Nada Alkis' Master Thesis, Novo Nordisk & University of Copenhagen

UNIVERSITY OF COPENHAGEN
FACULTY OF HEALTH AND MEDICAL SCIENCES
Fixed Dose Combinations – Regulatory
Aspects and Real World Measures on
Xultophy Therapy
Master’s Thesis
Nada Bassam Alkis
Internal Supervisor: Ole Jannik Bjerrum
External Supervisors: Mark Joseph Root, Sascha Eichendorff
Submitted on: 31 December 2017
Department of: Drug Design and Pharmacology
Copenhagen Centre for Regulatory Science (CORS)

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Table of contents
ACKNOWLEDGMENTS.....................................................................................................4
ABSTRACT .........................................................................................................................5
ABBREVIATIONS...............................................................................................................6
PART I
1 INTRODUCTION.........................................................................................................2
2 RESEARCH QUESTION AND OBJECTIVE................................................................4
3 HYPOTHESIS ..............................................................................................................4
4 BACKGROUND ...........................................................................................................4
5 MATERIALS AND METHODS ....................................................................................8
6 RESULTS ...................................................................................................................12
7 DISCUSSION..............................................................................................................21
8 CONCLUSION ...........................................................................................................24
PARTII
1 INTRODUCTION.......................................................................................................26
2 RESEARCH QUESTION AND OBJECTIVES............................................................27
3 HYPOTHESIS ............................................................................................................27
4 BACKGROUND .........................................................................................................28
5 MATERIALS AND METHODS:.................................................................................31
6 RESULTS ...................................................................................................................34

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7 DISCUSSION..............................................................................................................39
8 CONCLUSION ...........................................................................................................40
APPENDIX 1: FIRST- AND SECOND-VISIT PATIENT QUESTIONNAIRE: ...................41
APPENDIX 2: XULTOPHY – SOLIQUA: EPAR – EU/SUMMARY REVIEW – US...........49
APPENDIX 3: DEFINITIONS............................................................................................51
REFERENCES...................................................................................................................52

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Acknowledgments
This work was carried out under the supervision of Professor Ole J. Bjerrum, Department of
Drug Design and Pharmacology, SUND, Copenhagen University; Mark Joseph Root, Senior
Regulatory Affairs Professional, Novo Nordisk A/S, and Sascha Eichendorff, Principal
Regulatory Professional, ALK – Abello A/S.
I would like to sincerely thank Ole Bjerrum, Mark Root, and Sascha Eichendorff for their great
enthusiasm throughout the project and for providing constant support and advice. Their very
different approaches and guidance were vital for the success of the project – I have learned an
enormous amount from you all.
I would also like to thank the many different people at Novo Nordisk who went out of their way
to provide me with information and contacts and were so helpful and friendly, both within and
outside the Regulatory Affairs Department. I am particularly grateful to all the people who gave
their time to give their perspective and feedback. I am very impressed with the kindness of
everyone I have met in the pharmaceutical field.
Finally, I would like to thank my father Bassam, my mother Ahlam, and my husband Yasin
Alnashawati, who are always ready to listen and discuss ideas and put up with me working late
and on the weekends. I would also thank my brother Mohammed, my sisters Monera and Shaza,
and my sister in law Salma, for their support. Without my families support, I would not have
made it to the end.
Nada Alkis
Copenhagen, January 2018.

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Abstract
This thesis consists of two parts. The first part is based on the research question:
Are the FDA and EMA aligned in their approval decisions regarding fixed dose combination
(FDC) medical products? This question was explored by evaluating the labels of all the FDCs
approved between: January 2000 – April 2017 within 5 chronic therapeutic areas: type-2 diabetes
mellitus (T2DM), asthma, chronic obstructive pulmonary disease (COPD), hypertension, and
human immunodeficiency virus (HIV). In fact, it was found that there were differences between
the FDA and EMA approval decisions with regards to the approved and used in pre-defined sub-
populations. Some of the reasons for these discrepancies are discussed.
The second part of this thesis attempts to apply for the conceptual issues addressed
in the first part to a practical setting. Specifically, assessing the real-world patient reported
outcomes (PROs) for patients switched to a certain FDC product, Xultophy. And how the PROs
collected from this real-world use might compare to the clinical trial PROs used to support
labelling claims. It was found that real-world data, in the form of PROs collected in a community
pharmacy setting, is a novel and interesting approach to gathering important information and
could be explored further in future research.

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Abbreviations
ADA American Diabetes Association
AE Adverse Event
API Active Pharmaceutical Ingredients
AdComm Advisory Committee
COA Clinical Assessment Outcome
CBER Centre for Biologics Evaluation
and Research
CDER Centre for Drug Evaluation and
Research
CHMP Committee for Medicinal Products
for Human Use
COPD Chronic obstructive Pulmonary
Disease
CPG Clinical Practice Guideline
DDT Drug Development Tool
DPP-4i Dipeptidyl Peptidase-4 inhibitor
EASD European Association for the Study
of Diabetes
EHR Electronic Health Record
EPAR European Public Assessment
Report
EU European Union
FDA US Food and Drug Administration
FDC Fixed Dose Combination
FPG Fasting Plasma Glucose
FRC Fixed Ratio Combination
EMA European Medicine Agency
FDA Food and Drug Administration
HbA1c Haemoglobin A1c
HIV Human Immunodeficiency Virus
HR-QoL Health Related Quality of Life
IAD Injectable Antidiabetic Drug
ICH International Conference on
Harmonization
GI AE Gastrointestinal Adverse Event
GLP-1 RA Glucagon Like Peptide-1 Receptor
Agonist
NID New Investigational Drugs
NME New Molecular Entities
OAD Oral Antidiabetic Drug
OCP Office’s Combination Product
PI Package Insert
QoL Quality of Life
PPG Post Prandial Glucose
PRO Patient Reported Outcome
RCT Randomized Clinical Trial
RWD Real World Data
RWE Real World Evidence
SGLT-2i Sodium-Glucose Cotransporter-2
inhibitor
SME Small Molecular Entities
SmPC Summary of Product Characteristic
SOC Standard of Care
SU Sulfonylurea
T2DM Type 2 Diabetes Mellitus
TRIM-D Treatment Related Impact
Measure-Diabetes
TZD Thiazolidinediones
UCPH University of Copenhagen
USA United States of America
WHO World Health Organizatio

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Part I – Differences of EMA and FDA Label Indications for
FDC Products Approved Between Jan 2000 and Apr 2017
1 Introduction
The use of fixed dose combination (FDC) therapy is increasing (1). The European
medicine agency (EMA) and the food and drug administration (FDA) are open toward approving
FDCs. Their approval decisions are given for each FDC individually and after consideration of
the submitted evidence, a target patient population is defined. The target patient population is
defined in the label under therapeutic indication section. The label is called Summary of Product
Characteristics (SmPC) in Europe and package insert (PI) in the US. This label defines what is
known as “therapeutic indication” (2), which describes as “[The] indication section…that state[s]
that the drug is indicated for the treatment, prevention, mitigation, cure, or diagnosis of a
recognized disease or condition…” (3-5). With respect to the FDA guideline for FDC, the
definitions of the therapeutic indications were well explained in the EMA guideline. According
to the EMA guideline, the therapeutic indications for fixed-dose combination products are
divided into three categories:
(a) Initial combination (naïve patient to both components, A and B),
(b) Add-on (patient on either monocomponent A or monocomponent B), and
(c) Substitution therapy (patient on both monocomponents A and B taken
simultaneously).
For the purpose of this thesis the above definitions are used. Each category has its
own studied patient population and its clinical development. The clinical development must be
performed in the clinical trials when specific use is intended in the respective population. Later
on, the intended therapeutic indication of the FDC may be approved by the medicine agencies.
This project investigated whether the EMA and FDA differ in their approval decisions with
respect to the three defined subpopulations.
For this project five chronic therapeutic areas were selected:
 Type-2 diabetes mellitus (T2DM)

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 Asthma
 Chronic obstructive pulmonary disease (COPD)
 Hypertension
 Human immunodeficiency virus (HIV).
For these selected therapeutic areas, the FDCs have become an important
alternative to monotherapy by offering several advantages including patients compliance, simple
dosage schedule, superior efficacy, and reduced risk of adverse events (1, 6). These therapeutic
areas were selected although they differ from each other in their clinical development
recommendations as well as in the clinical practice, i.e. if T2DM patients are not well controlled
the risk for complications increases, without having immediate life-threating implications. This
is in contrast to diseases such as HIV. For this project, what matters, if the FDA and EMA
approval decisions are aligned or not. While multiple therapeutic areas will be discussed, this
project will focus on T2DM FDCs and briefly assess EMA and FDA approvals of FDCs for the
other selected therapeutic areas. It is important to explore multiple therapeutic areas, because we
learn about medicine agency perspectives through their approval habits. A benchmark has
therefore been established to acquire a comprehensive perspective of medicine agency approval
tendencies. Discrepancies of medicine agency approval in any therapeutic area can then be
stressed.
First, this project reviewed the general guideline recommendations for the clinical
development of the FDC therapy. Additionally, the disease specific guideline, which is in
particular for the diabetes treatment was also reviewed. This guideline was reviewed due to the
project focus on T2DM FDCs. Second, the approved therapeutic indications by EMA and FDA
were analysed. These approvals presented their perspectives on when to initiate FDC in each
selected therapeutic area. The FDA and EMA describe the rational beyond their approval
decisions in a document called European public assessment report (EPAR) and the summary
basis of approval, respectively. During the assessment of a combination product named
“Xultophy”, an issue was raised by the FDA. The question was “does a strategy that relies on
initiating two drugs at once (dual therapy) confer an advantage in the long-run over a strategy
that relies on sequential addition of drugs (sequential add-on)? Do the long-term benefits gained
by more rapid achievement of glucose control outweigh the potential added risks that come with
being exposed to two drugs compared to one? Put in another way, if a patient is able to get to

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the desired therapeutic goal with a single agent (an unknown when deciding to initiate dual
therapy), are risks associated with a second agent justified?” (7) This question expressed
uncertainties from a medicine agency perspective which sub-population a FDC product should
be approved for. This raises a question, if the medicine agency expressed uncertainty regarding
which subpopulation they approve the FDC for, then for which subpopulation they approve?
And are their approval decisions aligned?
2 Research question and objective
The objective of the study is to explore the alignment between EMA and FDA
approval decisions in regards to the therapeutic indications of FDCs within five therapeutic
areas: T2DM, COPD, asthma, hypertension and HIV. The FDA and EMA do not approve any
FDC before an intensive examination of the clinical studies submitted by the sponsors, which
ultimately leads to a decision on the approval or disapproval of the FDC for use in the above-
defined sub-populations.
Objective:
 Investigate whether or not the therapeutic indications are aligned between EMA and
FDA for selected FDCs.
3 Hypothesis
“The approved FDC labels by EMA and FDA are aligned in regard to the
therapeutic indications”
4 Background
EMA and FDA guidelines recommendations for FDCs clinical development
The guidelines are developed to answer frequent clinical development questions
regarding trial design, sample size, clinical endpoints, appropriate number of clinical studies,
statistical methods, and appropriate indications/claims. This project focus is the therapeutic

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indication. For each therapeutic indication in order to be approved must be performed in studied
patient population within clinical trials. The studied patient population must represent the target
patient populations in clinical practice (8, 9). After the assessment by medicine agencies of the
studied patient population in clinical trials, the medicine agencies may or may not approve a
product for use in a specific (sub-)population. For example, although Glyxambi
(empagliflozin/linagliptin) was studied for initial combination and add-on use in representative
patient populations, EMA and FDA approved Glyxambi for sequential add-on therapy. While for
initial combination use, Glyxambi was only approved by the FDA and not by EMA (10).
However, in order for the FDC therapies to reach the patients, they must be safe
and effective from the medicine agencies’ perspective (11). If a drug was not safe or effective
both medicine agencies would not approve. Thus, it is expected that the FDA and EMA are
aligned. To study a FDC, EMA and FDA had published specific FDC clinical development
guidelines; which are general guidelines.
I - EMA guideline (12) covered two categories of the FDC therapy for the clinical
development (13);
(a) FDC of (authorized drug + authorized drug), and
(b) FDC of (authorized drug + new investigational drug).
II- While the FDA guideline (14) covered one category:
(c) FDC of (new investigational drug + new investigational drug).
All studied T2DM FDCs are combinations of (a) combination of two authorized
drugs. Thus, EMA guideline is the only applicable. In this case, the sponsors are able to develop
FDCs for patients in the EU by following EMA guideline. But for patients in the US, the
sponsors have no FDA guideline. Therefore, the sponsors will organize early meetings with the
FDA in order to discuss the potential for the clinical development of a FDC. In the case of
T2DM FDCs, there are diabetes clinical development guidelines published by EMA (15) and the
FDA (16). Thus, sponsors are able to develop T2DM FDCs by following general FDC guideline
“if available”, the disease specific guideline, as well as the early meetings with the medicine
agency. In the case where there are no general guideline and no disease specific guideline, the
clinical development of a FDC is subject to the early meetings with the medicine agency.
For this project, the EMA and FDA guideline recommendations were similar for
the studied patient population and the study design for each therapeutic indication, as shown in
Table 1.

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Table 1: EMA (12, 15) and FDA (16) clinical development guideline recommendations for
each therapeutic indication category:
EMA FDA
I. Studied patient population in clinical trials
(i) Initial combination Performed in naïve patients to both components A and B
(ii) Sequential add-on
Performed in patients on either monocomponent A or
monocomponent B
(iii) Substitution
therapy
Performed in patients on both monocomponents A and B taken
separately
II. Study design
(i) Initial combination
Factorial study design:
Patients receiving monocomponent A vs. patients receiving
monocomponent B vs. patients receiving FDC consisting of A and
B (vs. patients receiving placebo)
(ii) Sequential add-on
(iii) Substitution
therapy
- Bridging studies comparing
PK between the fixed
combination and authorized
substances taken
simultaneously is key and
bioequivalence must be
demonstrated
- PD and/or clinical data are
needed to show
pharmcoequivalence
Pharmacoequivalent study on
healthy subjects: fixed
combination AB vs.
monocomponents A and B
taken simultaneously
PK= pharmacokinetic, PD= pharmacodynamic
The interesting aspects, however, may lie within the guidelines, specifically, for
what the guidelines suggest within clinical study design. The clinical study design should be in
accordance with the indication sought. EMA and FDA guidelines considered the factorial study

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design is appropriate to be combined with the approval of the FDCs for both add-on and initial
combination therapy.
Factorial study design
The medicine agencies use the generated study data in order to decide on the
therapeutic indications; they required clinical study data that support the approval in each sub-
population. Thus, the study design of the clinical trial should be aligned with the guidelines
recommendations in order to design a trial that is most in line with the medicine agencies
thinking, and more likely to obtain their approval. However, in practice, this does not always
occur, i.e. the question was raised after the assessment of Xultophy drug. The factorial study
design did not resemble the clinical practice; therefore the FDA was in doubt whether the
sequential add-on is better over the initial combination therapy. Although Xultophy was studied
in naïve patients, the FDA did not approved Xultophy for initial combination use. The factorial
study design is one among other approaches such as parallel group, cross-over, dose escalation,
and fixed dose-dose response (17-20). The factorial study design is the umbrella of two
processes. First, to identify the appropriate dosages for the fixed combination in which several
doses of each drug, e.g., a test drug T and another drug D, and their combinations are compared.
This comparison is made to decide which doses (T1, T2, or T3) for drug T, and (D1, D2, or D3)
for drug D, will be combined and used for the combination of both drugs (or drug T and D)”, as
seen in Table 2. Second, confirms the contribution of the components to the claimed effect. This
design is recommended by EMA and FDA, as laid out in the FDC guideline document (12, 16),
is consistent with the above regulations. Additionally, the factorial study design can be used to
show that the combination has a greater effect than either drug alone, but cannot confirm
whether the sequential add-on therapy is preferred over the initial combination therapy. This may
explain why the FDA raised uncertainty regarding initial combination vs. sequential add-on
therapy. However, this is the only recommendation on study design from the FDA and EMA
guideline to obtain their approval for these two indications: initial combination and add-on
therapy.

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Table 2: Factorial study design:
Placebo T1 T2 T3
D1 T1D1 T2D1 T3D1
D2 T1D2 T2D2 T3D2
D3 T1D3 T2D3 T3D3
5 Materials and Methods
5.1 Data sources
The fixed dose combination medicinal products were relevant for the comparison,
where the drugs approved by EMA and FDA in the period between January 2000 and April
2017. Relevant products were identified by searching the EMA and FDA websites for FDC
medicinal products. The FDC medicinal products were sorted using the “Drug Approvals by
Month” feature on the FDA drug search database (www.fda.gov/drugsatfda). The relevant
information was collected from the label. The FDCs’ intended therapeutic use that represents the
target patient population were obtained and compared. To be able to compare the FDC
therapeutic indications, information was collected on the following therapeutic areas: T2DM,
hypertension, COPD, asthma, and HIV infection.
5.2 Methodology
To analyse the data, the full list of approved FDC medicinal products by EMA and
FDA within the five disease areas was searched and downloaded between January – February
2017. Label information on therapeutic indications was transferred to a spreadsheet. This work
was repeated for all five therapeutic areas. The FDA and EMA approval decisions of FDCs were
compared, with respect to the use in the pre-defined sub-populations. The analysis was done,
through reading the therapeutic indication section within the label of each approved FDC and
interpreting its wording, and important to explain that the interpretation was not always
unambiguous (a weakness of the dataset). For example, in T2DM FDCs, the FDA has indications
“when treatment with both monocomponents A and B is appropriate”, i.e. no formal restriction

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of using the FDC as initial combination therapy. In general, the assumption was when the FDA
and EMA did not specifically restrict a particular indication; it is an acceptable (“approved”)
treatment option. For example, substitution indication, EMA and FDA wording within their
labels, in some cases e.g. Xultophy (GLP-1RA/basal insulin), there was no specific wording
describing whether EMA and FDA approval decision was given or not. So, the yes(s) for
substitution indications in such cases were assumptions. In contrast, the wording that described
the substitution use was included in other cases e.g. Glyxambi (empagliflozin/linagliptin). EMA
precisely considered the substitution therapy when the patient adequately treated with the free
combination of empagliflozin and linagliptin taken separately and simultaneously. Thus, this
indication was approved by EMA. While, the FDA considered this indication when the treatment
with empagliflozin and linagliptin is appropriate, which reflected in the Table 4 as precise “yes”
by EMA, and assumed “yes” by FDA. For add-on therapy, the FDA label wording considered
this indication in general when the treatment with monocomponent A and monocomponent B is
appropriate, while EMA label considered add-on therapy when the treatment with
monocomponent A alone is inadequate, which reflected in the Table 4 as assumed “yes” by
FDA, and precise “yes” by EMA. Unlike EMA, the FDA considered the initial combination use
when the treatment with monocomponent A and monocomponent B is appropriate, which
reflected in the Table 4 as precise “no” by EMA, and assumed “yes” by FDA. An example,
Soliqua EU (GLP-1 RA/basal insulin), EMA considered its use as initial combination by when
the patient is naïve (neither GLP-2RA nor basal insulin). Unlike EMA, the FDA rejected the
initial combination use of Suliqua US, which reflected as precise “yes” by EMA, and precise
“no” by FDA. In some cases the authorities strictly restrict an indication and in other cases the
indication is more open and only defined at the level of the therapeutic area with no mention of
use in subgroups (“open label”). As the case is with both HIV and COPD FDCs, the “yes” was
assumed for all three sub-populations, as see in Table 3.

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Table 3: Examples of interpretation of EMA and FDA label wording for the studied
therapeutic areas:
Label wording for: EMA FDA
T2DM FDCs
(i) Initial
combination therapy
Patient treated with either
monocomponent A or
monocomponent B – (precise
“no”)
When treatment with
monocomponent A and B is
appropriate – ( assumed “yes”)
(ii) Add-on therapy When treatment with
monocomponent A is
inappropriate – (precise “yes”)
(iii) Substitution
therapy
Patient adequately treated with
monocomponent A and B taken
separately and simultaneously –
(precise “yes”)
Asthma FDCs
(i) Initial
combination therapy
Patient must be treated with either
monocomponent A or B – (precise
“no”)
“Open label” (assumed “yes”)
(ii) Add-on therapy Patient inadequately treated with
either monocomponent A or B –
(precise “yes”)
(iii) Substitution
therapy
Patient treated with
separately – (precise “yes”)
COPD FDCs
(i) Initial
combination therapy
“Open label” (assumed “yes”)
(ii) Add-on therapy
(iii) Substitution
therapy

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Hypertension FDCs
(i) Initial
combination therapy
Patient must be treated with either
monocomponent A or
monocomponent B – (assumed
“no”)
Initial therapy for patient
likely to need multiple
monocomponents to achieve
their blood pressure goals –
(precise “yes”)
(ii) Add-on therapy Patient inadequately treated with
either monocomponent A or
monocomponent B – (precise
“yes”)
Patient inadequately controlled
with monocomponent (precise
“yes”)
(iii) Substitution
therapy
Patient adequately treated on
separately – (precise “yes”)
No wording – (assumed “yes”)
HIV FDCs
(i) Initial
combination therapy
“Open label” (assumed “yes”)(ii) Add-on therapy
(iii) Substitution
therapy

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6 Results
6.1 Translation of studied patient population data of FDC by EMA and FDA into
label (therapeutic indications)
According to the therapeutic indication classification, all approved FDCs within the
five studied therapeutic areas were analysed and collected from January 2000 – April 2017. Due
to the focus on T2DM FDCs, approved T2DM FDCs by EMA and FDA were analysed and
collected, as shown in Table 4. Based on EMA and FDA approval decisions, each sub-
population has been given a yes or no. The analyses classified according to the three sub-
populations are: (i) initial combination, (ii) add-on, and (iii) substitution therapy.
There were 26 approved T2DM FDCs between January 2000 – April 2017. The
number of T2DM FDCs approved by EMA and FDA were 21, and 19, respectively. There were
only 14 T2DM FDCs approved by both EMA and FDA. There were three FDCs not approved in
EU, they were from one drug class SU/Biguanide, and they were marketed in US. Two drugs
were withdrawn after approval in EU (Avandamet (TZD/biguanide) and Avaglim (TZD/SU)).
Both Avandamet and Avaglim have Rosiglitazone as a monocomponent, which EMA and FDA
had expressed safety concerns. In contrast, the combinations that included vildagliptin (DPP4i)
monocomponent were not marketed in the US; they were three that only marketed in the EU.
There were four generic FDCs authorized in the EU, as shown in Table 4.

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Table 4: T2DM FDCs authorized by FDA and EMA (January 2000 – April 2017) as categorized by the therapeutic indications and subdivided
into nine APIs drug classes and two routes of administration.
T2DM FDC monocomponents -
drug classes
Trade Name
Therapeutic Indications
Authorization date*(i) Initial
combination
*(ii) Add-on *(iii) Substitution
EMA FDA EMA FDA EMA FDA EMA FDA EMA FDA
Injection therapy
Glucose like peptide 1 receptor antagonist (GLP-1 RA)/basal insulin
Insulin glargine/lixisenatide Suliqua Soliqua Yes No Yes Yes Yes Yes Mar 17 Nov 16
Insulin degludec/liraglutide Xultophy Xultophy Yes No Yes Yes Yes Yes Sep 14 Nov 16
Oral therapy
Dipeptidyl peptidase 4 inhibitor (DPP-4 i)/Biguanide
Linagliptin/metformin Jentadueto Jentadueto No Yes Yes Yes Yes Yes Jul 12 Jan 12
Alogliptin benzoate/metformin HC Vipdomet Kazano No Yes Yes Yes Yes Yes Oct 13 Jan 13
Saxagliptin HC/metformin HC Komboglyze Kombiglyze No Yes Yes Yes Yes Yes Nov 11 May 10
Sitagliptin/metformin HC Janumet Janumet No Yes Yes Yes Yes Yes Dec 08 Mar 07
Vildagliptin/metformin HC Icandra No Yes Yes Dec 08
Sitagliptin/metformin HC Ristfor No Yes Yes Mar 10
Sitagliptin/metformin HC Efficib No Yes Yes Jul 08
Sitagliptin/metformin HC Velmetia No Yes Yes Jul 08
Vildagliptin/metformin HC Zomarist No Yes Yes Dec 08
Vildagliptin/metformin HC Eucreas No Yes Yes Nov 07
Dipeptidyl peptidase 4 inhibitor (DPP-4i)/Sodium Glucose coTransporter 2 inhibitor (SGLT-2i)
Linagliptin/Empagliflozin Glyxambi Glyxambi No Yes Yes Yes Yes Yes Nov 16 Jan 15

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Saxagliptin/Dapagliflozin Qtern Qtern No No Yes Yes Yes Yes Jul 16 Feb 17
Dipeptidyl peptidase 4 inhibitor (DPP-4i)/Thiazolidinediones (TZD)
Alogliptin/pioglitazone Incresync Oseni No Yes Yes Yes Yes Yes Sep 13 Jan 13
Sodium Glucose coTransporter 2 inhibitor (SGLT-2i)/Biguanide
Canagliflozin/metformin HC Vokanamet Invokamet No Yes Yes Yes Yes Yes Apr14 Aug 14
Empagliflozin/metformin Synjardy Synjardy No Yes Yes Yes Yes Yes May15 Aug 15
Dapagliflozin propanediol
monohydrate/metformin HC
Xigduo Xigduo No Yes Yes Yes Yes Yes Jan 14 Oct 14
Sulfonylurea (SU)/Biguanide
Glyburide/metformin HC Glucovance Yes Yes Yes Jul 00
Glipizide/metformin HC Metaglip Yes Yes Yes Oct 02
Repaglinide/metformin HC Prandimet No Yes Yes Jun 08
Thiazolidinediones (TZD)/Biguanide
Rosiglitazone HC/metformin HC Avandamet Avandamet No Yes Yes Yes Yes Yes Oct 03 Oct 02
Pioglitazone HC/metformin HC Glubrava No Yes Yes Dec 07
Pioglitazone/metformin HC Competact Actoplus Met No Yes Yes Yes Yes Yes Jul 06 Aug 05
Thiazolidinediones (TZD)/Sulfonyl urea (SU)
Pioglitazone/glimepiride Tandemact Duetact No Yes No Yes Yes Yes Jan 07 Jul 06
Rosiglitazone/glimepiride Avaglim Avandaryl No Yes Yes Yes Yes Yes Jun 05 Nov 05
*(i) Initial combination (naïve patient to both components, A and B), *(ii) add-on (patient on either monocomponent A or monocomponent B), and *(iii)
substitution therapy (patient on both monocomponents A and B taken simultaneously). Yes=approved, No= not approved, red=withdrawn, blue=generic,
and yellow= presumably not marketed.

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For this research purpose, the generic products, not marketed products, and withdrawn
products were excluded, as seen in Figure 1. There were fourteen approved T2DM FDCs by both
EMA and FDA.
Figure 1: Flow chart for identification of T2DM FDCs:
6.2 FDC alignments and disparities between EMA and FDA
EMA and FDA label for the approved T2DM FDCs between January 2000 – April
2017 was consistently aligned in regards to substitution therapy (100 % alignment, 14 of 14
drugs). The decision was aligned in 93 % of the cases, for the use as add-on therapy (13 of 14
drugs). The exception was Tandemact EU (TZD/SU), where EMA did not approved for add-on
therapy, while FDA did. In contrast, for the initial combination therapy, EMA and FDA approval
decisions were only aligned for 7 % of all decisions (1 out of 14 drugs).This is shown in Table 5.
For initial combination therapy, EMA and FDA were consistently not aligned. As
the case with the Qtern EU/US (saxagliptin/dapagliflozin), which represents the exception, both
medicine agencies were aligned in their decision for the use as initial combination therapy (both
medicine agencies disapproved). EMA consistently disapproved the use of T2DM FDCs as
initial combination therapy, while the FDA consistently approved the T2DM FDCs for initial
combination therapy for the oral T2DM drugs. The exact opposite is true for injectable FDC
product: Suliqua EU/ Soliqua US and Xultophy EU/US (both combinations of GLP-1 RA/basal
insulin), EMA approved these two FDCs for initial combination use and the FDA disapproved.
26 approved T2DM FDCs
In total, 14 FDCs authorized in EU and US
are included
3 FDCs not marketed in US
and 4 generic FDCs excluded
19 T2DM FDCs marketed in US21 T2DM FDCs marketed in EU
3 FDCs not marketed in EU and
2 FDCs withdrawn excluded

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Soliqua EU/Suliqua US, Xultophy EU/US, and Qtern EU/US are among the most
recently approved T2DM FDC products. Thus, these three drugs not only show disparity
between EMA and FDA, they also show reverse shift of EMA and FDA approval consideration
for T2DM FDCs as initial combination therapy. Additionally, the FDA disapproved Qtern
EU/US for initial combination use, and approved the other drug from the same drug class, that is
Glyxambi EU/US (linagliptin/empagliflozin), as shown in Table 5.

17
Table 5: Disparity and alignment between EMA and FDA approvals of T2DM FDCs according to the three therapeutic indications:
Drug classes
Trade Name
Therapeutic Indications
(i) Initial combination (ii) Add-on (iii) Substitution
EMA FDA EMA FDA Alignment EMA FDA Alignment EMA FDA Alignment
GLP-1RA/Basal
insulin
Suliqua Soliqua Yes No No Yes Yes Yes Yes Yes Yes
Xultophy Xultophy Yes No No Yes Yes Yes Yes Yes Yes
DPP-4i/Biguanide
Jentadueto Jentadueto No Yes No Yes Yes Yes Yes Yes Yes
Vipdomet Kazano No Yes No Yes Yes Yes Yes Yes Yes
Komboglyze Kombiglyze No Yes No Yes Yes Yes Yes Yes Yes
Janumet Janumet No Yes No Yes Yes Yes Yes Yes Yes
DPP-4i/SGLT-2i
Glyxambi Glyxambi No Yes No Yes Yes Yes Yes Yes Yes
Qtern Qtern No No Yes Yes Yes Yes Yes Yes Yes
DPP-4i/TZD Incresync Oseni No Yes No Yes Yes Yes Yes Yes Yes
SGLT-
2i/Biguanide
Vokanamet Invokamet No Yes No Yes Yes Yes Yes Yes Yes
Synjardy Synjardy No Yes No Yes Yes Yes Yes Yes Yes
Xigduo Xigduo No Yes No Yes Yes Yes Yes Yes Yes
TZD/Biguanide Competact Actoplus Met No Yes No Yes Yes Yes Yes Yes Yes
TZD/SU Tandemact Duetact No Yes No No Yes No Yes Yes Yes
Total Alignment% 7 % 93 % 100 %
T2DM FDCs approved/green and not approved/red, and aligned/green and not aligned/red. The FDCs classified into 7 drug classes; GLP-1RA=glucose like
peptide-1 receptor agonist, DPP-4i=dipeptidyl peptidase-4 inhibitor, TZD=thiazide, SGLT-2i=thiazolidinedione inhibitor, and SU=sulfonyl urea.

18
6.3 Therapeutic indications for FDCs studied within the other four therapeutic
areas
For comparison purpose with T2DM FDCs, similar analysis of FDCs was
conducted within other chronic therapeutic diseases identified. These therapeutic areas are
hypertension, human immunodeficiency virus (HIV), asthma and COPD. The number of
approved FDCs differs in EU and US, as seen in Table 6.
Table 6: Number of approved FDCs in each therapeutic area and FDCs approved by both
EMA and FDA:
Therapeutic areas→
T2DM Asthma COPD Anti-hypertension HIV
FDCs approved by↓
FDA 19 11 16 37 18
EMA 21 7 14 26 19
EMA and FDA 14 6 10 8 17
(i) Initial combination therapy
For asthma FDCs, and the use as initial combination therapy, EMA and FDA were
not aligned. The approval percentages for this sub-population were 0 % and 100 %, respectively.
For COPD, EMA and FDA agreed to approve a few FDCs as initial combination
therapy for the treatment of COPD, namely (a) Ultibro Breezhaler EU/Utibron Neohaler US
(indacaterol/glycopyrronium bromide), (b) Laventair (umeclidinium bromide/vilanterol), (c)
Duaklir Genuair EU/US (aclidinium bromide/formoterol fumarate dihydrate), and (d) Anoro
EU/Anoro Ellipta US (umeclidinium bromide/vilanterol trifenatate). For all other FDCs, EMA
refused the approval as initial combination therapy, while FDA approved all COPD FDCs as
initial combination therapy. EMA and FDA approval percentages in this COPD sub-population
were 50 % and 100 %, respectively, as shown in Figure 2.
For anti-hypertension FDCs, EMA consistently disapproved the FDCs as initial
combination therapy. The FDA disapproved only few antihypertensive FDCs for use as initial
combination therapy. The FDA and EMA approval percentage as initial combination therapy
was 56 % and 0 % for anti-hypertensive FDCs, respectively, as shown in Figure 2.

19
For HIV FDCs, the FDA and EMA almost consistently approved the FDCs as
initial combination therapy. EMA and FDA are aligned, and only two drugs; Trizivir EU/US
(abacavir (as sulfate)/lamivudine/zidovudine), and Atripla EU/US
(efavirenz/emtricitabine/tenofovir disoproxil fumarate) were not approved for use as initial
combination therapy by EMA. FDA and EMA approval percentage of the FDCs as initial
combination therapy was 100 % and 89 % for the HIV FDCs, respectively, as shown in Figure 2.
Figure 2. Comparison between EMA and FDA approvals regarding initial combination
therapy within the therapeutic areas: T2DM, Asthma, COPD, Hypertension, and HIV
infection. The number of approvals by EMA and FDA is shown as percentage for the
approved FDCs in the period January 2000 – April 2017.
(ii) Add-on therapy
For Asthma FDCs, EMA consistently disapproved anti-asthmatic FDCs for add-on
therapy, but the FDA consistently approved. The approval percentages for this sub-population
were 0 % and 100 %, respectively, as shown in Figure 3.
For COPD FDCs the approval decisions from EMA and FDA were aligned with
respect to add-on therapy; the approval percentage was 100 % for both agencies, as shown in
Figure 3.
For anti-hypertensive FDCs, the FDA consistently approved the FDCs for add-on
therapy. Unlike the FDA, EMA disapproved two FDCs; Exforge HCT EU/US (amlodipine
0%
50%
100%
Approval%
Chronic therapeutic areas
Initial combination therapy
EMA
FDA

20
besylate/valsartan/hydrochlorothiazide), and Rasitrio EU/Amturnide US (aliskiren/amlodipine
/hydrochlorothiazide). FDA and EMA approval percentage for anti-hypertensive FDCs was 100
% and 77 %, respectively, as shown in Figure 3.
For the HIV FDCs, EMA and FDA were consistently aligned, except for one drug;
Trizivir EU/US (abacavir (as sulfate)/lamivudine/zidovudine), that was not approved by EMA
for add-on therapy. EMA and FDA approval percentage for HIV FDCs was 100 % and 93 %,
respectively, as shown in Figure 3.
Figure 3. Comparison between EMA and FDA approvals regarding add-on therapy within
the therapeutic areas: T2DM, Asthma, COPD, Hypertension, and HIV infection. The
number of approvals by EMA and FDA is shown as percentage for the approved FDCs in
the period January 2000 – April 2017.
(iii) Substitution
For substitution therapy, when two (or more) monocomponents are taken together
separately before switching patient to the monocomponents in a FDC, EMA and FDA approval
decisions were aligned. The assumption is that if FDA and EMA do not specifically restrict a
particular indication, then it is an acceptable treatment option. Both EMA and FDA did not
restrict the approval to the substitution use, their FDA approval percentage for substitution
therapy was100 % for FDCs within each of the studied therapeutic areas, as shown in Figure 4.
0%
50%
100%
Approval%
Add-on therapy
EMA
FDA

21
Figure 4. Comparison between EMA and FDA regarding substitution therapy within the
therapeutic areas: T2DM, Asthma, COPD, Hypertension, and HIV infection. The number
of approvals by EMA and FDA is shown as percentage for the approved FDCs in the
period January 2000 – April 2017.
7 Discussion
EMA and FDA had similar guideline recommendations for the clinical
development of the FDCs, as well as similar definition of the therapeutic indications. This
suggests that similar approval decisions by EMA and FDA could be expected. The project
showed similarity in approval decisions for add-on and substitution therapy, and a disparity in
initial combination therapy. For initial combination therapy, EMA and FDA had opposite
decisions on initiating FDC in a naïve patient (with respect to the FDC components) before being
exposed to at least one of the monocomponents in the combination. This was in particular
evident for therapeutic areas such as T2DM, hypertension, and asthma. From the interpretation
of labels wording, the FDA seems open toward approving FDCs within the studied therapeutic
areas with broad (unspecific) therapeutic indications. In contrast, EMA often restricts the FDC to
add-on and substitution therapy for T2DM, asthma, and hypertension, and approved FDCs with
broader indications for HIV and COPD. This may be, because EMA considered HIV and COPD
at a high level of chronicity/severity compared to the other diseases.
0%
50%
100%
Approval%
Substitution therapy
EMA
FDA

22
The disapproval of a specific therapeutic indication for the FDC therapy could also
indicate that the studied patient population within the clinical trials was inadequately
representing the target patient population in clinical practice. Thus, the generated clinical data
did not inform the authorities whether the approval in these sub-populations was appropriate. For
example, the approval of two drugs from the same drug class; Qtern EU/US and Glyxambi
EU/US. Qtern was not studied in a naïve patient population and therefore, the initial combination
therapy was not granted by EMA and FDA. In contrast, Glyxambi was studied in a naïve patient
population, interestingly, the initial combination was granted by the FDA, but not EMA, which
indicate that performing in a patient population for a specific therapeutic indication will not
guarantee the approval of this specific indication. The same happened with two FDCs from the
same drug class; Xultophy EU/US, and Suliqua EU/Soliqua US. They were studied in a naïve
patient population, but in this case the FDA did not grant their use as initial combination therapy,
while EMA approved it. EMA and FDA, both had shown ambiguity in their approvals and
decisions, which were not necessarily based on the studied patient populations.
After reading through the labels and interpreting their wording, it was easy to
assume “yes”, when there was no wording preventing the use of a particular therapeutic
indication. Additionally, although the FDC studied in a specific patient population with positive
trial data for a particular intended therapeutic indication, this did not guarantee its approval. This
may also lead to the inclusion of study data not pertinent to the approved indications from labels.
Thus, in some labels the prescribers cannot get the full picture how the FDC was studied, but
only read approved or not for this particular indication. In this project, there were some FDCs
that were studied in a specific patient population and approved by one medicine agency and
disapproved by another for a particular therapeutic indication. For example, if the FDC approved
in the US, and the patient/prescriber lives in the US, then they know it was studied. However, if
the patient lives in the EU, this FDC was not approved by EMA, and the patient/prescriber will
not necessarily be made aware of all available study data from the pivotal trials. When a patient
or prescribers know about this disparity regarding initial combination therapy, will this not
confuse them, especially, if the patient/prescriber reads the assessment reports, which reflect the
rationale behind this particular approval/disapproval? For example, although a similarity was
recognized in the EMA and FDA assessment for Xultophy EU/US, and Suliqua EU/Soliqua US,
the EMA and FDA had opposite approval decision (see appendix Table 8).

23
Back to the guideline recommendations, where a disparity identified, the initial
combination therapy will be discussed. EMA and FDA recommended the factorial study design
for initial combination therapy, in order to obtain their approval. FDA raised the point that the
clinical trials, in particular factorial study design, do not necessarily inform when to initiate the
FDC. There was no evidence supporting the sequential add-on therapy over the initial
combination, and vice versa. So, does factorial study design provide enough information to
support their approval decision for pre-defined sub-populations? Or are the approval decisions
made by the medicine agencies based more on their own philosophy rather than evidence for
these therapeutic indications? If they have no evidence how they decide for which sub-
populations the product should be recommended?
It is still to some degree unclear which patient population should be studied.
Additionally, the factorial study design cannot answer when to initiate the FDC in the clinical
practice, but in clinical practice, the prescribers need to decide when to initiate the FDC therapy,
as seen in Figure 5.
Figure 5. Clinical practice prescribing options regarding FDC therapy
What the clinical trials cannot answer could be addressed by real-world
observations. At the same time, the physician’s societies can generate data support and guide the
medicinal products use. Thus, the scientific societies of physicians had developed a standard
therapeutic guideline that standardize the treatment choice and ease the prescribing practice for
the new prescribers. Regardless of these guidelines, prescribers are still freely deciding on the
patient naive to
monocomponent A (possibly
later add monocomponent B)
monocomponent B (possibly
later add monocomponent A)
combination of
(FDC)
taken separately

24
treatment choice taking the individual patient into account. When the EMA and FDA disagree on
the approval/disapproval of the FDCs as initial combination therapy, the real world observations
by physicians recommended the use of the FDC as initial combination therapy. For example, for
T2DM there are European Association for the Study of Diabetes (EASD) (21) and the American
Association for Diabetes (ADA) (22). EASD and ADA therapeutic guidelines included an option
to start patients on several agents, if they fulfil certain conditions, e.g. high HbA1c. (23). This
may help guide some prescribers on how to use FDC products. But to ensure that the majority of
the patient/prescriber are aware. When a FDC is studied in a specific patient population, the label
under therapeutic indication section must state information on the approval/disapproval of the
FDC for a particular therapeutic indication, and the rationale behind the decision. The label
should provide the patient/prescribe with information that eases their treatment decisions. When
a disparity in approval decision by medicine agencies does exist, the label may state “if possible”
whether other medicine agency approved/disapproved a particular therapeutic indication.
8 Conclusion
This study demonstrates disparities between two major medicine agencies when
approving the therapeutic indication for FDC products. The clinical trials with the regulatory
guideline recommendations are specialized in studying the safety and efficacy of the medicinal
products for each therapeutic indication. In contrast, the clinical trials cannot compare the
sequential add-on vs. initial combination vs. substitution therapy, which may support the
regulators decisions on whether to restrict particular indication or not. This study demonstrated
that even though guideline recommendations for FDC development are similar, approval practice
is not. FDA decides for the US patient population and EMA for European patient population and
it is their right to deviate and sometimes there are good reasons for it, e.g. differences in the
clinical reality. There were no apparent reasons for the disparity found in the T2DM FDCs
discussed. Especially, when similar clinical trials submitted for the medicine agencies and their
assessment reports were similar as well. Except if the medicine agencies agree that the factorial
study design is not always the ideal study design for the clinical development of all FDCs, and in
particular for initial combination therapy. Because the factorial studies design did not mimic the
clinical practice and could not answer when to initiate the FDC therapy. If the disparity for the
initial combination was related to the lack of relevant data, it is important to start applying study

25
designs that resembles the clinical practice. Or, by let the factorial study design answers about
the efficacy and safety of a FDC, while the decision on the approval/disapproval of therapeutic
indications is after real world studies that supports the approval/disapproval of a FDC for the
pre-defined sub-populations. Alternatively, post marketing study could be generated to support
how FDC products should be used. Therefore, further study is required that answer when to
initiate the FDC in clinical practice and compare the initial combination vs. sequential add-on vs.
substitution therapy. Otherwise, the recommendations for use in the discussed sub-populations
for the FDCs may be imprecise.

26
Part II – A novel Approach to Collecting
Real-World Patient Reported Outcome
Applied to T2DM FDC Users
1 Introduction
Granted therapeutic indications do not always correlate with the use in the clinical
practice. Sometimes, the studied patient population in clinical trials may not fully represent the
target patient population in clinical practice. In order to find which target patient population
benefits the most after initiating fixed dose combination (FDC) therapy, this pilot study
measured patient satisfaction, using patient reported outcome (PRO) tools, in the real world.
Such information may enhance the understanding of patients’ preferences. Here a pilot study
presented in the form of a patient questionnaire that measure PROs before and after initiation of
new treatment that recorded the patients’ perspective on the FDC named “Xultophy”. Xultophy
is a FDC product with a basal insulin component (insulin degludec) and a GLP-1 receptor
agonist (liraglutide) treats type-2 diabetes mellitus (T2DM), developed by Novo Nordisk A/S.
The questionnaire records measurements on four domains; daily life (e.g. do you have to limit
your daily activities?), diabetes management (e.g. help you control your diabetes?), compliance
(e.g. miss a dose), and psychological health (e.g. worried about side effects from my
medication?). Additionally, treatment literacy (e.g. do you know that your new medicine
Xultophy contains two anti-diabetic drugs?). The patient questionnaire resembled treatment
related impact measure-diabetes (TRIM-D) developed by Novo Nordisk A/S, which was used in
some registration studies. The study was conducted at Danish community pharmacies. Patients
were asked to fill in the questionnaire when picking up their medicine.
Clinical trials are designed to study the safety and efficacy of a drug in a controlled
environment, and to collect systematic information on the benefit/risk profile of the drug. Real-

27
world data are supplementary to the “classical” approach. Although the PRO measures in clinical
trials are collected directly from patients enrolled in the clinical trials, the studied patient
population within clinical trials is highly selected exposed to exclusion/inclusion criteria with
higher possibility of biased PRO measures. In other words, clinical trials are not intended to
study all potential target populations. Thus, clinical trials alone are unable to generate data on
necessary intervention to adequately represent the target patient populations in a real world
setting. However, post-marketing studies such as this study can be performed to assess how the
drug is used by patients in the real world and to collect information from the patient’s
perspective, e.g. patient preference or patient satisfaction.
Real world data (RWD) indicates that adherence to regulatory guidelines is only
partially met by prescribers in their general practice (24). Health authorities do not normally
interfere with the prescribers’ choice of treatment of patients. By authorizing a particular
therapeutic indication does not mean other possibly unrelated therapeutic indications are
prohibited, i.e. in form of off-label use (25). Based on the prescribers experience or judgment
he/she is responsible for deciding on the treatment and prescribing a drug according to the
circumstances, such as the patient preference, and the chronicity of the disease.
2 Research question and objectives
The objective of this study was to explore treatment satisfaction with Xultophy
therapy in the three previously defined sub-populations in real world practice in Denmark.
Objective:
 Compare and describe patient satisfaction in patients before and after initiating FDC
Xultophytherapy.
3 Hypothesis
“Xultophy FDC therapy for T2DM improves patient satisfaction in real world
clinical practice compared to previous treatment when it is given as; (i) initial combination
therapy, (ii) add-on therapy, or (iii) substitution therapy”.

28
4 Background
In part I study, a disparity for FDC’s was found in the approval decisions between
EMA and FDA. This pilot study data on real world use of Xultophy is preliminary and based on
a very small data set.
4.1 Effectiveness vs. efficacy
The efficacy of an intervention is well established by both pharmaceutical
companies and medicine agencies, but the transition from efficacy to effectiveness of a medical
intervention is challenging (26-28). The efficacy corresponds to the performance of an
intervention with medicines under ideal and controlled circumstances. Thus, efficacy studies are
always randomized double blind placebo controlled clinical trials to investigate the benefits and
risks of the intervention. Here, the target patient population is under restriction, i.e. it is highly
selected and homogenous. This is an ideal design for efficacy evaluation based on high internal
validity and minimal bias. Under such highly controlled conditions, the efficacy trials are less
likely to include the entire target population for the intervention. In contrast, studies of
effectiveness answer whether the intervention works in real-world setting of heterogeneous
target population of outpatients in presence of pharmacists at the community pharmacy. This is
an ideal design for evaluation of effectiveness of an intervention since it creates high external
validity together with solid knowledge from clinical trials (internal validity) of the medicine
dispensed from the pharmacy (29-31).
4.2 Real-world data converted into real-world evidence on FDC
Randomized clinical trials (RCT) are capable of generating data on efficacy and
safety of the FDCs with the limitation that the studied patient populations only represents a
fraction of the real world patients, due to the selectivity and control conditions. Therefore, it is
important to assess the effectiveness of an intervention after authorization, and to find which
patient population in clinical practice benefits most of the FDCs (32, 33).
The term real world evidence (RWE) on safety is used by the medicine agencies
(27), e.g. EMA’s draft guideline “Scientific Guidance on Post-authorization Efficacy Studies”
(34). The FDA occasionally generates RWE through collecting and assessing registry data (35,
36). This post-marketing data collection generates RWE in post-marketing phase, usually with

29
the purpose to assess the safety aspects of the medicines, but rarely the effectiveness (27, 37).
Ideally, RWE should be able to answer whether the new-marketed intervention is effective or not
and thereby contribute to the interpretation of the RCT results (38). It is addressed in the FDA
definition of the real world evidence Real world evidence (RWE), derived from collecting and
analysing RWD elements, can provide data about patients in the setting of their environments—
whether at home or at work—and in the social context of their lives. Researchers can tap into
these sources to address questions about patient health and the safety and effectiveness of
medical products (39).
However, collecting real world data needs careful consideration. This is because
the data extracted in the real world setting is expected to generate new data that either supports
or challenges the data generated under controlled RCT. This fact especially concerns the data
that relates to the definition of the target patient population, i.e. due to the inclusion/exclusion
criteria of patient populations within RCT. Excluded patients may be those who benefit the most
from the treatment, and vice versa (40).
4.3 Real world data collection
Regarding collection of RWD, it should be noted that RWD (35, 41):
 Tends to be structured, i.e. the data reside in a fixed field as for example in
databases and spreadsheets like electronic health records (EHR),
 Has more in common with epidemiological data than big data, e.g. data
from social media. However, the term big data is sometimes used more
broadly, also referring to more structured RWD,
 Can be collected both prospectively and retrospectively from observations
of routine clinical practice, and
 May include data related to clinical and economic outcomes, PROs and
health-related quality of life (HR-QoL).
Maybe adaptive licensing concepts will encompass RWE to inform whether the use
of FDC products can be recommended in specific sub-populations (42). RWE aims to generate
new data, and not to repeat or bring perfect data, similar to already collected data from
traditional RCT. Therefore, designing the RWE studies like in pragmatic trials (43) as well as
choosing the analysis method is important. Another challenge is data standardization and

30
common understanding among regulators. Questions may arise such as; will the intended RWE
bring in different target patient population than the already studied one? Is the collected RWD
valid and reliable? Additionally, the multi resources, i.e. EHR, social media, and post-marketing
studies may give pieces of the individual patient information but not the full data. Therefore,
linking all different data resources as much as possible will eliminate uncertainties and minimize
the bias (44).
Collecting RWD from the databases such as registries gives the physicians’
perspective rather than the patient’s perspective as the physicians “filters” the data (45). In
contrast, the present study aims to show the impact of involving community pharmacies in the
RWD collecting process through bridging the local prescription databases with data provided
directly from the patients. Community pharmacies are an excellent place for finding patients and
link them to the medicines types, and the reimbursement characteristics, etc. (46, 47). All
patients visit the pharmacy to pick-up their prescription. Here they are distant from their
physicians and they can provide “a true patient perspective”.
4.4 Patient-reported outcomes
To improve the quality of the healthcare system within clinical practice (48), a
range of patient-reported outcome measures has been developed and validated. (49). The FDA
defined PROs as “any report of the status of a patient’s health condition that comes directly from
the patient, without interpretation of the patient’s response by a clinician or anyone else” (49).
The FDA had published a guideline to measure the PROs. This guideline is giving the reviewers
of the centre of drug evaluation and research (CDER) confidence of the application of the drug
development tools (DDTs) in the interpretation. The guideline describe three topics; biomarkers,
animal models, and clinical outcome assessments (COAs) (50). Correspondingly, to increase
patient’s involvement in the health care, the patient’s perspectives of health, illness, and
treatment should be included in physicians’ therapeutic guidelines. For example, the PRO
measures are commonly self-completed questionnaires related to QoL, treatment satisfaction and
convenience, disease management, physical-, emotional-, and social well-being, and adverse
drug reactions (51). Such investigation will impact the understanding of the adherence to
medication, especially in patients with chronic diseases such as hypertension, diabetes, HIV,
COPD, and asthma. Poor adherence commonly appears in patients with chronic disease, once
they are in a weak control of their illness leading to reduction of their QoL (52-54).

31
However, it was important to explain the above aspects, to highlight the importance
of such study. This study provided real world evidence via PRO measures applied on completely
heterogeneous patient population, which in turns will challenge or support the efficacy results
and/or the PROs generated via clinical trials. Away from what sponsors want to prove when they
design the clinical trial, in order to obtain the medicine agency approval. The novel aspect of this
pilot study is that for the first time, the collection of RWE via PROs is collected from patients in
community pharmacies (“the real world”) instead of controlled clinical trials. Further the study
aimed to compare patient satisfaction with FDCs in specific sub-populations.
5 Materials and Methods:
This pilot study evaluated the possibility to investigate when to initiate the FDC
therapy in the real world setting by using a developed questionnaire to be filled-in by patients
with T2DM who received their first prescription of Xultophy (IDegLira). The aim was to
compare the patient perception before and after initiating the treatment. The previous treatment
determined which sub-population the patient stem from, i.e. initial combination (naïve patient to
the monocomponents), sequential add-on, or substitution therapy. Xultophy (IDegLira) is the
first combination of GLP-1 RA (liraglutide) and basal insulin (insulin degludec). Xultophy
indicated to treat T2DM, and has been marketed in Denmark since March 2017.
When a patient enters the pharmacy with a prescription on Xultophy the role of
pharmacists and students was the following:
 Obtain informed consent from the patient who participate;
 Provide a place to the patient to fill-in the questionnaire; and
 Fill-in the patient previous treatment by asking the patient and checking the pharmacy
database.
The questionnaire was intended to measure patient’s satisfaction before and after
initiating Xultophy therapy. Therefore, it is split into two visits:
 The first visit” (before initiating Xultophy therapy) as a baseline
measurement; and
 The second visit” (when receiving the Xultophy therapy).

32
The questions were formulated, to capture the patient perception of their health
before and after receiving Xultophy therapy. The patient questionnaire was developed based on
the TRIM-D questionnaire that developed by Novo Nordisk A/S (55). The patient questionnaire
consisted of 4 domains. Those domains are scored on a 1–5 point scale; a higher score indicates
a better health state. Domain scores are calculated by summing up across items in the same
domain, and the total score is calculated by summing scores from all the domains. The highest
possible summed score within a domain ranges from 15 (daily life domain) to 35 (psychological
health domain) points and the highest possible total score is 95 points.
The questionnaire consisted of total of 26 items for the first visit and 27 items for
the second visit divided into four domains:
 Daily life domain consists of 3 items (5a, 5b, and 5c),
 Diabetes management domain consists of 5 items (1a, 1b, 1c, 1d, and 1e),
 Compliance domain consists of 4 items (3a, 3b, 3c, and 3e), and
 Psychological health domain consists of 7 domains (3d, 4a, 4b, 4c, 4d, 4e,
and 4f).
There were additional questions asked to the patients such as their treatment
literacy with respect to the FDC therapy, as well as whether the patient speculates if the previous
treatment was better. The full questionnaire is included in the appendix.
The patient reported outcomes were classified according to the last antidiabetic
therapy the patient was taken before switching to Xultophy therapy. It was aimed at assess
treatment satisfaction before and after starting Xultophy therapy for each of the three target
patient populations:
 Initial combination therapy (naïve patients to GLP-1 RA and basal insulin
at baseline),
 Add-on therapy (patients receiving either GLP-1 RA or basal insulin
therapy at baseline), and
 Substitution therapy (patients receiving both GLP-1 RA and basal insulin as
separate injections at baseline).

33
Due to the lack of data generated during the second-visit, the measured patient
health perception with GLP-1RA before initiating Xultophy therapy was later compared to a
proxy study that measured PRO of patients enrolled in a clinical study. This study was
performed using a similar questionnaire (TRIM-D). TRIM-D questionnaire was comparable to
the patient questionnaire in compliance, and diabetes management with 5 items each. In contrast,
for daily life domain, there were 5 items in TRIM-D vs. 3 items in the patient questionnaire, and
for psychological health domain there were 8 items in TRIM-D vs.7 items in the patient
questionnaire. To allow comparison the mean patient questionnaire domain scores and total score
as normalised to a 1–100 scale. The proxy data was taken from two studies; one study compared
GLP-1RA vs. Xultophy therapy (56), and the other compared basal insulin vs. Xultophy therapy
(57).
5.1 Location
A questionnaire was distributed to eight pharmacies in Denmark (Horsens, Sorø,
Rødovre, Frijisenborg, and Værløse). Eleven pharmacists and students participated. Eight out of
the eleven participants were enrolled in the “Studieophold på Apotek” course at the University of
Copenhagen. The eligible students were invited to a meeting where the students chose to
participate in the project. The other three pharmacists were contacted directly. Patient
satisfaction data was collected during the four months course period between March – September
2017.
5.2 Patients
The study group consisted of patients who received at least one prescription of
Xultophytherapy. All patients signed informed consent before filling-in the questionnaire.
5.3 Patient characteristics
The following characteristics were captured for the patients in the study: age
(years), gender, duration of T2DM (years), comorbidities and diabetic complications. All
baseline characteristics were self-reported by the patients.
5.4 Data management

34
Data wascollected by pharmacists/students, and later on, sent by email to the
investigator. The Danish personal identification (CPR) number of the patients was not recorded.
The pharmacists and students provided the patients with the questionnaire when dispensing their
Xultophy prescription. For patients who were in hurry, the pharmacists/students had two options,
first, ask the patients to fill-in the questionnaire at home and return it to the pharmacy; second, the
pharmacist/student offered to read the questions to the patients and fill-in the questionnaire on their
behalf.
6 Results
After collecting the filled-in patient questionnaires, there were three patients filled
the patient questionnaire, but none of them had filled-in both first- and second visits. Hence, it
was impossible to compare the patients’ perception before and after initiating Xultophy therapy
in order to conclude whether the patients’ health perception was better on the FDC compared to
the treatment at baseline. For this reason, only analysis of the major questions was performed
and discussed on a population basis rather than on the change from baseline for each patient
group.
One patient filled-in the first-visit on GLP-1 RA. This patient represented the add-
on therapy group. The other two patients filled-in the second-visit; one patient switched from
basal insulin represented the add-on therapy group, and one switched from GLP-1 RA and basal
insulin taken separately, represented the substitution therapy group, see Table 7.
Table 7: Filled-in patient questionnaire categorized into the three therapeutic indications:
Previous treatment categorized into three
therapeutic indications
First-visit
number of patients
Second-visit
number of patients
(i) Initial combination therapy 0 0
(ii) Add-on therapy
of
(ii.a) Basal insulin 0 1
(ii.b) GLP-1 RA 1 0
(iii) Substitution from free combination
therapy of GLP-1 RA + basal insulin
0 1
GLP-1RA= glucose like-peptide-1 receptor agonist

35
Two patients from the age group of 46-60 and one patient was > 61 years old. All
were men. Regarding their FDC therapy literacy, whether they received enough information on
Xultophy and knew that Xultophy combines two monocomponents, they answered “yes”. The
two patients who had experienced Xultophy were satisfied with the treatment, and indicated that
they did not speculate that their previous treatment was better.
The analysis was carried out according to the two target patient populations
available: (ii.a) add-on to GLP-1RA, the patient questionnaire was filled-in on the first-visit by
patient switched from GLP-1RA. Because the patient filled-in the questionnaire before starting
on Xultophy therapy, the provided data represented his perception of GLP-1 RA therapy. The
patient’s health perception was normalised. The mean of the total score on GLP-1RA was 75.9
compared to the patients enrolled in the two arms of the proxy study (56), which were 78.4
(GLP-1 RA therapy) and 82.4 (Xultophy therapy). The normalised mean of diabetes
management domain score on GLP1-RA was 52 and was low compared to the patients enrolled
in the two arms of proxy study: 67.2 (GLP-1 RA therapy) and 72 (Xultophy therapy). The
normalized mean of psychological health domain score was 71.4. This score was lower
compared to the patients enrolled in the proxy study for both arms, which was 80.5 (GLP-1 RA
therapy) and 85.9 (Xultophy therapy). The normalised mean of compliance was similar to the
study proxy both GLP-1RA and Xultophy (IDegLira), which was 80 vs. 84.4, and 87.2,
respectively. The normalized mean of the daily life domain score was 100 and this is higher
compared to the patients enrolled in the proxy study 81.5 (GLP-1 RA therapy) 84.5 (Xultophy
therapy). Figure 6 depicts the comparisons.

36
Figure 6. Comparison of patient reported outcomes (PROs). It measures PRO of patient
who filled-in the first-visit questionnaire on GLP-1RA before initiating Xultophy vs. a
proxy study (56) measured PRO for patients enrolled on either GLP-1RA or Xultophy
(IDegLira) arm, using TRIM-D questionnaire. The questionnaire consists of 4 domains,
which are scored according to a 1–5 point scale with a higher score indicating a better
health state. Mean patient questionnaire domain scores and total score were later
normalised to a 1–100 scale. Domain scores were calculated by summing up across items in
the all domains, whereas total score represents the sum scores from all the domains. GLP-
1RA=glucose like peptide-1 receptor agonist.
(ii.b) Add-on to basal insulin, the patient questionnaire was filled-in on the second-
visit by a patient switched from basal insulin. This patient’s health perception after being on
Xultophy therapy was 81.7, which was similar compared to patients enrolled in the proxy study
(57), which were 83.3 (basal insulin therapy), and 80.3 (Xultophy therapy), see Figure 7. The
normalised mean of psychological health domain score was 88.6, which was similar compared to
patients enrolled in the proxy study in both arms, which were 88.3 (Xultophy therapy), and 86.7
(IGlar therapy). The normalised mean of compliance domain score after initiating Xultophy was
0 50 100
Daily Life
Diabetes Management
Compliance
Psychological Health
Total score
Mean of domains/total score
PRO measures in add-on therapy on first visit
(GLP-1RA vs. Proxy study)
GLP-1RA
GLP-1RA (proxy)
Xultophy (IDegLira) (proxy)

37
90, this was similar compared to patients enrolled in the proxy study in both arms, which were
88.3 (Xultophy therapy), and 87.3 (IGlar therapy). The normalised mean of diabetes
management domain score after initiating Xultophy therapy for this patient was 68, this was
similar compared to the proxy data 71.3 (Xultophy therapy) . Both scores were higher than the
proxy data for patients on basal insulin (63.7). The normalised mean score of daily life domain
score was 80, this was slightly lower compared proxy data for both arms: 85.4 (Xultophy
therapy) and 83.5 (IGlar therapy), as depicted in Figure 7.
Figure 7. Comparison of patient reported outcomes (PROs). It measure PROs for patient
filled-in the second-visit patient questionnaire after initiating Xultophy for patient switched
from basal insulin vs. a proxy study (57) measured PRO for patients enrolled on either
IGlar or Xultophy (IDegLira) arm, using TRIM-D questionnaire. The questionnaire
consists of 5 domains, which are scored according to a 1–5 point scale with a higher score
indicating a better health state. Mean patient questionnaire domain scores and total score
later normalised to a 1–100 scale. Domain scores are calculated by summing up across
items in the same domain, whereas total score represents the sum scores from all the
domains. IGlar= insulin glargine.
0 50 100
Daily Life
Diabetes Management
Compliance
Psychological health
Total score
PRO measures in add-on therapy on the second visit
(Xultophy vs. Proxy study)
IGlar (proxy)
Xultophy (IDegLira) (proxy)
Xultophy (IDegLira)

38
(iii) Substitution therapy, the patient filled-in the second-visit questionnaire after
initiating Xultophy therapy switching from the “free combination” of GLP-1RA and basal
insulin. There were no available studies comparing PRO measures from free combination of
GLP-1 RA and basal insulin and corresponding FDC therapy. Therefore the PRO of this patient
was not compared to proxy data. The normalised mean of total score after initiating Xultophy
therapy was 80.8. From highest to the lowest normalised mean for the daily life, psychological
health, compliance, and diabetes management domain score was 93.3, 82.9, 75, and 72,
respectively, as depicted in Figure 8.
Figure 8. Comparison of patient reported outcome (PROs). It measures PROs of patient
filled-in questionnaire at the second-visit after initiation of the Xultophy treatment being
switched from the free combination of GLP-1RA and basal insulin. The 5 domains are
scored according to a 1–5 point scale where higher score indicate a better health state.
Mean patient questionnaire domain scores and total score was normalised to a 1–100 scale.
Domain scores are calculated by summing up across items in the same domain, whereas
total score represents the sum scores from all the domains.
0 50 100
Daily Life
Diabetes Management
Compliance
Psychological health
Total score
PRO meaures in substitution therapy with
Xultopy (second visit)
Xultophy (IDegLira)

39
7 Discussion
The number of patients participated was not enough to answer the hypothesis
“Xultophy FDC therapy for T2DM improves patient satisfaction in real world clinical practice
compared to previous treatment when it is given as; (i) initial combination therapy, (ii) add-on
therapy, or (iii) substitution therapy”. However, the pilot study showed that it was possible to
get the answers of a questionnaire in the community pharmacies setting without any external
interference. Through comparison of the patients’ PRO collected through this project with proxy
data, the means of the four domains and the total score was comparable. Interestingly, the patient
who switched from free combination of GLP-1RA and basal insulin seemed most satisfied with
Xultophy therapy, which was expected.
Due to the lack of valuable data no further conclusions can be drawn. If we had
been able to reach more patients and obtained data from first and second-visit, it would allow
comparison of the treatment in real world clinical practice. It would elucidate which therapy the
patients prefer, i.e. the initial combination or the sequential add-on, a question that is highly
relevant for decision making in clinical practice, and the clinical trials could not answer. Such
studies would also support the recommendation in therapeutic guidelines. Supporting the
prescribers with valid and reliable PROs will ensure better advice to their patients.
The following limitations appeared during the study period:
 Xultophy FDC therapy was newly marketed in Denmark (March 2017), which contributed to
the limited number of filled-in questionnaire. In March, there were fewer users of Xultophy
therapy,
 Most of the patients were in hurry, and refused to participate. The participating
pharmacist/students were not full time in the pharmacy,
 Due to the personal privacy policy it was difficult to collect missing data,
 The introduction of the study was suboptimal due to short preparation time for study set-up
which leads to few engaged pharmacists/students.

40
8 Conclusion
An evaluation of the hypothesis “Xultophy FDC therapy for T2DM improves the
PROs in real world clinical practice compared to current treatment whether it is given as; (i)
initial combination therapy, (ii) add-on therapy, or (iii) substitution therapy” was not possible
due to incompleteness of the data collected.
However, the following learnings from the study can be drawn:
 The study approach is feasible,
 Patient reported outcomes is possible to obtain in the community pharmacy setting,
 The outcome from the few reporting patients were similar to published studies (proxy study),
and
 Useful information of real life behaviour among patients on newly introduced drugs is
possible through a controlled cooperation between the pharmaceutical companies and the
pharmacies.
Further studies like this may reduce the ambiguous hesitancy from initiating FDC
and consider the initiation of FDC as a possible treatment choice.

41
Appendix 1: First- and Second-Visit Patient Questionnaire:
Patient Questionnaire on Xultophy®
for Type 2 Diabetes Mellitus (T2DM)
Informed Consent
Please do not write the CPR number of the patient on this questionnaire.
Base the answers only on the consultations you have had today.
Please mark the box like this X
Introduction question:
Since you have received new medicine for your type 2 diabetes mellitus, we would like to ask you about “How you
experiencing treatment in the past month”. There is a row of questions, and it will take about 10 minutes.
Are you willing to participate?................................................................
□ Yes □ No
For research purpose, may I look into your medication file, we will
only look at your diabetes medicine?.......................................................
□ Yes □ No
For a follow up on your treatment with Xultophy®
medication, do you
mind participating in a 2nd
follow up by our colleague or when you
come for renewal of your Xultophy®
medication?.................................
□ Yes □ No
DD/MM/YY: __ __/__ __/__ __ __ __
May I have your address and telephone number in case we would like to ask you extra questions?
Name: ……………………………………………………………………………………
Address: …………………………………………………………………………………
Phone: ……………………………………………………………………………………
Have you already taken Xultophy®
medication (e.g. product
received from your doctor?)……………… □ Yes □ No
If the patient had received Xultophy treatment before, start with Question 7 of the first visit and continue
filling-in the second visit. If the patient remembers his/her health perception on previous diabetes treatment,
the patient fill-in the entire first visit
If the patient did not have diabetes treatment before, start with Question 7 of the first visit
√

42
First Visit - Current Type 2 Diabetes Mellitus Medication
All the questions should be answered, if impossible use “Don’t know”
Gender
□ Man □ Women
Age
□ ≤18 □ 19 – 30 □ 31 – 45 □ 46 – 60 □ ≥ 61
For how long you have been diabetic?
□ Newly diagnosed □ 6 – 12
months
□ 1 – 3 years □ 4 – 5 years □ ≥ 6 years
Your attitude to your current diabetes medication
1. With your current
diabetes medication,
are you satisfied
with:
Not At
All
Satisfied
Somewhat
Satisfied
Satisfied
Very
Satisfied
Extremely
Satisfied
Don’t
know
a. Controlling your
diabetes…………… □ □ □ □ □ □
b. Avoiding low blood
sugar
(hypoglycemia)…..
□ □ □ □ □ □
c. Avoiding high blood
sugar
(hyperglycemia)…
□ □ □ □ □ □
d. Maintaining my
weight…………….. □ □ □ □ □ □
e. Preventing feeling
tired or having a lack
of energy………….
□ □ □ □ □ □
2. How convenient
are you:
Not At
All
Convenie
nt
Somewhat
Convenient
Convenient
Very
Convenient
Extremely
Convenient
Don’t
know

43
a. With current diabetes
treatment………… □ □ □ □ □ □
b. With tablet therapy.
□ □ □ □ □ □
c. With injection
therapy.................... □ □ □ □ □ □
3. With your current
diabetes medication,
how often do you:
Never Rarely Sometimes Often Always
Don’t
know
a. Miss a dose………..
□ □ □ □ □ □
b. Delay or postpone
taking my
medication………..
□ □ □ □ □ □
c. Take my medication
at a different time
than prescribed……
□ □ □ □ □ □
d. If taking an injection,
feel embarrassed or
awkward when
taking my
medication………...
□ □ □ □ □ □
e. Worry that I forgot
to take/or missed my
last dose of
medication…………
□ □ □ □ □ □
4. When you take
your current diabetes
medication:
Don’t
know
a. It gives me a feeling
of improving my
health……………….
□ □ □ □ □ □
b. It depresses me or
makes me sad……….
□ □ □ □ □ □
c. It angers me that I am
bound to do so……..
□ □ □ □ □ □
d. I am worried that the
medication is not
helping to slow down
or prevent
complications from
my diabetes……….
□ □ □ □ □ □
e. I am worried if your
blood sugar is too
high or too low…….
□ □ □ □ □ □
f. I am worried about
possible side effects
□ □ □ □ □ □
5. WITH your Never Rarely Sometimes Often Always Don’t

44
current diabetes
medication, how
OFTEN:
know
a. Do you have to limit
your daily activities… □ □ □ □ □ □
b. Do you accomplish
less than you would
like to……………….
□ □ □ □ □ □
c. Are your relationships
with family and
friends stressed…….
□ □ □ □ □ □
6. In the past month,
how often did you
worry about having
low blood sugar events
(hypoglycemia)?............
□ □ □ □ □ □
7. Do you have any of these diseases that you are aware of?
Don’t
know
□ Liver
problem
□ Heart
Problem
□ Mild-moderate kidney
problem
□ Severe kidney
problem
□
Extra questions:
8. Were the Xultophy®
Product benefits explained clearly to you by your
physician?
□ Yes □ No
9. Do you know that your new medicine Xultophy®
contains two antidiabetic
drugs?
□ Yes □ No
For students and pharmacists, to be extracted from the computer system:
10. Which of these drug’s classes was the patient taking?
□ Glucose like
peptide-1
receptor agonist
(GLP-1)
□ Basal insulin □ Sulfonylurea
(SU)
□ Dipeptidyl peptidase-4
(DPP-4)
□ Sodium-glucose
cotransporter-2
inhibitor (SGLT-
2)
□ Thiazides (TZs) □ Biguanide □ None
11. The questionnaire was filled-in by:
□ Pharmacist/student □ Patient

45
Second Visit – Xultophy®
prescription renewal – The next portion of
Xultophy®
medicine is picked up
Date: _ _/_ _ / _ _ _ _ (DD/MM/YY)
Introduction question:
We would like to ask you about “How you experiencing treatment in the past month”. There is a row of questions,
and it will take about 10 minutes.
Name:…………………………………………………………………………………………..
Gender
□ Man □ Women
Age
□ ≤18 □ 19 – 30 □ 31 – 45 □ 46 – 60 □ ≥ 61
For how long you have been diabetic?
□ Newly diagnosed □ 6 – 12
months
□ 1 – 3 years □ 4 – 5 years □ ≥ 6 years
All the questions should be answered if impossible use “Don’t know”
1. After being on
your Xultophy®
medication, how
satisfied are you
with:
Not At
All
Satisfied
Somewha
t Satisfied
Satisfied Very Satisfied
Extremely
Satisfied
Don’t
know
a. Controlling
your diabetes… □ □ □ □ □ □
b. Avoiding low
blood sugar
(hypoglycaemi
a)
□ □ □ □ □ □
c. Avoiding high
blood sugar
(hyperglycaemi
a)
□ □ □ □ □ □

46
d. Maintaining
my weight…… □ □ □ □ □ □
e. Preventing
feeling tired or
having a lack
of energy……
□ □ □ □ □ □
2. How
convenient are
you:
Not At All
Convenient
Somewhat
Convenient
Convenient
Very
Convenient
Extremely
Convenient
Don’t
know
a. With injection
therapy □ □ □ □ □ □
b. With Xultophy
□ □ □ □ □ □
d. With pen used
□ □ □ □ □ □
3. Thinking about
your Xultophy®
medication, how
often do you:
Don’t
know
a. Miss a dose…
□ □ □ □ □ □
b. Delay or postpone
taking my
medication…
□ □ □ □ □ □
c. Take my
medication at a
different time than
prescribed
□ □ □ □ □ □
d. If taking an
injection, feel
embarrassed or
awkward when
taking my
medication………
□ □ □ □ □ □
e. Worry that I
forgot to take/or
missed my last
dose of
medication.......
□ □ □ □ □ □

47
4. When you take
Xultophy®
medication:
Don’t
know
a. It gives me a
feeling of
improving my
health…
□ □ □ □ □ □
b. It depresses me or
makes me sad….. □ □ □ □ □ □
c. It angers me that I
am bound to do so □ □ □ □ □ □
d. I am worried that
the medication is
not helping to
slow down or
prevent
complications
from my diabetes
□ □ □ □ □ □
e. I am worried if my
blood sugar is too
high or too low…
□ □ □ □ □ □
f. I am worried
about possible
side effects……
□ □ □ □ □ □
5. After start taking
Xultophy®
medication, how
OFTEN:
Don’t
know
a. Do you have to
limit your daily
activities………
□ □ □ □ □ □
b. Do you
accomplish less
than you would
like to………….
□ □ □ □ □ □
c. Are your
relationships with
family and friends
stressed………..
□ □ □ □ □ □
6. Do you speculate
if the old medicine
was better?..
□ □ □ □ □ □
7. In the past month,
how often did you □ □ □ □ □ □

48
worry about having
low blood sugar
events
(hypoglycemia)......
Extra questions
8. Do you now think that you have got enough information about the therapy
of Xultophy?......................................................................................................
□ Yes □ No
9. Do you know that Xultophy contains two antidiabetic drugs?.....................
□ Yes □ No
10. Are you satisfied with your expectations of your Xultophy®
medication?....................................................................................................... □ Yes □ No
For students and pharmacists, to be extracted from the computer system:
11. Which of these drug’s classes was the patient taking?
□ Glucose like
peptide-1 receptor
agonist (GLP-1)
□ Basal insulin □ Sulfonylurea (SU) □ Dipeptidyl
peptidase-4 (DPP-4)
□ Sodium-glucose
cotransporter-2
inhibitor (SGLT-2)
□ Thiazides
(TZs)
□ Biguanide □ None
12. The questionnaire was filled-in by:
□ Pharmacist/student □ Patient

49
Appendix 2: Xultophy – Soliqua: EPAR – EU/Summary Review – US
Table 8: Benefit-Risk Assessment of Xultophy EU/US and Suliqua EU/Soliqua US from EMA and FDA perspectives according to the
target patient population and in general:
Table : Benefit-Risk in general and according to the target patient populations before switching to GLP-1/basal insulin FDC – Xultophy
treatment
Benefits
(1) Initial combination (2.a) Add-on to GLP-1 (2.b) Add-on to basal insulin Substitution
1. ↓Hypoglycemia
2. ↑Glycemic control
(↓HbA1c)
3. ↓Weight increase
1. ↑Hypoglycemia
(↓HbA1c)
3. ↓PPG
4. ↓GI-AE
5. ↓Injection burden
1. ↓Hypoglycemia
(↓HbA1c)
3. ↔Weight
4. ↓FPG
1. ↔Hypoglycemia
2. ↔Glycemic control
(↔HbA1c)
3. ↔Weight
4. ↔FPG
Shared benefits
1. Concomitant/complementary treatment approach (glycemic control and weight stability or reduction)
2. ↑Convenient leads to ↑compliance
3. Ideal situation, one drug at a time to treat metabolic conditions + fixed-dose relationship allow physicians to titrate the product in their
intended patients anyway
4. Effectively and rapidly achieving glycemic goal (e.g. HbA1c≈7%)
5. Treatment individualization
Risks

50
(i) Initial combination (ii) Add-on (iii) Substitution
(ii.a) Add-on to GLP-1 (ii.b) Add-on to basal insulin
1. Oral to injection
2. ↑GI AE
3. ↑Injection burden
1. ↑Weight 1. ↑GI AE 1. ↔GI AE
Shared risks
1. Medication errors in case of increasing insulin dosing over 50 units, leads to overdose of GLP-1RA
2. Dosing inflexibility due to different terms (unit vs. mg), not conventionally dosed in the same manner (unit-by-unit, and range dosing)
3. Starting two drugs at a time: may increase cost and whether the second drug is needed – difficulties in establishing AE
4. Aggressive glucose lowering approach
5. Lesser possibilities to individualize treatment in terms of dosing
6. Fixed-dose relationship would not allow to adjust the dose optimally
7. GLP-1RA (class effect) hepatitis and C-tumor
↓= decrease, ↑= increase, ↔= equal, PPG= post prandial glucose, FPG= fasting plasma glucose, GP-1RA= glucose like peptide-1 receptor
agonist, GI AE= gastrointestinal adverse event, AE= adverse event, and HbA1c= Haemoglobin A1c.

51
Appendix 3: Definitions
 Adherence/Compliance: the following by a patient of a recommended course of
treatment—e.g., taking all prescribed medications, adhering to a recommended diet and
exercise plan and reducing or eliminating alcohol or tobacco intake, and so on.
 Clinical inertia: Inaction by a prescriber for switching treatment when guidelines or
optimal care recommend a more aggressive course.
 Convenience: is a reduction in the amount or consumer time and/or energy required to
acquire, use, and dispose or a product or service relative to the time and energy required
by other offerings in the product/service class.
 Drug-naïve patients: who have not before been exposed to any of the active
pharmaceutical ingredients (APIs) combined within the fixed dose combination.
 Effectiveness of treatment: refers to its performance of a drug under ‘real-world’
conditions.
 Efficacy: defined as the performance of a drug of an intervention trial under ideal and
controlled circumstances.
 Label/Prescribing information: provided by agencies to help the physicians prescribing
the medicines choice.
 Monotherapy: In drug therapy, monotherapy refers to the use of a single drug to treat a
disease or condition.
 Real World Data: a term used to refer to data that is collected outside standard RCTs.
 Regulatory scientific guidelines: issued by medicine agencies to describe what sponsor
may develop of data to get the drugs authorized.
 Target patient population: the population who the drug was to be prescribed for,
especially when the restriction to patient populations applies.
 Therapeutic indication scenario: defined by medicine agencies guidance for clinical drug
development classifying which population the drug is pretended to be examined in.
 Therapeutic guidelines: issued by governmental institutions, scientific societies, and
physicians associations to support the prescribing by physicians of the drugs within
specific disease areas.

52
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Nada Alkis' Master Thesis, Novo Nordisk & University of Copenhagen

Nada Alkis' Master Thesis, Novo Nordisk & University of Copenhagen

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