Vyndaqel Capsules Special Investigation -Investigation on Long-term Use-
Conditions: Transthyretin Familial Amyloid Polyneuropathy
Sponsor: Pfizer

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(Appendix) 
 
 
 
Vyndaqel Capsules Special Investigation 
- Investigation on long-term use - 
Protocol 
 
 
 
 
 
 
 
 
 
Pfizer Japan Inc. 
 
This document contains confidential information belonging to Pfizer. Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes. In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 

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STUDY INFORMATION 
Title 
Vyndaqel Capsules Special Investigation 
- Investigation on long-term use -
Protocol number  
B3461042 
Protocol version identifier 
5.0 
Date of last version of protocol 
1 December 2018 (Ver. 4.0) 
Active substance 
Tafamidis meglumine 
Medicinal product 
 
Vyndaqel® Capsules 20 mg 
Research question and objectives 
To comprehend information on the safety (e.g., 
onset status of adverse reactions) and efficacy of 
this drug in the long-term use under the 
post-marketing actual use in all patients receiving 
this drug. Review on the onset status of 
hepatotoxicity will be set as a major investigation 
item in this study. 
<<Conditions for approval: Because the number of 
study participants in Japan is very limited, a drug 
use investigation in all patients should be 
conducted during the reexamination period to grasp 
the background information on patients using this 
drug, collect data on the safety and efficacy of this 
drug early, and take necessary measures for proper 
use of this drug.>> 
Author 
 
Post Marketing Study Strategy and Management 
PMS Planning & Operation Group 1 
PPD

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................... 3 
1. 
LIST OF ABBREVIATIONS ........................................................................................................ 6 
2. 
RESPONSIBLE PARTIES ............................................................................................................ 7 
3. 
AMENDMENTS AND UPDATES ............................................................................................... 8 
4. 
MILESTONES ............................................................................................................................. 10 
5. 
RATIONALE AND BACKGROUND ........................................................................................ 10 
6. 
RESEARCH QUESTION AND OBJECTIVES .......................................................................... 11 
6.1. Safety specifications ....................................................................................................................... 12 
7. 
RESEARCH METHODS ............................................................................................................. 12 
7.1. Study design.................................................................................................................................... 12 
7.2. Setting ............................................................................................................................................. 12 
7.2.1. Sites for this study .............................................................................................................. 12 
7.2.2. Duration of study ................................................................................................................ 12 
7.2.3. Study procedures ................................................................................................................ 12 
7.2.3.1. Study method ...................................................................................................... 12 
7.2.4. Observation period ............................................................................................................. 12 
7.3. Registration items and study items ................................................................................................. 14 
7.3.1. Registration items ............................................................................................................... 15 
7.3.2. Study items ......................................................................................................................... 15 
7.3.2.1. Information to identify the subject ..................................................................... 15 
7.3.2.2. State of concurrent medical examination ........................................................... 15 
7.3.2.3. Patient characteristics ......................................................................................... 16 
7.3.2.4. Previous treatment drugs .................................................................................... 16 
7.3.2.5. Pregnancy ........................................................................................................... 17 
7.3.2.6. Targeted drug use record .................................................................................... 17 
7.3.2.7. Concomitant therapy .......................................................................................... 17 
7.3.2.8. Tests/clinical laboratory tests ............................................................................. 17 
7.3.2.9. Medical assessment of physical symptoms ........................................................ 21 
7.3.2.10. End-of-study (discontinuation) record .............................................................. 22 
7.3.2.11. Effectiveness evaluation ................................................................................... 22 
7.3.2.12. Adverse events ................................................................................................. 22 
7.3.2.13. Confirmation of survival .................................................................................. 23 
7.3.2.14. Major investigation items ................................................................................. 24 

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7.3.2.15. Confirmation of description concerning adverse events corresponding to 
major investigation item .................................................................................. 24 
7.4. Data sources .................................................................................................................................... 24 
7.5. Study size ........................................................................................................................................ 24 
7.5.1. Planned sample size ........................................................................................................... 24 
7.5.2. Rationale for sample size ................................................................................................... 24 
7.6. Data management ........................................................................................................................... 25 
7.6.1. Case report forms (CRFs)/ Electronic data record ............................................................. 25 
7.6.2. Record retention ................................................................................................................. 25 
7.6.3. Data collection method ....................................................................................................... 25 
7.6.4. Patient registration.............................................................................................................. 25 
7.6.4.1. Procedure of patient registration ........................................................................ 25 
7.6.4.2. Confirmation of patients registered .................................................................... 26 
7.6.5. Reminders concerning completing, revising, and submission of case report form ............ 26 
7.6.5.1. Completing ......................................................................................................... 26 
7.6.5.2. Revising .............................................................................................................. 26 
7.6.5.3. Confirming ......................................................................................................... 26 
7.6.5.4. Submitting .......................................................................................................... 26 
7.7. Data analysis ................................................................................................................................... 26 
7.8. Quality control ................................................................................................................................ 26 
7.9. Limitations of the research methods ............................................................................................... 27 
7.10. Other aspects ................................................................................................................................. 27 
8. 
PROTECTION OF HUMAN SUBJECTS ................................................................................... 27 
8.1. Patient information ......................................................................................................................... 27 
8.2. Patient consent ................................................................................................................................ 27 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ...................................... 27 
8.4. Ethical conduct of the study ............................................................................................................ 27 
9. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ............................................................................................................................................... 28 
9.1. Requirements .................................................................................................................................. 28 
9.2. Reporting period ............................................................................................................................. 29 
9.3. Causality assessment....................................................................................................................... 29 
9.4. Definitions of safety events ............................................................................................................ 29 
9.4.1. Adverse events ................................................................................................................... 29 
9.4.2. Serious adverse events ....................................................................................................... 30 

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9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours ................................... 32 
9.5. Single reference safety document ................................................................................................... 34 
10. 
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS .................. 34 
11. 
ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION ...................................... 34 
12. 
NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON WHO 
WAS CONTRACTED WITH THE OPERATIONS ................................................................................... 35 
13. 
ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE 
SURVEY RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION ...................... 35 
14. 
SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR 
REPORTING OF STUDY IMPLEMENTATION STATUS AND EVALUATION OF OBTAINED 
RESULTS TO THE PMDA ......................................................................................................................... 35 
15. 
OTHER NECESSARY MATTERS ............................................................................................. 35 
16. 
CONTACT INFORMATION ...................................................................................................... 35 
16.1. Contact information for the contents of the study ......................................................................... 35 
17. 
REFERENCES ............................................................................................................................. 37 
18. 
LIST OF TABLES ....................................................................................................................... 37 
19. 
LIST OF FIGURES ...................................................................................................................... 37 
20. 
LIST OF STAND ALONE DOCUMENTS ................................................................................. 37 
21. 
ADDITIONAL INFORMATION ................................................................................................ 37 

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1. 
LIST OF ABBREVIATIONS 
Acronym 
Title  
AE
Adverse event
ALT
Alanine transaminase
AL-P
Alkaline phosphatase
AST
Aspartate transaminase
EDP
Exposure during pregnancy
FT4
Free thyroxine
GOT
Glutamic oxaloacetic transaminase
GPT
Glutamic pyruvic transaminase
-GTP
-glutamyl transpeptidase
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LDH
Lactate dehydrogenase isozyme
mBMI
modified body mass index
N/A
Not applicable
NIS
Non interventional study
NIS
Neuropathy Impairment Score
QOL
Quality of life
QOL-DN
Quality of Life-Diabetic Neuropathy
SAE
Serious adverse event
T4
Thyroxine
THAOS
Transthyretin-Associated Amyloidosis Outcomes Survey
TTR
Transthyretin
TTR-FAP
Transthyretin familial amyloid polyneuropathy
SRSD
Single Reference Safety Document
TSH
Thyroid-stimulating hormone

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2. 
RESPONSIBLE PARTIES 
The Good Post Marketing Study Practice officer 
 
Principal Investigator(s) of the Protocol 
N/A 

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3. 
AMENDMENTS AND UPDATES 
Amen
dment 
numbe
r 
 
Date 
Substantial or 
administrative 
amendment 
Protocol 
section(s) 
changed 
 
Summary of 
amendments 
Reason 
5.0 
28 March 
2019 
Amendment of 
the investigated 
contents 
Sections 7.2.4, 
7.3.2.10, 
7.3.2.13, 8.2 
If the dose of 
Vyndaqel is changed 
for the treatment of 
ATTR-CM, the 
investigation will be 
discontinued. 
Since the special 
investigation of 
ATTR-CM (all-cases 
survey) will be 
conducted in 
association with the 
added indication of 
ATTR-CM, the 
withdrawal criteria for 
the investigation were 
set in order to 
prioritize registration 
to the investigation on 
major diseases for 
treatment.
Other 
amendment(s) 
Section 7.6 
Additional 
descriptions of 
Sections 7.6.1 and 
7.6.2 and 
improvement of 
descriptions of Section 
7.6.5.2 accordingly 
Additional descriptions 
due to amendment of a 
company template and 
improvement of 
descriptions 
accordingly, which 
will not affect the 
contents of 
investigation.  
Because the contents 
of descriptions were 
reexamined and 
improved.
Other 
amendment(s) 
Sections 8 and 
9 
Update of contents of 
descriptions 
Amendment due to the 
amendment of a 
company template, 
which will not affect 
the contents of 
investigation. 
Other 
amendment(s) 
All 
Change of wording 
without change of 
meaning such as 
correction of errors in 
writing and 
unification/change, 
etc. of terms
Because the contents 
of descriptions were 
reexamined and 
improved. 
4.0 
1 December 
2018
Other 
amendment(s)
Study items 
Correction of errors in 
writing
Because of errors in 
writing

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Other 
amendment(s) 
Definitions of 
safety events 
The definition of 
“discontinuation of 
treatment” was 
changed to “drug 
withdrawal”.
Due to reexamination 
of Japanese translation
Other 
amendment(s) 
NAME, 
ADDRESS 
AND 
OUTSOURCE
D 
OPERATION
S OF THE 
PERSON 
WHO WAS 
CONTRACTE
D WITH THE 
OPERATION
S
Addition of a 
contractor 
Addition as a result of 
establishment of Pfizer 
R&D Japan G.K. 
Other 
amendment(s) 
CONTACT 
INFORMATI
ON
Change of the 
company name 
Change as a result of 
establishment of Pfizer 
R&D Japan G.K.
3.0 
19 May 
2017 
Amendment of 
the planned 
contents
Study items 
Addition of 
“confirmation of 
survival”
Because it was 
necessary to confirm 
the survival status
Other 
amendment(s) 
Registration 
items 
Addition of “Presence 
or absence of having 
received/used 
Vyndaqel at other 
sites, and if Yes, 
patient’s duration of 
treatment (name of the 
site if the treatment 
period is 3 years or 
longer)”
Because patients who 
have received/used 
Vyndaqel at other sites 
for more than 3 years 
are not subject to this 
study 
Other 
amendment(s) 
Study items 
Change in the timing 
of evaluation of 
physical symptoms
Because there was 
inconsistency with the 
CRF
Other 
amendment(s) 
Observation 
period 
The observation 
period for subjects 
who discontinued the 
treatment was clearly 
stated.
Because the 
observation period was 
accurately described 
Other 
amendment(s) 
Planned 
period of 
investigation 
It was described as 
“the transition to 
registration only after 
the registration period 
will be implemented 
after consultation with 
the PMDA”.
Added as instructed by 
PMDA 

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Other 
amendment(s)
All 
Correction of errors in 
writing
Because of errors in 
writing
2.0 
10 August 
2015 
Other 
amendment(s) 
All 
Adverse 
events 
Response to a new 
company form 
The form used in the 
company was changed 
and the description of 
requirements for 
reporting of adverse 
events which had been 
handled as Appendix 
was added to the text, 
and other items to be 
described were added. 
Therefore, a new form 
was applied. 
Other 
amendment(s) 
Observation 
period 
The definition of 
patients whose 
observation period is 
1.5 years was changed 
from “Patients 
registered after May 
2018” to “Patients 
who started to receive 
Vyndaqel after May 
2018”.
The definition of 
patients with the 
observation period of 
1.5 years was 
accurately described. 
1.1 
7 November 
2013 
Other 
amendment(s) 
Patient 
registration 
Additional description 
of FAX number of 
Patient Registration 
Center
Because new 
information was 
obtained 
1.0 
8 October 
2013
N/A 
N/A 
N/A 
N/A 
 
4. 
MILESTONES 
Milestone 
Planned date 
Start of data collection
November 2013
End of data collection
May 2021
Final study report
To be determined
 
5. 
RATIONALE AND BACKGROUND 
Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, highly heritable disease in which 
amyloid derived from transthyretin (TTR) is deposited in the peripheral and autonomic nervous systems, 
thereby causing dysfunction. In Japan, patients are accumulated in Nagano and Kumamoto prefectures. It 
is known that the onset of the disease in the accumulated area is young in the 30s and the duration of 
survival after the onset is approximately 10 years, which is extremely poor prognosis. However, the only 
treatment for TTR-FAP in Japan has been symptomatic treatment for each of the various symptoms 
associated with the disease. Liver transplant has been performed as the only method to suppress the 

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disease progression, but the target patients for liver transplant are very limited due to problems such as 
lack of donors and risk of transplant surgery. 
 
Vyndaqel (generic name: tafamidis meglumine) is a therapeutic agent for TTR-FAP with a novel 
mechanism of action that suppresses amyloid formation by binding to the thyroxine (T4) binding site of 
the TTR tetramer, stabilizing the TTR tetramer, and inhibiting its dissociation into monomers. The 
overseas clinical studies started in 2007 demonstrated the efficacy of Vyndaqel not only in delaying the 
progression of peripheral neuropathy, suppressing the decline of quality of life (QOL) and improving 
nutritional condition in patients with TTR-FAP but also in stabilizing TTR early after the start of treatment 
and maintaining TTR stabilization throughout the study period. As a result, Vyndaqel was approved in 
Europe in November 2011 and has been in the market. In Japan, the phase 1 study confirmed no difference 
in pharmacokinetics, TTR stabilization, and safety between Japanese and non-Japanese subjects. 
Furthermore, the domestic phase 3 clinical study in Japanese adult patients with TTR-FAP also 
demonstrated the efficacy and safety of Vyndaqel equivalent to those in the results of the overseas clinical 
studies. As a result, the application for approval was filed in February 2013 and the drug was approved in 
September 2013. 
 
The Special Investigation of Vyndaqel Capsules - Investigation on long-term use - (hereinafter referred to 
as this study) will be conducted to comprehend information on the safety (e.g., onset status of adverse 
reactions) and efficacy of Vyndaqel in the long-term use under the post-marketing actual use in patients 
receiving Vyndaqel Capsules (hereinafter referred to as this drug). This study will be conducted in all 
patients receiving this drug on the basis of the conditions for approval. The information collected in this 
study will be used to provide information on proper use and prepare application dossiers for reexamination. 
Therefore, this study must be conducted in strict compliance with the “Ordinance Concerning Standards 
for Conducting Post-Marketing Study and Studies on Pharmaceutical Products” (MHLW Ordinance No. 
171 dated December 20, 2004). The case data collected in this study will be reported to the Ministry of 
Health, Labour and Welfare (MHLW) according to the Pharmaceuticals and Medical Devices (PMD) Act. 
In this case, the data may also be publicly posted in MHLW's “Pharmaceutical and Medical Device Safety 
Information” and “Pharmaceuticals and Medical Devices Information Website” 
(http://www.info.pmda.go.jp) as a listing of patients, which will include the information on names of drugs, 
adverse reactions, gender, and age (increment of 10 years). Furthermore, data collected may also be 
disclosed if the MHLW is required to disclose such information in accordance with the “Act on Access to 
Information Held by Administrative Organs” (Law No. 42 dated May 14, 1999); provided that in no event 
will the names of physicians, medical institutions, and other personal information be subject to such 
disclosure, nor will it be posted or disclosed in any form or shape.  
 
6. RESEARCH QUESTION AND OBJECTIVES 
To understand information on the safety (e.g., onset status of adverse reactions) and efficacy of this drug 
in the long-term use under the post-marketing actual use in all patients receiving this drug. Review on the 
onset status of hepatotoxicity will be set as a major investigation item in this study. 
 
 
 
  [Conditions for approval] 
Because the number of study participants in Japan is very limited, a drug use investigation in all patients 
should be conducted during the reexamination period to grasp the background information on patients 
using this drug, collect data on the safety and efficacy of this drug early, and take necessary measures for 
proper use of this drug. 

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6.1. Safety specifications 
[Important potential risks] Hepatotoxicity, hypersensitivity reaction, reproductive and developmental 
toxicity, infection 
[Important missing information] Patients with severe hepatic impairment 
 
7. RESEARCH METHODS 
7.1. Study design 
This study is a multi-center, cohort study of patients receiving/using this drug. The investigators complete 
the case report form (CRF) based on the information extracted from the medical charts created in daily 
medical practice. 
 
7.2. Setting 
All patients who received/used this drug will be targeted in this study. 
 
The indication, dosage and administration, and contraindications of this drug are as follows. When using 
this drug, refer to the latest package insert of this drug. 
[Indication] Suppression of progression of peripheral neuropathy in transthyretin familial amyloid polyneuropathy 
(TTR-FAP) 
 
[Dosage and administration] The usual adult dosage for oral use is 20 mg of tafamidis meglumine once daily. 
 
[CONTRAINDICATIONS] Patients with a history of hypersensitivity to any of the ingredients of this drug
 
7.2.1. Sites for this study 
This study will be conducted at all sites and medical departments that use this drug. 
 
7.2.2. Duration of study 
The planned period covered by this study is as follows. 
Duration of study: November 2013 to May 2021 (7.5 years) 
Registration period: November 2013 to November 2019 (6 years) 
A contract will be concluded after the start date of the study period, and then, the patient registration will 
be started. The transition to registration only after the registration period will be implemented after 
consultation with the Pharmaceuticals and Medical Devices Agency (PMDA). 
 
7.2.3. Study procedures 
7.2.3.1. Study method 
This study will be conducted by all-cases survey (including retrospective survey). 
 
 
7.2.4. Observation period 
3 years from the first day of treatment with this drug (156 weeks) 
However, the observation period for patients who started to receive this drug after May 2018 will be 1.5 
years (78 weeks). 

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If the treatment with this drug is discontinued during the observation period, the observation period will be 
until the day of discontinuation. If the dose of this drug is changed for the treatment of ATTR-CM, the 
observation period will be up to the date of last dose of 20 mg. 
This study will be conducted using booklet type CRF. 
The safety and efficacy assessments will be performed at the first visit (including the end date of the 
observation period) on or after the end date of the observation period (day of discontinuation if the 
treatment is discontinued during the observation period or date of the last dose of 20 mg if the dose was 
changed for the treatment of ATTR-CM). However, if a subject is lost to follow-up halfway through, the 
safety and efficacy assessments will be performed using the information on the last visit date. 
Booklet No. 
Observation period 
Booklet 1
First day of treatment to Week 78 (1.5 years)
Booklet 2
Week 79 to Week 156 (3 years)
 

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7.3. Registration items and study items 
This study will be conducted according to the following schedule of observation. 
Table 1. 
Schedule of observation 
Item 
Registr
ation 
form 
Booklet 1 
Booklet 2 
At start 
of the 
study 
Week 
52 
(1 year)
Week 
78 
(1.5 
years)
Week 
104 
(2 
years)
Week 
156 
(3 
years)
Information to identify the subject 
● 
● 
- 
- 
- 
- 
First day of treatment with this drug 
● 
 
- 
- 
- 
- 
Presence or absence of having received/used this 
drug at other sites, and if Yes, patient’s duration of 
treatment
● 
 
 
 
 
 
THAOS registration status/THAOS registration ID 
● 
 
 
 
 
 
State of concurrent medical examination 
- 
 
 
 
 
 
Background variables 
- 
● 
- 
- 
- 
- 
History of previous treatment drugs for the targeted 
disease
- 
● 
- 
- 
- 
- 
Targeted drug use record 
- 
 
 
 
 
 
Concomitant therapy (drug therapy/ non-drug therapy)
- 
 
 
 
 
 
General tests (height, body weight, pulse, blood 
pressure)
- 
 
 
 
 
 
Clinical laboratory tests 
- 
 
 
 
 
 
Plasma concentration of tafamidis 
(to be performed only for patients with severe hepatic 
impairment)
- 
 
 
 
 
 
Cardiovascular evaluation (ECG, echocardiography) 
- 
 
 
 
 
 
Assessment of neurological function (NIS) 
- 
● 
- 
● 
- 
● 
Quality of Life (QOL-DN) 
- 
● 
- 
● 
- 
● 
Ambulatory state 
- 
● 
- 
● 
- 
● 
Neurological assessment (motor function, tendon 
reflex, tactile sense, pain sensation, vibration sense, 
positional sense)
- 
● 
● 
- 
● 
● 
Medical assessment of physical symptoms 
- 
 
 
- 
 
 
Pregnancy 
- 
 
 
 
 
 
Record of study discontinuation 
- 
 
 
 
 
 
Confirmation of description concerning adverse 
events corresponding to major investigation item
- 
 
 
 
 
 
Adverse events and tests for adverse events 
- 
 
 
 
 
 
Confirmation of survival 
 
 
 
 
 
● 
 
 

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7.3.1. Registration items 
Enter the following information at the start of treatment with this drug in the registration form. The day 
when the treatment with this drug is started will be defined as “first day of treatment”. However, for 
subjects who participated in the clinical studies (including post-marketing clinical studies), the day when 
the treatment with a commercially available product of this drug is started will be defined as “first day of 
treatment”. For patients who have received/used this drug at other sites, the day when the treatment is 
started at the own site will be defined as “first day of treatment”*. However, if the drug is prescribed at 
another site and only the diagnosis of TTR-FAP is made at the own site, the day when the treatment with 
this drug is started at another site will be defined as “first day of treatment”. 
 
*If the patient has been receiving this drug for more than 3 years at the first day of treatment with this 
drug at the own site and the name of the site is known, only the patient registration will be made. 
 
(1) Name of site/department 
(2) ID number 
(3) Gender 
(4) Date of birth (age at the start of treatment with this drug at the site if the information cannot be 
disclosed) 
(5) First day of treatment with this drug 
(6) Presence or absence of having received/used this drug at other sites, and if Yes, patient’s duration 
of treatment (name of the site if the treatment period is 3 years or longer) 
For sites participating in THAOS** at the time of registration, the following information should also 
be entered: 
(1) THAOS registration status 
(2) THAOS case number 
**THAOS (Transthyretin-Associated Amyloidosis Outcomes Survey) is a multinational disease 
registry of all patients with TTR-associated amyloidosis (hereinafter referred to as ATTR) and 
participants who are not diagnosed with ATTR but have TTR mutations. 
 
7.3.2. Study items 
Enter the following information in CRF. 
 
7.3.2.1. Information to identify the subject 
(1) ID number 
(2) Gender 
(3) Date of birth (age at the start of treatment with this drug at the site if the information cannot be 
disclosed) 
 
For sites participating in THAOS within the observation period, the following information should also be 
entered: 
 
(1) THAOS registration status 
(2) THAOS case number 
 
7.3.2.2. State of concurrent medical examination 
Regarding the status of concurrent medical examination after the start of treatment with this drug until the 
end of observation period, enter the following information: 
 
(1) 
Prescription of this drug or treatment of the target disease at sites other than this hospital 

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(2) 
If Yes for concurrent medical examination, name of site 
 
7.3.2.3. Patient characteristics 
Enter the following information at the start of treatment with this drug. 
 
(1) Experience of treatment with this drug 
(2) Classification of inpatient/outpatient 
(3) Target disease and onset timing 
(4) Diagnosis of TTR amyloidosis 
(Mutant genotype and timing of identification, diagnostic method [including the conduct of tissue 
biopsy], Karnofsky index*) 
(5) Family history of TTR-FAP 
(6) Classification of accumulated cases/non-accumulated cases 
 Enter the classification of accumulated/non-accumulated area as the patient’s birthplace. 
 In this study, Nagano, Kumamoto, and Ishikawa prefectures are defined as accumulated areas. 
(7) History of organ transplant (timing of transplant, name of transplanted organ [including the 
presence or absence of liver transplant and its timing]) 
(8) Presence/absence and severity of hepatic/renal impairment 
 If “Yes” for hepatic impairment, enter the reason for judgment of severity. 
(9) Medical history (past history/complications) 
 
Table 2.  Karnofsky index 
 
*Karnofsky index (Karnofsky Performance Status) (%)2) – 8) 
100： Normal; no complaints; no evidence of disease. 
 90： Able to carry on normal activity; minor signs or symptoms of disease. 
 80： Normal activity with effort; some signs or symptoms of disease. 
 70： Cares for self; unable to carry on normal activity or to do active work. 
 60： Requires occasional assistance, but is able to care for most of their personal needs. 
 50： Requires considerable assistance and frequent medical care. 
 40： Disabled; requires special care and assistance. 
 30： Severely disabled; hospital admission is indicated although death not imminent.  
 20： Very sick; hospital admission is necessary although death not imminent.  
 10： Moribund; fatal processes progressing rapidly. 
  0： Dead 
 
7.3.2.4. Previous treatment drugs 
Enter all drugs used for the treatment of the target disease from 24 weeks before the start of treatment with 
this drug until the day before the first day of treatment (including NSAIDs). 
 
(1) Drug name, dosage form 
(2) Dose and frequency of daily dose 
(3) Duration of treatment 
(4) Reason for discontinuation 
 

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7.3.2.5. Pregnancy 
If the patient is female, enter the presence or absence of pregnancy (if she is pregnant, date of delivery or 
expected date of delivery) from the first day of treatment with this drug until the end of observation period 
(or date of discontinuation of treatment with this drug) in each booklet. 
 
7.3.2.6. Targeted drug use record 
Enter the following information on the status of using this drug from the first day of treatment with this 
drug until the end of observation period (or date of discontinuation of treatment with this drug). 
 
(1) Dose 
(2) Frequency of daily dose 
(3) Duration of treatment 
(4) Reason for change/washout 
 
7.3.2.7. Concomitant therapy 
7.3.2.7.1. Drug therapy 
For all drugs used from the first day of treatment with this drug until the end of the observation period (or 
date of discontinuation of treatment with this drug), enter the information on administration (e.g., name of 
drug [product name], route of administration, dose, duration of treatment, and presence or absence of any 
action taken for adverse events). Also, enter drugs administered for the treatment of adverse events. 
 
7.3.2.7.2. Non-drug therapy 
For all non-drug therapies provided from the first day of treatment with this drug until the end of the 
observation period (or date of discontinuation of treatment with this drug), enter the name of therapy, 
implementation period, and presence or absence of any action taken for adverse events. Also, enter 
therapies provided for the treatment of adverse events. 
 
7.3.2.8. Tests/clinical laboratory tests 
For the following test items conducted from the first day of treatment with this drug until the end of the 
observation period (or date of discontinuation of treatment with this drug), enter the test dates (dates of 
measurement) and test results. For the tests conducted before the start of treatment with this drug, enter the 
test results immediately before the first day of treatment (including the first day of treatment). For 
clinically significant fluctuations compared to those before the start of treatment with this drug, enter the 
details in the adverse event column. 
 
7.3.2.8.1. Clinical laboratory tests 
(1) Hematology: White blood cell count, neutrophil count, lymphocyte count, red blood cell count, 
platelet count, hemoglobin, prothrombin time 
(2) Biochemistry: AST (GOT), ALT (GPT), AL-P, LDH, γ-GTP, total bilirubin, triglycerides, serum 
creatinine, serum albumin 
(3) Endocrine test: Thyroid-stimulating hormone (TSH), total T4, free thyroxine (FT4) 
(4) Urinalysis: Urine protein (qualitative) 
 

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7.3.2.8.2. General tests 
(1) Height 
(2) Weight 
(3) Pulse 
(4) Blood pressure (systolic/diastolic) 
 
7.3.2.8.3. Plasma concentration of tafamidis (to be performed only for patients with severe hepatic 
impairment) 
If the patient has severe hepatic impairment, measure the plasma concentration of tafamidis as much as 
possible and enter the following information. If the patient has hepatic function disorder at the start of 
treatment with this product, enter the details in the section of “Presence or absence of hepatic/renal 
impairment” and if it occurred during the observation period, enter the details in the section of “Adverse 
Events”. If a laboratory test related to hepatic impairment is performed, enter the test results in the section 
of “Laboratory tests” or the section of “Tests for adverse events”. 
For the detailed method of measuring plasma concentration of tafamidis, refer to the Appendix to 
Guidelines for Special Investigation “Procedures for Measurement Plasma Concentration of Tafamidis in 
Patients with Severe Hepatic Impairment” (Appendix 1). 
 
(1) Record of medicines immediately before blood sampling (date and time of medicines) 
(2) Record of blood sampling (date and time of blood sampling) 
(3) Plasma concentration of tafamidis 
 
Table 3.  Child-Pugh Classification 
*Overseas clinical studies were conducted by defining moderate hepatic impairment as Child-Pugh score of ≤9. 
[Reference: Child-Pugh classification] The scores for each item are totaled and 5 to 6 points are classified as A, 7 to 9 points as B, 
and 10 to 15 points as C. 
[Child-Pugh classification] 
1 point 
2 points 
3 points 
Hepatic encephalopathy 
None 
Mild 
Occasional coma
Ascites 
None 
Small amount 
Moderate amount
Total serum bilirubin (mg/dL) 
<2.0 
2.0-3.0 
3.0< 
Serum albumin (g/dL) 
3.5< 
2.8-3.5 
<2.8 
Prothrombin time (%) 
70< 
40-70 
<40 
 
7.3.2.8.4. Cardiovascular assessment 
(1) Standard 12-lead ECG 
(2) Echocardiography 
 
7.3.2.8.5. Assessment of neurological function (NIS) 
Enter scores for the following (1) to (4) items according to the assessment indicators for neurological 
function shown below by using Neuropathy Impairment Score (NIS)9). 
 
[Timing of assessment] Before the start of treatment (results immediately before treatment 
including the first day of treatment), Week 78 (1.5 years later), Week 156 (3 years later) (or at 
discontinuation of treatment with this drug) 
 

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(1) Cranial Nerves: Items 1 to 5 
(2) Muscle Weakness: Items 6 to 24 
 
Cranial nerves and muscle weakness will be graded on the following 8-point scale: 
0 = Normal 
1 = 25% Weak 
2 = 50% Weak 
3 = 75% Weak 
3.25 = Move against gravity 
3.5 = Movement, gravity eliminated 
3.75 = Muscle flicker, no movement 
4 = Paralysis 
 
(3) Reflexes: Items 25 to 29 
(4) Sensation: Index finger (items 30 to 33), great toe (items 34 to 37) 
 
Tendon reflexes (reflexes) and sensation of index and great toes (sensation; tactile sense, pain 
sensation, vibration sense, joint sense) will be graded on the following 3-point scale: 
0 = Normal 
1 = Decreased 
2 = Absent 
 
7.3.2.8.6. Quality of life (QOL) 
The QOL will be assessed using Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN)10), 11). 
Norfolk QOL-DN is a self-completed assessment scale for patients with neuropathy that can quantify the 
impact of neuropathy on QOL. This scale consists of 35 questions, each of which relates to the following 
functions and symptoms: 
TQOL score, physical function/large nerve fiber disorder score, activities of daily living score, symptom 
score, small nerve fiber disorder score, autonomic neuropathy score 
For data collection, the Norfolk QOL-DN questionnaire (Appendix 2) will be used to answer all questions 
by the patient himself or herself as much as possible. The investigator will complete the study items by 
referring to the questionnaires. 
 
[Timing of assessment] Before the start of treatment (results immediately before treatment 
including the first day of treatment), Week 78 (1.5 years later), Week 156 (3 years later) (or at 
discontinuation of treatment with this drug) 
 
 
7.3.2.8.7. Ambulatory status 
Ambulatory status will be assessed using the ambulatory ability scale in the polyneuropathy dysfunction 
score. 
 

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[Timing of assessment] Before the start of treatment (results immediately before treatment 
including the first day of treatment), Week 78 (1.5 years later), Week 156 (3 years later) (or at 
discontinuation of treatment with this drug) 
 
 
Walking ability rating scale 
0: Good 
1: Able to walk without difficulty despite of sensory 
disorder in the lower extremities 
2: Able to walk without assistance despite of some 
difficulties 
3a: Able to walk with one stick or crutch 
3b: Able to walk with two sticks or crutches 
4: Unable to walk, restricted to wheelchair or bedridden 
 
7.3.2.8.8. Neurological assessment 
Enter the test results for the following neurological assessments (1) to (6). The observation period is 
defined as follows and, if the observation period is discontinued, enter the test results at the time of 
discontinuation as much as possible. 
 
[Timing of assessment] Before the start of treatment (results immediately before treatment 
including the first day of treatment), Week 52 (1 year later), Week 104 (2 years later), Week 156 
(3 years later) (or at discontinuation of treatment with this drug) 
 
 
(1) Motor 
The motor will be assessed using a Medical Research Council (MRC) Scale. 
Medical Research Council Scale (MRC) MRC Scale12) 
0 
No contraction 
1 
Flicker contraction 
2 
Muscle contraction with active motion with gravity eliminated 
3 
Full range of motion against gravity 
4 
Full range of motion against gravity with some resistance 
5 
Full range of motion against gravity with maximum resistance for that muscle 
 
(2) Reflexes 
Reflexes will be assessed with the following items: 
Present, Absent 
 
(3) Light Touch 
(4) Pin Prick 
(5) Vibration 
(6) Position Sense 

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Light touch, pin prick, vibration, and position sense will be assessed with the following scales: 
Normal, Decrease, and Absent 
 
7.3.2.9. Medical assessment of physical symptoms 
The following diseases or syndromes will be confirmed for the presence or absence, time of 
onset/disappearance, relationship with ATTR, severity*, etc. 
[Timing of assessment] At the start of treatment (results immediately before treatment) to the end 
of observation period or at discontinuation of treatment with this drug 
 
*Follow the following classification for the assessment of severity. 
1: Mild 
The symptom is mild and usually transient. It may require short-term treatment (drug or non-drug 
therapy) but does not limit the patient's daily activities. 
2: Moderate 
The symptom is moderate. The symptom may require continuous treatment (drug, special 
treatment) and limit the patient's daily activities. In most cases, the patient is capable of self-care, 
but may require occasional assistance or other procedure (hospitalization or medical procedure).
3: Severe 
The symptom is severe. Severe symptoms may be transient but are accompanied by marked 
disability or pain. They require treatment (drug therapy or hospitalization) and special assistance 
to improve symptoms. Severe symptoms may be progressive and/or life-threatening and require 
further treatment to maintain the patient's condition, although improvement of symptoms cannot 
be expected. 
 
(1) Neurologic 
(2) Eye 
(3) Cardiovascular 
 
Follow the following classification for the severity of heart failure: 
[NYHA Grade 
New York Heart Association Classification] 
Class I: 
Subjects with cardiac disease but without resulting limitations of physical activity. 
 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or 
anginal pain. 
Class II: 
Subjects with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest.  
 
Ordinary physical activity results in fatigue, palpitation, dyspnea, or 
angina pain. 
Class III: 
Subjects with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. 
 
Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or 
anginal pain. 
Class IV: 
Subjects with cardiac disease resulting in inability to carry on any physical activity 
without discomfort.  
 
Symptoms of cardiac insufficiency or of the anginal syndrome may be present 
even at rest. If any physical activity is undertaken, discomfort is increased. 
 
(4) Genitourinary/Renal/Reproductive 
(5) Gastrointestinal 
(6) Endocrine/Metabolic 
(7) Musculoskeletal 
(8) Respiratory 

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(9) Psychiatric 
 
7.3.2.10. End-of-study (discontinuation) record 
Confirm whether or not treatment can be continued by this drug during the observation period. If treatment 
with this drug cannot be continued or if the study is discontinued because the dose of this drug was 
changed for the treatment of ATTR-CM, enter the date of the last visit (date of the last dose of 20 mg if the 
dose of this drug was changed for the treatment of ATTR-CM) and reason for discontinuation. If an 
adverse event was selected as the reason for discontinuation, enter the detailed information in the adverse 
event column. 
 
(1) Date of the last visit (date of the first visit after the last dose of this drug) 
(2) Reason for discontinuation 
 
7.3.2.11. Effectiveness evaluation 
The following 10 items should be evaluated for effectiveness: 
 
(1) NIS (See Section 7.3.2.8.5.) 
Evaluate the NIS total score, the NIS Upper Limb (NIS-UL) total score, the NIS Lower Limb 
(NIS-LL) total score, scores of cranial nervous system (sum of items 1 to 5), muscle weakness (sum of 
items 6 to 24), tendon reflex (sum of items 25 to 29), and sensation (index finger: sum of items 30 to 
33, great toe: sum of items 34 to 37). 
(2) Norfolk QOL-DN (See Section 7.3.2.8.6.) 
Evaluate the TQOL scores (sum of all 35 items) and 5 domain scores (physical function/large nerve 
fiber disorder score, activities of daily living score, symptom score, small nerve fiber disorder score, 
and autonomic neuropathy score). 
(3) Modified Body Mass Index (mBMI) 
mBMI is calculated by multiplying BMI by serum albumin level. 
(4) Ambulatory status (ambulatory ability scale in polyneuropathy dysfunction score) 
Evaluate the ambulatory status (see Section 7.3.2.8.7 for details). 
(5) Motor 
Evaluate the motor function with MRC (16 items in total) (see Section 7.3.2.8.8 for details) scale. 
(6) Reflexes 
Evaluate the tendon reflexes (5 items in total) (see Section 7.3.2.8.8 for details). 
(7) Light Touch 
Evaluate the tactile (11 items in total) (see Section 7.3.2.8.8 for details). 
(8) Pin Prick 
Evaluate the pain sensation (11 items in total) (see Section 7.3.2.8.8 for details). 
(9) Vibration 
Evaluate the vibration sense (6 items in total) (see Section 7.3.2.8.8 for details). 
(10) Position Sense 
Evaluate the positional sense (4 items in total) (see Section 7.3.2.8.8 for details). 
 
 
 
7.3.2.12. Adverse events 
Occurrence of adverse events (AEs) from the start date of administration of this drug to the end date of 
observation period should be confirmed and the following information should be recorded. If any AE is 

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observed, the investigator will take appropriate measures, promptly report it to Pfizer, and in principle, 
transcribe and confirm the course until the symptom disappears. 
Also, further investigation should be separately conducted, if deemed necessary by Sponsor for patients 
who experienced a serious adverse reaction, an unexpected adverse reaction or other adverse reactions not 
listed in the package insert. 
 
(1) Presence/absence of AE 
(2) Name of AE 
(3) Date of occurrence 
(4) Intervention 
(5) Seriousness 
(6) Outcome 
(7) Causal relationship to this drug 
 
If the AE is associated with abnormal laboratory values, i.e., clinical laboratory tests, the following 
information should also be recorded: 
 
(1) Laboratory parameter 
(2) Site reference value 
(3) Unit 
(4) Date measured 
(5) Results 
 
Note: AEs are any and all unfavorable events (including clinically significant abnormal changes in 
laboratory tests) occurring in patients after starting the targeted drug treatment regardless of their causal 
relationship. Serious adverse events (SAEs) are any unfavorable medical occurrences that result in death, 
are life-threatening, require (or prolong) hospitalization, cause persistent or significant 
disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which 
represent significant health hazards. 
 
7.3.2.13. Confirmation of survival 
For patients who completed the study, the following information will be entered 3 years after the start of 
treatment with this drug at the own site for confirmation of survival: 
(1) In the case of survival: Date of survival confirmed 
(2) In the case of death: Date of death, cause of death (TTR-FAP/other than TTR-FAP) 
(If the date of death is unknown, the last date of survival confirmed and the date of information 
on death obtained) 
 
Among the patients who discontinued the study, their survival will be confirmed using the attached CRF 3 
years after the start of treatment for patients who discontinued the study because the reason for 
discontinuation as follow-up after discontinuation of treatment is other than transfer to another 
hospital/department, no return to the hospital, or having adverse events resulting in death as outcome and 
for patients who discontinued the study for the treatment of ATTR-CM. 
(1) In the case of survival: Date of survival confirmed 
(2) In the case of death: Date of death, cause of death (TTR-FAP/other than TTR-FAP) 

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(If the date of death is unknown, the last date of survival confirmed and the date of information 
on death obtained) 
(3) If survival or death is unknown: Last date of survival confirmed 
 
For patients who started the treatment with this drug after May 2018 (1.5-year observation period), their 
survival should be confirmed using the attached CRF 1.5 years after the start of treatment at the own site. 
 
7.3.2.14. Major investigation items 
Hepatotoxicity should be evaluated in this study as a major investigation item and, if information on 
hepatotoxicity is obtained, it will be separately investigated in detail. 
 
[Rationale for setting] 
Although necrosis and hypertrophy of hepatocytes were observed in the repeated-dose toxicity study in 
mice, since the Japanese clinical data at the time of approval application are limited, hepatotoxicity was set 
as the major investigation item in this study to confirm the post-marketing safety profile. 
 
7.3.2.15. Confirmation of description concerning adverse events corresponding to major 
investigation item 
The investigator will confirm that the AEs corresponding to hepatotoxicity, the major investigation item in 
this study, have been entered in the AE column. 
 
7.4. Data sources  
In this study, the investigators extract the necessary information from the medical record in accordance 
with the full protocol. 
 
7.5. Study size 
7.5.1. Planned sample size 
All patients who received/used this drug will be targeted in this study. 
 
7.5.2. Rationale for sample size 
On the basis of the review of data on patients with familial amyloid polyneuropathy who were registered 
in the database from the Amyloidosis Clinical Survey Forms of the Specific Diseases Treatment Research 
Program by the Ministry of Health, Labour and Welfare for 3 years from 2003 to 2005, it is reported that 
the number of patients with familial amyloid polyneuropathy is 64 to 88 patients/year, and the estimated 
prevalence of familial amyloid polyneuropathy in Japan is 0.87 to 1.1 per population of 1 million people 
after the number of patients was corrected and calculated from the acquisition rate of data1) . When this 
prevalence is multiplied by the Japanese population (127.54 million, as of November 2012), the estimated 
number of patients with TTR-FAP (hereinafter referred to as this disease) is approximately 111 to 140. On 
the website of the Japan Intractable Diseases Information Center, the estimated annual number of patients 
treated for this disease is approximately 130 on the basis of the nationwide epidemiological survey 
conducted in 1991. As described above, considering that this disease is a rare disease and the safety and 
efficacy information of this drug based on Japanese clinical studies are limited, all patients who 
received/used this drug will be collected as much as possible. 
 

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7.6. Data management 
7.6.1. Case report forms (CRFs)/ Electronic data record 
As used in this protocol, the term CRF should be understood to refer to a paper form, depending on the 
data collection method used in this study. A CRF is required and should be completed for each included 
patient. The completed original CRFs are the sole property of Pfizer and should not be made available in 
any form to third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the CRFs are 
securely stored at the study site in paper form and will be secured in a locked room to prevent access by 
unauthorized third parties. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, safety, and 
laboratory data entered on the CRFs and any other data collection forms (source documents) and ensuring 
that they are accurate, authentic/original, attributable, complete, consistent, legible, timely 
(contemporaneous), enduring, and available when required. The CRFs must be signed by the investigator 
or by an authorized staff member to attest that the data contained on the CRFs are true. Any corrections to 
entries made in the CRFs or source documents must be dated, initialed (or stamped “correction seal”), and 
explained (if necessary) and should not obscure the original entry. 
The source documents are the hospital or the physician's chart. In these cases, data collected on the CRFs 
must match those charts. 
7.6.2. Record retention 
The records related to this study should be retained at the study site until the End of Study Letter by Pfizer 
is received or during the period defined by the study site, whichever is longer. 
7.6.3. Data collection method 
Registration and study data for this study will be collected and recorded in the registration form and CRFs 
to be supplied by Pfizer. Investigator will complete (each volume of forms) promptly after (each) 
observation period and submit them to Pfizer. 
7.6.4. Patient registration 
7.6.4.1. Procedure of patient registration 
The investigator will complete the designated registration form provided by Pfizer after the start of 
treatment with this drug and send it to Patient Registration Center via FAX. 
 
 
 
1. After the end of patient registration, a “registration confirmation sheet” will be sent by FAX from 
Patient Registration Center to the investigator. 
2. If there is something to be confirmed found in the registration form, confirmation will be requested 
with the investigator. In the case of confirmation, “request form of confirmation” and “registration 
form (copy) ” will be sent from the registration center to the investigator by FAX. 
 
[Patient Registration Center] 
 FAX: 
(Available 24 Hours) 
 Business hours: 9:00 to 17:00 on Mondays through Fridays [except for national holidays, and New 
Year holidays (29 December to 4 January)] 
PPD

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7.6.4.2. Confirmation of patients registered 
During the registration period, Pfizer will confirm with the investigator that all patients have been 
registered at the study sites conducting the study every year using an “all-cases survey confirmation 
sheet”. 
 
7.6.5. Reminders concerning completing, revising, and submission of case report form 
7.6.5.1. Completing 
The investigator will check the study items and complete the CRFs based on consultation records and 
medical records including the results of various tests using indelible ink such as ballpoint pen. 
 
7.6.5.2. Revising 
Upon receiving Pfizer's inquiry on the contents of the CRF (query forms), the investigator will again 
confirm the contents of consultation records, and as required, correct relevant sections of the CRF and 
submit it. 
 
7.6.5.3. Confirming 
After the entry and revision of the CRFs (or CRFs for resurvey) are fully completed, the investigator will 
confirm any inadequacies in the study items again and affix the printed name and seal or sign the CRFs. 
 
7.6.5.4. Submitting 
The investigator will promptly submit the CRFs to Pfizer upon completion. 
 
7.7. Data analysis 
1. Definition of analysis set 
The safety analysis set (SAS) consists of all patients who received this drug at least once. The 
effectiveness analysis set consists of those for whom the effectiveness evaluation was conducted at least 
once among the SAS. The details will be described in the separately prescribed Statistical Analysis Plan 
(SAP). 
 
2. Method of analysis 
(1) Major analysis for safety evaluation 
The occurrence of ADRs and the incidence of ADRs (percentage of patients with AEs for which the causal 
relationship with this drug cannot be ruled out) will be calculated in the SAS. 
(2) Major analysis for effectiveness evaluation 
For NIS, QOL-DN, and mBMI, their values and changes from baseline at each time point will be 
calculated in the effectiveness evaluation set. For ambulatory status, motor function (MRC), tendon reflex, 
tactile sense, pain sensation, vibration sense, and positional sense, changes from baseline at each time 
point will be calculated. In addition, survival time analysis will be performed using survival information 
obtained up to 3 years after the start of treatment. 
 
Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a SAP, which will be dated, filed and maintained by Pfizer. The SAP may modify the plans 
outlined in the protocol; any major modifications of primary endpoint definitions or their analyses would 
be reflected in a protocol amendment. 
 
7.8. Quality control 
The site staff will explain the contents of the protocol, etc. to the investigator prior to the implementation 
of this study and ask the investigator to prepare a CRF based on medical charts 

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7.9. Limitations of the research methods 
The following matters are considered for this study: 
1. Since no control group is set in the study, there is a limit to the judgment on whether or not a risk of 
developing AEs and adverse reactions increases due to the administration of the study drug.  
2. The consideration for confounding factors may not be adequate because the background information 
may not be sufficiently obtained. 
3. Since this is a study that collects the information described in medical charts, the set data may not be 
collected or there may be missing information. 
 
7.10. Other aspects 
N/A 
8. 
PROTECTION OF HUMAN SUBJECTS 
8.1. Patient information 
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures to ensure protection of patient personal data. Such measures will 
include omitting patient names or other directly identifiable data in any reports, publications, or other 
disclosures, except where required by applicable laws. The personal data will be stored at the study site in 
encrypted electronic and/or paper form and will be password protected or secured in a locked room to 
ensure that only authorized study staff have access. The study site will implement appropriate technical 
and organizational measures to ensure that the personal data can be recovered in the event of disaster. In 
the event of a potential personal data breach, the study site shall be responsible for determining whether a 
personal data breach has in fact occurred and, if so, providing breach notifications as required by law. 
To protect the rights and freedoms of natural persons with regard to the processing of personal data, when 
study data are compiled for transfer to Pfizer and other authorized parties, patient (subject) names will be 
removed and will be replaced by a single, specific, numerical code, in accordance with a numbering 
system defined by Pfizer. All other identifiable data transferred to Pfizer or other authorized parties will be 
identified by this single, patient-specific code. The study site will maintain a confidential list of patients 
who participated in the study, linking each patient’s numerical code to his or her actual identity. In case of 
data transfer, Pfizer will maintain high standards of confidentiality and protection of patients’ personal 
data consistent with the clinical study agreement and applicable privacy laws. 
 
8.2. Patient consent 
As this study does not involve data subject to privacy laws according to applicable legal requirements, or it 
is an information provision based on the law (even though that involve data subject to privacy laws 
according to applicable legal requirements), obtaining informed consent from patients by Pfizer is not 
required. 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
In this study, review by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) is not 
required. However, this does not apply if it is required by the rules of the medical institution. 
8.4. Ethical conduct of the study 
This study will be conducted in compliance with the “MHLW Ordinance on the Standard for 
Post-Marketing Studies and Clinical Trials of Medical Products” (MHLW Ordinance No. 171, dated 
December 20, 2004). Also, the study will be conducted in accordance with legal and regulatory 
requirements, as well as with scientific purpose, value and rigor. 

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9. 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS 
The site staff will request the investigator to report the events that need to be reported within 24 hours at 
the start of the study and also request the report by regularly visiting the investigator during the study 
period. 
The handling of each event in the case where the investigator becomes aware of any event concerning the 
safety information should be prescribed as follows: 
For an event that needs to be reported to the sponsor within 24 hours, the investigator must report it using 
the designated “Non Interventional study AE Report Form (hereinafter referred to as “NIS AE Report 
Form”). 
The NIS AE Report Form will be handled as part of the case report form. 
9.1. Requirements 
The table below summarizes the requirements for recording safety events on the CRF and for reporting 
safety events on the non-interventional study (NIS) adverse event monitoring (AEM) Report Form to 
Pfizer Safety. These requirements are delineated for three types of events: (1) SAEs; (2) non-serious AEs 
(as applicable); and (3) scenarios involving drug exposure, including exposure during pregnancy (EDP) , 
exposure during breast feeding, medication error, overdose, misuse, extravasation, lack of efficacy, and 
occupational exposure. These events are defined in the section “Definitions of safety events.” 
Safety event 
Recorded on the CRFs 
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAEs
All
All
Non-serious AE
All
None
Scenarios involving exposure to a 
drug under study, including EDP, 
exposure during breast feeding, 
medication error, overdose, misuse, 
extravasation, lack of efficacy, and 
occupational exposure 
All (regardless of whether 
associated with an AE), except 
occupational exposure 
All (regardless of whether 
associated with an AE) 
Note: Any associated AE is 
reported together with the 
exposure scenario. 
 
For each AE, the investigator must pursue and obtain information adequate both to determine the outcome 
of the AE and to assess whether it meets the criteria for classification as a SAE (refer to section “Serious 
Adverse Events” below). 
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness of the event 
by the investigator regardless of whether the event is determined by the investigator to be related to 
Vyndaqel. In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available event information. This timeframe also applies to 
additional new (follow-up) information on previously forwarded safety event reports. In the rare situation 
that the investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time of his/her first 
awareness of the events. 
For safety events that are considered serious or that are identified in the far right column of the table above 
that are reportable to Pfizer within 24 hours of awareness, the investigator is obligated to pursue and to 
provide any additional information to Pfizer in accordance with this 24-hour timeframe. In addition, an 
investigator may be requested by Pfizer to obtain specific follow-up information in an expedited fashion. 

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This information is more detailed than that recorded on the CRF. In general, this will include a description 
of the AE in sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Any information relevant to the event, such as concomitant 
medications and illnesses, must be provided. In the case of a patient death, a summary of available autopsy 
findings must be submitted as soon as possible to Pfizer or its designated representative. 
9.2. Reporting period 
For each patient, the safety event reporting period begins at the time of the patient’s first dose of 
Vyndaqel , and lasts through the end of the observation period of the study, which must include at least 28 
calendar days following the last administration of a drug under study; a report must be submitted to Pfizer 
Safety (or its designated representative) for any of the types of safety events listed in the table above 
occurring during this period. If a patient was administered a drug under study on the last day of the 
observation period, then the reporting period should be extended for 28 calendar days following the end of 
observation. 
If the investigator becomes aware of a SAE occurring at any time after completion of the study and she/he 
considers the SAE to be related to Vyndaqel, the SAE also must be reported to Pfizer Safety. 
9.3. Causality assessment 
The investigator is required to assess and record the causal relationship. For all AEs, sufficient information 
should be obtained by the investigator to determine the causality of each AE. For AEs with a causal 
relationship to Vyndaqel, follow-up by the investigator is required until the event and/or its sequelae 
resolve or stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment. 
An investigator’s causality assessment is the determination of whether there exists a reasonable possibility 
that vyndaqel caused or contributed to an AE. If the investigator’s final determination of causality is 
“unknown” and she/he cannot determine whether Vyndaqel caused the event, the safety event must be 
reported within 24 hours. 
If the investigator cannot determine the etiology of the event but she/he determines that Vyndaqel did not 
cause the event, this should be clearly documented on the CRF and the NIS AEM Report Form. 
9.4. Definitions of safety events 
9.4.1. Adverse events 
An AE is any untoward medical occurrence in a patient administered a medicinal product. The event need 
not necessarily have a causal relationship with the product treatment or usage. Examples of AEs include 
but are not limited to: 
 
Abnormal test findings (see below for circumstances in which an abnormal test finding constitutes an 
AE); 
 
Clinically significant signs and symptoms; 
 
Changes in physical examination findings; 
 
Hypersensitivity; 
 
Progression/worsening of underlying disease; 

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 
Lack of efficacy;  
 
Drug abuse; 
 
Drug dependency; 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
 
Drug overdose; 
 
Drug withdrawal; 
 
Drug misuse; 
 
Off-label use;  
 
Drug interactions; 
 
Extravasation;  
 
EDP; 
 
Exposure during breastfeeding; 
 
Medication error; 
 
Occupational Exposure. 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as an AE are as 
follows: 
 
Test result is associated with accompanying symptoms, and/or 
 
Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
 
Test result leads to a change in study dosing or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy, and/or 
 
Test result is considered to be an AE by the investigator or Pfizer. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
9.4.2. Serious adverse events 
An SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional product 
(including pediatric formulas) at any dose that: 
 
Results in death; 

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 
Is life-threatening; 
 
Requires inpatient hospitalization or prolongation of hospitalization (see below for circumstances that 
do not constitute AEs); 
 
Results in persistent or significant disability/incapacity (substantial disruption of the ability to conduct 
normal life functions); 
 
Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important medical 
event. An important medical event may not be immediately life-threatening and/or result in death or 
hospitalization. However, if it is determined that the event may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above, the important medical 
event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical symptoms or laboratory 
findings indicating an infection in a patient exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are considered unexpected and 
handled as serious expedited cases by pharmacovigilance (PV) personnel. Such cases are also considered 
for reporting as product defects, if appropriate. 
Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or equivalent 
healthcare facility or any prolongation to an existing admission. Admission also includes transfer within 
the hospital to an acute/intensive care unit (e.g., from the psychiatric wing to a medical floor, medical floor 
to a coronary care unit, neurological floor to a tuberculosis unit). An emergency room visit does not 
necessarily constitute a hospitalization; however, an event leading to an emergency room visit should be 
assessed for medical importance. 
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For example, 
the following reports of hospitalization without a medical AE are not to be reported. 
 
Social admission (e.g., patient has no place to sleep) 
 
Administrative admission (e.g., for yearly exam) 
 
Optional admission not associated with a precipitating medical AE (e.g., for elective cosmetic 
surgery) 
 
Hospitalization for observation without a medical AE 

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 
Admission for treatment of a pre-existing condition not associated with the development of a new AE 
or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-treatment lab 
abnormality) 
 
Protocol-specified admission during clinical study (e.g., for a procedure required by the study 
protocol) 
9.4.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours 
Scenarios involving EDP, exposure during breastfeeding, medication error, overdose, misuse, 
extravasation, lack of efficacy, and occupational exposure are described below. 
EDP 
An EDP occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been exposed to (e.g., 
environmental) Vyndaqel, or the female becomes, or is found to be, pregnant after discontinuing 
and/or being exposed to Vyndaqel (maternal exposure).  
An example of environmental exposure would be a case involving direct contact with a Pfizer product in a 
pregnant woman (e.g., a nurse reports that she is pregnant and has been exposed to chemotherapeutic 
products). 
2. A male has been exposed, either due to treatment or environmental exposure to Vyndaqel prior to or 
around the time of conception and/or is exposed during the partner pregnancy (paternal exposure).  
As a general rule, prospective and retrospective EDP from any source are reportable irrespective of the 
presence of an associated AE and the procedures for SAE reporting should be followed. 
If a study participant or study participant’s partner becomes, or is found to be, pregnant during the study 
participant’s treatment with vyndaqel, this information must be submitted to Pfizer, irrespective of whether 
an AE has occurred using the NIS AEM Report Form and the EDP Supplemental Form. 
In addition, the information regarding environmental exposure to Vyndaqel in a pregnant woman (e.g., a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or spillage) 
must be submitted using the NIS AEM Report Form and the EDP Supplemental Form. This must be done 
irrespective of whether an AE has occurred. 
Information submitted should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up is 
conducted to obtain information on EDP outcome for all EDP reports with pregnancy outcome unknown.  
A pregnancy is followed until completion or until pregnancy termination (e.g., induced abortion) and 
Pfizer is notified of the outcome. This information is provided as a follow up to the initial EDP report. In 
the case of a live birth, the structural integrity of the neonate can be assessed at the time of birth. In the 
event of a termination, the reason(s) for termination should be specified and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are reported). 

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If the outcome of the pregnancy meets the criteria for an SAE [e.g., ectopic pregnancy, spontaneous 
abortion, intrauterine fetal demise, neonatal death, or congenital anomaly (in a live born, a terminated fetus, 
an intrauterine fetal demise, or a neonatal death)], the procedures for reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows: 
 
Spontaneous abortion includes miscarriage and missed abortion; 
 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to causality, as 
SAEs. In addition, infant deaths after 1 month should be reported as SAEs when the investigator 
assesses the infant death as related or possibly related to exposure to investigational product. 
Additional information regarding the EDP may be requested. Further follow-up of birth outcomes will be 
handled on a case-by-case basis (e.g., follow-up on preterm infants to identify developmental delays). 
In the case of paternal exposure, the study participant will be provided with the Pregnant Partner Release 
of Information Form to deliver to his partner. It must be documented that the study participant was given 
this letter to provide to his partner. 
Exposure during breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of an associated 
AE. An exposure during breastfeeding report is not created when a Pfizer drug specifically approved for 
use in breastfeeding women (e.g., vitamins) is administered in accord with authorized use. However, if the 
infant experiences an AE associated with such a drug’s administration, the AE is reported together with 
the exposure during breastfeeding. 
Medication error 
A medication error is any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product that may cause or lead to inappropriate medication use or patient harm while in the 
control of the health care professional, patient, or consumer. Such events may be related to professional 
practice, health care products, procedures, and systems including: prescribing; order communication; 
product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; 
education; monitoring; and use. 
Medication errors include: 
 
Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous administration, 
which is the accidental use of a product outside of labeling or prescription on the part of the healthcare 
provider or the patient/consumer); 
 
Confusion with regard to invented name (e.g., trade name, brand name). 
The investigator must submit the following medication errors to Pfizer, irrespective of the presence of an 
associated AE/SAE: 
 
Medication errors involving patient exposure to the product, whether or not the medication error is 
accompanied by an AE. 

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 
Medication errors that do not involve a patient directly (e.g., potential medication errors or near 
misses). When a medication error does not involve patient exposure to the product the following 
minimum criteria constitute a medication error report: 
 
An identifiable reporter; 
 
A suspect product; 
 
The event medication error. 
Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are reported to 
Pfizer by the investigator, irrespective of the presence of an associated AE/SAE. 
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, irrespective of the 
presence of an associated AE/SAE or the indication for use of the Pfizer product. 
Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the investigator, irrespective 
of the presence of an associated AE/SAE. 
9.5. Single reference safety document 
A Single Reference Safety Document (SRSD) refers to a document that contains the information on the 
known safety profile. The package insert of this product will be the SRSD in this study. Pfizer will 
evaluate the safety information reported by the investigator during the study period using the SRSD. 
The investigator will also prescribe the drug and give the drug administration guidance on the basis of the 
SRSD. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
The survey results may be published during scientific meetings, in research paper, etc. for the purpose 
of providing proper use information, etc. 
COMMUNICATION OF ISSUES 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable Competent 
Authority in any area of the world, or if the investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of a Pfizer product, Pfizer should be informed 
immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken by the 
investigator to protect the study patients against any immediate hazard, and of any serious breaches of this 
study protocol that the investigator becomes aware of. 
 
11. ORGANIZATIONAL SYSTEM FOR STUDY IMPLEMENTATION 
The organizational system for study implementation in this study is equivalent to that for operations of 
post-marketing study in the risk management plan. The director of the post-marketing study strategy and 
management will be responsible for post-marketing study. 
 

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12. NAME, ADDRESS AND OUTSOURCED OPERATIONS OF THE PERSON WHO WAS 
CONTRACTED WITH THE OPERATIONS 
(1) Contractor 
    
 
    Company name: 
 
    Scope of work contracted: 
    Works related to planning and drafting of study, operation of study, etc. 
 
 
(2) Contractor 
Address: 
 
Company name: 
 
Scope of work contracted: 
Preparation of contract documents for the study, Patient Registration Center, data management, 
preparation of ledger, etc., operations other than management of post-marketing surveillance in the 
operations related to this study 
 
13. ADDITIONAL MEASURES THAT MAY BE IMPLEMENTED BASED ON THE SURVEY 
RESULTS AND CRITERIA FOR DETERMINATION OF THE INITIATION 
- Review the risk management plan (RMP) including the following contents at the scheduled timing of 
milestones. 
- Review the necessity for changing the contents of this study plan including the presence or absence of 
new safety specifications. 
- Review the necessity for formulating risk minimization measures for new safety specifications. 
 
14. SCHEDULED TIMING OF MILESTONES AND THEIR RATIONALES FOR REPORTING 
OF STUDY IMPLEMENTATION STATUS AND EVALUATION OF OBTAINED RESULTS 
TO THE PMDA 
At the time of Periodic Safety Update Report. To make a comprehensive review of the safety information. 
 
15. OTHER NECESSARY MATTERS  
1) Amendment of the protocol 
Based on the new knowledge to be obtained according to the progress of this study, the need for 
amendment of the protocol will be examined and the protocol will be amended if necessary. Also, the need 
for amendment of the protocol will be examined and the protocol will be amended even if the partial 
change in the dosage and administration or indication is approved during the reexamination period (except 
the case when the reexamination period is newly designated), etc. 
 
2) Actions to be taken for any problem or issue 
Revision of the RMP should be considered and, if necessary, the PV activities and risk minimization 
activities should be taken for the following cases: any serious and unknown adverse reaction is suggested; 
a significant increase in the frequency of adverse reactions is observed; any problem is found in the safety. 
 
16. CONTACT INFORMATION 
16.1. Contact information for the contents of the study 
Name 
Post-Marketing Study Strategy and Management, 
 
PPD
PPD
PPD
PPD
PPD

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Address 
 
E-mail address 
 
 
PPD
PPD

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17. REFERENCES 
(1) Honzaki Y, Yamada M. Molecular epidemiology of familial amyloid polyneuropathy (FAP). Igaku no 
ayumi. 2009;229:357-362. 
(2) Crooks, V, Waller S, et al. The use of the Karnofsky Performance Scale in determining outcomes and risk 
in geriatric outpatients. J Gerontol. 1991;46:M139-M144. 
(3) de Haan R, Aaronson A, et al. Measuring quality of life in stroke. Stroke. 1993;24:320- 327. 
(4) Hollen PJ, Gralla RJ, et al. Measurement of quality of life in patients with lung cancer in multicenter trials 
of new therapies. Cancer. 1994;73:2087-2098. 
(5) O'Toole DM, Golden AM. Evaluating cancer patients for rehabilitation potential. West J Med. 
1991;155:384- 387. 
(6) Oxford Textbook of Palliative Medicine, Oxford University Press. 1993;109. 
(7) Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: Reliability, validity, and 
guidelines. J Clin Oncology. 1984;2:187-193. 
(8) Fukui T, Kurokawa K. Harrison’s Principles of Internal Medicine 2nd Edition (Original 16th Edition). 
Medical Science International. Tokyo. 2006; p449-55. 
(9) Reference: Apfel SC, Schwartz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve 
growth factor in patients with diabetic polyneuropathy: A randomized controlled trial. rhNGF Clinical 
Investigator Group. JAMA. 2000;284:2215-2221. 
(10) Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic 
neuropathy, retinopathy, and nephropathy in a population-based cohort: The Rochester Diabetic 
Neuropathy Study. Neurology. 1993;43:817-824. 
(11) Vinik AI. Advances in diabetes for the millennium: new treatments for diabetic neuropathies. Med Gen 
Med. 2004;6:13. 
(12) Medical Research Council of the UK. Memorandum No. 45, London, Pendragon House, 1976, pp.6-7, 
Aids to the investigation of Peripheral Injuries. 
 
18. LIST OF TABLES 
 
 Page 14. Table 1. Schedule of observation  
 Page 16. Table 2. Karnofsky index 
 Page 18. Table 3. Child-Pugh Classification 
 
19. LIST OF FIGURES 
N/A 
 
20. LIST OF STAND ALONE DOCUMENTS 
 
 Appendix 1: Procedures for measurement of plasma concentration of tafamidis in patients with severe 
hepatic impairment 
 Appendix 2: Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) Questionnaires (sample) 
 
21. ADDITIONAL INFORMATION 
N/A 
 

 
 
 
 
 
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PPD
PPD
PPD
PPD
PPD