Drug Discoveries & Therapeutics. 2021; 15(2):101-107.

Original Article

101

DOI: 10.5582/ddt.2021.01028

Evaluation of rapid drug safety communication materials forpatients in Japan§§

Akiko Yaguchi-Saito1,3, , Ken Yamamoto2, , Tami Sengoku3, Machi Suka4, Tsugumichi Sato5,
Miwa Hinata6, Toshiaki Nakamura7, Takeo Nakayama3, Michiko Yamamoto8,*
1

Behavioral Science Division, Behavioral Sciences and Survivorship Research Group, Center for Public Health Sciences, National Cancer Center,
Tokyo, Japan;
2Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, Tokyo, Japan;
3
Department of Health Informatics, Kyoto University Graduate School of Medicine & School of Public Health, Kyoto, Japan;
4
Department of Public Health and Environmental Medicine, The Jikei University School of Medicine, Tokyo, Japan;
5
Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba, Japan;
6
Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo, Japan;
7
Education and Research Center for Clinical Pharmacy, Osaka University of Pharmaceutical Sciences, Takatsuki, Osaka, Japan;
8
Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.

SUMMARY

Since 2011, pharmaceutical companies in Japan have been required to issue two types of documents
regarding severe adverse drug reactions reported post-marketing, namely the Rapid Safety
Communication Materials for Patients and the Related Materials. However, the adequacy of these
documents has not yet been systematically assessed. The aim of this study was to evaluate theadequacy of these two types of materials. The Rapid Safety Communications for Patients wereobtained from the Pharmaceuticals and Medical Devices Agency (PMDA) website. The RelatedMaterials were obtained from pharmaceutical companies or the PMDA website. Three assessors
independently scored the Rapid Safety Communication for Patients and the Related Materials using
the Centers for Disease Control and Prevention Clear Communication Index (CCI). In addition,
the contents and descriptions of the materials were analyzed. In total, 13 materials for seven drugs
were assessed. Almost all materials contained the "main message" and "call to action". However,
the average CCI scores for the Rapid Safety Communication for Patients and Related Materials forPatients were 68.8 and 74.3 (out of 100), respectively. Further, none of the evaluated materials werescored above the CCI threshold score (i.e., ≥ 90%). Descriptions regarding "language", "state ofscience", and "risk" were not adequate. In particular, the terminology used in materials seemed difficultfor patients to understand. In conclusion, the Japanese Rapid Communication Materials for Patientsrequire improvement. Furthermore, a system for evaluating these materials prior to publication shouldbe established.

Keywords

Risk communication, Clear Communication Index, drug safety

1. Introduction
Japan has experienced several pharmaceutical drugrelated disasters ("Yakugai" in Japanese), and apossible reason for these is the lack of prompt risk
communication to the public, including patients. Risk
communication refers to "communication intended
to supply lay people with information they need tomake informed, independent judgment about risks tohealth, safety, and the environment" (1). For effective
risk communication, adequate drug safety informationmust be provided to patients, which can prevent severe
adverse drug reactions.

In 2011, the Ministry of Health, Labour, and Welfare(MHLW) set up a risk communication frameworkfor patients based on the post-marketing phase of
drug evaluation, in addition to the framework alreadyavailable for healthcare professionals. The MHLW
requires pharmaceutical companies to immediately issue
two types of special warning communication letter,for healthcare professionals and patients, when severeor fatal adverse drug reactions occur (2): the Rapid
Safety Communication (Blue Letter) and the Emergent
Safety Communication (Yellow Letter) (3). The latter
is issued in more serious cases, especially when urgent
safety measures are necessary. These communicationwww.ddtjournal.com

102

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.

letters for patients are A4-sized, single-page documents,
based on a template standardized by the MHLW. As
of January 2020, seven Blue Letters for patients andno Yellow Letters have been issued. In addition, the
MHLW requests that pharmaceutical companies prepare
similar, easily understood Related Materials documents
using their own format (4). Generally, these documents
are handed directly to the patients at the medical
institution and also made available on the website of thePharmaceuticals and Medical Devices Agency (PMDA),
which is the Japanese national regulatory body, or onthat of the pharmaceutical companies. However, thequality of these communication letters has not yet beensystemically evaluated.
Clarity is critical in order for written communicationmaterials to be comprehensible to a general audience
with varying literacy levels. Recently, governmentalorganizations in developed countries have introduced
standards (criteria) for providing clear health information
to patients. In the USA, "Clear & Simple" (5) fromthe National Institutes of Health and the "Toolkit for
Making Written Material Clear and Effective" (6)are issued by the Center for Medicare and Medicaid
Services. Furthermore, the Centers for Disease Control
and Prevention (CDC) published the "CDC Clear
Communication Index (CCI)" (7) in 2014. The CCI
has been used to identify important communication
characteristics that enhance clarity and help readers
to understand public messages and materials (8). This
index is the most comprehensive and widely used
tool for assessing and developing such materials (912). However, to the best of our knowledge, no study
has applied the CCI for the assessment or during thedevelopment of rapid safety communication materials
intended for patients. In this study, we aimed to evaluate
the adequacy of all Blue Letter and Related Materials
documents in Japan using the CCI.
2. Materials and Methods
2.1. Target materials
We searched the PMDA website for Blue Letters(including the Blue Letters for Healthcare Professionals
and Blue Letters for Patients) issued as of April
2017 for the following six drugs: RANMARK ®
Subcutaneous Injection, Careram ® Tablets, YAZ ®,XEPLION ® Aqueous Suspension, SOVRIAD ®
Capsules, and Lamictal® Tablets. Because the RelatedMaterials for Patients were not available on thewebsites of PMDA or the pharmaceutical companies,
we obtained the respective Related Materials forPatients directly from the companies. In November
2019, we obtained the Blue Letter for Healthcare
Professionals and Patients as well as the RelatedMaterial for Patients for another drug, Verzenio®, fromthe PMDA website.

2.2. Blue Letter basic information
The international nonproprietary names (INNs) andindications were extracted from the package insert foreach drug by T.S. (a pharmacist). Thereafter, information
regarding severe adverse reactions was extracted fromthe Blue Letters by T.S. in January 2020.
2.3. Format and contents of the Blue Letters for Patientsand Related Materials for Patients
In January 2020, A.Y. (Master of Public Health,
MPH) and T.S. independently counted the pages of
the Related Materials for Patients and extracted thedate of development as well as contents from each
Related Materials for Patients document. Thereafter,
the materials were assessed. To count the characters in
the materials, the PDF documents were converted to
Microsoft Word® format, and the software's charactercounting tool was used.
2.4. Assessment of materials based on the CCI
The CCI was downloaded from the CDC website (13)along with the user's guide (8) and full index (14). The
author and co-authors confirmed the criteria in the CDC
CCI user's guide for the assessment of materials.
The CCI is divided into the following sevencategories: main message and call to action, language,
information design, state of science, behavioral
recommendations, numbers, and risk. Each of thesecontains 20 items, with a rating of 0 or 1. The individual
scores were converted to an overall score of 100. A
CCI percentage score of ≥ 90 would indicate that theevaluated material is clear and understandable.
The materials were assessed between January 20
and February 26, 2020. A.Y. (MPH), M.Y. (Pharmacist),
K.Y. (Pharmacist), and T.N. (MD) discussed anddefined "the main message" and "call to action" inorder to understand the details and factors that led tothe issue of the document (i.e., the Blue Letter), with afocus on severe adverse reactions as well as signs andsymptoms. Furthermore, three assessors (A.Y., M.Y.,and K.Y.) confirmed the "behavioral recommendations"and "risk" in these materials. Based on "the main
message" and "call to action", the three assessors
independently scored the Blue Letter for Patients andRelated Materials for Patients, with one point for "yes"and zero for "no" per CCI item. After the first round of
scoring, the first author (A.Y.) collected the scores fromthe other assessors and compared them. For items withdifferent scores, each author described their reason forscoring, and the assessors once again scored the items
independently (the second round of scoring). After
discussing differences in the third round of scoring, thescores were revised to obtain the final scores. Finally,
A.Y. compiled all the scores.

www.ddtjournal.com

103

www.ddtjournal.com

646
696
639
636
657
Blue Letters: Rapid Safety Communications. Excerpt from the drug package inserts.

1002
1005
Number of characters

2

6-1
5-1
4-1
3-1
2-1
1-1
Material No.

Blue Letters for Patients1

7-1

2019.5.17
2015.2.4
2014.10.24
2014.4.17
2013.5.17
2012.9.11
Issue date for professionals

2014.1.17

Interstitial
pneumonia
Serious skin disorders
Hyperbilirubinemia
Fatal cases
Serious bleeding
Serious hypocalcemia
Severe adverse reactions

Thrombosis

Breast cancer
Bipolar disorder, epilepsy
Chronic
hepatitis C
Schizophrenia
Rheumatoid arthritis

Dysmenorrhea

Lamotrigine

Bone lesion associated with multiple
myeloma or bone metastases from solid
tumorsCareram® Tablets
RANMARK® Subcutaneous Injection
Product name

The "main message" and "call to action" were defined
as follows:
Main message: Because severe adverse reactions
have occurred, be aware of the relevant signs andsymptoms.
Call to action: If these signs and symptoms appear (orin the case of contraindication), consult your physician or
pharmacist.

Blue Letters for healthcare professionals

3.3 Evaluation of materials in accordance with the CCI

Table 1. Characteristics of Blue Letters1

Table 2 presents a summary of the format and contentsof the obtained Related Materials for Patients. Somepatient materials did not contain an issue date. Theyvaried in the number of pages (between 1 and 6) andcharacters (between 447 and 2832). All materials were
presented in color, with illustrations lacking only in one.
Three materials contained the indications of the relevant
drugs. Two of the materials included photographs ofthe drug. All materials, excluding that for SOVRIAD®
Capsules, contained information on the signs andsymptoms of severe adverse reactions, and all materials
contained the recommendation to consult a physician
or pharmacist. We then searched materials for thecontact information for the pharmaceutical companies
and medical institutes. One material contained only theformer, another included only the latter, three contained
both, and two included no contact information at all.

YAZ®

3.2. Format and contents of the Related Materials forPatients

Indication2

XEPLION® Aqueous
Suspension

Seven Blue Letters, one for each of the seven drugs,
were issued before January 10, 2020. For each drug, theINN, indications, and severe adverse reactions list, as
well as the issue date and the number of characters in
the relevant Blue Letter for Patients, are summarized inTable 1. The number of characters varied between 636
and 1005.
In addition, we obtained seven Related Materials
for Patients from pharmaceutical companies or the
PMDA website. The material for XEPLION® Aqueous
Suspension was not available, and we obtained two
separate documents for Lamictal® Tablets.

Simeprevir

SOVRIAD® Capsules

3.1. Materials obtained

Drospirenone,
Paliperidone
Ethinyl estradiol

3. Results

Iguratimod

Lamictal® Tablets

The internal agreement of assessors for CCI scoring
was computed using the Fleiss's κ-value (15). Other
statistical analyses (the mean score and standard errorof mean, t-test to assess the difference in the averagescores of two materials) were performed using R ®
software version 3.4.3. and Microsoft Excel®.

International Nonproprietary Name (INN) Denosumab

Verzenio®

2.5. Statistics

Abemaciclib

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.

104

Main adverse
effects##
Mention in FAQ.

○○
Supervisor○○○● How to store the medicine.
● Symptoms of main adverse
reactions.
● Caution on pregnancy andbreastfeeding during treatment.

○

○#
○#
○
○
○
○

○

○
○
○#
○#
○#

○

○
○

○

7-2
2019.61513
6-3
2015.662832
6-2
2015.3
3
447
5-2
2016.52
1164

Based on the "main message" and "call to action,"
three assessors graded the seven Blue Letters and six
Related Materials for Patients with a score of 0 or 1 per
CCI item. The assessment results are presented in Table 3.
The material for SOVRIAD® Capsules was excluded
from CCI base assessment because it did not mention
severe adverse events and only provided information
on how to take the medicine. In total, 13 materials
were assessed. Reliability analysis showed substantial
agreement among the assessors (κ = 0.64). The averagescores and standard errors of the means for the threeassessors were 68.8 ± 2.8 and 74.3 ± 2.8 for the Blue
Letters for Patients and Related Materials for Patients,
respectively. None of the materials reached a CCI scoreof 90%, which is the threshold for patient materials to
be considered comprehensible.
3.3.1. Core
The "main message" (item #1) and "call to action" (#5)
were found in almost all the Blue Letters for Patients.
All Blue Letters for Patients were evaluated with
"No" for #4 (visual support). However, some of theillustrations supported the main message in four of theRelated Materials for Patients. All text in the RelatedMaterials for Patients was in the active voice (#6). In a
few of the Blue Letters for Patients, the main message
was written in the passive voice. Approximately
half of the materials included words that are notcommonly used by the primary audience (#7). Bulleted
or numbered lists were included (#8), and the mostimportant information (main message) was presented
at the top of the materials (#10) in all documents
evaluated. "What's known and what's not" (#11, state ofscience,) was explained in only one material (4-1).

● Be cautious of the adverse
reactions in carriers of the card.
● Instruction to follow doctor's
directions.
● Space for medical center use.

○

○
○
○
○
○
○
○
○

○
○

Two reviewers extracted data from each material and summarized them.

Material No.
1-2
Issue date for patients
Not foundNumber of pages
6
Number of characters1732
1
Contents
Indication
Contraindication
Risk of severe adverse reactions○
Subjective symptoms of severe adverse reactions○
How to take the drug
Drug photo–
Recommendation to consult a doctor○
Recommended preventive behavior○
Taking the drug as directed
Contact information; pharmaceutical company○
Contact information; medical institute○
Others● High-risk patients● Mechanism ofserious adverse
reaction

3.3.2. Behavioral recommendation"Call to action" was regarded as a "behavioral
recommendation," and #12-14 were scored with "Yes"for all materials, except one (2-2).
3.3.3. Numbers and risk
We evaluated only the numbers related to severe
adverse reactions. None of the materials were scoredon this part. Thus, part C was excluded from thecalculation of total score percentage. The nature of therisk (#18) was not explained in three of the Blue Lettersfor Patients and four of the Related Materials, while therisks and benefits of the recommended behaviors (#19)
were not addressed in any of the materials.
4. Discussion
In this study, we evaluated the adequacy of two typesof rapid safety communication materials regarding

1

○

○
○

○
○

3-2
Not found
4764
2-2
2016.52855

No material

YAZ®
Careram® Tablets
RANMARK®
Subcutaneous
Injection
Product name

Table 2. Characteristics of the Related Materials for PatientsXEPLION®
AqueousSuspension

SOVRIAD® Capsules

Lamictal® Tablets

Verzenio®

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.

www.ddtjournal.com

www.ddtjournal.com

Part B: Behavioral
Recommendations

20

15
16
17
18
19

14

Does the material contain one main message statement?
Is the main message at the top, beginning, or front of the material?
Is the main message emphasized with visual cues?
Does the material contain at least one visual that conveys or supports
the main message?
Does the material include one or more calls to action for the primary
audience?
Do both the main message and the call to action use the active voice?
Does the material always use words the primary audience uses?
Does the material use bulleted or numbered lists?
Is the material organized in chunks with headings?
Is the most important information the primary audience needssummarized in the first paragraph or section?
Does the material explain what authoritative sources, such as subject
matter experts and agency spokespersons, know and don't know about
the topic?
Does the material include one or more behavioral recommendations forthe primary audience?
Does the material explain why the behavioral recommendation(s) is
important to the primary audience?
Does the behavioral recommendation(s) include specific directions
about how to perform the behavior?
Does the material always present numbers the primary audience uses?
Does the material always explain what the numbers mean?
Does the audience have to conduct mathematical calculations?
Does the material explain the nature of the risk?
Does the material address both the risks and benefits of therecommended behaviors?
If the material uses numeric probability to describe risk, is theprobability also explained with words or a visual?
Mean total score % for 3 reviewers
Standard error of mean

Questions

2-1

3

3

3

3

4-1

5-1

6-1

7-1

3
0

3

3

3

0

3
3
3
3
3

3

3
3
3
0

3
0

3

3

3

2

1
3
3
0
3

3

3
0
0
0

0
0

3

3

3

0

3
0
3
3
3

3

3
3
3
0

0
0

3

3

3

0

3
3
3
3
3

3

3
3
2
0

0
0

3

3

3

0

3
0
3
3
3

3

3
3
3
0

68.8 58.3 81.3 62.5 68.8 72.9 68.8
3.6 2.1 0.0 0.0 0.0 2.1 0.0

0
0

3

3

3
0

3

0

3

0

1
0
3
0
3

3
3
3
0

3
3
3
0

1
2
3
0
3

3-1

No. of reviewers who answered 'Yes'

1-1

Blue Letter for Patients1

68.8
2.8

1.3
0.0

3.0

3.0

3.0

0.3

2.1
1.6
3.0
1.7
3.0

3.0

3.0
2.6
2.4
0.0

Mean scoreof 3 reviewers
for 7 materials
3-2

0
0

3

0

3

0

3
3
3
3
3

3

2
2
2
0

0
0

3

3

3

0

3
3
3
3
3

3

3
3
2
0

5-2

6-2

6-3

-

-

-

-

-

-

-

-

-

7-2

0
0

3

3

3

0

3
0
3
3
2

3

3
3
3
3

3
0

3

3

3

0

3
0
3
3
3

3

3
3
3
3

0.64

75 72.9 81.3
0.0 2.1 0.0

0
0

3

3

3

0

3
3
3
0
3

3

3
3
3
3

Overall κ-value

81.3 62.5 72.9
0.0 6.3 2.1

3
0

3

3

3

0

3
0
3
3
3

3

3
3
3
3

2-2

No. of reviewers who answered 'Yes'

1-2

74.3
2.8

1.0
0.0

3.0

2.5

3.0

0.0

3.0
1.5
3.0
2.5
2.8

3.0

2.8
2.8
2.7
2.0

Mean scoreof 3 reviewers
for 6 materials

Related Materials for Patients2

Blue Letter for Patients; 1-1 RANMARK® Subcutaneous Injection, 2-1 Careram® Tablets, 3-1 YAZ®, 4-1 XEPLION® Aqueous Suspension, 5-1 SOVRIAD® Capsules, 6-1 Lamictal®. 2Related Materials for Patients; 1-2
RANMARK® Subcutaneous Injection, 2-2 Careram® Tablets, 3-2 YAZ®, 5-2 SOVRIAD® Capsules, 6-2 Lamictal® Tablets, 6-3 Lamictal® Tablets

1

Part D: Risk

Part C: Numbers

12State of Science

13

11

Information Design

5

1
2
3
4

No.

6
7
8
9
10

Language

Part A: Core
Main Message andCall to Action

Part

Table 3. Clear Communication Index Scores for Blue Letters for patients and the Related Materials

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.
105

106

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.

severe adverse reactions for patients in Japan and foundthat these materials have several areas that require
improvement. In particular, none of the assessed materials
achieved the threshold (≥ 90%) CCI score. Furthermore,
the descriptions regarding "language," "state of science,"and "risk" were not adequate. The effectiveness of risk
communication is often judged based on whether theintended audience took effective action (16). Fischhoff(16) lists the following requirements for adequate risk
communication: (a) the information needed for effective
decision making, (b) accessibility of the information, and(c) comprehensibility. The results of our study suggest
that, overall, Japanese rapid safety communicationmaterials for patients have a few issues, particularly
related to the comprehensibility of risks.
Most of the materials in the Blue Letters for Patientsand Related Materials for Patients contained a "mainmessage" (#1, i.e., "the occurrence of severe adverse
reactions and warning of the symptoms") and a "call toaction" (#5, i.e., "consult a physician or pharmacist").
These items are considered sufficient minimum
information with which to make a decision (16).
However, there was a lack of information on "what's
known and what's not" provided by authorities (state ofscience, #11), such as the details and number of severe
adverse reaction cases or the uncertainty of association
between adverse reactions and the drug concerned, as
well as on the "risks and benefits of the recommended
behaviors" (#19). Davis reported that patients preferred
specific, detailed information about adverse effects (17).
According to Suka et al., several Japanese lay peopleindicated that they believe all information should be
disclosed (18). These patients' information needs should
be considered.
In the current study, we did not find detailed
information on adverse reaction frequency in any ofthe materials (Part C). The quality of information on
severity and frequency affects risk perception in relation
to adverse reactions (19). Further research is required
to establish effective adverse reaction risk perception in
Japanese patients.
Accessibility refers to the following two aspects:
access to information sources (i.e., drug safety materials)
and access to message content (i.e., main message andcall to action) (16). The CCI user's guide highlights how
to disseminate rapid safety communication materials,
and Japanese authorities have requested that materials be
widely disseminated to the public as well as patients. To
the best of our knowledge, there are no studies assessing
ease of access to rapid safety communication materials.
Accessibility, defined as access to message content, canbe evaluated based on CCI items #2-4 (7,10). The Blue
Letters for Patients lacked visual components (#4), suchas illustrations, due to the requirement for their rapid
publication. Nevertheless, the materials were concise,and the main messages were accessible because they
were presented in the front (#2) and emphasized withvisual cues (#3), except for one material. In contrast,
most Related Materials for Patients varied in format
and content, were colorful, and had a user-friendly
appearance. However, their main messages may beunclear to patients, due to the substantial amount of
information distributed across several pages, including
extensive information on dosage.
In the current study, we identified some key issues
regarding the comprehensibility of Japanese rapid drug
safety information materials for patients. First, therisks of severe adverse reactions were not explicitly
mentioned in some of the materials. To prevent severe
adverse reactions, it is of utmost importance thatpatients are able to perceive the signs and symptoms
and take appropriate actions (20). However, somematerials did not clearly explain the severity of healthoutcomes (for example, "interstitial pneumonia").
Second, some materials used only medical terms (forexample, "jaundice"), while it is necessary to explain
risks and symptoms in a manner that lay people canunderstand. Illustrations may help promote a better
understanding of medical terms. Third, with regard
to voice (#6 in the CCI), the main messages of somematerials were presented in the passive voice, as in"the case was reported." Japanese people tend to use
the passive voice more often than Westerners, due tothe characteristics of the language. However, in theJapanese language, the passive voice is also used to
imply possibility, spontaneity, and respect. For thisreason, drug safety materials should be written in theactive voice as much as possible, in order to improve
comprehensibility among the broader readership.
The current study had some limitations. First,
although the Related Materials were obtained from thepharmaceutical companies, some materials might havebeen developed with intentions other than warning
patients about serious adverse reactions. Further, as
pharmacists and/or MPH professionals, the assessors
might have been generous in scoring item #7 "usewords that the primary audience use."
In conclusion, several concerns regarding
the comprehensibility of Japanese rapid safety
communication materials on drugs for patients wereidentified in this study. In particular, the language
used and the explanation of the nature of risks shouldbe improved. In addition, Japanese authorities should
build a system for evaluating materials for patients
based on indices, such as CCI, for use prior to material
publication.
Acknowledgements
We thank the companies that kindly provided relevant
information and literature. We thank Saito Y, Fujimoto
S, Shinohara K, Tsuji N, Neff Y, Sasaki S, and Kitazawa
K for performing the pilot assessment as well as
Yaguchi T and Editage for proofreading the manuscript.

www.ddtjournal.com

Drug Discoveries & Therapeutics. 2021; 15(2):101-107.
Funding: This work was supported by the Japan Agency
for Medical Research and Development [grant number
JP19mk0101114].
Conflict of Interest: The authors have no conflicts ofinterest to disclose.
References
1.

Morgan MG, Fischhoff B, Bostrom A, Atman CJ. Risk
Communication: A Mental Models Approach. Cambridge
University Press, Cambridge, UK, 2002; p.4.
2. Ministry of Health, Labour and Welfare (MHLW).
Guidelines for provision of emergency safety information.
https://www.mhlw.go.jp/file/06-Seisakujouhou-11120000Iyakushokuhinkyoku/0000064222.pdf (accessed June 12,2018). (in Japanese)
3. Pharmaceuticals and Medical Devices Agency (PMDA).
The list of Blue Letters. https://www.pmda.go.jp/safety/
info-services/drugs/calling-attention/esc-rsc/0001.html(accessed June 12, 2018). (in Japanese)
4. Pharmaceuticals and Medical Devices Agency (PMDA).
The list of Blue Letters for patients. https://www.pmda.
go.jp/safety/info-services/drugs/calling-attention/
properly-use-alert/0005_c.html (accessed June 12,2018). (in Japanese)
5. National Institutes of Health. Clear & Simple. https://www.nih.gov/institutes-nih/nih-office-director/officecommunications-public-liaison/clear-communication/clear-simple (accessed June 12, 2018).
6. Centers for Medicare & Medicaid Services. Toolkit formaking written material clear and effective. https://www.cms.gov/Outreach-and-Education/Outreach/
WrittenMaterialsToolkit (accessed June 12, 2018).
7. Baur C, Prue C. The CDC Clear Communication Index isa new evidence-based tool to prepare and review healthinformation. Health Promot Pract. 2014; 15:629-637.
8. Centers for Disease Control and Prevention. CDC Clear
Communication Index User's Guide. https://www.cdc.
gov/ccindex/pdf/ClearCommUserGuide.pdf (accessed
June 12, 2018).
9. Phetxumphou K, Roy S, Davy BM, Estabrooks PA,
You W, Dietrich AM. Assessing clarity of message
communication for mandated USEPA drinking water
quality reports. J Water Health. 2016; 14:223-235.
10. Lopez Ramos C, Williams JE, Bababekov YJ, Chang DC,
Carter BS, Jones PS. Assessing the understandability andactionability of online neurosurgical patient educationmaterials. World Neurosurg. 2019; 130:e588-e597.
11. Porter KJ, Alexander R, Perzynski KM, Kruzliakova N,
Zoellner JM. Using the clear communication index toimprove materials for a behavioral intervention. HealthCommun. 2019; 34:782-788.
12. Suka M, Yamauchi T, Yanagisawa H. Comparing
responses to differently framed and formatted persuasive
messages to encourage help-seeking for depression in
Japanese adults: a cross-sectional study with 2-monthfollow-up. BMJ Open. 2018; 8:e020823.

107

13. Centers for Disease Control and Prevention. The CDC
Clear Communication Index. https://www.cdc.gov/
ccindex/index.html (accessed June 12, 2018).
14. Centers for Disease Control and Prevention. CDC Clear
Communication Index Score Sheet. https://www.cdc.gov/
ccindex/pdf/full-index-score-sheet.pdf (accessed June 12,2018).
15. Bartko JJ, Carpenter WT, Jr. On the methods and theoryof reliability. J Nerv Ment Dis. 1976; 163:307-317.
16. F i s c h h o f f B . C h a p t e r 4 : D u t y t o I n f o r m . I n :Communicating Risks and Benefits: An Evidence-Based
User's Guide (Fischhoff B, Brewer NT, Downs JS, eds.).
U.S. Department of Health and Human Services, Foodand Drug Administration, MD, USA, 2012; pp. 19-29.
17. Davis JJ. Consumers' preferences for the communicationof risk information in drug advertising. Health Aff(Millwood). 2007; 26:863-870.
18. Suka M, Odajima T, Orii T, Doi Y, Nakayama T,
Yamamoto M, Sugimori H. A questionnaire survey on
drug information — information-seeking behaviors
and public attitudes toward drug information. J Jpn Soc
Healthcare Admin. 2011; 48:235-241. (in Japanese)
19. Berry D, Michas I, Bersellini E. Communicating
information about medication side effects: Effects on
satisfaction, perceived risk to health, and intention tocomply. Psychol Health. 2002; 17:247-267.
20. Andrews JC. Chapter 15: Warnings and Disclosures. In:
Communicating Risks and Benefits: An Evidence-Based
User's Guide (Fischhoff B, Brewer NT, Downs JS, eds.).
U.S. Department of Health and Human Services, Foodand Drug Administration, MD, USA, 2012; pp. 149-161.
Received March 22, 2021; Revised April 21, 2021; Accepted
April 25, 2021.
§

These authors contributed equally to this work.
*Address correspondence to:Michiko Yamamoto, Graduate School of Pharmaceutical
Sciences, Kumamoto University, 5-1, Oe-honmachi,
Kumamoto, 862-0973 Japan
E-mail: m-yamamoto@kumamoto-u.ac.jp
Released online in J-STAGE as advance publication April 30,
2021.

Supplementary Material
The Blue Letters for patients
1-1 https://www.pmda.go.jp/files/000148240.pdf
2-1 https://www.pmda.go.jp/files/000148446.pdf
3-1 https://www.pmda.go.jp/files/000148622.pdf
4-1 https://www.pmda.go.jp/files/000148732.pdf
5-1 https://www.pmda.go.jp/files/000147341.pdf
6-1 https://www.pmda.go.jp/files/000198340.pdf
7-1 https://www.pmda.go.jp/files/000229599.pdf

www.ddtjournal.com