Drug Utilization Study for Olodaterol
Conditions: Pulmonary Disease, Chronic Obstructive
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Protocol for observational studies based on existing data
Document Number:
c02329987-02
BI Study Number:
1222.53
BI Investigational
Product(s):
Olodaterol
Title:
Drug Utilisation Study for Olodaterol
Protocol version 
identifier:
Version 2.0
Date of last version of 
protocol:
13 Feb 2014
PASS:
Yes
EU PASS register 
number:
Study not registered
Active substance:
Olodaterol
Medicinal product:
Striverdi, Respimat
Product reference:
BI 1744
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Boehringer Ingelheim GmbH
Joint PASS:
No
Date:
14 Oct 2014
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Additional Information
Research question and 
objectives:
This study aims to characterise the use of single-agent olodaterol 
and single-agent indacaterol, the only marketed long-acting 
beta2-agonist (LABAs) authorised for chronic obstructive 
pulmonary disease (COPD), but not for asthma, in clinical 
practice. Study objectives are as follows:
Primary objectives:

Quantify the frequency of off-label use of olodaterol 
among new users of these medications (i.e., the 
proportion of new users who do not have COPD)

Describe the baseline characteristics of new users of 
olodaterol
Secondary objective:

Quantify the frequency of off-label use of indacaterol (a 
LABA approved for COPD but not for asthma) among 
new users of these medications (i.e., the proportion of 
new users who do not have COPD), in order to put into 
perspective the results for olodaterol initiators 

Describe the baseline characteristics of new users of 
indacaterol
Country(-ies) of study:
The Netherlands, Denmark, and Sweden
Author:
Marketing authorisation 
holder(s):
MAH contact person:
EU-QPPV:
Signature of EU-QPPV:
The signature of the EU-QPPV is provided electronically

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1.
TABLE OF CONTENTS
TITLE PAGE.................................................................................................................. 1
1.
TABLE OF CONTENTS....................................................................................... 3
2.
LIST OF ABBREVIATIONS................................................................................ 6
3.
RESPONSIBLE PARTIES.................................................................................... 8
4.
ABSTRACT........................................................................................................... 9
5.
AMENDMENTS AND UPDATES..................................................................... 11
6.
MILESTONES..................................................................................................... 12
7.
RATIONALE AND BACKGROUND................................................................ 13
8.
RESEARCH QUESTION AND OBJECTIVES ................................................. 14
9.
RESEARCH METHODS .................................................................................... 15
9.1
STUDY DESIGN............................................................................................ 15
9.2
SETTING........................................................................................................ 15
9.2.1
Source population.................................................................................... 18
9.2.2
Study period ............................................................................................ 18
9.2.3
Study groups............................................................................................ 18
9.2.3.1
Inclusion criteria ..................................................................................19
9.2.3.2
Exclusion criteria .................................................................................19
9.3
VARIABLES .................................................................................................. 19
9.3.1
Exposures ................................................................................................ 19
9.3.2
Indication and potential off-label prescribing ......................................... 19
9.3.2.1
On-label prescribing: indication of COPD ..........................................20
9.3.2.2
Off-label prescribing............................................................................21
9.3.2.3
Review of patient profiles and medical records...................................22
9.3.2.4
Classification of patients......................................................................22
9.3.3
Characterisation of new users of olodaterol and indacaterol .................. 23
9.3.3.1
Demographics and lifestyle habits at the index date............................23
9.3.3.2
Respiratory comorbidity and allergies.................................................23
9.3.3.3
Severity of COPD ................................................................................24
9.3.3.4
Definition of COPD severity ...............................................................26
9.3.3.5
Other comorbidity and conditions .......................................................27
9.3.3.6
Comedications......................................................................................28
9.3.3.7
Health care resource utilisation............................................................28
9.3.4
Outcomes................................................................................................. 28

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9.3.4.1
Primary outcome..................................................................................28
9.3.4.2
Secondary outcomes ............................................................................29
9.3.4.3
The secondary outcome is the prevalence of off-label prescribing among 
new users of indacaterol.......................................................................................29
9.3.5
Covariates................................................................................................ 29
9.4
DATA SOURCES........................................................................................... 29
9.4.1
PHARMO Database Network................................................................. 29
9.4.1.1
Database characteristics.......................................................................29
9.4.2
Denmark.................................................................................................. 30
9.4.3
Sweden .................................................................................................... 30
9.4.4
Summary of study databases................................................................... 31
9.5
STUDY SIZE.................................................................................................. 34
9.6
DATA MANAGEMENT................................................................................ 35
9.7
DATA ANALYSIS......................................................................................... 36
9.7.1
Main analysis........................................................................................... 36
9.7.2
Indication and potential off-label prescribing ......................................... 36
9.7.3
Number of users and patterns of use ....................................................... 36
9.7.4
Characterisation of new users at the index date ...................................... 36
9.8
QUALITY CONTROL................................................................................... 38
9.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 38
9.10
OTHER ASPECTS ......................................................................................... 39
9.10.1
Bias.......................................................................................................... 39
10.
PROTECTION OF HUMAN SUBJECTS .......................................................... 40
11.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 41
12.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 42
13.
REFERENCES .................................................................................................... 43
13.1
PUBLISHED REFERENCES......................................................................... 43
13.2
UNPUBLISHED REFERENCES................................................................... 47
ANNEX 1.
LIST OF STAND-ALONE DOCUMENTS........................................... 48
ANNEX 2.
ENCEPP CHECKLIST FOR STUDY PROTOCOLS ........................... 49
ANNEX 3.
EVALUATION OF COPD SEVERITY IN AUTOMATED HEALTH 
DATABASES...................................................................................................... 56
ANNEX 4.
CODES FOR COMORBIDITIES AND OTHER MEDICATIONS...... 58

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ANNEX 5.
DETAILS ON EACH DATABASE FROM THE FEASIBILITY REPORT 
(1 NOVEMBER 2013)........................................................................................ 64

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2.
LIST OF ABBREVIATIONS
AMI
Acute Myocardial Infarction
ATC 
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BMI
Body Mass Index
CAT
COPD Assessment Test
COPD
Chronic Obstructive Pulmonary Disease
DAMD
Danish General Practice Database
DDD
Defined Daily Dose
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance
FEV1
Forced Expiratory Volume in 1 Second
GOLD
Global Initiative for Chronic Obstructive Lung Disease
GP
General Practitioner or General Practice
ICD
International Classification of Diseases
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision
ICD-10-CM
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision, Clinical Modification
ICD-9
International Classification of Diseases, 9th Revision
ICD-9-CM
International Classification of Diseases, 9th Revision, Clinical Modification
ICPC
International Classification of Primary Care
ICS
Inhaled Glucocorticosteroid
LABA
Long-Acting Beta2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
mMRC
Modified British Medical Research Council Questionnaire
NCSP
Nordic Medico-Statistical Committee Classification of Surgical Procedures
NPR
National Patient Register (Sweden)
PASS
Post-Authorisation Safety Study
PHARMO
Institute for Drug Outcomes Research (the Netherlands); also short for the 
PHARMO Database Network 
PHARMO-GP
a data subset of PHARMO Database Network with information from GPs
PPV
Positive Predictive Value

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PRO
Patient-Reported Outcome
SABA
Short-Acting Beta2-Agonist
SAMA
Short-Acting Muscarinic Antagonist
SD
Standard Deviation
WHO
World Health Organization

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3.
RESPONSIBLE PARTIES
The following individual is the author of this protocol: 
The following individuals have collaborated with the author on protocol development. 
, RTI Health Solutions
 RTI Health Solutions
The following institutions will implement the study: 
PHARMO Institute, the Netherlands
Denmark – To be determined
Karolinska Institutet, Sweden
Note: Investigators at these institutions will be named after they have reviewed the protocol 
and agreed to participate.

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4.
ABSTRACT
Name of company:
Boehringer Ingelheim GmbH
Name of finished medicinal product: 
Striverdi, Respimat
Name of active ingredient:
Olodaterol
Protocol date:
Study number:
Version/Revision:
Version/Revision date:
13 Feb 2014
1222.53
2.0
14 Oct 2014
Title of study:
Drug Utilisation Study for Olodaterol
Rationale and 
background:
Boehringer Ingelheim GmbH (BI) developed olodaterol, an inhaled 
long-acting beta2-agonist (LABA), for the indication of chronic 
obstructive pulmonary disease (COPD). LABAs are used in COPD to 
relieve bronchial constriction and, consequently, to improve 
symptoms. Because the use of LABAs has been associated with 
increased morbidity and mortality in patients with asthma, within the 
“Decentralised Procedure for Striverdi Respimat” the health 
authorities of the European Union/European Economic Area Member 
States requested the conduct of a post-approval drug utilisation study 
to assess potential off-label use of olodaterol in asthma and to 
characterise the use of olodaterol in clinical practice.
Research question and 
objectives:
This study aims to characterise the use of single-agent olodaterol and 
single-agent indacaterol, the only marketed LABAs authorised for 
COPD, but not for asthma, in clinical practice. Study objectives are as 
follows:
Primary objectives:

Quantify the frequency of off-label use of olodaterol among new 
users of these medications (i.e., the proportion of new users who 
do not have COPD)

Describe the baseline characteristics of new users of olodaterol
Secondary objective:

Quantify the frequency of off-label use of indacaterol (a LABA 
approved for COPD but not for asthma) among new users of these 
medications (i.e., the proportion of new users who do not have 
COPD), in order to put into perspective the results for olodaterol 
initiators

Describe the baseline characteristics of new users of indacaterol
Study design:
This is a cross-sectional study using information collected in health 
care databases among new users of olodaterol or indacaterol in the 
Netherlands, Denmark, and Sweden.

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Population:
The source population is all subjects enrolled in the selected study 
databases at the date olodaterol and indacaterol are available in each 
database’s country. The study groups are those subjects from the 
source population who receive a first dispensing for single-agent 
formulations of olodaterol for the primary objective or indacaterol for 
the secondary objective and have at least 12 months of continuous 
enrolment in the study databases.
Variables:
Indication and potential off-label use of olodaterol and indacaterol;
characterisation of new users of olodaterol and indacaterol by 
demographic variables, medical history, and use of other medications.
Data sources:
The study is planned to be conducted in the following databases: the 
PHARMO Database Network in the Netherlands, the National 
Registers in Denmark, and the National Registers in Sweden
A description of each database is provided in Section 9.4; further
details from the feasibility report are provided in ANNEX 5. The 
study will be conducted by using data on drug prescriptions and 
disease occurrence routinely collected on an ongoing basis for large 
population-based automated health care databases in the Netherlands, 
Denmark, and Sweden. 
Study size:
Actual counts of numbers of patients using olodaterol in European 
countries are not yet available since it is not yet marketed in Europe.
Data analysis:
Number and proportion of new users by indication and potential off-
label use. Number and proportion of new users according to medical 
history and use of comedications..
Milestones:
Start of data collection (contingent on approval, reimbursement, and
uptake of olodaterol):

Denmark: Q1 2015

The Netherlands: Q4 2015

Sweden: Q4 2015
End of data collection: Q1 2018
Interim reports of study results: Q3 2017
Final report of study results: Q3 2018

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5.
AMENDMENTS AND UPDATES
Version 2.0 includes clarification to the milestone table and revision of the primary and 
secondary study objectives in the context of regulatory review of the protocol.
Number
Date
Section of 
Study 
Protocol
Amendment or 
Update
Reason
1
30 Sep 
2014
6
Update of milestones 
Delay in finalization of 
protocol to respond to 
regulatory authority review
2
30 Sep 
2014 
8
Research objectives 
Modified in response to 
regulatory authority review
3
30 Sep 
2014
9.3.4
Clarification of 
primary outcomes 
Modified in response to 
regulatory authority review 

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6.
MILESTONES
Milestone
Planned Date 1
Start of data collection (expected 
availability of data on earliest exposure 
group entry)2:
Denmark: Q1 2015
The Netherlands: Q4 2015
Sweden: Q4 2015
End of data collection (latest possible 
exposure group entry):
Denmark:  Q1 2018
The Netherlands: Q1 2018
Sweden:  Q1 2018
Study progress report(s):
TBD
Interim report(s) of cumulative study 
results:
Q3 2017
Registration in the EU PAS register:
After regulatory endorsement of the 
protocol
Final report of study results from all 
databases:
Q3 2018
TBD = to be determined. Contact with database custodians is pending.  
1
Preliminary; dependent on market uptake of olodaterol and contracts with MAH and research partners.
2
Considering launch dates and approximately 1-year lag time in database. Launch dates are March 2014 in Denmark,
February 2014 in the Netherlands, and August 2014 in Sweden.

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7.
RATIONALE AND BACKGROUND
Chronic obstructive pulmonary disease (COPD) is a serious, chronic disease that affects 
millions of people worldwide.[P13-02399] COPD typically involves persistent limitation of 
airflow, a progressive course, and chronically enhanced inflammatory response of the 
airways to airborne particulates and gases. [P13-02399]
Worldwide, the estimated number of patients with COPD is 63.6 million.[R09-2531] In 2004, 
the World Health Organization estimated that the European region had approximately 
11.3 million patients with prevalent, symptomatic COPD.[R09-2531] A systematic review 
and meta-analysis of 67 studies conducted in 28 countries between 1990 and 2004 showed
that the prevalence of COPD is higher in subjects over 40 years of age than those under 40.
The pooled prevalences were 3.1% in subjects under 40 years of age and 9.9% in those 40 
years old or older, 8.2% for ages 40-64, and 14.2% for ages 65 years or older.[R06-4117] The 
health, social, and economic burdens of COPD are predicted to increase in the next several 
decades because of continuing exposure to tobacco smoke and other risk factors and because 
of the increasing age of the general populations in many countries. [P13-02399]
Inhaled long-acting beta2-agonist (LABA) drugs are used in COPD and in asthma. At 
present, the approved indication for the three major LABAs in COPD, formoterol, salmeterol, 
and indacaterol, is maintenance or long-term use. Formoterol and salmeterol are also 
approved for use in asthma; for this condition, simultaneous use with corticosteroids is 
strongly recommended. Within the Decentralised Procedure for Striverdi Respimat, the health 
authorities of the European Union/European Economic Area Member States requested the 
conduct of a post-approval drug utilisation study to assess the potential off-label use of 
olodaterol in asthma patients and to characterise the use of olodaterol in clinical practice.
This protocol is a core protocol describing the study design, methods, and analysis for 
implementing the study in three European health care databases in the Netherlands, Denmark, 
and Sweden. This core protocol will need to be adapted to the specifics of each database 
regarding the type and availability of the recorded information and the coding systems used 
to record diagnoses and medications.

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8.
RESEARCH QUESTION AND OBJECTIVES
This study aims to assess the use of single-agent olodaterol in clinical practice. The single 
agent indacaterol, the only marketed LABA authorised in clinical practice for COPD but not 
for asthma, will also be assessed. Study objectives are as follows:
Primary objectives:

Quantify the frequency of off-label use of olodaterol among new users of these 
medications (i.e., the proportion of new users who do not have COPD)

Describe the baseline characteristics of new users of olodaterol 
Secondary objectives:

Quantify the frequency of off-label use of indacaterol (a LABA approved for COPD 
but not for asthma) among new users of these medications (i.e., the proportion of new 
users who do not have COPD), in order to put into perspective the results for 
olodaterol initiators

Describe the baseline characteristics of new users of indacaterol

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9.
RESEARCH METHODS
9.1
STUDY DESIGN
This is a cross-sectional study using information collected in health care database(s) among 
new users of olodaterol or indacaterol in the Netherlands, Denmark, and Sweden. The study 
period will be 3 consecutive years, with annual cross-sectional descriptions of new users of 
olodaterol and indacaterol. Evaluation of off-label use and characterisation of new users will 
be conducted at the index date, defined as the date an eligible patient receives the first 
dispensing of olodaterol or indacaterol. 
9.2
SETTING
The study is planned to be conducted in the following databases: the PHARMO Database 
Network in the Netherlands, the National Registers in Denmark, and the National Registers in 
Sweden. The type of data available in each database is summarised in Table 1. A detailed 
description of each study database is provided in Sections 9.4, 9.4.2 and 9.4.3.

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Table 1
Selected characteristics of the study databases
Type of Data 
PHARMO, 
the Netherlands 
National 
Registers, 
Denmark 
National 
Registers, 
Sweden 
Hospital inpatient 
discharge diagnoses 
Yes
Yes
Yes
Hospital inpatient 
procedures
Yes
Yes
Yes
Hospital/clinics 
outpatient diagnoses
No
Yes
Yes
General practitioner 
diagnoses
Yes, in data subset 
PHARMO-GP1
Yes, for selected 
general practices 
in the Danish 
General Practice 
Database2
Yes, for general 
practices from the 
counties of 
Stockholm and 
Göteborg3
Pharmacy-dispensed 
medications
Yes
Yes
Yes
Prescribed 
medications
Yes in data subset 
PHARMO-GP1
Yes2
Yes3
GP = General Practitioner.
1
PHARMO-GP includes approximately 440,000 subjects.
2
The Danish General Practice Database includes approximately 1 million subjects.
3
Population from the counties of Stockholm and Göteborg is about 25% of the total Swedish population
In each country, new users of olodaterol and indacaterol will be identified in the prescription 
databases, which record information on the medications dispensed in the pharmacies (Figure 
1). New users will be characterised in terms of past medical history and use of medications. 
Past medical history will be evaluated by linkage via unique patient-specific identifiers using 
the hospitalisation databases, which provide information on hospital and outpatient discharge 
diagnoses and procedures. Use of medications will be evaluated using the prescription 
databases. Off-label prescribing will be evaluated for those new users for whom general 
practitioner diagnoses are available because information from general practitioners is 
considered the most appropriate for evaluating the indication and potential off-label use of 
medications.

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Figure 1
Overall study design
The coding of diagnoses and procedures varies across databases (Table 2). In PHARMO, 
diagnoses are coded using the International Classification of Diseases, 9th Revision (ICD-9); 
whereas in Denmark and Sweden, diagnoses are coded using the International Statistical 
Classification of Diseases and Related Health Problems, 10th Revision (ICD-10). In 
PHARMO, procedures are coded using ICD-9 codes; in Denmark, using ICD-10 codes; and 
in Sweden, using the 2012 Nordic Medico-Statistical Committee’s Classification of Surgical 
Procedures, version 1.16.[R14-0443] The Anatomical Therapeutic Chemical (ATC)
classification is used in all three databases to code dispensed medications.
Prescriptions 
Database
(new users of olodaterol
and indacaterol)
Patients
Database 
(hospital  discharge and 
outpatient diagnoses)
General Practice 
Database
(general practitioner 
diagnoses)
Full linkage
Partial linkage
Partial linkage
Characterization 
of users
Indication/off-label 
evaluation

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Table 2
Types of diagnosis, procedures, and medication codes in the study 
databases
Type of 
Code 
PHARMO, 
The Netherlands 
National Registers, 
Denmark 
National 
Registers, Sweden 
Diagnoses 
Hospital: ICD-9
Primary health care: 
ICPC1
ICD-10 
Primary health care: 
ICPC1
ICD-10 
Procedures 
ICD-9 
ICD-10
NCSP 1.16, 2012
Medications 
ATC 
ATC 
ATC 
ATC = Anatomical Therapeutic Chemical; GP = General Practitioner; ICD-9 = International Classification of Diseases, 9th 
Revision; ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; 
ICPC = International Classification of Primary Care; NCSP = Nordic Medico-Statistical Committee’s Classification of 
Surgical Procedures.
1
Available for PHARMO-GP, a data subset of PHARMO with information from GPs.
9.2.1
Source population
The study source population includes all subjects enrolled in the selected study databases at 
the date olodaterol and indacaterol are available in each database’s country.
9.2.2
Study period
The start of the study period is at the index date, defined as the dates of the first recorded 
dispensings of olodaterol and indacaterol in each database. New users of olodaterol and 
indacaterol will be identified in each of 3 consecutive years, with annual cross-sectional 
evaluations of off-label use and of characteristics of users. 
9.2.3
Study groups
Study groups are those subjects from the source population who (1) receive a first dispensing 
for single-agent formulations of olodaterol or indacaterol and (2) have at least 12 months of 
continuous enrolment in the study databases preceding the index date. Two study groups will 
be created: (1) a group of new users of olodaterol and (2) a group of new users of indacaterol.
New users of olodaterol are defined as patients who, with at least 12 months of continuous 
enrolment before the index date, have their first record of a dispensing for olodaterol.
Similarly, new users of indacaterol have their first record of a dispensing for indacaterol in 
the database (after at least 12 months of continuous enrolment). Patients who receive a 
dispensing for olodaterol or indacaterol before they meet the criteria of 12 months of 
continuous enrolment in the database are not eligible to enter the corresponding study groups
(olodaterol or indacaterol).
Each group of new users of olodaterol and new users of indacaterol will be divided into two 
subgroups: (1) LABA naïve in the short term (3 months) and (2) switchers from another 
LABA. Patients who are LABA naïve in the short term are defined as any new users of 
olodaterol or indacaterol who did not receive any dispensing for LABAs within 3 months 

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before the index date. Switchers are defined as any new user of olodaterol or indacaterol who 
received a dispensing for a different LABA within the 3 months before the index date. Within 
the olodaterol group and within the indacaterol group, LABA-naïve patients and switchers 
will be described and compared.
9.2.3.1
Inclusion criteria
To be included in a study group, patients must have at least 12 consecutive months of 
enrolment in the database before the index date. This will allow evaluation of the medical 
history and prior use of medications of included patients.
9.2.3.2
Exclusion criteria
Because the study aims to assess the use of olodaterol and indacaterol in regular clinical 
practice, no exclusions regarding age, sex, or comorbidity will be defined. However, 
individuals with missing or implausible values for age or sex will be excluded. 
9.3
VARIABLES
9.3.1
Exposures
New users of olodaterol and indacaterol will be identified at the first record of a dispensing 
for the relevant medication code specific to each database. New users are defined in Section 
9.2.3. The ATC code for indacaterol is R03AC18, classified as a selective beta2-
adrenoreceptor agonist in the category of inhalant adrenergics. Indacaterol is available as 
inhalation powder with a defined daily dose (DDD) of 0.15 mg. The ATC code for olodaterol 
is R03AC19.
9.3.2
Indication and potential off-label prescribing
The indication for the prescribing of medications are not recorded in the study databases;
therefore, the indication of treatment and potential off-label use of olodaterol and indacaterol 
will be inferred from the diagnoses codes recorded before the index date or at the index date 
and complemented by the clinical review of the computerised information. The indication 
and potential off-label use will be evaluated in the subset of new users whose information is 
linked to the general practice (primary care) registers that include diagnoses recorded by 
general practitioners. Information from general practitioners is considered the most 
appropriate for assessing the indication and potential off-label use of medications. Primary 
care data are available in the following study databases:
●
PHARMO-GP covering about 440,000 population
●
Danish General Practice Database covering about 1 million population
●
Swedish General Practice Database in the counties of Stockholm and Göteborg
Potential off-label use will be evaluated separately by the following age groups:
●
0 to 17 years
●
18 to 29 years
●
30 to 39 years

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●
40 to 49 years
●
50 to 59 years
●
60 to 69 years
●
70 to 79 years
●
80 years and older 
9.3.2.1
On-label prescribing: indication of COPD
The indication of COPD is defined as any patient with a diagnosis of COPD, chronic 
bronchitis, or emphysema recorded in the database at any time before the index date or at the 
index date. Because COPD can occur in association with asthma, patients with a recorded 
diagnosis for both COPD and asthma will be considered on-label. [R14-0350] [R07-2620] 
[R08-1492].
For this study, classification of COPD status will be based on general practice diagnoses and 
hospital outpatient and inpatient discharge diagnoses. No validation data are available for 
COPD diagnoses recorded in PHARMO. In general, in Denmark and Sweden, validation has 
been performed for COPD diagnoses ascertained via hospital (inpatient and outpatient) 
diagnoses. ICD diagnoses codes for COPD have shown a good positive predictive value 
(PPV). In the Danish National Registers, the PPV for the hospital discharge diagnosis of 
COPD (ICD-10 code J44) was 92%. [R14-0359] In Sweden, a COPD validation study 
showed that the COPD diagnosis (ICD-9: 491-492, 496; ICD-10: J41-J44) recorded in the 
National Inpatient Registry was considered as proven in 21.7% of cases, probable in 35.5%, 
possible in 34.0%, uncertain in 2.1%, and unlikely in 7.0%. [R14-0456] The proportion of 
patients with asthma misclassified as having COPD was 2.1%, and the overall degree of 
misclassification was less than 10%. The registry was considered of acceptable validity for 
epidemiological research of COPD.
The ICD-10 and ICD-9 codes to identify the diagnosis of COPD are detailed in Table 3. 
Diagnosis codes include COPD, chronic bronchitis, and emphysema.

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Table 3
ICD-10 and ICD-9 diagnoses and codes to identify patients with 
COPD
ICD-10 Code Description 
ICD-10 Code
ICD-9 Code
Chronic bronchitis
J41-J42
491
Emphysema
J43
492
Other COPD
J44
496
COPD with acute lower 
respiratory infection
J44.0
—
COPD with acute exacerbation, 
unspecified
J44.1
—
Other specified COPD
J44.8
—
COPD, unspecified
J44.9
—
COPD = Chronic Obstructive Pulmonary Disease; ICD-9 = International Classification of Diseases, 9th Revision; ICD-
10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision.
9.3.2.2
Off-label prescribing
Patients without a recorded diagnosis of COPD at any time before the index date or patients 
with a recorded diagnosis of asthma in the absence of a diagnosis for COPD will be 
considered off-label users. The off-label prescribing of olodaterol and indacaterol for the 
treatment of asthma is of special interest because this class of medication is often used in
asthma but olodaterol and indacaterol have not been developed or approved for asthma.
Few studies have examined the validity of ICD codes for identifying patients with asthma. In 
a validation study conducted in Sweden, the PPV for the diagnosis of asthma (ICD-10 J45) 
associated with visits to outpatient specialty clinics and inpatient stays and recorded in the 
National Patient Registry among patients 18 to 45 years of age treated with asthma 
medications was 89% (95% confidence interval, 83%-93%). [R14-0349] The proportion of 
subjects misclassified as COPD was 1.6%. In another study conducted in the RAMQ Medical 
Services database of the province of Quebec in Canada, the PPV for having one or more 
recorded diagnoses of asthma (ICD-9 493) over a 1-year period in patients aged 16 to 44 
years was 75% when the diagnosis was recorded by respiratory physicians and 67% when it 
was recorded by family physicians. The PPV increased to 77% for respiratory physicians and 
to 78% for family physicians when two or more recorded diagnoses of asthma were 
required.[R14-0352] Another study conducted in children under 4 years of age using data 
from the Rochester Epidemiology Project database showed that the overall agreement of ICD 
code 493 and information from the medical chart was 81.6%.[R14-0351]
The ICD-10 and ICD-9 codes to identify patients with asthma are detailed in Table 4.

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Table 4
ICD-10 and ICD-9 diagnoses and codes to identify patients with 
asthma
ICD-10 Code Description 
ICD-10 Code
ICD-9 Code
Asthma
J45
493
Predominantly allergic asthma
J45.0
493.01
Non-allergic asthma
J45.1
493.11
Mixed asthma
J45.8
—
Asthma, unspecified
J45.9
493.91
Chronic obstructive asthma
—
493.21
Other forms of asthma
—
493.8
Status asthmaticus 
J46
ICD-9 = International Classification of Diseases, 9th Revision; ICD-10 = International Statistical Classification of Diseases 
and Related Health Problems, 10th Revision.
1
The following fifth-digit subclassification is for use with category 493.0-493.2, 493.9: 0, unspecified; 1, with status 
asthmaticus; 2, with (acute) exacerbation
9.3.2.3
Review of patient profiles and medical records
The prescribed indication for olodaterol and indacaterol and the potential for off-label 
prescribing of these medications will be further evaluated through the clinical review of 
patient profiles of a random sample of about 100 new users of each medication prior to the 
first exposure to the respective drug. Patient profiles are chronological listings of the codes 
that represent clinical events recorded in the study databases for individual patients. These 
listings include general practitioner diagnoses, outpatient and hospital discharge diagnoses 
and procedures; and dispensings of medications. The clinical review of patient profiles will 
provide the most accurate information for evaluation of the indication and potential off-label 
use of olodaterol and indacaterol. This information will be useful for developing clinical 
algorithms that can be applied to the evaluation of all new users of olodaterol and indacaterol 
whose information is linked to general practitioner diagnoses.
The random sampling of patient profiles for review will be stratified by age (0-17 years, 18-
39 years, ≥ 40 years) and sex because PPVs are expected to vary by prevalence of COPD, 
which in turn varies by age and sex.
9.3.2.4
Classification of patients
According to the presence of a recorded diagnosis of COPD and/or asthma, new users of 
olodaterol and new users of indacaterol will be classified into the following categories: (1) 
on-label prescribing (indication of COPD), (2) off-label prescribing for asthma, and (3) off-
label prescribing with no evidence of COPD or asthma (Table 5).

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Table 5
Classification of patients according to indication or off-label 
prescribing of olodaterol and indacaterol
Recorded diagnosis1
On-Label 
Prescribing: 
Indication of 
COPD
Off-Label 
Prescribing for 
Asthma
Potential Off-
Label Prescribing
Other than 
Asthma
COPD
Yes
COPD and asthma
Yes
Asthma
Yes
No COPD, no asthma
Yes
COPD = Chronic Obstructive Pulmonary Disease.
1
Diagnosis recorded at any time before the index date or at the index date.
9.3.3
Characterisation of new users of olodaterol and indacaterol
New users of olodaterol and new users of indacaterol will be characterised at the index date 
according to demographic variables, available data on lifestyle habits, comorbidity, and use 
of medications. Comorbidity will be ascertained through diagnosis codes and procedures 
recorded at any time before the index date. Use of medications will be ascertained for the 
12 months before the index date.
In the following sections, we list the variables that will be used to characterise new users of 
olodaterol and new users of indacaterol. The variables will be assessed according to the 
availability of information in each study database (see Table 8 on page 30 for availability of 
variables of interest). Some of the variables (e.g., lifestyle habits or socioeconomic 
indicators) may be partially or completely unavailable in the study databases. We provide 
ICD-10 and ICD-9 codes for diagnoses and procedures and ATC codes for medications. 
9.3.3.1
Demographics and lifestyle habits at the index date
●
Age
●
Sex
●
Calendar year
●
Body mass index
●
Smoking status
●
Alcohol consumption
●
Socioeconomic indicators or proxies (e.g., deprivation index, education level, postal 
code)
9.3.3.2
Respiratory comorbidity and allergies
●
Time since first diagnosis of COPD

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●
Respiratory conditions recorded at any time before the index date (Table 6).
Time between the first recorded diagnosis of COPD in the database and the index date will be 
ascertained for new users of olodaterol and indacaterol.
Table 6
Respiratory comorbidity and allergies
Disease Description
ICD-10
ICD-9
COPD
J41-J44
491, 492, 496
Chronic bronchitis
J41-J42
491
Emphysema
J43
492
Other COPD
J44
496
Asthma
J45, J46
493
Pneumonia
J09-J18
480-486
Allergic rhinitis
J30
477
COPD = Chronic Obstructive Pulmonary Disease; ICD-10 = International Statistical Classification of Diseases and Related 
Health Problems, 10th Revision. ICD-9 = International Classification of Diseases, 9th Revision.
9.3.3.3
Severity of COPD
The guidelines of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 
recommend that physicians evaluate the severity of COPD and its impact on the health of 
patients by the combination of (1) the current level of symptoms, (2) the severity of the 
spirometric abnormality, and (3) the risk of exacerbations. [P13-02399] The presence of 
comorbidities also determines the severity of COPD and is a predictor of morbidity and 
mortality. According to these parameters, severity of COPD is classified in four severity 
groups as illustrated in Figure 2.

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Risk
GOLD classification of 
airflow limitation
4
3
C
D
≥2
Risk
Exacerbation 
history
2
A
B
≤ 1
1
mMRC 0-1
CAT < 10
mMRC ≥ 2
CAT ≥ 10
COPD Severity Categories
Severity 
Category
Characteristics
Spirometric 
Classification
Exacerbations 
per Year
mMRC
CAT
A
Low risk, fewer 
symptoms
GOLD 1-2
(mild-
moderate)
≤ 1
0-1
< 10
B
Low risk, more 
symptoms
≥ 2
≥ 10
C
High risk, fewer 
symptoms
GOLD 3-4
(severe-very 
severe
≥ 2
0-1
< 10
D
High risk, more 
symptoms
≥ 2
≥ 10
CAT = COPD Assessment Test; COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global Initiative for Chronic 
Obstructive Lung Disease; mMRC = Modified British Medical Research Council Questionnaire.
Source: Adapted from GOLD, 2013. [P13-02399]
Figure 2
Association between symptoms, spirometric classification, and future 
risk of exacerbations according to the Global Initiative for 
Obstructive Lung Disease
Some of the parameters to evaluate the severity of COPD are not available or are only 
partially recorded in automated health databases. These parameters include the level of 
symptoms of COPD and the results from spirometric tests. Therefore, severity of COPD in 
studies conducted in health databases is usually evaluated by other parameters that serve as 
proxies of severity. [R08-1492] [R09-0579] [R13-1392] [P09-04948] [P11-13226]
A summary of the evaluation of severity of COPD in health database studies is presented in 
ANNEX 3. In a study conducted in the General Practice Research Database (now known as 
the Current Practice Research Database) from the United Kingdom, the definition of severity 
was based on the intensity of use of bronchodilators and the use of oxygen therapy or 
nebulised therapy.[R08-1492] A modification of this definition of severity was used in a 
recent study conducted in the Integrated Primary Care Information Project database in the 
Netherlands.[P11-13226] The definition used in that study included hospitalisations for 
COPD, the use of antibiotics for the treatment of respiratory tract infections, and the use of 
systemic glucocorticosteroids for the treatment of COPD exacerbations. The classification of 
severity based on these factors had a PPV of 82% when compared with results from 
spirometry. In another study conducted in the Saskatchewan Health databases in Canada,
determinants of COPD severity were the presence of emphysema, the use of nebuliser 
therapy, the use of oxygen therapy, the use of inhaled and/or systemic glucocorticosteroids, 
the intensity of bronchodilator use, pneumonia, and prior COPD exacerbation.[R09-0579]
These factors were associated with increased cardiovascular morbidity and mortality.

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9.3.3.4
Definition of COPD severity
Severity of COPD will be evaluated among new users of olodaterol and indacaterol that have 
a recorded diagnosis of COPD before the index date. Severity of COPD will be evaluated at 
the index date by a modified version of the algorithm developed by Verhamme and 
colleagues [P11-13226] (see Table 7).
Table 7
Definition criteria of COPD severity
Severity of 
COPD
Definition
Mild
Less than 2 dispensings of the same COPD drug class with a 
maximum interval of 6 months in the 12 months before the index date.
Moderate
Regular bronchodilator treatment, defined as having at least 2 
dispensings of the same COPD drug class with a maximum interval of 
6 months in the 12 months before the index date1,2
Severe
Occurrence of at least one of the following events in the year before 
the index date:

Hospitalisation for COPD2

Recorded diagnosis of pneumonia2

Third course of antibiotics for respiratory tract infections2

Second course of systemic corticosteroids for the treatment of 
COPD exacerbation2
Very severe
Occurrence of at least one of the following events in the year before 
the index date unless other time period is specified:

Dispensed oxygen therapy1,2

Dispensed nebuliser therapy1,2

Diagnosis of emphysema at any time before the index date2
COPD = Chronic Obstructive Pulmonary Disease.
Sources: modified from Verhamme et al., 2012 [P11-13226]; Soriano et al., 2001 [R08-1492]; and Curkendall et al., 2006.
[P07-09136]
1
Severity criteria also included in definition from Soriano et al., 2001. [R08-1492]
2
Severity criteria also included in definition from Curkendall et al., 2006. [P07-09136]
The use of antibiotics and oral corticosteroids and hospitalisations for COPD haven been 
used by other authors as markers of severity of COPD exacerbations. [P12-09396] [P12-
09395] [P12-14293]
The operational definitions to be applied when assessing the severity of COPD are as follows:
●
Same-class bronchodilators. The following bronchodilators classes will be considered 
(see Annex Table 4:2):

Inhaled short-acting muscarinic antagonists (SAMAs)

Inhaled long-acting muscarinic antagonists (LAMAs)

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
Inhaled short-acting beta2-agonists (SABAs)

Inhaled LABAs

Inhaled glucocorticosteroids (ICSs)

Fixed combinations of SABAs and SAMAs

Fixed combinations of SABAs and ICSs

Fixed combinations of LABAs and ICSs

Systemic glucocorticosteroids

Systemic beta2-agonists

Xanthines

Roflumilast
●
Hospitalisation for COPD

Primary or secondary hospital discharge diagnosis for COPD

ICD-10 codes: J40-J44; ICD-9 codes: 491, 492, 496
●
Recorded diagnosis of pneumonia

Primary or secondary hospital discharge diagnosis for pneumonia

ICD-10 codes J09-J18; ICD-9 codes: 480-486
●
Third course of antibiotics for respiratory tract infections

A course with antibiotic is defined as that involving consecutive dispensings of 
antibiotics with less than 7 days between the end of days of supply of one dispensing 
and the date of the next dispensing

ATC codes for antibiotics: J01 (antibacterials for systemic use)
●
Second course of systemic glucocorticosteroids for the treatment of COPD exacerbation

A course with systemic corticosteroids is defined as that involving consecutive 
dispensings with less than 7 days between the end of days of supply of one dispensing 
and the date of the next dispensing.

ATC codes for systemic glucocorticosteroids: H02AB
●
Oxygen therapy, ATC code: V03AN01
●
Nebuliser therapy (to be identified in each database using national drug codes)
●
Primary or secondary hospital outpatient or inpatient discharge diagnosis of emphysema
at any time before the index date

ICD-10 code: J43; ICD-9 code: 492
9.3.3.5
Other comorbidity and conditions
The following comorbidities and conditions recorded at any time before the index date will 
be evaluated: cardiovascular diseases, hyperlipidaemia, diabetes mellitus, renal disease, 

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anaemias, peptic ulcer disease, liver disease, osteoporosis, rheumatoid arthritis, systemic 
connective tissue diseases, malignancy, depressive disorders, and pregnancy. Specific 
diseases and conditions and ICD-10 and ICD-9 codes are provided in Annex 4, Annex Table 
4:1
9.3.3.6
Comedications
The following comedications dispensed within 12 months before the index date will be 
evaluated: respiratory medications, cardiovascular medications, antithrombotic agents, 
systemic antibacterials, iron preparations, proton pump inhibitors, drugs used in diabetes, 
drugs for musculoskeletal system conditions, antidepressants, antineoplastic agents, 
immunosuppressants, antivirals for systemic use, hormone-replacement therapy, and drugs 
used in nicotine dependence.
Specific medications and ATC codes are provided in Annex Table 4:2.
9.3.3.7
Health care resource utilisation
Health care resource utilisation will be evaluated for the 12 months before the index date.
●
Total number of dispensing; all medications included in Annex Table 4:2
●
Total number of dispensings for respiratory medications; all medications included in the 
section of respiratory medications in Annex Table 4:2
●
Total number of dispensings for systemic glucocorticosteroids; ATC code H02AB
●
Total number of dispensings for LABAs; ATC codes R03AC012 (salmeterol) and 
R03AC013 (formoterol)
●
Total number of hospitalisations; number of hospitalisations for any cause
●
Total number of hospitalisations for COPD; number of hospitalisations with a primary 
discharge code for COPD; ICD-10 codes J40-J44; ICD-9 codes: 491, 492, 496
●
Total number of hospitalisations for asthma; number hospitalisations with a primary 
discharge code for asthma; ICD-10 codes J45, J46; ICD-9 code: 493
9.3.4
Outcomes
9.3.4.1
Primary outcome
The primary outcome is the prevalence of off-label prescribing among new users of 
olodaterol.

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9.3.4.2
Secondary outcomes
9.3.4.3
The secondary outcome is the prevalence of off-label prescribing among new 
users of indacaterol
9.3.5
Covariates
Not applicable.
9.4
DATA SOURCES
The study will be conducted in the following databases:
●
PHARMO Database Network
●
National Registers in Denmark
●
National Registers in Sweden
A description of each database is provided in the following sections; further details are 
provided from the feasibility report, dated 1 November 2013, and in ANNEX 5. The study 
will be conducted by using data on drug dispensings and disease occurrence routinely 
collected on an ongoing basis for large population-based automated health care databases in 
the Netherlands, Denmark, and Sweden (see Table 1 and Table 2 for characteristics of these 
databases). New users will be characterised in terms of past medical history and use of 
medications. Off-label prescribing will be evaluated for those new users for whom general 
practitioner diagnoses are available. An overview of the information on diagnoses and 
procedures by data source is shown in the table below (Table 8).
9.4.1
PHARMO Database Network
9.4.1.1
Database characteristics
The PHARMO Database Network consists of multiple databases containing data files on 
approximately 3.2 million community-dwelling inhabitants in geographically defined areas 
covering approximately 20% of the Netherlands. Data sources include information from 
general practitioners (GPs), community pharmacies, hospitals, and laboratory sources.
The patients covered in each database are not necessarily included in all of the databases, as 
some of the geographical areas overlap partially, but if they are in more than one database, 
they can be linked to construct the medical history as shown in Figure 3. Thus, high-quality 
research can be conducted with ascertainment of patient demographics, drug dispensings, 
hospital morbidity, clinical laboratory results, and date of death.
The dispensing (outpatient pharmacy) database covering 3.2 million individuals can use a 
validated algorithm to identify patients with COPD, asthma, or other respiratory conditions. 
All patients are linked with the hospitalisation database (100% overlap between outpatient 

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and hospitalisation database).
severity indicators as recorded
GP = general practitioner.
Figure 3
Schem
the PH
The GP database covering 1.4
including forced expiratory vo
half of the population (440,00
(outpatient pharmacy) and hos
9.4.2
Denmark
The Danish health care system
(5.5 million inhabitants). Heal
admissions, and outpatient vis
health system. The centralised
identification of each person i
to all Danish registries contain
Registry of Patients, Danish N
Central Denmark Region, and
these registries are available fo
Practice Database (DAMD) is
for research. It provides inform
purposes of promoting and im
data for research concerning g
1 million population. 
For 1980-2008, The National 
hospital contact for COPD. [R
45 to 84 years, the prevalence 
residents of two counties. [R1
9.4.3
Sweden
Since 1987, Sweden has mand
surgery and psychiatric care h
data are held in the Swedish N
Discharge Register), along wi
admissions to hospital care an
dies based on existing data
14 Boehringer Ingelheim International GmbH or one or more of its 
Approximately 440,000 patients can be linke
d by the GP.
matic overview of overlap example among dat
HARMO Database Network
4 million individuals has information as record
olume in 1 second (FEV1) and spirometry dat
00) in the GP database can be linked to both d
spitalisation data.
m provides universal coverage to all Danish re
lth care coverage includes visits to GPs and sp
sits. The costs of medicines are partially cove
d Civil Registration System in Denmark allow
n the entire Danish population and for the po
ning civil registration numbers, such as the D
National Prescription Database, the Prescriptio
d the Danish Registry of Causes of Death. Dat
for research purposes. The availability of the D
s a recent development in the group of Danish
mation from selected general practices nation
mproving the quality of care in general practic
general practice. [R13-5415] The DAMD curr
Registry of Patients counted 236,494 patients
R12-3324] From the National Health Service, 
 of COPD was estimated at 12%, using a sam
2-3265]
dated collection of hospital care data national
have since been added to the database. [R14-0
National Patient Register (NPR) (sometimes c
th a Cause of Death Register. The Swedish N
nd hospital outpatient diagnoses. Primary and 
Page 30 of 65
c02329987-02
affiliated companies
ed to GP data for 
tabases included in 
ded by the GP, 
ta. Approximately 
dispensing 
esidents 
pecialists, hospital 
ered by the Danish 
ws for personal 
ossibility of linkage 
anish National 
on Databases of the 
ta collected in 
Danish General 
h databases used 
nwide, with the 
e and providing 
rently covers about 
s with a first 
for persons aged 
mple of 299,000 
ly; same-day 
0444] The hospital 
called the Hospital 
NPR comprises all 
several secondary 

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diagnoses are recorded. With the national personal identification number, patients can be 
tracked over time and from one hospital to another. As of 2004, few admissions were missing 
a personal identification number; for example, for stroke, 0.5% of hospitalisations lacked an 
identification number in a study of two counties. For acute hospital care, more than 99% of 
the hospital stays had at least a primary diagnosis recorded. [R14-0356] A validation review 
of the NPR by the National Board of Health and Welfare showed that 85% to 95% of all 
diagnoses are valid. [R14-0357]
Primary care data in Sweden may be available for the counties of Stockholm and Göteborg 
through the County Council health registers. The population of these two counties covers 
approximately 25% of the total Swedish population.
Ascertained from the Obstructive Lung Disease in Northern Sweden study, the prevalence of 
patients with diagnosed COPD in a subset of the study cohort and aged 46 years or older was 
14.3%, when evaluated by GOLD criteria, and 8.1% when evaluated by British Thoracic 
Society criteria. [R13-1576] From the National Oxygen Register, the estimated number of 
patients with severe COPD was 8,712. [R14-0353]
9.4.4
Summary of study databases 
Table 8 shows and compares the characteristics of the study databases.
Table 8
Overview of the study databases
Data Element
PHARMO
(Netherlands)
National Registers, 
Denmark 
National Registers, 
Sweden 
Database type
Patient-centric data 
obtained from 
community 
pharmacies and with 
variable linkage rates 
to other health care 
files 
National health 
record and 
prescription 
databases linked 
through the unique 
civil personal 
registration number
National health 
record databases 
capable of linkage 
through the unique 
civil personal 
registration number
Database 
population
3.2 million
Denmark
Sweden
Country 
population1
16,779,575
5,602,628
9,555,893
Approximate 
proportion of the 
country’s 
population 
covered by the 
database
20%
100%
100%

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Table 8 (con’t)
Overview of the study databases
Data Element
PHARMO 
(Netherlands)
National Registers, 
Denmark 
National Registers, 
Sweden 
Representative-
ness of patients 
and practices
Known to be 
representative [P93-
73309] [P14-01899]
Complete, given that 
the total country 
population is 
included
Complete, given that 
the total country 
population is 
included
Data on 
medications
Dispensings from 
community 
pharmacies and 
prescriptions from 
GP database 
Pharmacy-dispensed 
prescriptions
All pharmacy-
dispensed 
prescriptions
Dose
Yes
Formulation strength
Formulation strength
Duration
Yes
Based on 
prescriptions
Based on dispensed 
prescriptions
Drug dictionary 
codes/therapeutic 
classification
ATC
ATC 
ATC 
Indacaterol
4,000
47,400 (2010-2011)
6,361 (2010-2011)
Number of users 
of indacaterol 
1,200
6,093 (2010-2011)
110 (2010)
2,565 (2011)
Clinical 
indication 
For approximately 
440,000 PHARMO 
subjects (included in 
outpatient database), 
via linkage to GP 
files and proximity of 
clinical diagnoses; 
for all subjects in GP 
database
Not recorded but may 
be surmised based on 
GP diagnoses for GP-
linked practices and 
proxies (i.e., 
prescribed 
medication and 
hospital discharge 
diagnosis history) for 
not-linked practices
Not recorded but 
may be surmised 
based on GP 
diagnoses for GP-
linked practices and 
proxies (i.e., 
prescribed 
medication and 
hospital discharge 
diagnosis history) for 
not-linked practices
Prescriber 
characteristics 
GP vs. specialist 
GP vs. specialist 
Profession
Level of education
Speciality

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Table 8 (con’t)
Overview of the study databases
Data Element
PHARMO 
(Netherlands)
National Registers, 
Denmark 
National Registers, 
Sweden 
Outpatient 
diagnosis
For all PHARMO 
subjects (included in 
outpatient databases): 
main diagnoses in 
ICD-9-CM for all 
admissions for 
> 24 hours and 
admissions for 
< 24 hours for which 
a bed is required; for 
subcohort of GP 
database patients 
with linkage to 
outpatient pharmacy 
database
Hospital outpatient 
diagnoses
General practitioner 
diagnoses for about 
1 million population
recorded via ICPC 
coding
Hospital diagnoses.
General practitioner 
diagnoses for the 
counties for 
Stockholm and 
Göteborg recorded 
via ICPC coding
Hospital 
diagnosis
Main hospital 
diagnostic/surgical 
procedures
Yes
Yes
Procedure codes
Available for 
approximately 
1 million of 
pharmacy file 
patients; GP 
laboratory tests for 
all patients in GP 
database
Yes, ICD-10
Yes, NCSP version 
1.16:2012
Pulmonary 
function testing 
With difficulty
From hospital clinics 
and also from 
primary care when 
recorded
From hospital clinics 
and also from 
primary care when 
recorded
Information on
death
Fact and date of 
death, Mortality 
Register 
Fact, date, and 
underlying cause of 
death available in 
National Death 
Register
Fact, date, and 
underlying cause of 
death available in 
National Death 
Register
Access to 
medical records
Variable
No
No

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Table 8 (con’t)
Overview of the study databases
Data Element
PHARMO 
(Netherlands)
National Registers, 
Denmark 
National Registers, 
Sweden 
Lifestyle risk 
factors (smoking 
status, BMI, 
alcohol intake)
Yes, if recorded by 
GPs
Yes, if recorded by 
GPs
Yes, if recorded by 
GPs
Data availability
Annual
Since 1994
Since 2005
Updates
Pharmacy data: 2 
months
All other data: 
annual; available 
following Q3-Q4
Annual
Annual
Approximate 
time lag 
No
1 year
2012 data will be 
available in 3Q-4Q 
2013
Data transfer
Review by the 
independent 
compliance 
committee STIZON/
PHARMO Institute
This committee 
consists of 
representatives of the 
individual data 
suppliers and is 
chaired by a privacy 
expert
No, requires 
collaboration with 
local investigator
No, requires 
collaboration with 
local investigator
Approval process
Data application and 
ethics committee 
approval required
Data application and 
ethics committee 
approval required
Data application and 
ethics committee 
approval required 
ATC = Anatomical Therapeutic Chemical; BMI = Body Mass Index; GP = General Practitioner; ICD-9-CM = International 
Classification of Diseases, 9th Revision, Clinical Modification; ICD-10 = International Statistical Classification of 
Diseases and Related Health Problems, 10th Revision; ICD-10-CM = International Classification of Diseases, 10th 
Revision, Clinical Modification; ICPC = International Classification of Primary Care; NCSP = Nordic Medico-
Statistical Committee’s Classification of Surgical Procedures.
1
Eurostat. 2013. Available at: website: 
epp.eurostat.ec.europa.eu/tgm/table.do?tab=table&init=1&language=en&pcode=tps00001&plugin=1. Accessed
January 28, 2014.
9.5
STUDY SIZE
Actual counts of numbers of patients using olodaterol in European countries are not yet 
available. Table 9 shows the confidence intervals around estimated prevalence of comorbidity 
and comedications under various exposure group size scenarios.

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Table 9
Confidence intervals around selected estimated prevalences for 
varying numbers of patients
Number of 
Patients
95% Confidence Intervals for Various Prevalences of Diseases (%)
1%
2%
5%
7%
10%
300
0.2-2.9
0.7-4.3
2.8-8.1
4.4-10.5
6.8-14.0
800
0.4-2.0
1.1-3.2
3.6-6.7
5.3-9.0
8.0-12.3
2,000
0.6-1.5
1.4-2.7
4.1-6.0
5.9-8.2
8.7-11.4
5,000
0.7-1.3
1.6-2.4
4.4-5.6
6.3-7.7
9.2-10.9
Note: This table was prepared with the use of Episheet—spreadsheets for the analysis of 
epidemiologic data. [R13-1396]
A small number of users of olodaterol in each database during the first years (2014-2016) 
after launch may result in imprecise prevalence estimates for conditions with a prevalence of 
10% and below, especially when stratified analyses are conducted.
9.6
DATA MANAGEMENT
Routine procedures include checking electronic files, maintaining security and data 
confidentiality, following analysis plans, and performing quality-control checks of all 
programs. Each database research partner will maintain any patient-identifying information 
securely onsite according to internal standard operating procedures.
Each collaborating data source has been reviewed and qualified by the RTI Health Solutions 
Office of Quality Assurance. Each research team will follow its own established procedures 
and generate appropriate result tables. All summary tables of results, and no individual 
patient identifiers, will be provided to RTI Health Solutions, which will compile the results 
and develop the report. RTI Health Solutions will follow quality-control procedures regarding 
transfer of data. 
Security processes will be in place to ensure the safety of all systems and data. Every effort 
will be made to ensure that data are kept secure so that they cannot be accessed by anyone 
except select study staff.
Appropriate data storage and archiving procedures will be followed. Standard procedures will 
be in place at each location handling the data to restore files in the event of a hardware or 
software failure.
The extent of missing data will be evaluated and described. Due to the nature of this study, no 
imputation of missing data is planned.
For requests to access to data for audit purposes, only aggregated data from all research 
centres will be available at the coordinating centre. The audit trail will consist of a detailed 
description of the methods to extract and process the electronic health records or claims data, 
as applicable. Access to raw data at each database research centre will require the data 

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requestor to obtain a license or apply for approval at a research committee and to fulfil the 
conditions required under the governance rules of each database research centre.
9.7
DATA ANALYSIS
All analyses will be conducted separately in each study database and will be further analysed 
separately by new users of olodaterol and by new users of indacaterol, further stratified by 
treatment-naïve subjects and switchers. Analyses will be conducted annually for three 
consecutive years. Each year will include all patients starting treatment with olodaterol or 
indacaterol in that specific year. Statistical analyses will be descriptive in nature. Descriptive 
statistics will include the absolute and relative number of subjects, mean, median, standard 
deviation, and range for continuous variables. Statistical inference will not be performed 
(e.g., no P values will be generated).
9.7.1
Main analysis
9.7.2
Indication and potential off-label prescribing
Number and proportion of new users for each indication (COPD only, COPD and asthma, 
asthma only, and no COPD or asthma) associated with the initiation of treatment. 
This analysis will be conducted using data linked to diagnoses recorded by general 
practitioners (primary care information):
●
PHARMO-GP, covering about 440,000 population
●
Danish General Practice Database, covering about 1 million population
●
Swedish General Practice Database for the counties of Stockholm and Göteborg
9.7.3
Number of users and patterns of use
The following analyses will be conducted:
Dose at the start date: Dose at the start date will be ascertained by the dispensed DDD and 
the estimation of the daily dose. The estimated daily dose dispensed at the index date will be 
calculated using the recorded information on strength and quantity dispensed and the days of 
supply of the first prescription for olodaterol and indacaterol. The mean (SD) number of 
packages and daily dose will be calculated.
Age and sex distribution of users at the index date: Number and percentage of users of 
olodaterol and indacaterol at the index date by sex and the following groups of age (in years): 
0-17, 18 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 69, 70 to 79, 80 or older.
9.7.4
Characterisation of new users at the index date
The number and percentage of each variable of interest (as specified in Section 9.3) at the 
index date will be estimated separately among new users of olodaterol and among new users 
of indacaterol. All analyses will be stratified by the following variables:
●
Age in years, categorised as 0 to 17 years, 18 to 39 years, and 40 years or older

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●
Sex
●
Switchers at the index date (as defined in Section 9.2.3) and treatment-naïve subjects
●
Indication

COPD only

COPD and asthma

Asthma only

Neither COPD nor asthma
●
Calendar year of index date: 2014, 2015, 2016
The following analyses will be performed:
Time since first recorded diagnosis of COPD: Mean (SD), median, 25th percentile, and 
75th percentile.
Lifestyle habits: Distribution of new users by categories of body mass index, smoking status, 
alcohol consumption, and socioeconomic status at the index date, according to the type of 
information available in each database.
Respiratory comorbidity and allergies: Number and proportion of new users with at least 
one diagnosis for each respiratory condition listed in Table 5 that was recorded at any time 
before the index date.
Severity of COPD: Number and proportion of new users for each category of severity of 
COPD: mild, moderate, severe, and very severe.
Other comorbidity: Number and proportion of patients with at least one diagnosis for each 
of the comorbidity conditions listed in Table 8 and recorded at any time before the index 
date.
Comedications. Number and proportion of patients with at least one dispensing for each of 
the medications listed in Annex Table 4:2 taking place in the 12 months before the index 
date.
Health care resources utilisation: Distribution of new users as defined by the following 
categories of variables evaluated within the 12 months before the index date:

Total number of dispensings: 0, 1 to 4, 5 to 9, 10 or more

Total number of dispensings for respiratory medications (Annex Table 4:2): 0, 1 to 4, 5 to 
9, 10 or more

Total number of dispensings for systemic glucocorticosteroids: 0, 1 to 4, 5 to 9, 10 or 
more

Total number of dispensings for LABAs: 0, 1 to 4, 5 to 9, 10 or more

Total number of hospitalisations: 0, 1, 2, 3 to 4, 5 or more

Total number of hospitalisations for COPD: 0, 1, 2, 3 to 4, 5 or more

Total number of hospitalisations for asthma: 0, 1, 2, 3 to 4, 5 or more

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9.8
QUALITY CONTROL
At the coordinating centre, an independent Office of Quality Assurance performs audits and 
assessments that involve various aspects of its projects, including but not limited to 
documentation of education and training, data entry, data transfer, and approval of the 
institutional review board at RTI International, of which RTI Health Solutions is a research 
unit. Such audits at RTI Health Solutions will be conducted by the Office of Quality 
Assurance according to established criteria in standard operating procedures and other 
applicable procedures. Each of the database research centres will follow its own quality and 
audit trail procedures. The quality and audit trails at each centre may be different.
Data management and analysis will be conducted in each database. Standard operating 
procedures at each database will be used to guide the conduct of the study. These procedures 
include internal quality audits and the opportunity for external audits, rules for secure and 
confidential data storage, methods to maintain and archive project documents, quality-control 
procedures for programming, standards for writing analysis plans, and requirements for 
senior scientific review. RTI Health Solutions will follow quality-control procedures for 
report generation, including senior review by an expert other than the author. 
9.9
LIMITATIONS OF THE RESEARCH METHODS
Existing population-based data are very useful for evaluating research questions about real-
world clinical practice because of the diversity of patients and medical practices represented 
therein. However, the results must be interpreted with caution because such data sources are 
known to misclassify information of interest, in the following ways:

The length of medical history in some databases will be limited, and earlier medical 
events or drug exposures may be unknown. Therefore, the prevalence of some conditions 
may be underestimated.

Information on prescriber characteristics is likely to be limited in some of the available 
databases.

Clinical differential diagnosis between COPD and asthma might be difficult, and it is 
even more challenging to differentiate these conditions in database studies.

For severity of COPD, ideally FEV1 would be useful to classify all individuals by 
application of standard criteria; however, it is anticipated that this information is not 
recorded systematically in the study databases. Therefore, classification of severity of 
COPD in database studies uses proxies, such as use of COPD medications and use of 
health care services.

For Denmark and Sweden, this study will be conducted by researchers affiliated with 
institutions that have access to the national registers. Thus, the conduct of the study in 
these countries will depend on the scientific and regulatory interest of these researchers, 
as well as on their availability during the study period.

Study size depends upon the uptake of olodaterol. 

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9.10
OTHER ASPECTS
9.10.1
Bias
The use of hospital outpatient and/or inpatient discharge diagnoses can overestimate potential 
off-label prescribing. For this reason, and because use of hospital discharge diagnoses does 
not ascertain patients diagnosed with COPD who are not hospitalised, off-label use will be 
assessed in the subset of new users linked to the general practice (primary care) registers. In 
the three countries primary care data are only available for a subset of the population. 

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10.
PROTECTION OF HUMAN SUBJECTS
The study will be conducted in accordance with the International Society for 
Pharmacoepidemiology’s Guidelines for Good Pharmacoepidemiology Practices [R11-4318]
and in accordance with the European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance (ENCePP) Guide on Methodological Standards in 
Pharmacoepidemiology. [R13-5419] The ENCePP Checklist for Study Protocols [R13-1395]
is completed (see ANNEX 2), and the study will be registered in the EU PAS Register. [R14-
0354]
The study is a drug utilisation study and will comply with the definition of the non-
interventional (observational) study provided in the 2012 Guideline on Good 
Pharmacovigilance Practice: Module VIII—Post-Authorisation Safety Studies. [R13-5420]. 
The study will comply with the nature of non-interventional (observational) studies referred 
to in the International Conference on Harmonisation’s harmonised tripartite guideline 
Pharmacovigilance Planning E2E. [R11-2259]

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11.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
Based on current guidelines from the International Society for Pharmacoepidemiology [R11-
4318] and the European Medicines Agency (EMA) Guideline on Good Pharmacovigilance 
Practices (GVP) Module VI - Management and Reporting of Adverse Reactions to Medicinal 
Products, [R13-1970] non-interventional studies such as the one described in this protocol 
conducted using aggregated patient data from electronic health care records do not require 
expedited reporting of suspected adverse events/reactions. Based on the data planned for this 
study, no suspected adverse events/reactions are expected.

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12.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The study protocol synopsis, study status, and report(s) will be included in regulatory 
communications in line with the risk management plan, Benefit-Risk Evaluation Report, and 
other regulatory milestones and requirements.
Study results will be published following the International Committee of Medical Journal 
Editors recommendations, [R13-5418] and communication in appropriate scientific venues 
(e.g., the International Society for Pharmacoepidemiology) will be considered.
When reporting results of this study, the appropriate Strengthening the Reporting of 
Observational Studies in Epidemiology checklist [R11-4902] will be followed.

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13.
REFERENCES
13.1
PUBLISHED REFERENCES
P07-09136
Curkendall SM, Lanes S, de Luise C, Stang MR, Jones JK, She D, 
et al. Chronic obstructive pulmonary disease severity and 
cardiovascular outcomes. Eur J Epidemiol. 2006;21(11):803-13. 
P09-04948
Ogale SS, Lee TA, Au DH, Boudreau DM, Sullivan SD. 
Cardiovascular events associated with ipratropium bromide in 
COPD. Chest. 2010 Jan;137(1):13-9. 
P11-13226
Verhamme KM, Afonso AS, van Noord C, Haag MD, Koudstaal 
PJ, Brusselle GG, et al. Tiotropium Handihaler and the risk of 
cardio- or cerebrovascular events and mortality in patients with 
COPD. Pulm Pharmacol Ther. 2012 Feb;25(1):19-26. 
P12-09395
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. 
Bronchodilator use and the risk of arrhythmia in COPD: part 1: 
Saskatchewan cohort study. Chest. 2012 Aug;142(2):298-304. 
P12-09396
Wilchesky M, Ernst P, Brophy JM, Platt RW, Suissa S. 
Bronchodilator use and the risk of arrhythmia in COPD: part 2: 
reassessment in the larger Quebec cohort. Chest. 2012 
Aug;142(2):305-11. 
P12-14293
Suissa S, Dell'Aniello S, Ernst P. Long-term natural history of 
chronic obstructive pulmonary disease: severe exacerbations and 
mortality. Thorax. 2012 Nov;67(11):957-63. 
P13-02399
GOLD. Global strategy for the diagnosis, management, and 
prevention of chronic obstructive pulmonary disease.  Updated 
2013. Global Initiative for Chronic Obstructive Lung Disease;  
2013. Available at: website: goldcopd.org/guidelines-global-
strategy-for-diagnosis-management.html. Accessed 17 October 
2013.
P14-01899
Herings RMC, Pedersen L. Pharmacy-based medical record linkage 
systems. In: Strom BL KS, Hennessy S, editor. 
Pharmacoepidemiology, 5th edition. 5th ed: John Wiley & Sons, 
Ltd.; 2012. p. 270-86. 
P93-73309
Herings RM, Bakker A, Stricker BH, Nap G. Pharmaco-morbidity 
linkage: a feasibility study comparing morbidity in two pharmacy 
based exposure cohorts. J Epidemiol Community Health. 1992 
Apr;46(2):136-40. 

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R06-4117
Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino 
DM. Global burden of COPD: systematic review and meta-
analysis. Eur Respir J. 2006 Sep;28(3):523-32. 
R07-2620
Soriano JB, Visick GT, Muellerova H, Payvandi N, Hansell AL. 
Patterns of comorbidities in newly diagnosed COPD and asthma in 
primary care. Chest. 2005 Oct;128(4):2099-107. 
R08-1492
Soriano JB, Maier WC, Visick G, Pride NB. Validation of general 
practitioner-diagnosed COPD in the UK General Practice Research 
Database. Eur J Epidemiol. 2001;17(12):1075-80. 
R09-0579
Curkendall SM, DeLuise C, Jones JK, Lanes S, Stang MR, 
Goehring E, Jr., et al. Cardiovascular disease in patients with 
chronic obstructive pulmonary disease, Saskatchewan Canada 
cardiovascular disease in COPD patients. Ann Epidemiol. 2006 
Jan;16(1):63-70. 
R09-2531
WHO. The global burden of disease: 2004 update. Table 7. 
Geneva: World Health Organization, Department of Health 
Statistics and Informatics;  2008. Available at: website: 
who.int/healthinfo/global_burden_disease/GBD_report_2004updat
e_full.pdf. Accessed 14 November 2013. 
R11-2259
ICH. Technical requirements for registration of pharmaceuticals for 
human use.  Pharmacovigilance planning. E2E. International 
Conference on Harmonisation; November 2004 2004. Available at: 
website: ich.org/products/guidelines/efficacy/efficacy-
single/article/pharmacovigilance-planning.html. Accessed 26 July 
2012. 
R11-4318
ISPE. Guidelines for good pharmacoepidemiology practices (GPP). 
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Available at: website: 
pharmacoepi.org/resources.guidelines_08027.cfm. Accessed 01 
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R11-4902
STROBE. STROBE checklist. Strengthening the Reporting of 
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R12-3265
Hansen JG, Pedersen L, Overvad K, Omland O, Jensen HK, 
Sorensen HT. The Prevalence of chronic obstructive pulmonary 
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Kornum JB, Svaerke C, Thomsen RW, Lange P, Sorensen HT. 
Chronic obstructive pulmonary disease and cancer risk: a Danish 

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nationwide cohort study. Respir Med. 2012 Jun;106(6):845-52. 
R13-1392
Eisner MD, Omachi TA, Katz PP, Yelin EH, Iribarren C, Blanc 
PD. Measurement of COPD severity using a survey-based score: 
validation in a clinically and physiologically characterized cohort. 
Chest. 2010 Apr;137(4):846-51. 
R13-1395
ENCePP. ENCePP checklist for study protocols (revision 2). 
European Network of Centres for Pharmacoepidemiology and 
Pharmacovigilance; 14 January 2013. Available at: website: 
encepp.eu/standards_and_guidances/checkListProtocols.shtml. 
Accessed 8 January 2014. 
R13-1396
Rothman KJ. Episheet--spreadsheets for the analysis of 
epidemiologic data.  October 25, 2011, version.  2011. Available 
at: website: epidemiolog.net/studymat/. Accessed 14 February 
2013. 
R13-1576
Lindberg A, Bjerg A, Ronmark E, Larsson LG, Lundback B. 
Prevalence and underdiagnosis of COPD by disease severity and 
the attributable fraction of smoking Report from the Obstructive 
Lung Disease in Northern Sweden Studies. Respir Med. 2006 
Feb;100(2):264-72. 
R13-1970
EMA. Guideline on good pharmacovigilance practices (GVP). 
Module VI – Management and reporting of adverse reactions to 
medicinal products. European Medicines Agency; 22 June 2012. 
Available at: website: 
emea.europa.eu/docs/en_GB/document_library/Scientific_guidelin
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R13-5415
Danish Quality Unit of General Practice. Danish General Practice 
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R13-5418
ICMJE. Recommendations for the conduct, reporting, editing, and 
publication of scholarly work in medical journals. International 
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R13-5419
ENCePP. Guide on methodological standards in 
pharmacoepidemiology (revision 2). EMA/95098/2010 Rev.2. 
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Pharmacovigilance; 18 June 2013. Available at: website: 
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Accessed 8 January 2014. 
R13-5420
EMA. Guideline on good pharmacovigilance practices (GVP). 

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Module VIII – Post-authorisation safety studies 
(EMA/813938/2011 Rev 1). European Medicines Agency; 19 April 
2013. Available at: website: 
emea.europa.eu/docs/en_GB/document_library/Scientific_guidelin
e/2012/06/WC500129137.pdf. Accessed 8 January 2014. 
R14-0349
Örtqvist AK, Lundholm C, Wettermark B, Ludvigsson JF, Ye W, 
Almqvist C. Validation of asthma and eczema in population-based 
Swedish drug and patient registers. Pharmacoepidemiol Drug Saf. 
2013 Aug;22(8):850-60. 
R14-0350
Marsh SE, Travers J, Weatherall M, Williams MV, Aldington S, 
Shirtcliffe PM, et al. Proportional classifications of COPD 
phenotypes. Thorax. 2008 Sep;63(9):761-7. 
R14-0351
Juhn Y, Kung A, Voigt R, Johnson S. Characterisation of children's 
asthma status by ICD-9 code and criteria-based medical record 
review. Prim Care Respir J. 2011 Mar;20(1):79-83. 
R14-0352
Blais L, Lemiere C, Menzies D, Berbiche D. Validity of asthma 
diagnoses recorded in the Medical Services database of Quebec. 
Pharmacoepidemiol Drug Saf. 2006 Apr;15(4):245-52. 
R14-0353
Ekström MP, Jogréus C, Ström KE. Comorbidity and sex-related 
differences in mortality in oxygen-dependent chronic obstructive 
pulmonary disease. PLoS One. 2012;7(4):e35806. 
R14-0354
ENCePP. EU PAS Register. European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance; 7 January 2014. 
Available at: website: 
encepp.eu/encepp_studies/indexRegister.shtml. Accessed 8 January 
2014. 
R14-0356
Köster M, Asplund K, Johansson A, Stegmayr B. Refinement of 
Swedish administrative registers to monitor stroke events on the 
national level. Neuroepidemiology. 2013;40(4):240-6. 
R14-0357
Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, 
Reuterwall C, et al. External review and validation of the Swedish 
national inpatient register. BMC Public Health. 2011;11:450. 
R14-0359
Thomsen RW, Lange P, Hellquist B, Frausing E, Bartels PD, Krog 
BR, et al. Validity and underrecording of diagnosis of COPD in the 
Danish National Patient Registry. Respir Med. 2011 
Jul;105(7):1063-8. 
R14-0443
NOMESCO. NOMESCO classification of surgical procedures, 
version 1.16:2012. Copenhagen: Nordic Medico-Statistical 
Committee;  2011. 

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R14-0444
Socialstyrelsen. The National Patient Register. Swedish National 
Board of Health and Welfare;  2013. Available at: website: 
socialstyrelsen.se/register/halsodataregister/patientregistret/inenglis
h. Accessed 13 February 2013. 
R14-0456
Inghammar M, Engstrom G, Lofdahl CG, Egesten A. Validation of 
a COPD diagnosis from the Swedish Inpatient Registry. Scand J 
Public Health. 2012 Dec;40(8):773-6. 
13.2
UNPUBLISHED REFERENCES
Not applicable

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None

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ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS

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Doc.Ref. EMA/540136/2009 
ENCePP Checklist for Study Protocols (Revision 2, amended)
Adopted by the ENCePP Steering Group on 14/01/2013
The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)
welcomes innovative designs and new methods of research. This Checklist has been developed by 
ENCePP to stimulate consideration of important principles when designing and writing a 
pharmacoepidemiological or pharmacovigilance study protocol. The Checklist is intended to 
promote the quality of such studies, not their uniformity. The user is also referred to the ENCePP 
Guide on Methodological Standards in Pharmacoepidemiology which reviews and gives direct 
electronic access to guidance for research in pharmacoepidemiology and pharmacovigilance.
For each question of the Checklist, the investigator should indicate whether or not it has been 
addressed in the study protocol. If the answer is “Yes”, the page number(s) of the protocol where 
this issue has been discussed should be specified. It is possible that some questions do not apply 
to a particular study (for example in the case of an innovative study design). In this case, the 
answer ‘N/A’ (Not Applicable) can be checked and the “Comments” field included for each section 
should be used to explain why. The “Comments” field can also be used to elaborate on a “No” 
answer. 
This Checklist should be included as an Annex by marketing authorisation holders when submitting 
the protocol of a non-interventional post-authorisation safety study (PASS) to a regulatory 
authority (see the Guidance on the format and content of the protocol of non-interventional post-
authorisation safety studies). Note, the Checklist is a supporting document and does not replace 
the format of the protocol for PASS as recommended in the Guidance and Module VIII of the Good 
pharmacovigilance practices (GVP).
Study title:
Drug Utilisation Study for Olodaterol
Study reference number:
1222.53
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
1.1.1 Start of data collection1
1.1.2 End of data collection2
1.1.3 Study progress report(s) 
1.1.4 Interim progress report(s)
1.1.5 Registration in the EU PAS register
1.1.6 Final report of study results.
12
12
12
12
12
12
Comments:
Timing of PAS registration has not yet been determined. 
Section 2: Research question
Yes
No
N/A
Page 
Number(s)
2.1 Does the formulation of the research question and 
objectives clearly explain: 
2.1.1 Why the study is conducted? (e.g. to address an 
important public health concern, a risk identified in the risk 
management plan, an emerging safety issue)
2.1.2 The objective(s) of the study?
13
14
2.1.3 The target population? (i.e. population or 
subgroup to whom the study results are intended to be 
generalised)
2.1.4 Which formal hypothesis(-es) is (are) to be 
tested?
2.1.5 If applicable, that there is no a priori
hypothesis?
15
Comments:
there is no a priori hypothesis and the objective is to measure the relative frequency of 
off label use among olodaterol and comparator
Section 3: Study design
Yes
No
N/A
Page 
Number(s)
3.1 Is the study design described? (e.g. cohort, case-
control, randomised controlled trial, new or alternative design) 
15
3.2 Does the protocol specify the primary and 
secondary (if applicable) endpoint(s) to be 
investigated?
28
3.3 Does the protocol describe the measure(s) of 
effect? (e.g. relative risk, odds ratio, deaths per 1000 
person-years, absolute risk, excess risk, incidence rate ratio, 
hazard ratio, number needed to harm (NNH) per year)
Comments:
1 Date from which information on the first study is first recorded in the study dataset or, in the case of 
secondary use of data, the date from which data extraction starts.
2 Date from which the analytical dataset is completely available.

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Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
18
4.2 Is the planned study population defined in terms 
of:
4.2.1 Study time period?
4.2.2 Age and sex?
4.2.3 Country of origin?
4.2.4 Disease/indication?
4.2.5 Co-morbidity?
4.2.6 Seasonality?
18
18
19
18
4.3 Does the protocol define how the study population 
will be sampled from the source population? (e.g. 
event or inclusion/exclusion criteria)  
19
Comments:
Section 5: Exposure definition and measurement
Yes
No
N/A
Page 
Number(s)
5.1 Does the protocol describe how exposure is 
defined and measured? (e.g. operational details for 
defining and categorising exposure)
19
5.2 Does the protocol discuss the validity of exposure 
measurement? (e.g. precision, accuracy, prospective 
ascertainment, exposure information recorded before the 
outcome occurred, use of validation sub-study)
5.3 Is exposure classified according to time windows?
(e.g. current user, former user, non-use)
5.4 Is exposure classified based on biological 
mechanism of action and taking into account the 
pharmacokinetics and pharmacodynamics of the 
drug?
5.5 Does the protocol specify whether a dose-
dependent or duration-dependent response is 
measured?
Comments:
This DUS is limited to characterizing the subjects on and before first use; exposure 
group of interest consists of all new users 
Section 6: Endpoint definition and measurement
Yes
No
N/A
Page 
Number(s)
6.1 Does the protocol describe how the endpoints are 
defined and measured? 
20
6.2 Does the protocol discuss the validity of endpoint 
measurement? (e.g. precision, accuracy, sensitivity, 
specificity, positive predictive value, prospective or 
retrospective ascertainment, use of validation sub-study)
19-22

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Comments:
Section 7: Confounders and effect modifiers
Yes
No
N/A
Page 
Number(s)
7.1 Does the protocol address known confounders?
(e.g. collection of data on known confounders, methods of 
controlling for known confounders)
7.2 Does the protocol address known effect modifiers?
(e.g. collection of data on known effect modifiers, anticipated 
direction of effect)
Comments:
Confounding and effect modification is not expected to be an issue for this descriptive 
study.
Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
8.1 Does the protocol describe the data source(s) 
used in the study for the ascertainment of:
8.1.1 Exposure? (e.g. pharmacy dispensing, general 
practice prescribing, claims data, self-report, face-to-face 
interview, etc.)
8.1.2 Endpoints? (e.g. clinical records, laboratory markers 
or values, claims data, self-report, patient interview including 
scales and questionnaires, vital statistics, etc.)
8.1.3 Covariates?
19
20
23
8.2 Does the protocol describe the information 
available from the data source(s) on:
8.2.1 Exposure? (e.g. date of dispensing, drug quantity, 
dose,  number of days of supply prescription, daily dosage,  
prescriber)
8.2.2 Endpoints? (e.g. date of occurrence, multiple event, 
severity measures related to event)
8.2.3 Covariates? (e.g. age, sex, clinical and drug use 
history, co-morbidity, co-medications, life style, etc.)
19
20
23
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
8.3.2 Endpoints? (e.g. Medical Dictionary for Regulatory 
Activities (MedDRA) for adverse events)
8.3.3 Exposure? (e.g. WHO Drug Dictionary, Anatomical 
Therapeutic Chemical (ATC)Classification System)
21-22
21-22
31
8.4 Is the linkage method between data sources 
described? (e.g. based on a unique identifier or other)
29
Comments:
Section 9: Study size and power
Yes
No
N/A
Page 
Number(s)
9.1 Is sample size and/or statistical power calculated? 
35

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Comments:
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1 Does the plan include measurement of excess 
risks?
10.2 Is the choice of statistical techniques described? 
36
10.3 Are descriptive analyses included?
36
10.4 Are stratified analyses included?
36
10.5 Does the plan describe methods for adjusting for 
confounding?
10.6 Does the plan describe methods addressing 
effect modification?
Comments:
Confounding and effect modification are not relevant to this descriptive study 
Section 11: Data management and quality 
control
Yes
No
N/A
Page 
Number(s)
11.1 Is information provided on the management of 
missing data?
35
11.2 Does the protocol provide information on data 
storage? (e.g. software and IT environment, database 
maintenance and anti-fraud protection, archiving)
38
11.3 Are methods of quality assurance described?
38
11.4 Does the protocol describe possible quality 
issues related to the data source(s)?
11.5 Is there a system in place for independent 
review of study results? 
Comments:
11.1-11.3 This is a core protocol that will be implemented by multiple research 
institution that are qualified and have available staffing at the time of study initiation, 
i.e. after EMA review, olodaterol is launched.  At that time the specifics of data 
management for each data source and corresponding research institution, including 
quality control and data security, can be specified. 
11. 5  To date no advisory board is planned. 
Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
12.1 Does the protocol discuss:
12.1.1 Selection biases?
12.1.2 Information biases?
(e.g. anticipated direction and magnitude of such biases, 
37-38

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Section 12: Limitations
Yes
No
N/A
Page 
Number(s)
validation sub-study, use of validation and external data, 
analytical methods)
12.2 Does the protocol discuss study feasibility? (e.g. 
sample size, anticipated exposure, duration of follow-up in a 
cohort study, patient recruitment)
37-38
12.3 Does the protocol address other limitations? 
37-38
Comments:
Section 13: Ethical issues
Yes
No
N/A
Page 
Number(s)
13.1 Have requirements of Ethics 
Committee/Institutional Review Board approval 
been described?
40
13.2 Has any outcome of an ethical review procedure 
been addressed?
13.3 Have data protection requirements been 
described?
35
Comments:
For this core protocol, the data protection procedures will be consistent with local 
procedures and more details will be added into data source-specific study documents 
Section 14: Amendments and deviations
Yes
No
N/A
Page 
Number(s)
14.1 Does the protocol include a section to document 
future amendments and deviations? 
11
Comments:
Section 15: Plans for communication of study 
results
Yes
No
N/A
Page 
Number(s)
15.1 Are plans described for communicating study 
results (e.g. to regulatory authorities)?
41
15.2 Are plans described for disseminating study 
results externally, including publication?
41
Comments:
Name of the main author of the protocol: ___________
________
Date: 30 September 2014
Signature: ___________________________

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ANNEX 3. EVALUATION OF COPD SEVERITY IN AUTOMATED
HEALTH DATABASES
Annex Table 3:1
Published definitions of COPD severity in studies conducted in 
automated health databases
Reference, Severity 
Criteria
COPD Severity
Mild
Moderate
Severe
Integrated Primary Care Information Project, Netherlands [P11-13226]
With spirometry data, 
used GOLD criteria
[P13-02399]
Without spirometry, 
used methods of 
Curkendall et al.,
[R09-0579] Eisner et 
al., [R13-1392] and 
Soriano et al. [R08-
1492]
At initial COPD 
symptoms
At least 2 
prescriptions of 
bronchodilators of 
the same drug class 
with a maximum 
interval of 6 
months in 1 year
Severe:

Hospitalisation for 
COPD, or

Third course of 
antibiotics for respiratory 
infection in 1 year, or

Second course of 
systemic corticosteroids 
for COPD exacerbation in 
1 year
Very severe:

Oxygen therapy, or

Scheduled for lung 
transplant
Saskatchewan Health, Canada [R09-0579]
Case-control study to 
find severity marker 
variables, using:

Pre-existing 
chronic conditions

Recent acute 
conditions

Recent high use of 
bronchodilators
Specific components 
of the above are 
detailed in the article’s 
appendix 
Patients ranked 
into 5 quintiles by 
likelihood of 
COPD 
hospitalisation, 
from conditional 
logistic 
regression model
Factors in previous 180 days 
associated with severe COPD:

Emphysema

Recent nebuliser use

Home oxygen therapy

Corticosteroid use

Frequent bronchodilator 
use

Pneumonia

Previous COPD 
exacerbation

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Annex Table 3:1 (con’t) 
Published definitions of COPD severity in studies conducted in 
automated health databases
Reference, Severity 
criteria
COPD Severity
Mild
Moderate
Severe
General Practice Research Database,1 United Kingdom Soriano [R08-1492]
Severity based only on 
drug data
At first diagnosis 
of COPD
At least 2 
prescriptions of the 
same COPD drug 
within 6 months, 
using data on 
inhaled or oral 
bronchodilators, 
xanthines, 
cromones, steroids, 
or combinations

Oxygen therapy, or

Nebuliser therapy
COPD = Chronic Obstructive Pulmonary Disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease.
1
This database is now known as Clinical Practice Research Datalink.

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ANNEX 4. CODES FOR COMORBIDITIES AND OTHER
MEDICATIONS
Annex Table 4:1
Other comorbidity
Disease Description
ICD-10 Code
ICD-9 Code
Cardiovascular diseases 
I00-I99
390-459
Ischaemic heart disease
I20-I25 or coronary 
reperfusion surgery and 
procedures
410-414 or coronary 
reperfusion surgery and 
procedures
Angina pectoris
I20
413, 411.1
Acute myocardial infarction
I21
410
Other acute or subacute ischaemic 
heart disease 
I22-I24
411.0, 411.8
Chronic ischaemic heart disease
I25
412, 414
Coronary reperfusion surgery and 
procedures 
List of codes to be 
developed according to 
each database dictionary
List of codes to be 
developed according to 
each database dictionary
Arrhythmias
I47-I49
427.0-427.4, 427.6-427.9
Paroxysmal tachycardia
I47
427.0-427.2
Ventricular tachycardia
I47.0, I47.2
427.1
Supraventricular tachycardia 
and unspecified
I47.1, I47.9
427.0, 427.2
Atrial fibrillation and flutter
I48
427.3
Other cardiac arrhythmias
I49
427.4, 427.6, 427.8, 427.9
Ventricular fibrillation and 
flutter
I49.0
427.4
Other cardiac arrhythmias 
I49.1-I49.9
427.6, 427.8, 427.9
Conduction disorders
I44-I45
426
Cardiac arrest
I46
427.5
Heart failure
I50
428
Cerebrovascular disease
I60-I69, G45
430-438
Cerebral haemorrhage 
(subarachnoid, intracerebral, other 
non-traumatic)
I60-I62
430-432

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Annex Table 4:1 (con’t)
Other comorbidity
Disease Description
ICD-10 Code
ICD-9 Code
Cardiovascular diseases 
I00-I99
390-459
Cerebral infarction and stroke 
I63, I64, G46.5
433.1, 434.1, 436
Transient ischaemic attack
G45
435
Other cerebrovascular disease and 
sequelae of cerebrovascular disease 
I65-I69
433.0, 434.0, 437, 438
Hypertension and hypertensive heart 
disease
I10-I15
401-405
Diseases of arteries, arterioles, and 
capillaries 
I70-I79, and peripheral 
arterial revascularisation 
procedures
440-449 and peripheral 
arterial revascularisation 
procedures
Peripheral arterial revascularisation 
procedures 
List of codes to be 
developed according to 
each database dictionary
List of codes to be 
developed according to 
each database dictionary
Other form of heart diseases
I00-I09, I30-I43, I80-I99
390-398, 420-425, 429, 
440-459 
Hyperlipidaemia 
E78
272
Diabetes mellitus
E10-E14
250
Renal disease
N00-N39
580-599
Chronic kidney disease
N18
585
Other renal disorders
N00-N17, N19, N25-N39
Anaemias
D50-D64
280-285
Nutritional anaemias
D50-D53
280-281
Iron deficiency anaemias 
D50
280
Other anaemias
D55-D64
282-285
Peptic ulcer disease
K25-K28
531-534
Liver disease
K70-K77
570-573
Osteoporosis
M80-M82
733.0
Rheumatoid arthritis and other 
inflammatory arthropathies
M05-M14
712-714, 716, 696.0
Systemic connective tissue diseases
M30-M36
710
Malignancy
C00-C97
140-209
Depressive disorders
F32-F33
311, 
Pregnancy (at the index date)
O00-O48
630-649
ICD-10 = International Statistical Classification of Diseases and Related Health Problems, 10th Revision; ICD-9 = 
International Classification of Diseases, 9th Revision.

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Annex Table 4:2 
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Respiratory medications
Inhaled SAMAs
Ipratropium bromide
R03BB01
Oxitropium bromide
R03BB02
Inhaled LAMAs
Tiotropium bromide
R03BB04
Aclidinium bromide
R03BB05
Glycopyrronium bromide
R03BB06
Inhaled SABAs
Salbutamol 
R03AC02
Terbutaline
R03AC03
Fenoterol
R03AC04
Rimiterol
R03AC05
Hexoprenaline
R03AC06
Isoetarine
R03AC07
Pirbuterol
R03AC08
Tretoquinol
R03AC09
Carbuterol
R03AC10
Tulobuterol
R03AC11
Clenbuterol
R03AC14
Reproterol
R03AC15
Procaterol
R03AC16
Bitolterol
R03AC17
Indacaterol
R03AC18
Inhaled LABAs
Salmeterol
R03AC12
Formoterol
R03AC13
Inhaled glucocorticosteroid
Beclometasone
R03BA01
Budesonide
R03BA02

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Annex Table 4:2 (con’t)
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Respiratory medications
Flunisolide
R03BA03
Betamethasone
R03BA04
Fluticasone
R03BA05
Triamcinolone
R03BA06
Mometasone
R03BA07
Ciclesonide
R03BA08
Fixed combinations of SABAs and SAMAs
ATC codes not available1
Fixed combinations of SABAs and ICSs
ATC codes not available1
Fixed combinations of LABAs and ICSs
ATC codes not available1
Systemic glucocorticosteroids
H02AB
Systemic beta2-agonists
R03CC
Xanthines and adrenergics
R03DA, R03DB
Roflumilast
R03DX07
Nasal glucocorticosteroids
R01AD
Omalizumab
R03DX05
Leukotriene receptor antagonists
R03DC
Cromoglicic acid
R03BC01
Nedocromil
R03BC03
Methotrexate
L04AX03
Ciclosporin
L04AD01
Gold preparations
M01CB
Oxygen therapy
V03AN01
Nebuliser therapy
ATC codes not available1
Cardiovascular medications
All codes listed below in section 
Cardiovascular medications
Cardiac glycosides and antiarrhythmics, Classes I and 
III
C01A, C01B 
Vasodilators used in cardiac diseases
C01D
Other cardiac preparations
C01B, C01C
Diuretics
C03
Peripheral vasodilators
C04

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Annex Table 4:2 (con’t)
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Cardiovascular medications
All codes listed below in section 
Cardiovascular medications
Beta blocking agents
C07
Calcium channel blockers
C08
Antihypertensives
C02
Agents acting on the renin-angiotensin system
C09
Angiotensin-converting-enzyme inhibitors
C09A, C09B
Angiotensin II receptor antagonists
C09C, C09D
Renin-inhibitors
C09X
Lipid-modifying agents
C10
HMG CoA reductase inhibitors (statins)
C10AA
Other lipid-modifying agents
C10AB, C10AC, C10AD, C10AX 
HMG CoA reductase inhibitors (statins), other 
combination
C10BX
Antithrombotic agents
B01
Platelet aggregation inhibitors
B01AC
Systemic antibacterials
J01
Iron preparations
B03A
Proton pump inhibitors
A02BC
Drugs used in diabetes 
A10
Insulins
A10A
Blood glucose–lowering drugs
A10B, A10X
Drugs for musculoskeletal system
M01A, N02BA, M01B, M01C
Antiinflammatory and antirheumatic products, 
non-steroids (nonsteroidal anti-inflammatory 
drugs)
M01A
Acetylsalicylic acid (other analgesics and antipyretics)
N02BA
Other antirheumatic agents: 
Antiinflammatory/antirheumatic agents in 
combination, specific antirheumatic agents
M01B-M01C
Antidepressants
N06A
Selective serotonin reuptake inhibitors
N06AB
Antineoplastic agents
L01

Boehringer Ingelheim
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Protocol for observational studies based on existing data
BI Study Number 1222.53
c02329987-02
Proprietary confidential information © 2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Annex Table 4:2 (con’t)
Anatomical Therapeutic Chemical codes for comedications
Medication Description
ATC Code
Immunosuppressants
L04
Antivirals for systemic use
J05
Hormone-replacement therapy: Estrogens, 
progestogensprogestogens, and estrogens in 
combination
G03C, G03D, G03F
Drugs used in nicotine dependence
N07BA 
ATC = Anatomical Therapeutic Chemical; ICS = Inhaled Glucocorticosteroid; LABA = Long-Acting Beta2-Agonist; 
LAMA = Long-Acting Muscarinic Antagonist; SABA = Short-Acting Beta2-Agonist; SAMA = Short-Acting 
Muscarinic Antagonist.
1
The national drug code of each database country will be used to identify medications without an individual ATC code.
Source: WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2013. Updated 20 December 2012. 
Available at: website: whocc.no/atc_ddd_index/. Accessed 21 January 2013.

Boehringer Ingelheim
Protocol for observational stud
BI Study Number 1222.53
Proprietary confidential information © 201
ANNEX 5. DETAILS O
FEASIBILI
PHARMO, THE NETHERL
Database Characteristics
Database Description
The PHARMO Database Netw
approximately 3.2 million com
covering approximately 20% o
included in the PHARMO Dat
community pharmacies, hospi
GP = General Practitioner; PRO = Patie
Annex Figure 5:1 
Data s
The patients covered in each d
some of the geographical area
database, they can be linked to
Thus, high-quality research ha
drug dispensings, hospital mo
dies based on existing data
14 Boehringer Ingelheim International GmbH or one or more of its 
ON EACH DATABASE FROM THE
TY REPORT (1 NOVEMBER 2013)
LANDS
work consists of multiple databases containin
mmunity-dwelling inhabitants in geographica
of the Netherlands. Annex Figure 5:1 shows t
tabase Network. Data sources include inform
itals, and laboratory sources.
ent-Reported Outcome.
sources within the PHARMO Database Netwo
database are not necessarily included in all of 
as overlap partially; but if patients are in more
o construct the medical history as shown in A
as been conducted with ascertainment of patie
rbidity, clinical laboratory results, and date o
Page 64 of 65
c02329987-02
affiliated companies
E 
)
ng data files on 
ally defined areas 
the databases 
mation from GPs, 
ork
f the databases, as 
e than one 
Annex Figure 5:2
ent demographics, 
f death.

Boehringer Ingelheim
Protocol for observational stud
BI Study Number 1222.53
Proprietary confidential information © 201
GP = general practitioner.
Annex Figure 5:2 
Schem
the PH
dies based on existing data
14 Boehringer Ingelheim International GmbH or one or more of its 
matic overview of overlap example among dat
HARMO Database Network
Page 65 of 65
c02329987-02
affiliated companies
tabases included in