My master thesis consisted 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.

1. Nada Bassam Alkis
Faculty of Health and Medical Science
Department of Drug Design and Pharmacology &
Copenhagen Centre for Regulatory Science (CORS)
Universitetsparken 2, 2100 København Ø
16 Jan 2018
Fixed Dose Combinations –
Regulatory Aspects And Real World
Measures On Xultophy Therapy

2. Table of Contents
Part I – FDC Regulatory Aspects
• Introduction
• Review of FDC Guidelines
• Materials and Methods
• Results
• Discussion and Conclusion
• Future
Part II – Patient Perspective
• Introduction
• Background
• Materials and Methods
• Results
• Discussion and Conclusion
• Limitations
• Future
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Introduction
Conclusion

3. Introduction
• Definition
Fixed dose combination (FDC) Two or more drugs combined in a single
dosage form.
• Objective
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FDC
Sponsors
RegulatorsPhysicians
Patients
What is the target patient population for FDC drugs?

4. Background
• Before switching patients to a fixed dose combination AB contains Drug A
and Drug B, there are three patient populations:
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i. Initial combination (naïve patient to Drug A and Drug B) X → AB
ii. Sequential add-on (patient on either Drug A or Drug B) A → AB or B → AB
iii. Substitution (patient on free combination of Drug A and Drug B
taken simultaneously and separately)
A + B → AB

5. Background
• Ease of the treatment decision before switching patient to the FDC:
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Patient populations iii. Substitution ii. Sequential add-on i. Initial combination
Pros
Replacing two drugs
taken simultaneously and
separately with single
FDC
Reduces tablet/injection
burden, when treatment
intensification is required
Rapid treatment-goal
approach
Cons
Cannot adjust the dose
optimally
Increase adverse events
Aggressive treatment-
goal approach
Ease of treatment
decision
Easy
Easy in patients that
need treatment
intensification
Difficult

6. Initiation Of FDC From Regulators Perspective
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Date: 24 April 2016
From: Jean-Marc Guettier, MD
Division Director
Division of Metabolism and Endocrinology Products
Office of Drug Evaluation II, Office of New Drugs, CDER

7. Part I
Differences Of EMA And FDA
Label Indications For FDC
Products Approved
Jan 2000 – Apr 2017

8. Introduction
Objective
Are the FDA and EMA aligned in their approval
decisions regarding FDC patient populations?
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Patient population
defined in the label

9. Review of FDC guidelines
• EMA and FDA guidelines recommendations for clinical studies performed in
each patient population:
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Patient populations EMA FDA
i. Initial combination Factorial study design:
1. Define and select dosage for the FDC
2. Compare Drug A vs. Drug B vs. combination
drug ABii. Sequential add-on
iii. Substitution
Clinical study
demonstrates
pharmacoequivalence
Study on healthy
volunteers only

10. Materials & Methods
1. EMA and FDA websites were searched, and
downloaded a list of all FDCs approved
between Jan 2000 and Apr 2017.
2. The analysis of the labels was conducted
through reading the therapeutic indication
section. This section says whether the FDC
was approved for a particular indication or
not.
3. Interpreting the FDA and EMA label
wording.
4. Reading the label was not easy, there were
many assumptions, e.g. when there is no
wording restricts a specific indication, this
considered as “assumed yes”, and vice
versa.
• Example of label wording interpretation:
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Initial combination Add-on Substitution
No Yes Yes

11. Results – Type 2 Diabetes Mellitus FDCs
Disparity and alignment between EMA and FDA in the common approved T2DM FDCs
(n=14), according to the pre-defined patient populations:
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 %
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12. Trends in EMA and FDA Approvals for T2DM FDCs
If a FDC was performed in its specific patient
population → not approved and even opposite
approval decisions
 Glyxambi was studied in initial combination
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If a FDC was not performed in its specific
patient population → not approved
 Qtern was not studied in initial combination

13. Trends in EMA and FDA Approvals for T2DM FDCs
Unlike Glyxambi, Soliqua and Xultophy were
approved by EMA, and were not approved by FDA.
Although, both FDA and EMA assessment reports
were also similar for these two drugs.
• Both drugs were studied in initial combination
• Injectable drugs
• Recently approved, this may indicate a shift in
EMA and FDA approval decisions toward FDCs
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Applying factorial study design does not guarantee approval of initial combination therapy

14. Results
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0%
50%
100%
Approval%
Chronic therapeutic areas
Initial combination therapy
EMA
FDA 0%
100%
Approval%
Chronic therapeutic areas
Add-on therapy
EMA
FDA 0%
50%
100%
Approval%
Chronic therapeutic areas
Substitution therapy
EMA
FDA
• Comparison between EMA and FDA approvals of FDCs within five
selected therapeutic areas:
1. Type 2 Diabetes Mellitus (T2DM),
2. Asthma,
3. Chronic Obstructive Pulmonary Disease (COPD),
4. Hypertension, and
5. Human Immunodeficiency Virus (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.

15. Discussion & Conclusion
• EMA and FDA approval decisions for FDCs wihtin the five
therapeutic areas, were aligned for add-on and substitution
therapy, and were not aligned for initial combination therapy.
• EMA label for FDCs is restricted for the add-on and
substitution therapy except for HIV FDCs, while the FDA label
for FDCs is open.
• Approval decisions for initial combination seemingly were
based on the medicine agencies’ philosophy (gut-feelings), or
there are other considerations than regulatory when it comes
to the approval decisions.
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16. Future
• This may answer if sequential add-on is preferred over initial combination therapy. And this is
what patient and physicians are interested to know.
• The other study design, may be lengthy as well as costly. Therefore, it is better to consider
applying post-marketing studies that contribute to the label claims and answer when to
initiate the FDC.
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NaïvepatientstoDrugA
andDrugB
Drug A
Drug B
Fixed dose
combination AB
NaïvepatientstoDrugA
andDrugB
Drug A (add Drug B)
Drug B (add Drug A)
Fixed dose combination
AB
Factorial study design
Study design resembles
clinical practice

17. Part II – Pilot Study
A Novel Approach To
Collecting Real-World
Patient Reported Outcome
Applied To T2DM FDC Users
Patient
Perspective

18. Introduction
• This pilot study designed to measure patient’s satisfaction before and after
initiating FDC drug named “Xultophy”.
• Xultophy (IDegLira) is a combination of GLP-1 receptor agonist (liraglutide) and basal
insulin (insulin degludec) to treat T2DM patients.
• Patient’s satisfaction on Xultophy will be measured in each patient
population:
i. Initial combination (naïve patients to GLP-1RA and basal insulin)
ii. Sequential add-on (patients on either GLP-1RA or basal insulin)
iii. Substitution (patients on free combination of GLP-1RA and basal insulin taken
simultaneously and separately)
• The patient satisfaction will be measured using patient reported outcomes
(PROs).
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19. Definition
A PRO* is 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. The outcome can be measured in absolute terms
(e.g., severity of a symptom, sign, or state of a disease) or as a change from a
previous measure.
*US Department of Health and Human Services FDA Center for Drug Evaluation and Research, US Department of Health and Human Se rvices FDA
Center for Biologics Evaluation and Research, US Department of Health and Human Services FDA Center for Devices and Radiologi cal Health.
Guidance for industry: patient-reported outcome measures: use in medical product development to support labeling claims: draft g uidance. Health
and Quality of Life Outcomes. 2006 Dec;4:1-20.
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20. Background
I. Clinical trials
• Selected patient populations
• Biased PRO measures
• Controlled
• Inclusion/exclusion criteria
• Small fraction of real-world patients
II. Routinely clinical practice
• Random out-patients
• Real-world PRO measures
• Using community pharmacies
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21. Materials & Methods
• PROs were measured using developed patient
questionnaire based on treatment related impact
measure-diabetes (TRIM-D) questionnaire.
• The patient questionnaire involved 4 domains:
1. Daily life domain, e.g. with Xultophy, do you have to limit
your daily activities?
2. Diabetes management domain e.g. with Xultophy
medication, are you satisfied with controlling your diabetes?
3. Compliance domain, e.g. with your Xultophy medication,
how often do you miss a dose?
4. Psychological health domain, e.g. when I take Xultophy
medication, it depresses me or makes me sad?
• To measure patient’s satisfaction before and after
initiating Xultophy therapy, the patient questionnaire
divided into:
 The first visit” (before initiating Xultophy therapy) as a
baseline measurement; and
 The second visit” (when receiving the Xultophy therapy).
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The role of pharmacists and students
during March and September 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

22. Results
• Number of filled-in patient questionnaire according to the three pre-defined
sub-population:
• None of the patients speculated that their previous treatment was better.
• All patients were aware of the fact that their medication contained two drugs.
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Previous treatment categorized into three
therapeutic indications
First-visit Second-visit
(i) Initial combination therapy 0 0
(ii) Add-on therapy
(ii.a) Basal insulin 0 1
(ii.b) GLP-1 RA 1 0
(iii) Substitution therapy (free combination of GLP-1 RA
and basal insulin)
0 1

23. Results
• Comparison of PROs for patient switched
from add-on vs. a proxy studies. The proxy
studies measured PROs for patients
enrolled on either GLP-1RA/basal insulin
vs. Xultophy (IDegLira) arm, using TRIM-D
questionnaire.
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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)
0 50 100
Daily Life
Diabetes Management
Compliance
Psychological health
Total score
Mean of domains/total score
PRO measures in add-on therapy on the second visit
(Xultophy vs. Proxy study)
IGlar (proxy)
Xultophy (IDegLira) (proxy)
Xultophy (IDegLira)
0 50 100
Daily Life
Diabetes Management
Compliance
Psychological health
Total score
Mean of domains/total score
PRO measures in substitution therapy with
Xultophy (second visit)
Xultophy
(IDegLira)

24. Discussion & 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:
a) The study approach is feasible,
b) Patient reported outcomes is possible to obtain in the community pharmacy setting,
c) The outcome from the few reporting patients were similar to published studies (proxy study),
and
d) Further studies like this may reduce the ambiguous hesitancy from initiating FDC and consider
the initiation of FDC as a possible treatment choice.
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25. Reasons For Limited Response
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,
• The participating pharmacist/students were not full time in the pharmacy,
• Due to the personal privacy policy it was difficult to collect missing data.
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26. Future
1. Collaboration between medicine
agencies, sponsors, and
pharmacists.
2. When the patients pick their
treatment voluntary fill-in
questionnaire on their new
treatment.
3. Patient data automatically sent to
the medicine agencies and
sponsors
4. This is an idea to inform medicine
agencies and physicians on what
real-world patient perspective is
on their new FDC drug.
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27. Conclusion
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FDC
Regulators’
Perspective
Patients’
Perspective
Drug A (or Drug B)
alone or FDC of AB

28. Appreviations
o COPD → Chronic Obstructive Pulmonary
Disease
o DPP-4i → Dipeptidyl Peptidase-4 Inhibitor
o EMA → European Medicine Agency
o EU → Europe
o FDA → Food and Drug Administration
o FDC → Fixed Dose Combination
o GLP-1RA → Glucose Like Peptide-1
Receptor Agonist
o HIV → Human Immunodefeciency Virus
o PRO → Patient Reported Outcome
o SGLT-2i → Sodium Glucose Co-
Transporter-2 Inhibitor
o SU → Sulfonylurea
o T2DM → Type 2 Diabetes Mellitus
o TRIM-D → Treatment Related Impact
Measure-Diabetes
o TZD → Thiazolidinedione
o US → United State
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