) above to review the details and period of this requirement.

- 21 -

7. Issues on signal detection and case control study (Signal detection and strengthening / testingof hypothesis)
When case reports of a serious possible ADR are continuously collected, and many of them have
temporal relationship with the use of a drug, and other factors are considered unlikely, causal
relationship with the drug is suspected. Regulatory actions such as Dear Dr Letters have been taken
after accumulation of individual case evaluation, however, researches are being globally conducted4)
for signal detection which can statistically find out significant (possible) ADRs to be reviewed withpriority.
WHO Uppsala Monitoring Center (UMC) defines the signal as “information concerning possibility of
causal relationship between an AE and a drug which was not identified or imperfectly confirmed”.
(1) Necessity and significanceAs it is historically shown in incidents such as the thalidomide issue, careful observation of individual
physician may become signal detection. Organized efforts of hospitals, companies and regulatory
authorities are essential for safety surveillance. In the future, a method of statistic signal detection,
which is called data mining, will become a significant procedure.
A signal is hypothetical information indicating that the event may be possibly related to the drug,
though, actually, there may be no causal relationship between the event and the drug. Hypothesis
strengthening/testing studies are required following to signal detection. Observational studies to
identify high risk subjects and to quantitate risk are important to establish appropriate use of drugs.
Case control study is effective, especially when suspected ADRs are few.
(2) Current situation and issues
In Japan, method of signal detection is not yet well developed, and hypothesis testing by observational
studies where case control studies are taking major part are scarcely conducted. In Western countries,
statistical methods were tried to be applied to signal detection by using large data from accumulated
spontaneous reports in 1990s. Signal parameters such as PRR (proportional reporting ratio) by MCA,
UK., and RR (signal score) by FDA, and IC (information component) by UMC have been put into
practical use. Signal parameters, which indicate whether causal relationship should be considered ornot, are now becoming indices common to regulatory authorities and companies. On the other hand,
there are no activities in Japan at this moment to utilize the signal parameters of this kind.
UMC is providing signal parameters of specific ADRs of specific drugs to companies as pay service.
In the US, there are companies which provides additional information signal index from the dataobtained from FDA. In Japan, Japan Drug Safety Research Unit will start a business to provide abrochure to summarize the result of the above mentioned method applied to spontaneous report data
published on Website by OPSR.
In Western countries, case control studies are carried out after signal detection concerning such issues
as Ryere’s syndrome. Many observational studies have been carried out as shown in appendix to
Section 9 of Detailed Discussion(not shown). Only a few studies are carried out in Japan except forthe study of relationship between development of haemorrhagic gastrointestinal ulcer and NSAIDs7)
conducted by Asaki et al7). Case control studies are often conducted as investigator initiated studies in
the West. It is recommended to improve environment to conduct studies as indicated in Section 1 and
4 of Detailed Discussion and to enhance interests of health care providers in safety surveillance.
Many safety studies are carried out using database in the West. There are opinions indicating thatcase control studies cannot be conducted in Japan since databases are not provided. As discussed in
Section 9 of Detailed Discussion, databases are not perfect even in the West and they are always usedwith compensation for their defects. Recently, studies have been started by utilization of electronic
data of hospitals, such as a study concerning ACE inhibitors and senile pneumonia conducted by
Okaishi et al8), a study concerning Ca antagonists and myocardial infarction by Ohyama et al9). Suchstudies are expected to increase in future. It is difficult to conduct such studies smoothly without- 22 -

cooperation among departments of hospitals for hospital based studies and without cooperation from
community for community based studies. Not only medical but also social and national consensus isnecessary to conduct such studies.
(3) Future direction
Observational studies concerning safety have not always had specific reasons of “Why should such
issues be discussed?”. When statistical methods are made practical for signal detection, way tohypothesis strengthening/testing studies and studies to quantitate risk could be clarified, and plan
would be appropriate. In the communication among regulatory authorities, companies andresearchers, if signal parameters are used commonly, safety surveillance system could be developed toa system different from current one, its transparencies could be increased, and it could respond tosocial needs sufficiently. The contents, scope, methodology, etc. of information disclosure will beconsidered in the following sections of Detailed Discussions.
(4) Recommendation: Following items are requested to intensify safety surveillance along withthe recommendations a-e in Section 6 of Detailed Discussion
1.
2.

3.

Regulatory authorities should recognize significance of statistical signal detection, and conduct
research for practical use of the parameters or support/promote such research.
Observational studies to strengthen/test hypothesis, especially case control studies should be
developed. These kinds of safety studies should be included in (3) of Section 1of Detailed
Discussion (public organizations select and organize tasks of PMS outside of companies.)
Signal detection and case control studies should be included in (3) and (4) of Section 4 of
Detailed Discussion (education and postgraduate training).

- 23 -

8. Issues on cohort study
CEI is regarded as follow-up investigation implemented to avoid intentional case selection in actualuse of the drug. It is regarded as a cohort study although there is no control group. Similar
investigation in special subjects is SI (special investigation) , and this is also a cohort study. Thoughsuch recognition may not be common, a cohort study is a significant method to strengthen and test
hypothesis, and it should be conducted scientifically and to fulfill its objectives.
(1) Necessity
Because progress of clinical studies in Japan is slower than the West in spite of various measures ofpromotion and improvement, number of Japanese subjects could be less when international
development is adopted, and development of products using bridging overseas data is increasing. It
may be necessary to add patients after launch, and there may be a challenge in cohort study to confirm
that the result of clinical trials in overseas is applicable to a domestic population with the samebackgrounds. Therefore, companies should conduct cohort studies as PMS, after consistent plan isestablished throughout before and after launch.
In clinical trials of development phase, infants, elderly patients and patients with special backgrounds
such as concurrent disease are often excluded from the studies, and efficacy and safety information of
concomitant therapies is not sufficient. Well planned cohort studies are effective to collect suchinformation. Because it is significant task of not only companies but also health care professionals tounderstand actual use of drugs in early phase of post-marketing, and to link the issue obtained in such
period with the information on appropriate use, cohort studies should be carried out in the manner
appropriate to the research objectives.
Spontaneous reports should be extended and intensified to detect serious unexpected ADRs. It isnecessary to understand number of subjects who are given the drug to find incidence of ADR/AEs
including expected ones by using cohort studies.
(2) Current issues
When SAMM Guideline (Guidelines for company-sponsored safety assessment of marketed
medicines) was being prepared in UK, several issues were discussed on cohort studies which follow
up registered drug users. Background of this discussion may include confusion with clinical trials
without control group, and inadequate understanding of characteristics, objectives and methods ofobservational studies. It includes following issues, which may be applicable to Japanese situation.
•

Studies including control groups are few, but comparison is essential to test causal relationshipbetween an AE and a drug. Comparison is desirable in studies to understand incidence of usual
ADR/AEs. Comparison of profile of incidence showing what ADR/AEs are frequent/rare in which
drug, will become review material of causal relationship, and also useful as information on theappropriate use to select pharmacotherapy.
• A drug prescribing for research purpose is intervention to treatment. As studies under actual
practice, intervention should be avoided by registering patients after prescription without exception,and inclusion/exclusion criteria should not be established. The patients are excluded only whenadministration of the drug is contraindicated to them. Although sequential registration in CEI is athoughtful method to avoid selection bias, actual condition should be examined whether theregistration is being carried out as planned, and whether bias could be avoided when theregistration is carried out appropriately.
• Results of cohort studies conducted by companies are scarcely published. Even if they are
published, the publication is late. There are no occasions to be criticized from relevant groups,
even if the results are actively published on medical journals, therefore, improvement of the study
method does not progress. Cleaning case report forms of CEI and SI and preparation of reexamination require enormous amount of time and resources. The issues that too muchinformations are included and the meaning of the investigations are ambiguous, may cause the factthat results are not published. It is time to review how PMS should be established by considering
the fundamentals of method for objectives.
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(3) Actions toward improvement
Obligation for companies to conduct 3,000 cases of CEI was abolished, but necessity of appropriate
cohort studies still exists. Companies have to conduct studies not in compliance with regulations but
by selecting methods of cohort studies according to the objective. At present, most of such studies
will be carried out by companies, however, such studies could be conducted by groups outside ofcompany and caution for the current issues discussed above should be necessary for studies conductedby outside of company as well as by companies.
Concerning issues of intervention and selection bias, retrospective study is one of the measures to betaken (Section 5 of Detailed Discussion). To make such studies feasible, it is expected that database
discussed in Section 9 of Detailed Discussion is established as soon as possible. In prospective
studies, it should be mandatory to select subjects after prescription, and methods of PEM(Prescription-Event-Monitoring) should be referred.
Although publication and disclosure of results is not issue only for cohort studies, results can bereferred to appropriate use of drugs if data are accumulated in each area and can be accessed byanyone. CEI data on more than 800 drugs and more than 7,000,000 patients have been alreadyaccumulated in regulatory authority. According to a study conducted by RAD-AR council in which
CEI data of several antihypertensive drugs were accumulated, useful information for appropriate use
could be obtained. In the future, it should be confirmed whether similar methods is applicable todrugs of other classes, and data should be accumulated in database which can be used at any time after
re-examination is finished.
When publication/disclosure become mandatory, quality of the study becomes concern and it thenwill be improved. Standardization of each area will be proceeded. When study results are published,
the data can be used as “historical control” of future studies, and it is useful for studies without control
groups.
(4) Recommendation: to make cohort study as potent method of PMS
CEI and SI are regulatory terminology which are not applicable internationally. As in Section 5 of
Detailed Discussion, the terminology for the methodology should be used and it is recommended touse as “cohort study”. Cohort study should be used as potent method of PMS as follows.
1. Guideline should include that intervention and selective bias should be avoided in cohort studies,and that control group should be put in the study if possible.
2. When a company plan a study in which the control group consists of users of other drugs inactual practice , mechanism to avoid bias should be established including consignment to a third
party.

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9. Issues on establishment of database
PMS observational studies can be conducted retrospectively with utilization of already accumulated
medical records. In the West, many studies are carried out by using database established in local areaor hospitals.
(1) Necessity and availability
Prospective studies require period to follow up subjects and to collect data, but subject follow-up is
not necessary in retrospective studies using accumulated data. Period of retrospective studies can beshortened, if medical records are input into study database, and the data such as disease names areaccurate and good quality with efficient data collection. It is specially effective, when a safety study
requires its result promptly.
Observational studies without intervention can be conducted, if database sufficiently reflects actual
drug use, and data is extracted carefully. Observational studies of high accuracy and quality on both
efficacy and safety are possible by a large scale study involving many patients and community people,
and such studies are specially effective for case control study of rare serious AE cases.
(2) Issues in the past and at present
From 1993 to 1996, MHW scientific research concerning database was conducted, but it did not leadto establishment of a database unfortunately. The time was not right for such initiative because
experience of observational studies was lacking and necessity of the database was not recognizedwidely at that time. However, observational studies have gradually increased and it seems that theopportunity is coming.
Concerning the use of hospital information system, case control studies have been carried out by
Okaishi et al8) for ACE inhibitors and senile pneumonia, and by Ohyama et al9) for Ca antagonist andmyocardial infarction. Workshop committee of our society conducted a drug utilization study14) ofantihypertensive and antibacterial agents. However, all of the studies are carried out in a single
medical institution with small scale and number of subjects in case control studies is small. In
addition, arrangement of data in communities has not yet advanced.
(3) Factors hindering arrangement of databaseIn the West, regional and hospital medical data are input into databases in cooperation with public
medical assurance (Medicaid), Health maintenance organization (HMO) and general practitioners,
and such databases contribute to PMS. However, there are some defects and difficulties relating tocreation in these databases, and there is no ideal database yet. Problems occurred during or after
creating such database are listed below. The situation is same in Japan. Databases should be createdafter overcoming difficulty, maintained and used with understanding and compensating their defects.
•

•

•
•
•

Cooperation of multiple hospitals is desirable in hospital information system. Standardization ofdata contents and their maintenance in each hospital is necessary in the first place. Standardizationof data and standardization after data-integration are difficult when data are integrated among
multiple hospitals and general practitioners, however, it will serve more practical use once
integrated.
When original systems are intended to improve daily routine work concerning payment andhandling of health insurance, etc are integrated for research purpose, there are many issues whichshould be overcome to integrate data for research purpose, such as data format and barrier between
administration bodies.
When medical and pharmacy data are integrated, age, sex and physician’s name are used as key
items to make record linkage, but complete linkage is difficult when private information isprotected.
When integration of different information systems is necessary, more advanced breakthrough of
IT technology is required than that in single system.
There is more or less bias between registered members of database and whole population.

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•All data such as disease name of health insurance are not always correct, and it may be necessary
to confirm the data and supplement them for implementation of appropriate studies by examining
the initial data such as patients’ medical records, etc.
• Hospital data include serious event data, but they often do not include symptoms in many cases.
• Because people may take the health insurance and may withdraw from it for their reasons,constituting members of a database may change. Some of them cannot be followed up. It may benecessary to make efforts to establish linkage to national/regional death/disease registration.
These problems can hinder creation of database, but related organizations must commonly recognize
significance of database creation, cooperate each other and make efforts to solve above problems.
Improvement of defects is eternal issue. GPRD was established as VAMP in 1987, and experienced
several large-scale revision, and is existing as current GPRD. MCA maintains and improves GPRD.
Companies can use it under certain conditions, if it is used for research purpose. It is available toforeign companies.
(4) Future direction
Hospital information systems are rapidly advanced in Japan. Integration of multiple hospital systems
is considered to be the earliest way of developing a database. Concerning regional data, electronic
medical record transfer is being attempted between large hospitals and regional clinics such as
International Medical Centre and Shinjuku-ku, Chiba prefectural Togane Hospital and Yamatake-area,
Kumamoto University and Kumamoto City in cooperation with Medical Information System
Development Centre. Development of regional database and use of such data for PMS are expected.
Medical fee bill receipts including broader drug use are important PMS data source. System shouldbe established within several years to advance computerization and to describe accurate disease names
related to comprehensive medical care, as well as to complete database for PMS.
(5) Recommendation: Towards establishment of database
It is recommended to incorporate data of medical practice into database to utilize it for observation
studies of PMS.
1. Some leading body should be established in regulatory authorities or their related organization toestablish database by building a system with financial support and with cooperation from
regulatory authorities, medical institutions, health insurance societies, academic societies andcompanies.
2. Maintenance and improvement of database should be conducted by a neutral, non-profitableorganization and by public funds. The organization should be managed to accept access fromoutside organization such as companies under a certain condition.

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10. Issues on clinical trials
Clinical trials have the leading role in new drug development. In PMS, randomized clinical trial(RCT) may be used as an efficacy study. RCT is mainly focused in this section, however, its nature in
PMS is different from that in development phase.
(1) Necessity and importance
Efficacy in long term use of a drug and concomitant use with other drugs are not yet confirmed inmany occasions before marketing. RCT in PMS is necessary for statistical testing of hypothesis
concerning efficacy. Results are important as reference for appropriate use of drugs.
(2) Epidemiological nature
Comparability between groups to be compared and internal validity in RCT are satisfied with random
allocation. In PMS, generalizability that the results of statistical test are applicable to common
medical practice, i.e. external validity (See Section 5 of Detailed Discussion) should be considered.
Therefore, subjects well representing source population such as hospital or region should be selected.
(3) Characteristics as long term large scale study
For example, in a study of an anti-hypertensive drug to test preventive effect on cardiovascularcomplications, the primary endpoint is changed to “true endpoint” of occurrence of complications
after launch from “surrogate endpoint” of anti-hypertensive effects used in the study before approval.
Therefore, in many cases, RCT in PMS requires much longer follow-up period than before approval.
When decrease of AEs including complications is expected, the study may become a prevention study,
but in many studies, many patients are required due to low incidence, then it has characteristics oflong term large scale study. For example, in US ALLHAT15) study, 33, 357 patients were followed up
for a mean of 4.9 years, and in WHI16) study, 16,608 women were followed up for a mean of 5.2 years.
In most RCTs before approval, reference drug is limited to one drug. In medical practice, many drugs
were compared relatively, or comparison of combination therapies is sought in studies of
prevention/treatment of cancers and life-style related diseases, etc. Therefore, it is difficult to conduct
such studies by one company. Number of group and patient number may increase if treatment arms
include non-treatment and/or placebo. Thus the study could become large-scale.
Long term and large-scale studies should be planned as simple as possible having “simple large”
characteristics are desirable. It is important to realize generalizability and feasibility. All RCTs of
PMS are not long term large-scaled studies, and RCTs similar to those before approval such as studies
to add new indication conducted by companies are also conducted in PMS, but attention to
generalizability should be necessary.
(4) Relationship with safety evaluation
Observational studies are considered as the first choice for safety studies, especially for studies ofserious AEs, however, differential use with RCT should be agreed by experience retention. Efficacy
studies of the primary or the secondary prevention expecting decrease of AEs are possibly conductedwith RCTs, but hypotheses expecting decrease of AEs are not always reliable, and it is difficult todetermine study method. Interim analysis should be carried out in consideration of possible
unexpected outcome, and examination is necessary for continuation of the study or change of thestudy plan in view of the interim analysis result.
In long term large scale studies, primary results on efficacy are most interested, but safety data as wellas primary endpoints should be carefully examined. Although efficacy endpoints may be different
among studies, safety data could be generalized and evaluation of AE grading should be standardized
to make comparison with other studies or to make comprehensive evaluation possible.
(5) Quality of the studies and data
Quality of long term large scale studies is evaluated according to elements such as whether theobjective was appropriate as PMS, whether the study has generalizability and comparability, whether- 28 -

the study was planned according to the principle of “simple large”, and whether the study was
conducted according to the plan and analyzed according to the principle of ITT (intent-to-treat).
In a study for a new indication conducted by a company, quality of data is assured by quality
assurance system which is standardized in conformity with GCP, and quality control activities inoperation. Inspection of the data is carried out at the study sites. Such standard does not actuallyexist in studies outside of companies, but even if a study is not related to NDA approval, the study
should be conducted with the procedures and written documents controlling plan/implementation of
the study and data collection/analysis. The study coordinators are necessary at study sites, but
qualified persons for this role are insufficient.
While long term large scale studies should also be conducted in conformity with GCP, detailed
procedures specified in GCP is not appropriate for the principle of “simple large”. Quality assurance
method considering balance with cost is necessary.
(6) Current situation in Japan and actions toward improvement
Long term large scale studies have just started in Japan, and experience of such studies is scarce.
However, public organizations and the third party organizations such as NIH and SWOG in the US,
and MRC in UK are operating such studies including management of plan and implementation, andanalysis/evaluation and publication of their results. Evidence of long term prognosis is essential for
improvement of public health, and development of clinical studies in PMS in Japan is necessary forevaluation of drug efficacy in prevention of cerebro/cardio-vascular diseases and life-style relateddiseases and for cancer treatment in Japanese population.
(7) Recommendation: It is recommended to take following measures in addition to 1-4
proposed in Section 1 of Detailed Discussion in order to develop clinical trials required in
PMS
1.

2.

A role of clinical study coordinator who is in charge of management of a study and quality
assurance of data should be established, and fulfillment of education and training to develop
qualified persons, and assignment of such persons to medical institutions and accumulation of
their experience in medical institutions should be sought.
In a long term large-scale study, idea of “simple and large” should be applied in plan,
implementation, management and analysis. Especially for quality assurance of data andinspection, caution should be given to balance between its implementation and cost, and it ispreferable to standardize the procedure with emphases on essential data related to primary
endpoint, significant baseline parameters and SAEs.

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11. Issues on meta-analysis
Each clinical study may have insufficient statistic accuracy and power, so that results may vary
among studies. In such condition, definitive result may not be available by individual studies. Metaanalysis is an analysis method to integrate existing study results to compile conclusions in suchsituation. When the method is used appropriately, it can be effective to confirm evidence of efficacy
and safety in PMS with the objective of appropriate use of the drug.
(1) Current situation
Meta-analysis is utilized for medical technology assessment in view of public health, and for decision
making in diagnosis and treatment of individual patients in clinical epidemiology. The concept ofchoosing pharmacotherapy to a patient based on appropriate evidence is clinical epidemiology, and it
is recently called EBM. This is linked to appropriate use. Meta-analysis has been mainly applied to
RCT to evaluate efficacy, however, it is also applied to evaluation of safety and observational studies
recently. Examples of such studies include a study17) merged with RCT suggesting safety issues that
nifedipine, a Ca antagonist, may increase risk of death dose-dependently, which was carried out as thesecondary prevention study of coronary artery diseases, and studies18), 19) of merged analysis ofmultiple observational studies concerning risk of breast cancer in oral contraceptives and hormone
replacement therapies.
(2) Issues and actions toward improvement
Following remarks should be taken into account to apply meta-analysis to observational studies:
1) Excessive expectation for estimation of overall index which indicates relationship between a drug
and an AE should be avoided.
2) Meta-analysis should be utilized for comparison of data between studies and analysis of different
results due to various factors, rather than to estimate overall risk index.
3) A score to evaluate quality of studies should not be used for selection of studies to be included.
This is also applicable to intervention studies. It may be related to the ex post facto feature of metaanalysis.
Above 1 and 2 explain the possible risk that meta-analysis may merge results of analysis given in
published literatures with stereotyped procedures and merged result is considered as absolute truth. Itmeans that when similar results are merged, the merged result would be estimated as a matter ofcourse. Points to be considered are regional difference of the subject population in studies,differences in results according to sub groups, and issues insufficient as evidence which require
further study. When homogeneity/heterogeneity of methods and results by individual studies arecarefully examined, deeper insight about study objective and result could be obtained compared to asingle study, and important suggestion could be provided to future study plan.
Meta-analysis retrospectively utilizes preexisting studies, and for PMS, which gradually accumulates
appropriate use information, it has greater significance in prospectively deciding the direction of
future studies. With regard to merger of published literature, the analysis mentioned in 2) above tends
to be insufficient, but, when researchers who conduct the studies combined their raw data together,significant analysis to determine future direction of the study is available. Ideally, investigators’
groups would proceed their own studies by placing meta-analysis in between.
3) mentioned above is related to the issue of selection bias. Publication bias that unpublished study
result can never be obtained has been always pointed out. 3) mentioned above is also related to issuesof evaluation bias. If selected studies include only studies having good quality, new bias may occur.
US Preventive Services Task Force has discussed this issue20).
If there is a trend that studies which resulted in unexpected results did not meet expectation or ended
incompletely with unclear results are scarcely published, it may cause publication bias. It is difficult
to solve such issues which are affected by the conscience of investigators and sponsors. Cause of the- 30 -

incomplete result lies in quality of individual studies but not in the meta-analysis (See Section 5 and
10 of Detailed Discussion), and it should be traced back to planning phase of individual studies suchas patient numbers.
Issues of publication bias are especially significant in safety studies for which transparency is required.
Meta-analyses have been carried out mainly to clarify effects of pharmacotherapies, but the methodshould rather be used to evaluate safety information in the studies of less frequent AEs. To utilize themethod to evaluate safety, it is necessary to standardize safety data including AEs in each study, andto widely publish the study results.
When quality of studies is the issue concerning 3 above, sensitivity analysis to examine change of themerged results, when selection range was changed, may be possible, but it is retrospective. When thegroup of investigators conducts studies of good qualities prospectively, and brings standardized data
together, it would be effective measures for selection bias.
(3) Perspectives
Concerning anti-hypertensive drugs and anti-platelet drugs, meta-analyses have been carried out inforeign countries, and such studies have affected on the use of drugs in Japan, but the meta-analyses
scarcely include Japanese studies. It is obvious that caution is required in terms of differences indrugs, dosages, and ethnic difference of metabolic enzymes to evaluate overseas study results in Japan.
Fundamentally, it is unreasonable to use merged results which do not include Japanese data and many
useful studies should be conducted in Japan regardless of issues concerning meta-analysis.
When Japanese studies increase, the data could be included in overseas meta-analyses. It is also
possible to conduct meta-analysis using Japanese data or data combined with overseas data in Japan.
Meta-analysis taking care of the issues 1), 2) and 3) in (2) above is important method to seek evidencein PMS, and it should be applied to safety studies. Quality of the studies can be improved by merging
studies, and it may progress standardization. Feed back between individual studies and meta-analysis
may contribute to development of PMS.

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12. Issues on ethical principles
The Declaration of Helsinki includes ethical principles of medical studies such as prevention of healthhazards of subjects including patients, protection of dignity, rights and privacy of individuals. ICHGCP discusses principles of clinical trials with drugs.
These principles are related to individuals, but PMS which aims establishment of appropriate use ofdrugs has public ethics such as feedback to national health services. Ethical issues of PMS lie in the
points between the aspects to provide precise information to society and to protect individuals. It
means that it is the premise to consider individual ethical issues that the study objective necessary for
appropriate use should be selected, the study is planned and implemented with scientifically soundmethods, and the result should be publicized or disclosed.
(1) Current situation
In Jun 2002 “Ethical guideline of epidemiological studies” of MECSST and MHLW was enforced.
Expert committee of clinical studies is discussing “Ethical guideline of clinical studies” While theprinciple of PMS has not yet been established, when the study methods are categorized into
epidemiological observational studies and intervention studies according to Section 5 of Detailed
Discussion, ICH-GCP or ethical guideline of clinical studies could be applied to clinical trials. Whenethical guideline of epidemiological studies are applied to PMS observational studies based on
pharmacoepidemiology, characteristics of pharmacoepidemiology or PMS should be considereddiscussed as follows:(2) Nature of PMS compared with other epidemiological studies
Primary target of Ethical guideline of epidemiological studies is considered to be prospective regional
cohort studies, and case control studies concerning outbreak of some disease. Focuses of these studies
are risk factors such as lifestyle, are risk factors such as life style, environmental factors or genes.
Major concern of a clinical epidemiological study collecting hospital information of multiple site isefficacy of a treatment or long term prognosis.
On the other hand, for PMS, such as prospective pharmacoepidemiology studies with marketed ethicaldrugs and pharmacoepidemiology studies using database, it seems that ethical guideline of
epidemiological studies is not intensely considered. Risk factors which PMS handles are marketeddrugs which are subject of regulation. It has following characteristics compared to the above common
epidemiological studies:• The marketed drugs, which is a risk factor, could be withdrawn from market with the discretion ofregulatory authority.
• Exposure to the risk factor may occur when specialists of physicians who expect effects
intentionally prescribe or administer the drug.
• Marketed drugs, which are risk factors, are commonly prescribed within the frame of national
health insurance in Japan.
• The guideline specifies the informed consent is not necessary for observational studies where only
existing data is used. The concept of “existing data” is often ambiguous in PMS. Data in databaseis, of course, existing, but data collected in routine examination in prospective PMS and in drug
compliance instructions from dispensing pharmacies can arise even if the PMS is not conducted,
therefore such data may be considered as existing data.
• PAL revision made the ADR reporting obligatory to health care professionals.
Discussion of ethical committee and protection of private information such as names, birth dates, sex
and address, etc should be handled with caution as same as those in common epidemiological studies.
Anonymity without linkage is preferable in database. Anonymity with the link of unbiased person isconsidered appropriate in studies having possibility of follow-up examination.
(3) Recommendation
It is recommended to specify ethical principles in conformity with “Ethical guidelines for
epidemiological studies” as follows:- 32 -

1.

2.
3.

4.

While case control studies with control arm of general population require consent fromindividuals, activities and studies for safety surveillance such as spontaneous reports and signal
detection, prospective cohort studies, and studies using database do not require consent fromindividuals.
Ethical committee should be required, but it is not required for studies conducted with different
drugs in similar system.
Concerning 1 and 2 above, “Ethical guidelines for epidemiological studies” is requested to berevised. Exception for disease based system such as cancer and additional description to avoid
inconsistency should be considered.
“PMS guideline” should be prepared in conformity with the ethical principles and scientific rules
in Section 5 of Detailed Discussion.

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