医薬品相互作用研究

Vol.45, No. 1（2021）

19（19）

医薬品相互作用研究
一
般論
文

45（1） 19-26 （2021）

Implementation of an Adverse Drug Reaction Monitoring System Basedon Risk Management Plans
Masami TSUCHIYA1, 2, Akihisa ESASHI1, Taku OBARA3, 4, Ryohkan FUNAKOSHI5, Nariyasu MANO2, 3
Department of Pharmacy, Miyagi Cancer Center
Laboratory of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences3
Department of Pharmaceutical Sciences, Tohoku University Hospital
4
Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization
5
Department of Pharmacy, Kameda General Hospital
1

2（Received July 26, 2020; Revised October 02, 2020; Accepted October 26, 2020）
Abstract
Objectives : Spontaneous adverse drug reaction（ADR）reporting by medical institutions is increasingly promoted forcollection of drug safety information. Encouraging hospital pharmacists to collect and report ADRs to the regulatory
authorities and pharmaceutical companies through the Risk Management Plan（RMP）-assisted hospital pharmacy work
would lead to the provision of new information to ensure appropriate use and contribute to new proposals for safetymeasures. Adjusting RMPs, as a repository of drug-associated risks, to use in the clinical settings would allow theirefficient use in adverse drug reaction monitoring. The aim of the study was to build an RMP-based ADR monitoring
system and implement this system in electronic medical record（EMR）system to bring about the efficient collectionof drug safety information and contribute to pharmacovigilance activities. Methods: An RMP database was built andcontains 429 risks of 35 drug products. RMP templates prepared for all drugs with an RMP were implemented in EMR
system. Results: RMP templates were used on 5 drug products in 123 patients from January 2016 to October 2017. The
patients with a suspected ADR had 194 events of any Common Terminology Criteria for Adverse Events（CTCAE）gradeand 7 events of CTCAE grade 3 or higher. Five ADR reports were submitted to the regulatory authority for the patientswith a suspected serious ADR. Conclusion: We successfully built an RMP-based ADR monitoring system and implemented
it in EMR system to bring about the efficient collection of drug safety information and contribute to pharmacovigilance
activities.
Keywords : Risk management plan, adverse drug reaction

INTRODUCTION

following marketing（pharmacovigilance

Since 2013, pharmaceutical companies in Japan

activities）, and （3） efforts to reduce the risks

plans（RMPs）as a component of their drug

information to healthcare professionals andhave been required to formulate risk management

safety activities. In a Japanese context, an RMP

i s a d o c u m e n t o f s u m m a r y, f o r a n i n d i v i d u a ldrug;（1）important adverse drug reactions andmissing informat ion w ith a clear or suspected

relationship to the drug（safety specification）,（2） information-collection activities conductedassociated with the drug, such as providing
establishing conditions for use（risk minimization

activities）. The risks listed in the safety

specification in item 1 are classified into thethree categories of “important identified risks”,“important potential risks”, and “important missing
i n f o r m a t i o n” p e r t h e I n t e r n a t i o n a l C o n f e r e n c e

47-1 Nodayama, Medeshimashiote, Natori, Miyagi, 981-1293, Japan.
1-1, Seriyo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
3
1-1, Seriyo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
42-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8573, Japan.
5929 Higashi-cho, Kamogawa-City, 296-8602 Chiba Japan.
Taku Obara, Ph.D.
Division of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization.
Tel: +81-22-717-8104; Fax: +81-22-717-8106;
E-mail: obara-t@hosp.tohoku.ac.jp12

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医薬品相互作用研究

on Harmonisation of Technical Requirements forVol.45, No. 1（2021）

risks, to use in the clinical settings would allow

Registration of Pharmaceuticals for Human Use

their efficient use in adverse drug reaction

to enhance pharmacovigilance activities throughno mention of efforts to use RMPs at medical（ICH）E2E guideline 1）. The purpose of an RMP is

m o n i t o r i n g . T h e l i t e r a t u r e , h o w e ve r, c o n t a i n s

the broad sharing of drug risk management

institutions as proposed above.

healthcare professionals. The Ministry of Health,

RMP-based adverse drug reaction monitoring

professionals are made aware of the information

medical record system to bring about theassociated with the drug and the status of safetycontribute to pharmacovigilance activities.

a c t i v i t i e s b y t h e p h a r m a c e u t i c a l c o m p a ny a n d

L a b o u r, a n d W e l f a r e r e q u i r e s t h a t h e a l t h c a r e

in RMPs to allow them to understand the risks
measu res for those r is ks for u t i li za t i on in t hea p p r o p r i a t e u s e o f t h e d r u g 2）. T o f a c i l i t a t e

The objective of the study was to build ansystem and implement this system in electronic

efficient collection of drug safety information and

METHODS

pharmacovigilance measures, medical institutions,（1）Construction of RMP Databaseauthorities must engage together in RMP-based

Access ® 2013. A total of 429 risks were extracted

the pharmaceutical company, and the regulatory
activities.

An RMP database was built using Microsoft

from the important ident ified risks, important

The Ministry of Health, Labour, and Welfare,potential risks, and important missing information. Under thesedrug pro ducts w ith an implemented RMP as ofJapan, issues notificat ions to facilitate the useof RMPs at medical institutions

3）

notifications, healthcare professionals are requiredin the safety specifications （risk names） of 35
January 2016. Then, the followings were created:to contribute to pharmacovigilance activities. The（1） table of risk names（risk table）,（2） table“On the Use of Drug Risk Management Plans in thet o t e r m s i n C o m m o n Te r m i n o l o g y C r i t e r i a f o r

Japanese Society of Hospital Pharmacists issued

Work of Hospital Pharmacists”

4）. This document

urges hospital pharmacists to understand RMPs,
which detail drug-associated risks and the status oflinking adverse events corresponding to risk names

Adverse Events（CTCAE）Japan Clinical Oncology

Group Japanese version 4.0（risk-CTCAE/symptom

table）,（3）table linking drug names to the risk

safety measures implemented for those risks, andnames for the respective drugs  （ drug-risk table）

medical institution so as to facilitate the proper（CTCAE table）. When there was no corresponding

create systems to utilize this information in theiruse of drugs and contribute to ensuring safety.

5）, and （4） table linking CTCAE terms to g rades

CTCAE term for a risk name, a symptom related to

Spontaneous adverse drug reaction reporting

the risk name was established based on patient-under the pharmaceuticals and medical devices

pharmaceutical company 6） . Then, the followings

by medical institutions is increasingly promoted

safety information reporting system establishedi n A r t i c l e 6 8 o f t h e A c t o n S e c u r i n g Q u a l i t y,
Efficacy and Safety of Pharmaceuticals, Medical

targeted pharmaceutical guides prepared by thew e r e c r e a t e d :    t a b l e l i n k i n g r i s k n a m e s t osymptoms（merged as risk-CTCAE/ symptom table）
and（5）list of all symptoms in the patient-targeted

Devices, Regenerative and Cellular Therapy

p h a r m a c e u t i c a l g u i d e f o r 3 5 d r u g s （ s ym p t o m

Encouraging hospital pharmacists to collect drug（2）Creation of RMP Templates

to the regulatory authorities and pharmaceutical

RMP database was made. Creating RMP templates,

Products, Gene Therapy Products, and Cosmetics.
safety informat ion and report this informat ion
companies through their RMP-assisted hospital

table）.

A tool for creating RMP templates based on thea g i ven d rug m ay b e sel ec t ed usi n g t h e que ry

pharmacy work would lead to the provision offunction of Microsoft Access ® 2013 to output acontribute to new proposals for safety measures.

C T C A E t e r m s a n d g r a d e s f o r t h a t d r u g （ Ta b l e

new information to ensure appropriate use andAdjusting RMPs, as a repository of drug-associatedtable containing the risk names and corresponding

1）. These tables, prepared for all drugs with

医薬品相互作用研究

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Vol.45, No. 1（2021）

Table 1. Portion of the RMP template for nivolumab

RMP terms

CTCAE

Grade 1

Grade 2Intestinal Lung

Shortness of breath

No

Yes

Dry cough

No

Yes

Fever

No

Yes

MyalgiaNo

Yes

Feeling of weakness

No

Yes

Myositis

Mild pain

DiseaseMyasthenia gravis

terms/symptoms

Grade 3

Grade 4

Grade 5Moderate pain

Pain associated--with weakness;

weakness;Deathassociatedpain limiting

instrumental
ADL
ColitisColitislimiting selfcare ADL

Asymptomatic;

Abdominal

SevereLife-diagnostic

blood in stool

pain; change

consequences;clinical or

observations

pain; mucus or

only;

abdominal
in bowelhabits; medical

intervention

intervention

not indicatedDiarrheawith severe

indicated;threatening
urgentintervention
indicated

peritoneal signs

Increase of <4

Increase of 4 -Increase of >=7Life-

over baseline;

over baseline;

over baseline;

consequences;stools per day

mild increase in
ostomy output
compared tobaseline

6 stools per day
moderateincrease in

ostomy output
compared tobaselinestools per day
incontinence;

hospitalization
indicated;severethreatening

Deathurgentintervention
indicated

increase in

ostomy output
compared tobaseline;a n R M P, w e r e i m p l e m e n t e d a s R M P t e m p l a t e s
in electronic medical record system. It allows

healthcare professionals in the hospital to conduct
adverse drug reaction monitoring based on RMP.

The system was configured so that the results

during patient encounters. The adverse drug

reaction cases were collected from January 2016

to October 2017. Adverse drug reactions judged

to be serious were reported to the regulatory

authority as required under the pharmaceuticals

o f a d ve r s e d r u g r e a c t i o n m o n i t o r i n g c o u l d b e

and medical devices safety information reporting

format.

（4）Ethics approval

recorded in electronic medical records in tabular（3）Use of the RMP Templates

Pharmacists employed by Miyagi Cancer Center

began using the RMP templates in January 2016

to evaluate the adverse drug reactions reported

system.

This study was approved by the ethics committeeof Miyagi Cancer Center （2018-061）, and therequirement to obtain informed consent was
waived.

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Vol.45, No. 1（2021）

Figure 1. Entity-relationship diagram of the RMP database

RESULTS（1）Construction of RMP Database

An entity-relationship diagram of the RMP

database is shown in Figure 1. The information
contained in the tables that make up the RMP
database is updated whenever an RMP is created

for a new drug or an existing RMP is updated.

（2）Creation of RMP Templates

A port ion of the RMP template of nivolumab

implemented in electronic medical records isshown in Figure 2. Radio buttons and othercontrols allow operators of all occupations andlevels of clinical experience to conveniently assess

grades according to set criteria.

Figure 2. Portion of the RMP template for nivolumab implemented in electronic medical record system

医薬品相互作用研究（3）Use of RMP Templates

Vol.45, No. 1（2021）

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2017. The patients with a suspected adverse drug

The adverse drug reaction monitoring system

reaction had 194 events of any CTCAE grade（23products in 123 patients（10 patients using

47 for pembrolizumab, 12 for ramucirumab, andc r e a t e d i n 1 a n d 2 a b o ve w a s u s e d o n 5 d r u g
a fluoropyrimidine drugs, 73 patients usingn i vo l u m a b, 3 4 p a t i e n t s u s i n g p e m b r o l i z u m a b,

4 p a t i e n t s u s i n g r a m u c i r u m a b, a n d 2 p a t i e n t susing lenvatinib）from January 2016 to October

for a fluoropyrimidine drugs, 106 for nivolumab,

6 for lenvatinib） and 7 events of CTCAE grade

3 or higher（2 for a fluoropyrimidine drugs,

1 f o r n i vo l u m a b, 2 f o r p e m b r o l i z u m a b, a n d 2
f o r l e n v a t i n i b ）（ Ta b l e 2 ） . F i v e a d v e r s e d r u g

Table 2. Patients with suspected adverse drug reactions extracted with the RMP templates（n=123）

Drug nameAdverse drug reaction（suspected）

Fluoropyrimidine drugs

Palmar-plantar erythrodysesthesia syndrome41Paronychia21Lacrimation

30

Dry skin

60Oral mucositis

20

Diarrhea

40

Nausea20Allergic reactions

60

Acne-like rash300Pruritus

29

1Hyperthyroidism

80Hypothyroidism

110Increased ALT

100

Increased AST

90Colitis30

Renal impairment

40

Acne-like rash

11

1

Pruritus

121

Hyperthyroidism

50Hypothyroidism

30Increased ALT

50

Increased AST

60

Colitis10Hypertension

40

Diarrhea

1

0

Proteinuria

20Epistaxis

10Alopecia

30Nausea10Palmar-plantar erythrodysesthesia syndrome10Hypertension

2

2

Diarrhea

1

0

Proteinuria

10Epistaxis

10

Nivolumab

Pembrolizumab

Ramucirumab

Lenvatinib

All grades（patients）

Grade 3 or higher（patients）

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医薬品相互作用研究

reaction reports were submitted to the regulatory

authority for the patients with a suspected serious

Vol.45, No. 1（2021）

to the detection of adverse events and the grade of

the first incident were studied in 11 patients who

adverse drug reaction（4 for nivolumab and 1 fordeveloped hypothyroidism. The results showed

60% of the patients surveyed in the present study

events was 67 days（interquartile range（IQR）:

pembrolizumab）（Table 3）. Since approximatelythat the median time to detection of adversew e r e u s i n g n i vo l u m a b, a n i m m u n e c h e c k p o i n t

59.5-75.5 days）, 9 patients（82%）were Grade 1

occurs relatively frequently as an immune-related

required discontinuation of treatment.

inhibitor, we focused on hypothyroidism, which

adverse event. The time from the start of treatment

and 2 patients（18%）were Grade 2, none of which

Table 3. Patients with adverse drug reaction reported to the regulatory authority

Drug nameAdverse drug reaction（suspected）

Nivolumab

Hyperthyroidism, hypothyroidism

Nivolumab

Rhabdomyolysis, Stevens-Johnson syndrome

Nivolumab

Hyperthyroidism

Nivolumab

Pancreatitis

Pembrolizumab

Myasthenia gravis, diabetes insipidus

DISCUSSION

actor in the adverse drug react ion monitoring

reaction monitoring system was built andfound that introducing templates for electronic

In this study, an RMP-based adverse drug

system built in this study. A previous investigation

implemented in electronic medical record system

medical records enables precise, clear, and fast

reactions and submit adverse drug reaction

reaction monitoring system at medical institutions

t o a l l o w p h a r m a c i s t s t o i d e n t i f y a d ve r s e d r u greports to the regulatory authority. By operatingin electronic medical record system, this adverse

drug reaction monitoring system allows not

only the collection of adverse drug reaction andother safety information associated with patient

information, but also adverse drug reactions to

be followed over time and accumulated data to

e n t r i e s 7）. S i n c e t h e u s e o f a n a d v e r s e d r u g
allows healthcare professionals with any level ofclinical experience to efficiently extract adverse

drug reaction information and immediately

make corresponding entries in medical records,

monitoring systems should be even more useful for
outpatient care, which demands rapid assessmentsof adverse drug reactions and the sharing of

be output and modified. Adverse drug reaction

information across disciplines. The system enables

adverse drug reaction reports to be submitted todifferent medical institutions and regulatory

data collected over time helps the preparation ofadverse drug reactions to be assessed acrossthe regulatory authority and should also proveauthorities because it uses existing assessment

and clinical trials. RMP templates are the central

Developed using Microsoft Access® 2013us efu l to c ollect d a ta i n ob s e r v a t i on a l s t ud i es

criteria for adverse drug reactions.

医薬品相互作用研究

Vol.45, No. 1（2021）

25（25）（Microsoft Corp., Redmond, WA, USA）, this systemdeveloped from the information integrated intoat medical institutions with minimal information

closely monitor adverse drug reactions and create

could be relatively inexpensively introduced even

RMPs are needed to help pharmacists in Japantechnology infrastructure. Tables that link drugs,

drug safety information. Pharmacovigilance,

be prepared to allow the adverse drug reaction

development through the postmarket ing phase

RMP risks, adverse events, and symptoms mustmonitoring system to operate. The RMPs now

which involves the monitoring of safety from drug
to ensure drug safety, is defined by the Worldavailable for 324 drugs are published only in

Health Organization（WHO）as “the science andto be extracted as plain text. This poses a large

understanding and prevention of adverse effects

PDF format, which does not allow the information

activities relating to the detection, assessment,

hurdle for initial database construction. The risko r any o t h er d rug- rel at ed p ro b l em” 9 ） . Pro pe r

Medical Dictionary for Regulatory Activities/

to be prepared and a pharmacovigilance plannames they contain, moreover, are not uniformly

pharmacovigilance requires a safety specification

Japanese version（MedDRA/J）terms: terminology

and risk minimization measures to be developed

discrepancies among these risk names and thenpharmacovigilance plan, drug safety information

varies among RMPs. The tasks of addressing thematching them to corresponding CTCAE terms andsymptoms would be t ime consuming and could
be affected by operator subjectivity. These issues

w h i l e c l i n i c a l t r i a l s a r e u n d e r w a y. U n d e r t h e
is collected and the causal relationship of adverse

events to the drug in question is evaluated alongwith severity to monitor for new risks arising after

would be solved if the regulatory authorities

marketing. Appropriate risk minimization measurescontain easily extractable by secondary users.

detected. Our adverse drug reaction monitoring

drug reactions to anticancer drugs. The system

postmarketing drug safety information as well as

standardized RMP entries and made the data theyWe established this system to monitor adversea l l o w e d u s t o i d e n t i f y a n d r e p o r t f i ve s e r i o u s

immune-related adverse events specific to

the immune checkpoint inhibitor nivolumab,

which was developed and first approved inJapan under the pharmaceuticals and medical

must be considered for any new potential riskssystem would be well-suited to the collection ofrisk monitoring activities in pharmacovigilance
programs.

CONCLUSION

We successfully built an RMP-based adverse drug

devices safety information reporting system. In

reaction monitoring system and implemented it intreatment to the detection of nivolumab-induced

the efficient collection of drug safety information

addition, we surveyed the time from the start ofelectronic medical record system to bring about

hypothyroidism and the grade of the first incident.

and contribute to pharmacovigilance activities.

Using the Japanese Adverse Drug Events Reporting
database, which includes a large number of serious

adverse drug reactions, the median duration ofnivolumab-induced hypothyroidism was 80.5 days

（IQR: 44.8-133.3 days）

8）. Although this study

was conducted in a small number of cases, it was

Funding

Declarations

This research was partially supported by the

Research on Regulatory Harmonization and

Evaluation of Pharmaceuticals, Medical Devices,suggested that the use of our template may allow

Regenerative and Cellular Therapy Products, Genea relatively early phase, and may contribute toAgency for Medical Research and Development

for the detection of non-serious side effects at

the prevention of serious adverse reactions andcontinuation of treatment.

Since Japan has overcome its drug-lag problem

and drugs are now developed and approved in
the country at the same pace as elsewhere, tools

Therapy Products, and Cosmetics from the Japan（AMED）.

Conflicts of interest

The authors declare no conflicts of interest

associated with this manuscript.

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医薬品相互作用研究

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