著者用Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

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Points to Consider for Operation andManagement to Ensure the Reliability ofRegistry Data for Use in Application Dossiersof Pharmaceuticals and Medical Devices［March 31, 2022 Ver1.0］

AMED Research on Regulatory Science of Pharmaceuticals and Medical Devices
Title of Research Project: Regulatory science research to achieve efficiency ofclinical research and development with the utilization of a patient registry［Grant Number: JP21mk0101154］

Subproject Title: Review of the quality management system and points to consider
Representative, Subgroup for“Review of the quality management system and points to consider”:
Hideki Oi（National Center of Neurology and Psychiatry）
Principal Investigator: Taro Shibata（National Cancer Center Japan）
Table of Contents
1．Introduction
2
2．Objectives and background of this proposal
2
3．Scope2
4．Objectives and background of patient registry establishment and operation（academic viewpoint）
3
5．Environment considering the use of patient registry data as application data
for the marketing approval of drugs, etc.
45.1 Circumstances in Japan4
5.1.1 Clinical Innovation Network（CIN）
4
5.1.2 Guidelines studied by the PMDA
4
5.2 Circumstances outside Japan4
5.2.1 Foreign regulatory authorities
4
5.2.2 Medical device field
5
5.2.3 Pharmaceutical field
5
6．Operation/management helping to ensure data reliability in the utilizationof patient registry data as application data for marketing approval ofdrugs, etc.
7
6.1 Items concerning patient registry design/operation（relationship between medical institutions and patient registry holders） 7
6.1.1 Purposes of primary studies related to registry establishment
7
6.1.2 Quality control of data
7
6.1.3 Quality assurance of registries8
6.1.4 Rules and operating procedures for primary studies related toregistry establishment
8
6.1.5 Considerations for personal information protection in primary studies

related to registry establishment
8
Costs of primary studies related to registry establishment and burdenof expenses
9
6.2 Matters required to determine that the reliability of information presented
in application data/documents is ensured at a sufficient level in lightof its intended use（relationship between the patient registry holder andthe applicant）
9
6.2.1 Protocols of studies using registry data, consent, and opt‒out
96.2.2 Data management procedures/plans for studies using registry data
96.2.3 Procedures/plans for ensuring data reliability of studies using
registry data（e.g., monitoring procedures/plans）
10
6.2.4 Statistical analysis procedures/plans of studies using registry data
10
6.2.5 Study reports of studies using registry data
10
6.3 Matters required to determine that the reliability of information presented
in application data/documents is ensured at a suf ficient level in light of its
intended use（relationship of the applicant to the application data/documents） 10
6.3.1 Standards of reliability of application data
10
6.3.2 Regulatory grade
12
6.3.3 Significance of PMDA consultation system related to registries
16
6.4 Other points to consider
17
6.4.1 Securing the transparency of research funds and management ofconflict of interest
17
6.4.2 Coordination of consortium activities and stakeholder management 17
7．Summary18
References
18
6.1.6

（Note）This document was prepared by the research team by compiling the research results from fiscal years 2019 to 2021.

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Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

1．Introduction

Pharmaceutical regulatory schemes concerning real‒world medical data and evidence（hereinafter referred toas“medical RWD/RWE”）, and derived from their analysis, have been undergoing remarkable changes considering both the development and post‒marketing phases ofdrugs, medical devices, and regenerative medicine products（hereinafter referred to as“drugs, etc.”）.1）
For the clinical development of drugs, etc., the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use（ICH）has
proposed the“GCP Renovation,”2）which includes themodernization of the E8 Guideline and subsequent revision of the E6 Guideline. According to the Concept Papers
and Business Plans issued in November 2019, the revised
E6 Guideline covers clinical studies incorporating pragmatic clinical trials and decentralized clinical trials in
Annex 2. In the US,“The 21st Century Cures Act”3）refers
to the proposal of speeding up the approval review bymaking clinical trials more efficient. Moreover, in somecases medical R WD/R WE was used in the approval
review for the expansion of applications. Also, in Japan,
the Clinical Innovation Network（CIN）
plan4）was proposedby the Japan Revitalization Strategy（Cabinet Decision
dated June 30, 2015）; furthermore, utilizing the natural
history data of patient registries as the control group inclinical trials for an approval review is now under consideration.
With regards to post‒marketing sur veillance, theimplementation of a conditional accelerated approval system for pharmaceuticals5）positioned medical RWD/RWE,
such as the medical information database network（MID‒NET）project6）and patient registries, as sur veys that
require implementation for marketing approval. Moreover,
the Ministr y of Health, Labour, and Welfare（MHLW）
ordinance related to standards for conducting post‒mar7）
provided a new
keting sur veys and studies on drugs”
post‒marketing database study, which was conductedusing medical databases like MID‒NET, and by utilizationof medical RWD/RWE for post‒marketing pharmacovigilance.
Additionally, concerning the utilization of registr ydata for regulatory purposes, basic principles on the utili8）
zation of the registry for applications”
and points to beconsidered for ensuring the reliability in the utilization ofregistry data for applications”9）were investigated by the
Pharmaceuticals and Medical Devices Agency（PMDA）
and issued by the MHLW on March 23, 2021.
This document aims to propose specific measures toensure the reliability of regulatory purpose utilization ofespecially“patient registry”data from medical RWD/RWE
s130

that were discussed by AMED/Shibata Group（CIN）.
2．Objectives and background of this proposal

The challenges in the utilization of patient registr ydata for regulatory purposes seem to be barriers between
the Pharmaceutical and Medical Device Act（ICH）and
ethical principles concerning life science and medical
research. These could be barriers on the regulatory side
as well as on the side of researchers. Similarly, there could
be a difference in understanding among interested parties
concerning“drugs”and“medical devices.”
To overcome such barriers and promote the utilization of patient registry data for regulatory purposes, this
proposal aimed to demonstrate the conduct of primar ystudies related to registry establishment, which could contribute to assuring the reliability of registry data, strategies of operation and management, and specific examplesof registry data utilization.
The“Handbook on the establishment and operation（hereinafter referred to as“Kokudo
of registries ver. 1.0”
10）
was created by AMED Kokudo
Group’s Handbook”）
Group（CIN）, considering that it would be utilized for an
academia‒based general patient registry, and not for regulatory purposes. The Shibata Group investigates the utilization of registry data for regulatory purposes, which has
not been referred to in Kokudo Group’s Handbook.
3．ScopeThis proposal is applicable not only to medical RWD
from patient registries（e.g., disease and product registries）, but also to the other medical RWD considering thedata source of patient registries such as electronic medical
records and electronic patient‒repor ted outcomes（ePROs）. The target diseases include rare diseases（rarecancers, rare intractable neurologic diseases, pediatricdiseases, etc.）, wherein conducting conventional randomized controlled trials（RCTs）is challenging; or diseases
wherein conducting placebo‒controlled studies are ethically challenging. Registry data could be used for regulatory purposes: 1）as an external control of clinical studies
for efficacy and/or safety evaluation in applications; 2）tocomplement or substitute clinical studies for efficacy and/or safety evaluation in applications; and 3）in the evaluationof drugs and medical devices with conditional approvaland of regenerative medicine products with conditional
and time‒limited approval. However, the abovementioned
scope should be flexibly revised based on various technological innovations and the development of regulatory science in the future.

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022
4．Objectives and background of patient registr y establishment and operation（academic viewpoint）

As in Kokudo Group’s Handbook,“registry”is a term
widely used in the fields of medicine and healthcare, but it
has no consistent definition. Kokudo Group’s Handbook
cites the following definitions presented by the US Agency
for Healthcare Research and Quality（AHRQ）“A: patientregistr y is an organized system that uses obser vational
study methods to collect uniform data（clinical and other）
to evaluate specified outcomes for a population defined bya par ticular disease, condition, or exposure, and thatserves one or more predetermined scientific, clinical, or
11）
Also citing other several definitions,policy purposes.”
Kokudo Group’s Handbook defines a patient registry as“asystem that collects medical information or health information on particular disease, disease group, health condition or exposur e, or a database established by it.”
Although not specified in this definition, registries generally use observational study approaches, as defined by the
AHRQ. Obtaining some outcome requires continuous datacollection, and therefore, prospective cohort or retrospective cohort approaches are likely to be applied as a study
design. The PMDA has investigated two guidelines, inwhich a registry is defined as“a systematic system to collect standardized data to evaluate specific outcomes
related to the following matters: the specific disease, theuse of drugs, medical devices and regenerative medicine
products, etc. or the populations defined by specific conditions（e.g., age, pregnant women, and specific characteris. Registr y data may be prospectively
tics of patients）
obtained or retrospectively used”. Most Use‒results surveys conducted for drugs and medical devices based on
the Pharmaceutical and Medical Device Act are, althoughoften not clearly recognized, have a design that can be
regarded as prospective cohort or retrospective cohort,
substantially similar to registries.
The characteristics, purposes, etc. of registries havealready been detailed in Kokudo Group’s Handbook. The
handbook describes various purposes of registry, including description of natural history of disease, assessment ofclinical practice, and evaluation of clinical usefulness andcost‒effectiveness. To achieve these purposes different
from those in interventional studies, registries are often
different from interventional studies in terms of research
protocol and operation: for example, registries for patientswith particular diseases or patients receiving a particular
medical technology are designed to enroll as many
patients as possible comprehensively without stringent
exclusion criteria; test data, which is unlikely to beobtained from all patients but is valuable even in a small
number of cases, is also included in the data collection

3

item; and management is performed for a long time withfew funds. Due to these characteristics, there may be
which are generally regarded as weaknesses in data quality control: for example, it is difficult to collect all data
without exception; occasionally, the primary outcome cannot be collected, and high‒quality and high‒cost systems
as recommended by interventional studies cannot be used
due to a low operating budget. In addition, even if patientregistries are comprehensive, the collected data may contain systematic bias for various reasons, including participating sites, budget, medical insurance covering of target
diseases, and method to provide incentives for registration.
Therefore, it is true that registries are more likely tohave characteristics that could be viewed as defects inquality control compared with interventional studies conducted under strict regulations, such as the Pharmaceutical and Medical Device Act. However, registries have been
regarded as an effective method of evidence accumulationin clinical practice where interventional studies are virtually impossible to be conducted. Even now, registries are
an important research approach, especially in the surgicalfield, including emergency medicine and medical transplantation, and in the field where the number of patients isextremely small, such as intractable diseases and rare diseases; they are also used for formulating clinical practiceguidelines. Recently, measures for the establishment andoperation of a reliable and good‒quality registr y havebeen considered. The AHRQ has published“Registries for
Evaluating Patient Outcomes: A User’s Guide”in 2007.
The 1st and subsequent editions refer to registry“Quality,”and the 3rd edition states“As a general rule, quality
should be evaluated by elements that directly impact theability of the registr y to achieve its main objectives. In
other words, a registry must be fit for its purpose”andpresents“essential elements of good practice”at eachstage of research designing and implementation. In 2018,a European group also released recommendations for
improving the quality of disease registries,12）providing a
total of 17 recommendations in terms of 11 elements,
including the registr y definition, classification, governance, data source, case report form, data standardization,
IT infrastructure, and data quality（Figure 1）. Presumably, in the discussion of registry“quality”based on these,
it is preferable to aim for the academic“fit‒for‒purpose”
quality control that each registry originally aims at, rather
than applying the“one‒size‒fits‒all”rule, and it is necessary to consider the balance of various elements associated with individual registries. Discussions that contributeto the improvement of the registr y quality as a whole
while keeping an eye on the recent activities of researchs131

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1．Establishment of a good governance system
2．Identification of the right data source
3．Development of data elements, case report form, andstandardizations

・Developing adequate documentation
・Training staff

4．Construction of a suitable IT infrastructure complying
with the“FAIR”principles

・Providing data quality audit

5．Production of data quality
6．Dissemination of a quality informationNote）“FAIR”: a set of four principles（Findable, Accessible, Interoperable, and Reusable）for humans andcomputers proposed by FORCE11 to describe how open data should be made public.
Figure 1

A framework for the quality management of rare disease registries（modified from Reference 12）

ers aiming to impr ove the quality of r egistries ar e
expected to help further improve medical standards inareas where interventional studies are difficult.
5．Environment considering the use of patient registr ydata as application data for the marketing approval ofdrugs, etc.
5.1 Circumstances in Japan
5.1.1 Clinical Innovation Network（CIN）

The Clinical Innovation Network（CIN）is a schemethat aims to improve the clinical development environment to facilitate efficient implementation of clinical trials/
studies by using the information on various diseases registered in disease registration systems（patient registries）,
etc., with the collaboration of relevant organizations. The
CIN was selected as one of the 2020 Japan Challenge Projects and as a specific scheme for the“Japan Revitalization
Strategy Revised in 2015 and 2016”and“Future Investment Strategy 2017 and 2018.”In the development of new
drugs and post‒marketing pharmacovigilance activities,
new approaches for clinical development and safety evaluation using patient registries have been garnering global
attention. Hence, there is a compelling need to establish a
network of relevant organizations and clinical trials consortium of industries and academic institutions to efficiently use patient registries for clinical trials/studies aswell as for conducting regulatory science studies concerning clinical evaluation methods using patient registry data.
5.1.2

Guidelines studied by the PMDA

The PMDA, an agency in charge of reviews forapproval, re‒examination, and the evaluation of the usage
results of drugs, etc., has established“Basic principles on
utilization of registry for applications”and“Points to cons132

sider for ensuring the reliability in utilization of registrydata for applications,”primarily for companies that could
be applicants for the marketing authorization of drugs,
etc. These notifications were issued by the MHLW on
March 23, 2021.
5.2 Circumstances outside Japan
5.2.1 Foreign regulator y authorities

In the field of medical devices, domestic as well asinternational cooperation has been promoted in terms ofutilization of data other than clinical trial data.
In the regulator y approval systems in the field of
medical devices, wide differences exist among Japan, US,
and European countries. The regional difference is particularly significant in Europe, where CE marking by anauthorized third party is essential; therefore, conducting
clinical trials is not always necessary for obtaining marketing approval. Under such circumstances, the Global Harmonization Task Force（GHTF）was founded in 1992 withthe participation of Japan, US, EU, Canada, and Australia
to promote international coordination. The deliverables of
GHTF are available on the PMDA website. After the dissolution of the GHTF in 2012, the International Medical
Device Regulators Forum（IMDRF）was established to
discuss various issues taken over from the GHTF. The
deliverables of the IMDRF are also available on the
PMDA website. Notably, the Registry Working Group, oneof the working groups of the IMDRF, focused on medical
device related registries, which were initially diverse innature, and summarized discussions on the definitions,analysis methodologies, and qualities of registries used byregulatory authorities.
During the working period of the IMDRF, an article

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

titled“Real‒world evidence―what is it and what can it tellus?”
was published in the New England Journal of Medicine
mainly by persons affiliated with the U. S. Food and Drug
Administration（FDA）at year‒end 2016, which immediately aroused public interest in the concepts of“real‒world.”In 2018,evidence（RWE）”and“real‒world data（RWD）
the medical device division as well as the FDA, as a whole,published the“Real‒world evidence program,”providing
definitions of relevant terms and a summary of basic concepts. In 2020, the European Medicines Agency（EMA）
published a draft guideline on registry‒based studies providing a definition of a registry‒based study and that of apatient registry separately to clarify requirements for registry‒based studies.
5.2.2

Medical device field

In this section, we wish to highlight the achievements of the IMDRF Registr y Working Group, which
worked ahead of other groups for the international harmonization of registries. The IMDRF published three documents presenting a definitions of terms（N33）, methodologies（N42）, and assessment tools（N46）, respectively.
In the N33 document, on the basis of international
harmonization, a medical device registry is defined as“anorganized system that primarily aims to increase theknowledge on medical devices contributing to theimprovement of the quality of patient care.”The document evaluates existing registries after establishing thefollowing indicators to evaluate the effects, value, and sustainability of each registry:（1）device identification data,（2）quality enhancement system,（3）stakeholder identifi（5）timely action,（6）transparency,
cation,（4）efficiency,（7）linkability, and（8）consideration for product lifecycle.
The N42 document summarizes the methodologies of
the international harmonization of registries. With respect
to medical devices, in particular, the same product is usedin dif ferent countries, and could therefore be applied
being aligned with regional registries. The document provides points to consider as well as the advantages and disadvantages considering the above situation. Note that theN42 document discusses registries with a focus on the
total product lifecycle（TPLC）of medical devices, whichis expected to contribute to the enhancement of the availability of information that could be significant evidence fordecision‒making, such as long‒term evaluation, evaluation of outcomes of diseases with a markedly low incidence, and comparative studies of effectiveness.
For cases described in the N33 or N42 document, see
Sase et al.
（2017）13）, wherein the cases are presented.
In the N46 document, seven cases were assumed torepresent categories to be used by medical device regulatory authorities. The document defines a list of require-

5

ments for each categor y and provides recommendationlevels for the discussion/handling of such factors whenrelevant regulatory authorities use registry data
（Table 1；. The seven categories cormodified from IMDRF N4614））
respond to registries having various natures in terms ofrobustness of the registry process. Based on the TPLC,
highly reliable, robust, and appropriate analysis methods
should be used for cases involved in highly sophisticateddecision‒making, such as initial marketing approval.
Meanwhile, there are some other cases for which decision‒making can be undertaken with fewer requirements
depending on the purpose of use, such as finding safety
signals. Although the document defines requirements for
initial marketing approval and additional indications, thisdoes not mean that the IMDRF Registry Working Group
recommends the use of registries in such activities while
preparing the relevant dossier. Attention should be paid tothe fact that the IMDRF Registry Working Group considers the above for limited cases, such as use of a medical
device for a rare disease, or as a simultaneous control in aclinical study for initial marketing approval, and cases
wherein an agreement is reached with relevant regulatory
authority for additional indications, taking account of local
circumstances.
For the respective factors, the definition of the medical device registry established in the N33 document could
serve as a useful reference.
5.2.3

Pharmaceutical field

In the third ICH conference held in Osaka in November 2016, the FDA proposed the renovation of GCP（i.e.,modernization of ICH E8 and continuation of revision of
ICH E6）. In 2017, the ICH headquarters issued a reflection paper on the GCP renovation on January 12 and conducted a public consultation until March 11.
According to a concept paper issued on November
17, 2019, the revised E6 guidelines（ICH E6［R3］）comprises three parts, viz.,“overarching principles”describing
common principles of any type of clinical studies; and twoannexes prepared depending on the type of clinical studies. Study designs such as those of clinical studies incorporating pragmatic or decentralized clinical trials areincluded in Annex 2, which provides points to consider
while conducting clinical studies to enhance generalizability, or while using computerized data sources. The scopeof application of ICH E6（R3）involves inter ventional
clinical studies in principle; furthermore, primary studies
related to registr y establishment, which generally use
observational study methods, are outside the scope. However, it is necessar y to understand GCP renovation toensure data reliability when using patient registry data as
application data for the marketing approval of drugs, etc.
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Table 1A list of requirements（modified from IMDRF N4614））
ELEMENTS

Legend（XX：Highly Recommended/X：Recommended/□：Optional/NR：Not Recommended）
InitialApproval

Broadening
Indication

Post market
study

Postmarket
Surveillance

Developmentof OPC/PG

DeviceTracking

Field Safety
Corrective

XX

XX

XX

X

XX

X

X

Legal requirements for data collection/handling

XX

XX

XX

X

XX

X

X

Information on Patient Data Protection（e.g.
if Exempt from consent, Opt‒out, Opt‒in）

XX

XX

XX

X

XX

X

X

Policy on access to data

XX

XX

XX

XX

XX

X

X

Essential information available for verification by relevant authority（e.g. competentauthority, notified body）

XX

XX

XX

XX

XX

XX

XX

Relevant Variables

XX

XX

XX

XX

X

X

X

Unambiguous Device Identification（preferably internationally recognized UDI system）

XX

XX

XX

X

X

X

X

Deterministic

XX

X

X

X

X

X

X

Probabilistic

NR

X

X

X

X

X

X

Use of Controlled Vocabularies

XX

XX

XX

X

X

X

X

Use of nationally/internationally harmonized minimum data model

X

X

X

X

X

X

X

XX

XX

XX

XX

XX

XX

XX

Conduct of analyses across different types ofanalysis frameworks

XX

XX

XX

XX

XX

X

X

Data Interpretation

XX

XX

XX

XX

XX

X

X

Repor t; Key elements and frequency ofreports

X

X

X

X

X

Website and web‒reporting

X

X

X

X

X

Governance
Governance structure and process
Quality Management System

Data Gathering

Linkability（Registry with other data source）:

Data Storage
Security Protection against hacking, altering, deleting or stealing data
Methodologies Leading to Actionable Data

Transparency/Display/Distribution

XNote）“With intervention（post‒marketing clinical study）”indicates a post‒marketing clinical study defined by the Pharmaceutical andMedical Device Act of Japan or a specific clinical study, etc., conducted within the approved dose and regimen based on the Clinical Trials Act of Japan.“Without intervention（post‒marketing survey）”indicates a use‒results survey defined by the GPSP Ordinance inJapan.

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6．Operation/management helping to ensure data reliability in the utilization of patient registr y data as
application data for marketing approval of drugs, etc.
6.1

Items concerning patient registr y design/operation（relationship between medical institutions
and patient registr y holders）
6.1.1 Purposes of primar y studies related to registr y establishment

As stated in Section 4, there are various types of registries in terms of characteristics and purposes. Whenplanning to start a primary study related to registry establishment, it is important to define the purpose of the study,
identify stakeholders, and clarify their requirements.
Aside from the registry holder, stakeholders may include
regulator y authority, applicant, patients, and research
institutions engaging in data entry.
Even if the purpose of the primar y study related toregistry establishment is defined, it should be consideredthat some registries are established, taking into accountthe following types of registr y use covered by this proposal, whereas some other registries are established without taking them into account:“use of registr y data as
external control, etc., in a clinical study to be used for efficacy and/or safety evaluation in application for marketing
approval, etc.,”“use of registr y data as supplement or
substitution for clinical studies for efficacy and/or safety
evaluation in application for marketing approval, etc.,”and“use of registr y data for evaluation of drugs or medical
devices approved with conditions or regenerative medicine products approved with conditions and time‒limit.”
Just as a registry is newly established for application
for marketing approval, it is important to take into accountthe use of a registr y for approval application from thestage of its designing and, if the purpose of use of the registr y is clearly defined, to have consultations with theapplicant from the early stage of its development based on
the purpose of use by reference to“Basic principles on
utilization of registry for applications”and“Points to consider for ensuring the reliability in utilization of registrydata for applications”in terms of informed consent obtainment method, requirements for ensuring data reliability,
patient population for the registry, endpoints, etc.
If a registry is established taking into account its use
for approval application without defining the purpose of its
use, consent should be obtained concerning the possibilities of secondary use of the registry data by a sponsoring
company and thir d par ties’ Note 2）access to medical
records. It is also needed to store history data concerning
data generation and data deletion/correction with its reasons and the names of persons engaging in such deletion/correction（audit trail）, manage passwords and persons in

7charge of the data entry, and provide training to persons
in charge of the data entry（registry user management）.
These activities can minimize the risk of data fabrication/
falsification and visualize the absence of fabrication, etc.,
and thereby enhance data reliability. Backup recovery procedures should be established to prevent overwriting withold data or deletion of data during data backup. Furthermore, given that a registr y study often requires a long
period of time, it is also necessary to consider the issue ofstudy expenses（e.g., how to cope with the costs of thestudy after the period of study funding obtained at thestart of the study is expired）and the issue of operation（e.g., breaking tasks into smaller par ts and assigningthem to respective doctors in a medical institution）. The
above methods are considered to have been taken for
usual studies. Procedure manuals and records should be
retained so that whether a company applying for marketing approval is suitable for the purpose of use of a registry
can be judged.
If the use of a registry for approval application is notconsidered at the establishment of the registry, the registry holder should provide the applicant with informationof the purpose of the registry at the time of its establishment, definition of data reliability, ethical considerations,etc. In such a case, procedure manuals and records canplay important roles.
Note 2）: Third par ties indicate monitors, auditors, andregulatory authorities etc. See“Points to consider
for ensuring the reliability in utilization of registry data for applications”issued by the MHLW.
6.1.2

Quality control of data

This section does not propose additional activities forregistr y studies but aims to deepen understanding byclearly describing what has often been performed in many
registry studies.
Monitoring conducted for quality control is classified
into several types, including on‒site monitoring conductedby monitors visiting medical institutions from which data
are collected and checking the consistency between
source documents and data, of f‒site monitoring conducted via telephone or FAX without visiting sites, andcentral monitoring conducted using completed registr ydata by checking systematic errors. Monitoring may be
performed by combining some of these monitoring types,
and procedures are specified depending on the purposes
and risks. It should be noted that monitors’ direct accessto medical records, etc., requires prior consent from relevant subjects.
Regarding the quality control of computer systems,
the necessity of computer system validation（CSV）ispresented in“Points to consider for ensuring the reliabilitys135Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

8

in utilization of registry data for applications”issued by
the MHLW. With CSV required for systems used in academia‒initiated clinical studies in mind, the details of CSV
should be devised based on the potential risks. A clinical
trial takes about 1 to 3 years to complete, whereas a registry study can take a much longer time. Even if CSV is conducted at the start of a registr y study, the status of thecomputer system may not be maintained throughout the
study. Therefore, in addition to CSV at the star t of thestudy, some sort of quality control should be performed
for the computer system. It is recommended to discussspecific quality control methods and their appropriatenessduring consultations with PMDA（e.g., registry use consultation, registry reliability survey consultation）.
Concerning computer system, the following tasks
should be performed: preparation of system design specification suitable for the study purpose, conduct of acceptance tests before delivery, and checking whether the system can run in accordance with the design specification.
In addition, the following 3 requirements for electronic
data should be met: 1）accurate and reliable data free fromfabrication or falsification（authenticity）, 2）readable data
（legibility）, and 3）storage of data for a necessary period（storability）. As stated in Section 6.1.1, it is important toestablish the outline of audit trail and procedures forbackup recovery and to specify methods of operation andpersons in charge for data storage. Care should be taken
not to create a situation where the person responsible fordata control is lost due to transfer of the principal investigator, etc.
6.1.3

Quality assurance of registries

For the quality assurance of registries, registry holders should check the implementation str ucture andwhether the registry operation, data collection, and handling of data collected are implemented in accordancewith the pre‒specified procedures depending on the purpose of r egistr y establishment and quality of dataobtained; they should also record the results of the check,including corrective measures taken as needed. In Japan,
the term“quality assurance”tends to be associated withaudit, and the term“audit”tends to be associated with
“audit performed by auditors in a clinical trial.”In thefield of clinical studies, however, there are no internationally accepted definitions of audit, which is interpreted invarious ways depending on countries, industries, or organizations.15）As mentioned earlier, registry studies often
take a long period of time to complete, whereas study
funding is limited in many cases. The balance of quality
and costs should be taken into consideration when devising the methods of quality assurance.

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6.1.4

Rules and operating procedures for primar ystudies related to registr y establishment

In“Items related to registry design/operation”prepared based on investigation by the CIN‒Hayashi Group,a proposal was made by reference to“Points to Consider
for Ensuring the Reliability of Post‒marketing Database
Study for Drugs,”16）a notification related to the use of
medical information database in post‒marketing pharmacovigilance activities. However, since these proposal andnotification were prepared with companies’ medical RWD
management structures in mind, their strict application to
the use of patient registr y data for regulator y approval,
etc., could be too idealistic to be feasible.17）Nevertheless,items that should be pre‒specified in conducting primarystudies related to registry establishment are well summarized in the above proposal. These rules are not necessarily proposed on the assumption that standard operating
should be prepared and are considered
procedures（SOPs）
to be replaceable with rules, etc., related to organizations
and operation/management of registry holders（operating
rules, etc.）
or protocols, monitoring procedures/plans, anddata management procedures/plans（DMPs）, etc., forprimary studies related to registry establishment.
Therefore, in the present proposal, a comparison
table with a summary of items to be presented required in“Items related to registry design/operation”（e.g., procedure manuals that should be prepared by registry holders）
proposed by the Hayashi Group, and example alternative rules, etc., such as SOPs is provided as an attachment.
In the attachment, documents of primar y studies
related to registr y establishment and those of studies
using registry data are presented separately. The goal of
the study is not to prepare procedure manuals but to specify relevant items and follow the procedures for each ofthese items. In other words, it is important to establish
and maintain an appropriate quality management system（QMS）and act in accordance with the QMS and thereby
ensure the reliability of registry data.
6.1.5

Considerations for personal information protection in primar y studies related to registr yestablishment

Legal regulations/guidelines to be observed in conducting primary studies related to registry establishment
vary depending on the purposes, etc., of studies. According to the“Ethical Guidelines for Medical and Biological
18）
individual particiResearch Involving Human Subjects,”
pant/patient data（IPD）are allowed to be provided to third
parties by opt‒out policies when obtainment of consent
from study participants is difficult. However, compliancewith the Act on the Protection of Personal Information isJpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

required in cases where the company’s commercial use is
expected, such as in regulator y approval application.
Therefore, in order to provide the IPD of study subjects tocompanies, it is necessar y to inform study subjects inadvance of the provision of their data to companies in andoutside Japan and secondary use of data by these companies by presenting such information in the patient information document and consent form for primar y studies
related to registry establishment as well as to obtain written consent from these subjects or their legal representatives（i.e., opt‒in）.
However, it is considered acceptable to provide summary statistics, not IPD, to companies by opt‒out policies
for the addition of companies’ regulatory use to the purposes of use of registry data.
Even if the intended use of a registry is not clear at
the establishment stage of the registry, it is desirable toobtain consent from subjects in terms of the possibilitiesof the commercial use, provision to third parties, and provision to foreign entities of IPD on the assumption that
IPD may be used for approval application, etc.
Concerning ethical considerations when using IPD as
approval application data while consent of subjects has notbeen obtained for the commercial use or provision to third
parties of IPD,“Basic Concept of Ethical Norms Related toCommercial Use of Patient Registry Data”19）can be consulted for reference.
6.1.6

Costs of primar y studies related to registr yestablishment and burden of expenses

Public funds can often be used for planning andshor t‒term operation/management of primar y studies
related to registr y establishment; however, given thatmost registries are held for a long period of time, the burden of expenses for operation/management can be a significant issue. If funding from a company who uses registr y data is desired, it is necessar y to understand registered data and quality level required by the company andtake measures accordingly from the early stage of registry
establishment. The relationship between quality and costs
for operation/management is of trade‒off. Care should betaken to set an optimal quality level taking into account thegoal of the primar y study related to registr y establishment and an estimated period of time to maintain the registr y. If funding from a company is expected, funding‒related policies should be specified and published inadvance to ensure the transparency of registry management.
“Study of Burden of Expenses for Use of Disease
20）
Registration System”
can also be consulted for reference.

6.2

9Matters required to determine that the reliabilityof information presented in application data/
documents is ensured at a sufficient level in lightof its intended use（relationship between thepatient registr y holder and the applicant）
6.2.1 Protocols of studies using registr y data, consent, and opt‒out

Studies using registr y data are database studies
based on secondary use of existing registry data in principle.
The pharmaceutical regulations applicable to thesestudies using registry data, similarly to primary studies
related to registry establishment, are the“Ethical Guidelines for Medical and Biological Research Involving
Human Subjects.”Because, these guidelines are administrative, not legal regulations, the studies are within thescope of the Act on the Protection of Personal Information.
From the ethical point of view, in order to provide
companies with IPD, it is ideal to clarify the possibilities ofprovision of patient data to companies in and outside
Japan, secondary use of data by these companies, and provision of data to third par ties in study protocols andpatient information documents/consent forms for primarystudies related to registr y establishment as well as toobtain written consent from study subjects or their legal
representatives in advance（i.e., opt‒in）. It is also desirable
to prepare new protocols and information disclosure documents of studies using registry data, apply to the ethicalreview board for prior review/approval, and provide an
opportunity of agreement/refusal of information disclosure（i.e., opt‒out）before using data.
In cases where a study is performed as a collaborative study by researchers belonging to an academic society and a company and summary statistics are only used
as analysis results for the regulatory purpose, the use ofdata is considered to be acceptable without consent for thecompany’s secondar y use or provision to third parties
with opt‒in policies.
Concerning ethical considerations and personal information protection related to database studies using existing samples/information, a separate study is currently
underway. The results of that study will be referred.
6.2.2

Data management procedures/plans forstudies using registr y data

In studies using registry data, registry data‒related
procedures, such as data cleaning, coding of previous/
concurrent diseases, adverse events, and prior/concomitant drugs and preparation of datasets for analyses, aregenerated at the time of secondary use of existing registrydata. These activities are specified in data managements137

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

10

procedures and data management plans prepared in studies using registry data.
6.2.3

Procedures/plans for ensuring data reliability of studies using registr y data
（e.g., monitoring procedures/plans）

In studies using registr y data, the measures toensure reliability of registry data include determination ofdata items to collect and unification of methods to collectdata as well as on‒site and central monitoring based on
potential risks.
Meanwhile, also in studies using registry data, activities such as preparation of protocols and informed consent‒related documents（including opt‒out cases withwritten re‒consent and guarantee of provision of an
opportunity of agreeing or refusing information disclosure）, activities to ensure the reliability of registry data
including data management and monitoring, statisticalanalyses, and preparation of study reports are conducted.
With the objective check and the assurance for the appropriate conduct of these activities by third parties, the conduct of audits may be considered according to the purposes of use of the registry data. The following 2 types ofaudits are likely to be conducted: 1）system audits tocheck the organization structures of registry holders andvarious procedures and the status of compliance with protocols and various procedures for primary studies related
to registry establishment; 2）audits of individual research
institutions to check the study implementation statuses
and data reliability at research institutions ser ving as
information sources of registry data in the context of theorganizational structures and management statuses ofregistry holders. The details are specified in audit procedures/plans of studies using registr y data and primar ystudies related to registry establishment.
Furthermore, there may be some cases where on‒site inspection by the registry holder or on‒site monitoring of the research institution via the registry holder are
required. On‒site monitoring via the registr y holder is
specified in the monitoring procedures and monitoringplans of studies using registry data.
6.2.4

Statistical analysis procedures/plans of studies using registr y data

In studies using registr y data, statistical analysis
activities such as specification of statistical analysis items
and analysis methods, designing of analysis programs,
and finalization of analysis datasets are performed. These
activities are specified in the statistical analysis procedures and statistical analysis plans of studies using registry data.
6.2.5

Study reports of studies using registr y data

In studies using registry data, study reports are pres138

pared based on the results of the statistical analyses conducted on the basis of protocols and statistical analysis
plans of such studies as well as registry data.
In cases where a study is performed as a collaborative study by researchers belonging to an academic society and a company and summar y statistics are used as
analysis results, the documents to be used for regulatory
purposes such as documents for approval application andre‒examination/use results assessments are preparedbased on the report of this study.
6.3

Matters required to determine that the reliabilityof information presented in application data/
documents is ensured at a sufficient level in lightof its intended use（relationship of the applicant
to the application data/documents）
6.3.1 Standards of reliability of application data

Article 14, paragraph（3）of the Pharmaceutical andMedical Device Act, specifies that application data submitted for manufacturing/marketing approval application for
drugs, etc.,“must be collected and prepared according to
the standards specified in the MHLW Ordinance,”andparagraph（6）of the same article specifies that“a document‒based or on‒site investigation is to be provided inorder to examine whether or not the document complies
with the standards”as well as Article 43 in the Enforcement Regulations of the Pharmaceutical and Medical
Device Act specified the standards of reliability. This section addresses points for discussion relating to the document‒based investigation（document‒based complianceassessment）and on‒site investigation（on‒site GCP
inspection）. The standards are defined as follows in the
Article 43 of the Regulation for Enforcement of the Act on
Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices.
Article 43 Data provided in the second sentence ofArticle 14, paragraph（3）of the Act（including as
applied mutatis mutandis pursuant to paragraph（9）of the same Article）
must be collected and prepared
via the following means beyond those specified by
the Ministerial Order on Standards for Non‒Clinical Studies Concerning Safety of Pharmaceuticals（Order of the Ministry of Health and Welfare No.
21 of 1997）and the Ministerial Order on Standards
for Clinical Studies of Pharmaceuticals（Order ofthe Ministr y of Health and Welfare No. 28 of
1997）:（ⅰ）the data is cor rectly prepared based on
results of the investigation or the test conducted for the purpose of preparing the data;Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022（ⅱ）if results of the investigation or the test in thepreceding item cast a doubt on whether pharmaceuticals and medical devices pertaining
to an application have sufficient quality, efficacy, or safety for the application, results of
the investigation and the test are reviewed
and evaluated and the results are describedin the data;（ⅲ）data on which the data is based is preserved
until the date of disposition when theapproval prescribed in the provisions of Article 14 of the Act is provided or not provided.
provided, however, that this does not apply tothe case where it is recognized that thenature of the data makes it extremely difficult
to preserve;
In other words, generally, the reliability from source
documents to application data is confirmed through document‒based compliance assessment and on‒site GCP
inspection from the above viewpoints. Usually, document‒
based compliance assessment confirms whether application data（clinical study report）is appropriately preparedfrom records retained by the sponsor（case report forms,etc.）. In addition to that, on‒site GCP inspection is conducted on the sponsor and study sites.
Checklists and management sheets have been provided for these actions, and changes in the R & D environment have been responded to by revision of notificationand issuance of new notification. Especially, the concept of, and theconfirmation through“EDC management sheets”
concept of on‒site GCP inspection such as“the status ofmanagement of the study site may be intensively investigated for persons requesting or conducting a clinical trial,and based on the results, the necessity of visit investiga21）
can be a starttion to the study site may be determined”
ing point when considering methods for ensuring reliability for utilizing patient registries and RWD to be considered in the future, as described later, although it is difficult to utilize them as they are without modification.. In
the near future, it appears to be beneficial to utilize materials such as EDC management sheets originally preparedfor clinical trials, ultimately reaching a consensus among
registry holders, regulatory authorities, and applicants.
For the utilization of patient registries and other
RWD sources, unlike with clinical trials, on‒site inspection of the medical institution generating data is not easyor, in some cases, impossible. In light of the actual situation of utilizing such data source other than clinical trials,
the adoption of a framework of document‒based compliance assessment, and on‒site GCP inspection that PMDA

11

conducts for usual clinical trials, i.e.
“the status of management of the study site may be intensively investigated for
persons requesting or conducting a clinical trial,”may bebeneficial. Regarding such approach, by presenting specific examples of“the status of management of the studysite”and categorizing criteria for requiring the implementation of intensive investigation, it may also be necessary
to organize points to consider for adopting these suitably
for the situation to utilize patient registries and other
RWD sources. Actually, the notification“Points to consider
for ensuring the reliability in utilization of registry data for
applications”does not state that it is essential for a third
party to view source documents but only states“If there isa possibility［...］will access source documents, etc.”Conditional approach also used in clinical trials as describedabove is likely to be applied. However, whether or not thisprinciple is adopted is officially uncertain at present, andtherefore, it is necessar y to confirm the rationale formethods which ensure reliability by the approach as
described above in advance in consultation with the
PMDA.
“Points to consider for ensuring the reliability in utilization of registry data for applications”presents the compliance matters for applicants utilizing registr y data,
points to consider for the registry utilized as application
data/documents for marketing approval, etc. An applicant
will consider whether or not each of these matters can beaddressed. However, as mentioned in the notification, an
applicant is not required to ensure all the matters in a unified manner. In addition, when the registr y holder’sactions for the matters covered are confirmed, it is notnecessary to prepare SOPs and documents for each matter. The essential requirement is considered that it can be
confirmed, by the third party, that the registry is operated
and managed transparently which allows confirmation ofthese items. Therefore, as presented in the attachment of
this document, if the situation can be confirmed based on
the description in the registry holder’s organizational regulations, research protocol, etc., there is not much need toadditionally require the creation of just formally prepared
SOPs and related documents.
Regarding the confirmation for situation of registries,
registr y holders are not always familiar with the procedures for regulatory approval applications, and due to thevariety of forms, registries are not always standardized interms of matters that are relatively standardized in clinical
trials, including the structure of related documents, procedures, and terms. Registries have many parts that are notsuitable for standardization in nature. Therefore, it may bedifficult to grasp the actual situation of registries just byformally asking the applicability of each item listed in the
s139

12

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

Figure 2 Points to be considered for the review staff involved in the evaluation process of new drug
（Derived from“Points to be considered for the review staff involved in the evaluation process of new drug”, PMDA, 2008）

PMDA points to consider document. For example, if there
is a fact that the data registered in the registry is periodically aggregated and reviewed among the par ties concerned, it is one of the actions for“data quality control”in
the PMDA points to consider document depending on the
purpose of utilization. That is, there may be room for utilization even of registries that seem superficially impossible
to utilize for regulatory purposes by obtaining information
on operation and management of the registry and organizing the correspondence between the matters listed in the
PMDA points to consider document and the actual situation. The attachment of this document will be useful forthat consideration. This also leads to the expansion of thetarget of potentially available registries. Of course, concerning this point, when the registry holder also considers the utilization for regulator y purposes of their data,
mutual communication is beneficial. That is because cooperation with the pharmaceutical company can be smoothby considering in advance whether the actual situation ofvarious operation and management is consistent with thes140matters listed in the PMDA points to consider document.
6.3.2

Regulator y grade

Regarding the utilization of patient registries for regulatory approval application, the diseases targeted for discussion in this document were limited to rare diseases（rare cancers, rare intractable neurologic diseases, pediat, in which conventional RCTs（randomric diseases, etc.）
ized controlled trials）are difficult to be conducted. Therefore, we start the discussion of the concepts such as“fit‒for‒purpose”and“regulatory grade”by looking back at
the discussion of a general application package structure
without patient registries in the field of these diseases.
“Points to be considered by the review staff involvedin the evaluation process of new drug”（Figure 2）, which
was issued by PMDA in 2008 as part of disclosure of theGood Review Practice, states that perfection is not necessarily required in terms of reliability assurance. For example, it has been clarified that even if the application material meets the condition“Recognized violations are crucial
and difficult to amend,”if it is“considerations are possi-

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

Figure 3

13Pre‒determined monitoringble”for some reason, it will be regarded as“approval ornon‒approval should be judged considering with the seriousness of the disease, availability of alternative therapy,
and other points,”and the judgment can be made flexibly.
Of course, when utilizing patient registries, it is outrageous claim that the utilization of data should be promoted unconditionally even for the data reliability is not
ensured. However, in a situation where it is clearly statedthat even GCP violations in some part of the dataset thatare difficult to amend may be acceptable in some cases, it
is unreasonable to determine that the registry is ineligible
for regulator y use just because the data quality control
status/registry quality assurance status is not equivalent
in those in clinical trials. Actually, the PMDA points toconsider document does not require the registries, etc., tobe equivalent to that in clinical trials.
On the other hand, if complete data without any
drawbacks are not assumed, confusion may occur as towhat the basis is for determining that quality is sufficient.
In the utilization of patient registries and RWD, theexpression of regulatory grade is used, but it is really notdefined specifically even if these above are not perfect.
We would like to mention two points as a proposal todiscuss what regulatory grade is:（1）The details of data
quality control, quality assurance for registry, etc., can be
confirmed from the outside or third party, and（2）it canbe inferred with some probability that the conclusion ofregulatory approval decision is within the range that does
not distort significantly even if these above are not perfect.

The former can be interpreted as what lies behind therequirements throughout the PMDA points to consider
document. In other words, the checking of procedures
and records can be interpreted as not asking for the existence of procedures and records themselves but asking
for the situation to be recognizable from the outside or thethird party through them. The latter is a point for discussion that can be inferred from the PMDA points to consider document for reviewers described above.
One of the issues to be considered in（1）is how to
implement monitoring. Predeter mined monitoring
method（Figure 3）, which is implemented in some of theregistries established as part of the CIN Project, can beconsidered as one of the standard methods, assuming theutilization of registries for regulatory purposes in Japan.
On the other hand, as mentioned even in the PMDA
points to consider document related to reliability, the registries supposed to be utilized are not always those thatcan be predetermined. An alternative in such cases can be
an adaptable monitoring approach（the idea of performing
add‒on monitoring separately in addition to routine monitoring when a plan of utilization for regulatory purposes is
proposed）, in which monitoring is added at the start of theutilization project. If such frameworks may be acceptable,
it is expected that the possibility of utilization of patientregistries, RWD, etc., for which the purpose of utilization
is not determined in advance, may increase. This supports
the development of treatment in the field of rare diseases
for which conventional development of drugs, etc., is difficult（i.e., diseases targeted in this document）. In terms ofs141Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

14

Figure 4

Adaptable monitoring

funding, the cost burden after the possibility of utilizationarises makes it easy to maintain the beneficiary pays principle and can be one of the means for establishing theecosystem of a multipurpose registry.
Regarding adaptable monitoring（Figure 4）, thereare some cases where the PMDA’s view presented no
objection at the drugs registr y utilization consultation.
However, requirements for add‒on monitoring maychange depending on the intended use, and therefore, it isrequired to consider specific methods that can ensure thequality of data. The PMDA also added a comment that at
the start of monitoring using this method, the applicant
should discuss the methodology with the PMDA again bypresenting the specific method of add‒on monitoring.
If add‒on monitoring is implemented after the analysis result for the purpose of utilization is obtained, somedoubt would be thrown on the validity of the final analysis
result obtained after that. It should be noted that add‒onmonitoring is assumed to be implemented before theanalysis of the primary endpoint related to the purpose ofutilization.
Even when monitoring is performed, its method andpoints to be focused must be different from those in clinical trials. Possible alternative approaches include omittingsome methods of data quality management in clinical trials or increasing the weight of central monitoring. For
patient registries or RWD derived from various datas142

sources to be considered in the future, in light of theactual status that the data collection method is different
from that used in clinical trials, there may be room to consider the methods of data quality management from a perspective different from that for the methods of data quality
management used in clinical trials.
One possibility is to consider adopting a methodology
of focusing on performance/characteristic evaluation of
persons who enter the data or perform the data entr y/
capture process（e.g., algorithm‒based e‒phenotyping）
rather than focusing on confirming the consistency of dataon the DB with source documents. For example, one possible method may be evaluation of the degree of coincidence when a person who enters the data enters the samedata multiple times and the degree of coincidence when
multiple persons who enter the data enter the same data,
by using some data or based on work log, etc.（Somecases of such an approach have been reported as efforts
by overseas companies）.
What is evaluated above is different from the degreeof coincidence of data on the DB with source documents.
However, unlike clinical trials, in patient registries andother RWD, when entering data on the DB, it is unlikelythat the same information is recorded in char ts, etc.,
assuming SDV to be implemented later, and therefore, it is
not uncommon to have to change the SDV principle itself.
Given this, the“accuracy”measure of the data should beJpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

reconsidered. This is expected to be a point for discussionthat may become an issue in the process of considering
how PMDA will specifically confirm the source documents in the future. At this time, no specific procedurethat may be justified has been established, but if the
PMDA’s case studies is published externally with categorization of examples, there may be room for industry andacademia to consider methods of data quality management accordingly, and therefore, active information disclosure is expected.
One of the issues to be considered in（2）is how toevaluate that the conclusion of regulatory approval decision is not significantly distorted. PMDA’s view regarding
this is expected to be presented, but as one assumption, it
can be one of the considerations that the type Ⅰ error
does not significantly increase. If the data quality is so lowthat systematic errors cannot be overlooked, using suchdata as an external control for a single‒arm clinical trial
will induce the bias of the therapeutic effect of the drug;
as a result, an ineffective drug may be mistakenly determined to be effective. Of note, this may also be caused by
the difference in the definition of endpoint. For example,
in the case of progression‒free survival（a time‒to‒event
endpoint, where an event is defined as disease progression or death）, which is commonly used in the oncology
field, within the framework of clinical trials, disease progressions are cases where only radiographic progression
by CT, etc., is an event as well as cases where radiographic progression or clinical progression is an event. If
the definition is different between a single‒group clinical
trial and a registry, there may be cases where the therapeutic effect cannot be estimated appropriately.
However, even if there is a systematic error, when it
is uniformly included in the data in the same registry, theeffect of bias may be small in comparison between groups
in the same registry, which is one of the utilization methods mentioned in the PMDA’s document on registry utilization.
In other words, the“characteristics”of data, which isa non‒negligible issue related to quality in one utilizationcase, may be negligible“characteristics”in another utilization case. This point differs from the cases of clinical trials
in that the purpose or analysis methods are predetermined, and this is one of the reasons for the difficulty inpredetermining monitoring, etc., for ensuring the data
quality at the stage when the use purpose, method, andproposed statistical methods are not determined inadvance in the registr y used for secondar y purposes.
However, this issue may be addressed using the adaptable
monitoring described above.
After thoroughly examining these issues, the final

15

quality management system will be appropriately constructed, and quality acceptance limits will be appropriately established. However, regarding the issues including
the concept of quality management system that was
explicitly introduced in ICH E6（R2）, and quality acceptance limits, discussion is still far from a clear policy andestablished consensus even in the area of clinical trials.
Based on such situation in clinical trials, it is currently difficult to hold similar discussion assuming the utilization ofpatient registry. As mentioned above, the reliability assurance of utilization of a registr y for regulator y purposes
was discussed, although limited to the main issues.
While the above discussion may give the impressionof denying the quality management system that has been
built up in clinical trials, this document does not argue that
quality assurance is not required. As a major basis of discussion, if data is utilized for regulatory purposes, it goes
without saying that it is necessary to assure a certain levelof quality considering the magnitude of the impact. However, proportionality is important in such action as discussed in the ICH GCP renovation. In addition, a solution
is being considered based on the fact that the problem
originally arises due to the difficulty of development basedon usual multiple full‒package clinical trials and clinical
trials that fully meet the external design requirements, atleast in terms of utilization for the purposes of this document. In this situation, it cannot be concluded that thesame response as the clinical trial is required. Regarding
this point, although the reason is not specified, there aresome statements in MHLW“Points to consider for ensuring the reliability in utilization of registry data for applications”that it does not necessarily require that monitoring
be carried out in the same way as in clinical trials. For
example, taking into account conditional expressions suchas“when monitoring is car ried out by the registr yholder,”suggesting that the regulatory authority shows acertain understanding the difference between clinical trials conducted by the company.
Therefore, as a conclusion at this point, it is possible
to judge that the recognition that“the same process/same（resulting）data quality as the clinical trial should besought”is not appropriate, even if data such as patientregistr y is included in the evaluation data as a control
group for clinical trials in the new drug application.
On the other hand, regarding what level is required,industr y‒gover nment‒academia discussion has notreached a conclusion yet. Previous cases of utilization may
need to be categorized, including examination of exception cases and others（including cases of utilizing data notcalled RWD）in terms of the following points:
・Patient registry data（including those in the previouss143Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

16

cases, not specified as patient registry, etc., but utilizing data other than clinical trials）, clinical study
report containing evidence derived from those data.
・Whether or not there are cases in which the clinical
trial is being receiving a document‒based complianceassessment as a pivotal study in application data.
・Whether or not there are cases in which patients
derived from a patient registry included in the clinicalstudy report of the clinical trial are under investigation.
With future progress of utilization of patient registries, accumulating and categorizing information, andtransmitting information from the PMDA, the predictability at the early stage of research and development is
expected to be improved in the future, although patientregistry aspects and utilization purposes/methods are varied.
6.3.3

Significance of PMDA consultation system
related to registries

The PMDA or MHLW presented the basic principles
required for the utilization of patient registr y, greatly
advancing improvement in environment for the utilizationof patient registries in Japan. However, there are still not
many cases. The utilization of patient registries for thedevelopment of drugs etc., especially the utilization of
those containing data and/or evidence in application data,
may not be actively addressed due to a notion that thedevelopment risk is high.
Although the basic principles were presented, it isinevitable to make judgments based on individuality due tothe great variety of registries. Therefore, it is currently
important both for industr y and academia to utilize theconsultation system related to registries provided by the
PMDA. On the other hand, the hurdles are high especiallyfor academia, and if the possibility of utilization of the registry cannot be estimated at an early stage of planning of
the company’s development strategy, it may be difficult tostart the project, and therefore, it is desirable to operate
the system so that consultations can be received more
flexibly. However, regarding this point, the PMDA has
proposed an operation to lower the hurdle of preparatory
consultation, and it is considered that starting discussions
under such a framework is a possible option at this time.
In the future, in addition to that, as one countermeasure, it
is expected that while considering the confidentiality of
individual cases, cases in the PMDA’s review and reliability investigation will be categorized and presented asexternal examples. In particular, for cases that have notbeen approved, industr y and academia cannot analyze
such cases, and therefore, it is strongly required for the
PMDA to categorize the cases and present issues in a way
s144

that avoids the identification of a company and in a waythat protects corporate secrets. In light of the fact that, in
Europe, the review details when the conclusion is not
approvable are published with the drug name and that,
also in the US, similar cases, which are discussed in theadvisory committee, are published with the drug name,there may be room for exploring categorization and information disclosure in a form in which individual cases cannot be specified.
If the issues assumed at registry consultation are categorized, it is more likely that the registry holder or theapplicant can utilize the consultation for registry with the
PMDA more rationally and effectively. It also facilitates toconsider the quality control method of data and the quality
assurance method of the r egistr y in advance. It is
expected that discussions at consultation can be more
intensive, leading to efficient clinical development andfacilitating the development of drugs, etc. In addition to
the above, we would like to point out that there are somecases where the actions taken by the academia to achieve
the research purpose meet the PMDA requirements, but it
is not noticed. For example, if reports, etc., summarizing
the data registration status are published regularly, it may
play a role in data quality control. Therefore, if it is possible to coordinate views for determining whether or notthere is an action that substantially meets the PMDA
requirements by interviewing the operation and management status of the registry, rather than formally inquiringfrom the applicant whether or not to comply with the
PMDA requirements, patient registries that were recognized as unavailable could be utilized. On the contrary, forregistr y holders, there is room to appeal to companies
that they can utilize registry for regulatory purposes bycarefully reviewing the operation and management statusfrom the perspective of regulatory purposes, not adding a
new approach, or not creating new SOPs, etc. In addition,
a company’s efforts to reduce investigation costs may promote the development projects, etc., for dr ugs, etc.,
required in clinical practice in the long run.
Methods for ensuring the reliability of the data inclinical trials/studies have been sophisticated since theenactment of ICH‒GCP. Accordingly, the division of work
based on standardization and specialization has progressed, and the concepts of“risk‒based monitoring”and“quality by design”have become widely recognized, leading to improved quality and making project progress management relatively easy. However, with the exception ofcompany‒sponsored registries supposing utilization forparticular regulator y purposes, in most cases, it is noteasy to introduce the concept of quality by design from thetime the registry is launched in order to utilize the patientJpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

registry and RWD. In addition, because of the difficulty ofstandardization due to the diversity of purposes, each project will require coordination of recognition of the current
situation and value standard for judgment between
experts/between industry‒government‒academia stakeholders. While this can be a factor that hinders the utilization of patient registries, it can also be a factor that supports development projects for drugs, etc., that were once
difficult if coordinating views leads to the possibility of utilization of patient registries, etc., that have not been considered to formally meet the requirements. The cost of
coordination is currently high, but in the future, efforts
will be made to generalize the experience of the PMDA,
and the cost required for coordination should be reducedby accumulating cases of industry, government, and academia.
The PMDA’s consultation system and categorizationof points for discussion and information transmission canbe a catalyst for such industr y‒academia activities, andmore activities are expected from the perspective of regulatory science in the future.
6.4 Other points to consider
6.4.1 Securing the transparency of research funds
and management of conflict of interest

It is widely known that the Clinical Trials Act22）was
enforced on April 1, 2018 as a consequence of misconduct
by certain companies.
The significance of the management of conflict ofinterest（COI）has been notified to relevant organizations
and institutions via“Management of conflict of interest in
23）
to ensure thatclinical trials under the clinical trials act”
any COI is managed based on this notification.
In the annex of the above notification, i.e.,“Guidance
for conflict of interest management under the Clinical Trials Act”（partially revised on November 30, 2018）, COI isdefined as“any circumstance where a third party could
have concerns about a risk that fair and appropriate judgment in a study could be affected by the involvement of acompany or a financially profitable relationship between acompany involved in the study and the researchers.”
According to the guidance, such concerns are not about
the involvement of the company or the presence of a financially profitable relationship but about a possibility that thepresence of such potential benefits could negatively influence the reliability of the study, and that the study subjects could have inadequate protection. Securing a certain
amount of funds is necessary to appropriately conduct a
clinical study; moreover, researchers can receive financial
support from a company. According to the guidance, a
COI does not indicate the“fact”that a study is actually17

under undue influence arising out of personal interests
but the“appearance”that the study appears to outsiders
to be under undue influence. In other words, the primary
aim of COI management is for researchers to appropriately manage a potential COI and achieve social accountability, and thereby earn the trust of subjects and the public for clinical studies.
In activities related to the use of registry data under
the pharmaceutical regulator y system, it is essential toensure collaboration between academia and industr y,secure transparency of research funds including expenses
for the operation/management of primary studies related
to registr y establishment and use of registr y data, andmanage COI appropriately.
6.4.2

Coordination of consor tium activities andstakeholder management

For registry holders, long‒term maintenance or continuation of patient registries is challenging. To address
this, the following schemes are considered: 1）A consortium is formed by multiple companies, which contribute toresearch funding for the operation/management of primary studies related to registry establishment; and 2）Acompany that actively works on the research and development of therapeutic drugs for rare diseases（e.g., rare
cancers, rare intractable neurologic diseases, pediatricdiseases）proposes and solely contributes to researchfunding for the operation/management of primary studies
related to registry establishment.
Meanwhile, for providing new treatments to patientsand their families, opportunities to use registry data under
the pharmaceutical regulator y system should also be
guaranteed for companies not par ticipating in consortiums, etc., or not contributing to research funding for theestablishment, operation, and management of registries.
Given that the beneficiary‒pays principle is applied tothe use of registry data under the pharmaceutical regulator y system as a rule, there seems to be no significant
problem if expenses for registr y use are borne by thecompany. However, based on fairness and transparency,
the registr y holder should pay adequate attention toresearchers providing data for the registr y or the company contributing to research funding. Creating systems
to minimize conflicts among stakeholders and to work on
stakeholder management is also important. For example,
exclusive rights to use registry data can be given for a certain period to researchers providing data for registr yestablishment or companies contributing to researchfunding; thereafter, data can be shared by restricted publication; or companies planning to newly use registry data
under the pharmaceutical regulatory system are asked to
pay an appropriate portion of research expenses needed
s145

18

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

for registry operation/management.
7．Summar yThis is a document for registry holders and investigators of primary studies related to registry establishment,
primarily considering rare diseases（rare cancers, rare
intractable neurologic diseases, pediatric diseases, etc.）,
wherein conducting conventional RCTs is challenging. It
describes the points to consider for the operation andmanagement, so as to ensure data reliability while utilizing
registr y data under the Pharmaceutical Affairs system,
especially the utilization of registry data: 1）as an external
control of clinical studies for efficacy and/or safety evaluation in applications; 2）to complement or substitute clinicalstudies for efficacy and/or safety evaluation in applications; and 3）in the evaluation of dr ugs and medical
devices with conditional approval and of regenerative
medicine products with conditional and time‒limited
approval.
Assurance of data quality and reliability of patientregistry, and considerations for the protection of personal
information require a high level of consciousness andunderstanding of registry holders and principal investigators, investigators, sub‒investigators, collaborators of primar y studies related to registr y establishment, healthprofessionals such as physicians at medical institutions
generating data; companies that under take research/development and manufacturing/marketing of drugs, etc.;
and patients and their family members. To promote further utilization of registry data under the Pharmaceutical
Affairs system in the future, it is essential to make efforts,
in Japan as a whole, and to gain experience and know‒
how in many examples.
There have been movements such as ICH’s future
promotion of GCP renovation and the PMDA’s developmental reorganization of the CIN‒working group and the
RWD working group, as well as the utilization of registrydata as well as medical RWD/RWE under the Pharmaceutical Affairs system, such as databases based on clinicalinformation collected from electronic medical records,
ePRO, and wearable devices. However, their basic principles and points to consider for ensuring reliability, etc.,
can be conducted based on a discussion of patient registries.
The clinical trials conducted in Japan are of highquality due to the uniformity of the evaluation criteria, andthe existence of few violations of selection/exclusion criteria, regular visits of subjects, certainty of follow‒up, anddata accuracy. These are similar in primary studies related
to registry establishment. Creating a mechanism to generate registry data by utilizing such strengths could triggers146

the practical use of new medical technologies such as
drugs in Japan and suitable post‒marketing pharmacovigilance, especially in the field of rare diseases wherein conventional RCTs cannot be conducted.
References
1）Oi H. and Nakamura H. The advance of utilizing real world data
under pharmaceutical regulator y schemes regarding theapproval review and post‒marketing safety assessment. Japanese Journal of Pharmacoepidemiology 2019; 24（1）: 2‒10. Doi:
https://doi.org/10.3820/jjpe.24.2.
2）The Inter national Council for Harmonisation of TechnicalRequirements for Pharmaceuticals for Human Use（ICH）. ICH
reflection on“GCP renovation”: Modernization of ICH E8 andsubsequent renovation of ICH E6, January 2017.
URL: https://www.ich.org/products/gcp-renovation.html
3）U. S. Food and Drug Administration. 21st Century Cures Act.
U R L : h t t p s :/ / w w w. f d a . g o v / r e g u l a t o r y i n f o r m a t i o n /lawsenforcedbyfda/significantamendmentstothefdcact/21stcent
urycuresact/default.htm4）Nakamura H. and Takeda S. Clinical innovation network. The
Journal of Orthopedics & Traumatology 2018; 61（4）: 419‒24.
5）Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministr y of
Health, Labour and Welfare. Implementation of conditional
accelerated approval system for pharmaceuticals, PSEHB/PED
Notification No. 1020‒1. October 20, 2017.
6）Pharmaceuticals and Medical Devices Agency. Medical Information Database Network（MID‒NET）.
URL: https://www.pmda.go.jp/safety/mid-net/0001.html
7）Ministry of Health, Labour and Welfare. Ordinance related tostandards for conducting post‒marketing surveys and studies
on drugs. MHLW Ordinance No. 116. October 26, 2017.
8）Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministr y of
Health, Labour and Welfare; and Director of the Medical Device
Evaluation Division, Pharmaceutical Safety and Environmental
Health Bureau, Ministry of Health, Labour and Welfare. Basicprinciples on utilization of registr y for applications. PSEHB/PED Notification No. 0323‒1/PSEHB/MDED Notification No.
0323‒1. March 23, 2021.
9）Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministr y of
Health, Labour and Welfare; and Director of the Medical Device
Evaluation Division, Pharmaceutical Safety and Environmental
Health Bureau, Ministry of Health, Labour and Welfare. Points
to consider for ensuring the reliability in utilization of registrydata for applications. PSEHB/PED Notification No. 0323‒2/
PSEHB/MDED Notification No. 0323‒2. March 23, 2021.
10）Establishment of registry information hub for the accelerationand promotion of CIN concept. Handbook on the establishment
and operation of registries version 1.0. 2019.
URL: https://cinc.ncgm.go.jp/?page_id=198
11）Agency for Healthcare Research and Quality. Registries for evaluating patient outcomes: A user’s guide. Third edition. 2014.

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022
URL: https://www.ncbi.nlm.nih.gov/books/NBK208616/
12）Kodra Y., Weinbach J., Posada‒de‒la‒Paz M., Coi A., Lemonnier
S. L., et al. Recommendations for improving the quality of raredisease registries. Int J Environ Res Public Health 2018; 15（8）:1644. Doi: 10.3390/ijerph15081644.
13）Sase K. et al. Generating real‒world evidence for innovative
medical devices: Strategically coordinated registr y network.
Phar maceutical and medical device r egulator y science（PMDRS）2017; 48（8）: 533‒41.
14）The International Medical Device Regulators forum Patient Registries Working Group, Tools for Assessing the Usability of Registries in Support of Regulator y Decision‒Making, 27 March2018.
URL: https://www.imdrf.org/sites/default/files/docs/imdrf/
final/technical/imdrf-tech-180327-usability-tools-n46.pdf
15）Health, Labour and Welfare Sciences Research Grants（General
Research Program for the Practical Application of Medical Technology）. Comparison of regulations and legal system of clinical
trial between Western countries and Japan. General research
repor t 2013 to 2014. Representative person in the research:
Tetsu Isobe（Professor, Graduate School of Law, Keio University）
16）Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministr y of
Health, Labour and Welfare. Points to consider for ensuring thereliability of post‒marketing database study for drugs. PSEHB/PED Notification No. 0221‒1. February 21, 2018.
17）Shibata T. Project title of AMED Research on Regulatory Scienceof Pharmaceuticals and Medical Devices: Utilization of realworld evidence using patient registry data to support regulatory
decision‒making“Proposal on Assuring the Reliability of Patient
Registry Data for Use in Application Dossiers of Pharmaceuti-

19

cals and Medical Devices.”Jpn Pharmacol Ther 2019; 47 suppl
1: s9‒s22.
18）Ministr y of Education, Culture, Sports, Science and Technology/Ministry of Health, Labour and Welfare/Ministry of Economy, Trade and Industr y. Ethical guidelines for medical andbiological research involving human subjects. MEXT/MHLW/METI Notice No. 1. March 23, 2021.
19）AMED clinical research/trial promotion project fiscal 2018“Study on measures to promote the clinical innovation network
project by effective utilization of disease registration systems.”
Study group of companies’ utilization of disease registration systems in compliance with the Act on the protection of personal
information. Basic concept of ethical norms related to commercial use of patient registry data.
20）AMED clinical research/trial promotion project fiscal 2018“Study on measures to promote the clinical innovation network
project by effective utilization of disease registration systems”
and“Study on burden of expenses for utilization of disease registration systems.”21）Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministr y of
Health, Labour and Welfare. Guidelines for document‒based
compliance assessment for new drug approval application dataand on‒site GPSP inspection. PSEHB/PED Notification No.
0831‒4. August 31, 2020.
22）Ministry of Health, Labour and Welfare. Clinical Trials Act. Act
No. 16 of 2017. April 14, 2017.
23）Director of the Research and Development Division, Health Policy Bureau, Ministry of Health, Labour and Welfare. Management of conflict of interest in clinical trials under the Clinical
Trials Act. HPB Notification No. 0302‒1. March 2, 2018.

List of authors
Corresponding author（index based on the kana syllabar y order）
Area ofresponsibility

Name

Affiliation

Ishiguro Chieko

National Center for
Global Health and Medicine

Section 5.2.1,
5.2.2

Uemura Yukari

National Center for
Global Health and Medicine

Section 5.2.1,
5.2.2

Oi Hideki

National Center of Neu- Chapter 1, 2, 3, 7,
rology and Psychiatry
Section 5.1, 5.2.3,
6.1, 6.2, 6.4

Ohtsu Hiroshi

Section 5.2.1,
National Center for
Global Health and Medi- 5.2.2
cine

Name

Affiliation

Area ofresponsibility

Kikuchi Kayoko

National Center for Child Section 6.1
Health and Development

Shibata Taro

National Cancer Center Section 6.3
Japan

Suzuki Keisuke

National Center for Geriatrics and Gerontology

Section 6.2

Minami Manabu

National Cerebral andCardiovascular Center

Chapter 4

Yamamoto Haruko

National Cerebral andCardiovascular Center

Chapter 4（Affiliation as of March 2022）

s147

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

20
List of reviewers

Author Collaborators（Review）（index based on the kana syllabar y order）
Name

Affiliation

Oba Mari

National Center of Neurology and Psychiatry

Ozawa Hitoshi

National Cancer Center Japan

Kuwaki Takako

National Cancer Center Japan

Kobayashi Tohru

National Center for Child Health and Development

Tsujimoto Masashi

National Center for Geriatrics and Gerontology

Acknowledgments
We would like to express our sincere appreciation to the members of
the Japan Pharmaceutical Manufacturers Association, the Japan Federation of Medical Devices Associations, the Forum for Innovative
Regenerative Medicine, and the members of Pharmaceuticals andMedical Devices Agency for their valuable comments and advice inthe process of preparing this report.

（Affiliation as of March 2022）（Attachment）

Comparison table summarizing items to be presented as required in“Items related to registr y design/operation”（e.g., procedure manuals that should be prepared by registr y holders）
and examples of alternative rules, etc., such as SOPs
Prepared on March 29, 2021

Concerning post‒marketing pharmacovigilance,“Points to consider for ensuring the reliability of post‒marketing database study for
drugs”（PSEHB/PED Notification No. 0221‒1 issued by the Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety
and Environmental Health Bureau, Ministry of Health, Labour and Welfare dated February 21, 2018）has been issued.
However, the standard operating procedures（SOPs）presented in this notification as documents to be established are shown considering the medical RWD management structure of the database companies. Therefore, strictly applying the above to the use of registrydata under the pharmaceutical regulatory system could be significantly idealistic to be feasible. These rules, etc., have not necessarily
been proposed with the assumption that SOPs should be prepared; furthermore, they are considered to be replaceable with rules, etc.,
related to organizations and operation/management of the registry holder（operating rules, etc.）or protocols, etc., of primary studies
related to registry establishment.
Based on the above, we have prepared a comparison table with items related to registry design/operation（e.g., procedure manuals
that should be prepared by registry holders）in the“Proposal on assuring the reliability of patient registry data for use in application1）and example alternative rules, etc., such as SOPs. Documents of primary studies
dossiers of pharmaceuticals and medical devices”
related to registry establishment and those of studies using registry data are presented separately in the table.

s148

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

Items related to registry
design/operation

No.

1

2

Rules related to establishment/management
Purpose/content（1）Establishment of operating/management structure
Activities/procedures needed
for registr y holders to handle
individual data appropriately andto continuously operate/manage
registries should be specified,and an appropriate management/
operating str ucture must be
established.
（2）Policies related to securing transparency
Considering the collection/
analysis of registry data as well as
the influence on decision‒making
based on the results of the analysis, registry holders must specify
and publish policies related toitems needed to ensure transparency in terms of registr y operation/management（conflict ofinterest, str ucture of registr yoperational entities, provision offunds for registries, purposes ofregistries, disclosure of data,etc.）.
（3）Policies related to access to registry data
As registries include sensitive
health‒r elated or tr eatment‒
related information of patients,
registr y holders must establishr ules concerning registr y data
users’ access to data（including
data access by the regulator yauthority）and the scope andrights of such access.
Additionally, the application
methods for access to registr ydata and criteria based on which
registry holders assess the appropriateness of the application forr egistr y data access must be
specified as needed.
＊Standards/procedures for data entry
into patient registries
Purpose/content
For registries, data are collectedusing various methods, including

Examples ofalternative
rules, etc.,
such as SOPs

No.

• Operating r ulesof registr y holders（e.g., academic societies andresearch groups）• Protocols for primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated• Protocols and/or
data management
procedures/plans（DMPs）for primar y studies

Items related to registry
design/operationp a p e r‒b a s e d c a s e r e p o r t f o r m s（CRFs）and electronic case repor t
forms（eCRFs）. Regardless of thesemethods, data must be gathered forpre‒specified sur vey items and byusing appropriate collection methods
in accordance with the specified procedures.
Examples of points to be checked• Procedures for data entry• Identification of persons in charge ofdata entry• Education/training of persons incharge of data entry

21
Examples ofalternative
rules, etc.,
such as SOPs
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated3Standards/procedures related to data • Protocols and/or
cleaning
DMPs for primar y studies
Purpose/content
related to regisThe data gathered must be handled
try establishment
in accordance with the procedurespre‒specified by the registry holders. • Rules of organizations/data cenData gathered from information
ters to which thesources and entered in databases
representative
must be locked and stored in accordance with the pre‒specified procepersons underdures.
taking primar y
Examples of points to be checkedstudies related to• Methods related to the anonymizaregistr y estabtion of data before providing thelishment are affildata or data‒access to r egistr yiatedusers considering that sensitive
information is included in the regis- • Protocols and/or
DMPs for studies
tries
using registr y•Procedures for data cleaningdata（including procedures for checking
information sources for doubtful
points arising due to data cleaning）• Procedures for recording history ofdata correction• Procedures for data coding• Procedures for data lock4Standards/procedures related to coding
Purpose/content
The gathered data are handled inaccordance with the procedures pre‒specified by the registry holders. The
data gathered from information
sources and entered in databases arelocked and stored in accordance withthe pre‒specified procedures.

• Protocols and/or
DMPs for primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ys149

Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

22

No.

Items related to registry
design/operation
Examples of points to be checked• Procedures for recording history ofdata correction• Procedures for data coding• Procedures for data lock

5

6

s150

Rules/procedures related to security
Purpose/content
The overall security of computer
systems used must be specified byregistr y holders and maintained inaccordance with the pre‒specified
procedures.
In particular, rules must be established for the following items:• Scope of access rights of computer
system users according to the registry data content• Education/training of computer system users considering overall computer systems, security requirements, and registr y‒specific handling• Network security

Rules/procedures related to data
backup and recovery
Purpose/content
Registr y data backup/recover ymust be per formed using methods
specified by registry holders in accordance with the specified procedures.

Examples ofalternative
rules, etc.,
such as SOPs

Items related to registry
design/operation

No.

• Definition of registry database（e.g.,E D C）r e q u i r e ments

studies related toregistr y establishment are affiliated• Protocols and/or
DMPs for studies
using registr ydata

7• Operating r ulesof registr y holders（e.g., academic societies andresearch groups）• Protocols and/or
DMPs for primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated• Operating r ulesof registr y holders（e.g., academic societies andresearch groups）• Protocols and/or
DMPs for primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated

Examples ofalternative
rules, etc.,
such as SOPs

8

Rules related to the quality control of
medical data gathered from information sources
Purpose/content
The gathered data are handled inaccordance with the procedures pre‒specified by the registry holders. The
data gathered from information
sources and entered in databases are
periodically locked and stored.
Examples of points to be checked• Methods related to the anonymization（pseudonymization）of data
before providing the data or data‒
access to registry users consideringthat sensitive information is
included in the registries•Procedures for data cleaning（including procedures for checking
information sources for doubtful
points arising due to data cleaning）• Procedures for recording history ofdata correction• Procedures for data coding• Procedures for data lock＊

Validation plans/reports related tocomputer systems
Purpose/content
Methods for computer system quality control can vary depending on the
purposes, etc., of individual registries.
Depending on the computer system
configurations, the following activities
must be performed by registry holders appropriately and efficiently:• Computer system validation basedon risk assessments while introducing or renewing computer systems• Checking the operational status of
the computer systems used
• Establishment of the authenticity,
legibility, and storability of electromagnetic records suitable for the
specifications/operation methods of• Operating r ulesof registr y holde r s（e . g . , a c a demic societies
and researchgroups）• Protocols, monitoring proced u r e s/ p l a n s ,and/or DMPs forprimar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated• Definition of registry database（e.g.,E D C）r e q u i r e ments• Operating r ulesof registr y holders（e.g., academic societies andresearch groups）• Protocols and/or
DMPs for primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y estab-Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

No.

9

10

Items related to registry
design/operation

Examples ofalternative
rules, etc.,
such as SOPs

the computer systems used.
The annex titled“Use of electromagnetic records and electronic signatures for application for marketing
approval or licensing of dr ugs, etc.
（ER/ES Guidelines）”（PFSB Notification No. 0401022, by the Director‒
General of Pharmaceutical and Food
Safety Bureau, MHLW, dated April 1,
2005）; and points to consider whenhandling data for approval application
as electromagnetic data, can also be
consulted for reference.

lishment are affiliated• Definition of registr y database（e.g., EDC）
requirements

Rules to validate whether the datasetsfor analysis have been appropriately
prepared, or whether analysis results
have been appropriately obtained
Purpose/content
During data extraction and preparation of datasets, the procedures forappropriately extracting informationfrom locked data must be pre‒specified by registr y holders, and data
must be extracted in accordance withthe procedures. In cases where companies and applicants‒to‒be receive
datasets, and where statistical analyses are per formed, the companies
should submit statistical analysis
plans, etc., to registry holders before
data extraction and agree with registr y holders in terms of the range ofdataset preparation. In cases whereregistr y holders conduct statisticalanalyses, these analyses should be
per formed in accordance with thepre‒specified procedures and plans
specified in the statistical analysis
plans, etc.

• Protocols and/or
statistical analysis procedures/plans（SAPs）ofprimar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliatedRules related to the reporting of quality control related plans and results ofinvestigation
Purpose/content
In cases where registr y holders
undertake monitoring, the procedures
for monitoring must be specified inadvance, while monitoring must be
under taken in accordance with theprocedures. In terms of monitoring,
registry holders must obtain the consent of patients who provide data for• Protocols, monitoring proced u r e s/ p l a n s ,and/or DMPs forprimar y studies
related to registry establishment• Rules of organizations/data centersto which the representative persons undertaking

No.

11

12

• Protocols and/or
SAPs of studies
using registr y
data

13

Items related to registry
design/operation

23
Examples ofalternative
rules, etc.,
such as SOPs

registries directly or via information
sources.
Companies and applicants‒to‒becould check records of monitoring
under taken in accordance with thespecified procedures as needed.
For the implementation pr oce dures,“Basic principles on risk‒based
monitoring in clinical trials”（PSEHB/PED Notification No. 0705‒7, by the
Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety
and Environmental Health Bureau,
MHLW dated July 5, 2019）, can also
be consulted for reference.

primar y studies
related to registry establishment
are affiliated• Definition of registr y database（e.g., EDC）
requirements

Rules related to quality assurance
Purpose/content
The registry holders must confirm
that the maintenance of organizational
str uctures and data quality control
have been performed depending on
the purposes of registr y establishment and quality of data obtained.
C o m p a n i e s a n d a p p l i c a n t s‒t o‒b e
could check records of monitoring
under taken in accordance with thespecified procedures as needed.

• Protocols and/or
auditprocedures/plans forprimar y studies
related to registry establishment

Rules related to the retention ofrecords while preparing application
documents for re‒examination, etc.
Purpose/content
When application documents formarketing approval are preparedusing registr y data, the suppor tingdata must be retained in accordancewith the pre‒specified procedures.
Companies and applicants‒to‒becould check records of monitoring
under taken in accordance with thespecified procedures as needed.

Rules related to education/training of
persons engaged in registry establishment/management• Protocols, monitoring proced u r e s/ p l a n s ,and/or DMPs forstudies using registry data

• Protocols and/or
auditprocedures/plans forstudies using
registry data
• Operating r ulesof registr y holders（e.g., academic societies andresearch groups）• Protocols of primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated• Protocols, monitoring proced u r e s/ p l a n s ,and/or DMPs for

s151Jpn Pharmacol Ther（薬理と治療）vol. 50 suppl. 2 2022

24

No.

Items related to registry
design/operation
Purpose/content
Education/training must be provided to computer system users considering overall computer systems,
security requirements, and registry‒
specific handling. Education/training
must also be provided to persons incharge of data entry considering procedures to appropriately gather dataon pre‒specified survey items.

14

s152

Examples ofalternative
rules, etc.,
such as SOPs
primar y studies
related to registry establishment• Rules of organizations/data centers to which therepresentative
persons undertaking primar ystudies related toregistr y establishment are affiliated＊Records on ethical considerations• Operating r ules
Purpose/content
of registr y holde r s（e . g . , a c a Protection of personal information
demic societies
must be considered regardless of theand research grodata quality control methods. Whenups）
registry data are used for an application for marketing approval, it is necessary to pay adequate attention to the • Protocols, monitoring proceprotection of personal information ofd u r e s/ p l a n s ,patients, as the registry data are to be
and/or DMPs forprovided by the registry holder to theprimar y studies
applicant.
related to regisIn accordance with the Act on thetry establishment
Protection of Personal Informationand other applicable regulations, the • Rules of organizations/data cenrequirements and procedures relatedters to which theto obtaining consent from patients
representative
providing data to registries must be
persons underspecified. If consent is to be obtained
taking primaryfrom patients, a patient information

No.

Items related to registry
design/operation
document presenting necessary information must be prepared.
If it is possible for third parties（e.g.,
monitors, auditors, and regulator yauthorities）to access source documents, etc., stored in infor mation
sources, this must be presented in thepatient infor mation document asneeded.

Examples ofalternative
rules, etc.,
such as SOPs
studies related toregistr y establishment are affiliated• Definition of registr y database（e.g., EDC）requirements• Protocols, monitoring procedures/plans, and/or
DMPs for studies
using registr y
data

Note: ＊Items that are not included in the Annex titled“Points toconsider for ensuring the reliability of post‒marketing database study for drugs”（PSEHB/PED Notification No. 0221‒1
issued by the Director of the Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental HealthBureau, Ministry of Health, Labour and Welfare dated February 21, 2018）.

References
1）Shibata T. Project title of AMED Research on Regulatory Scienceof Pharmaceuticals and Medical Devices: Utilization of realworld evidence using patient registry data to support regulatory
decision‒making“Proposal on Assuring the Reliability of Patient
Registry Data for Use in Application Dossiers of Pharmaceuticals and Medical Devices.”Jpn Pharmacol Ther 2019; 47 suppl
1: s9‒s22.

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