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Evaluation of biosimilars landscape in the MENA region: what lessons can be

learnt from the European experience to improve the biosimilars uptake in the
region?
Thesis · September 2019

DOI: 10.13140/RG.2.2.34948.68482
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EVALUATION OF BIOSIMILARS IN MENA REGION
School of Life Sciences
Dissertation submitted for the degree of MSc in Biotechnology, Bioprocessing and

Business Management
September 20, 2019
EVALUATION OF BIOSIMILARS LANDSCAPE IN THE MENA REGION: WHAT LESSONS CAN

BE LEARNT FROM THE EUROPEAN EXPERIENCE TO IMPROVE THE BIOSIMILARS UPTAKE
IN THE REGION?
Student ID number: 1893269
Supervisor: Dr Stuart Allen
Word count: 14810

ACRONYMS
AEs: Adverse Events ........................................................................................................................... 1

CAGR: Compound Annual Growth Rate ........................................................................................... 18
CDSCO: Central Drugs Standard Control Organisation .................................................................... 43
CHMP: Commitee for Medicinal Products for Human Use .............................................................. 10
DPM: Direction de la Pharmacie et du Médicament ....................................................................... 18
EDA: Egyptian Drug Authority .......................................................................................................... 23
EMA: European Medicines Agency .................................................................................................. 10
Epo: Erythropoietin .......................................................................................................................... 22
ERP: External Reference Pricing ....................................................................................................... 25

ESMO: European Society for Medical Oncology .............................................................................. 29
FDA: Food and Drug Administration .................................................................................................. 9
FOB: Follow On Biologics.................................................................................................................. 40
FTA: Free Trade Agreement ............................................................................................................. 34
GCC: Gulf Cooperation Council ......................................................................................................... vii
GDP: Gross Domestic Product ..............................................................................................................i
HAI: Health Action International ...................................................................................................... 46
HAQ: Healthcare Access & Quality ................................................................................................... 37
HCP: Healthcare Professional ........................................................................................................... 55
HIC: High Income Country ................................................................................................................ 31
HTA: Health Assessment Assesment ................................................................................................ 25
ICH: International Conference on Harmonisation............................................................................ 18
IMS: Institute For Healthcare Informatics .......................................................................................... 8
INAHTA: International Network of Agencies for Health Technology Assessment ........................... 22

INEAS: International Network of Agencies for Health Technology Assessment .............................. 22
INN: International Non-proprietary Name....................................................................................... 12
JFDA: Jordan Food and Drug Administration ................................................................................... 63
KOLs: Key Opinion Leaders .............................................................................................................. 53
KSA: Kingdom Saudi Arabia .............................................................................................................. 13
LMIC: Low-Middle-Income Countries .............................................................................................. 46
LMWH: Low Molecular Weight Heparin .......................................................................................... 18
MA: Market Authorisation ................................................................................................................. 6
MENA: Middle East North Africa ...................................................................................................... 13
ii
MOH: Ministry Of Health ................................................................................................................. 21

PAT: Process analytical technology .................................................................................................. 45
PR: Public Relation ........................................................................................................................... 51
QbD: Quality by Design .................................................................................................................... 45
rhEpo: recombinant human Epoetin ................................................................................................ 22
RMP: Reference Medicinal Product ................................................................................................. 18
RP: Reference Pricing ....................................................................................................................... 21
SFDA: Saudi Food Drug Authority .................................................................................................... 27
SPC : Summary Product Characteristics ........................................................................................... 74
UAE: United Arab Emirates .............................................................................................................. 13
UHC: Universe Health Coverage....................................................................................................... 31

WHO: World Health Organisation .................................................................................................... 18
WTO: World Trade Organisation ...................................................................................................... 34
iii
List of Figures
Figure 1: Number of biosimilars in development by country in 2017 ................................................2

Figure 2: Definition of Biological Medicines........................................................................................3
Figure 3: The possible variations during the protein synthesis from one genome............................4
Figure 4: potential variations inter-batches ........................................................................................6
Figure 5: Sales and market share growth of biosimilars worldwide ...................................................8
Figure 6: Patents cliff of biological originators in Europe and the US between 2013 &2019.............9
Figure 7: Biosimilars pipelines in Europe and the US between 2020 and 2030............................... 10
Figure 8: EMA biosimilars guideline summary ................................................................................. 11
Figure 9: The difference of requirements between the RMP and its biosimilar.............................. 12
Figure 10: Biosimilars approvals after the first European guideline ................................................ 13
Figure 11: An example of manufacturing flowsheet of LMWH (Enoxaparin) .................................. 20
Figure 12: Same Biological Medicine of EPO with different names in the various markets ............ 23
Figure 13: General requirements of Biosimilars in the Egypt guideline .......................................... 24
Figure 14: the prevalence of diabetes worldwide between 2017 and 2045 .................................. 26
Figure 15: An example of Insulin bioprocessing reference .............................................................. 28
Figure 16: MENA Countries wealth estimated according to GDP per capita (US dollars) adjusted for
purchasing power parity (PPP) ......................................................................................................... 32
Figure 17: How much easy to do business in the MENA region ?.................................................... 33
Figure 18: SWOT analysis of Biosimilar market in the MENA region ............................................... 35
Figure 19: Porter's Five Forces analysis of biosimilar market attractivity in MENA region ............. 36
Figure 20: Comparison of Tunisia, GCC and Egypt biosimilars guidelines ....................................... 40
Figure 21: the evolution of Biosimilars uptake in Europe ................................................................ 42
Figure 22: Decisional Algorithm of biosimilars Business Strategy in the MENA region .................. 52
iv
List of Tables
Table 1: The main differences between biological medicine and small molecule medicine ..............5
Table 2: Some highlighted differences between a biosimilar and the originator ...............................7
Table 3: Enoxaparin Biosimilars cost saving compared to the originator (Lovenox) in Tunisia ....... 21
Table 5: Epoetin biosimilars cost saving in Egypt............................................................................. 25
Table 7: MENA Market Access Mapping inspired by (Deloitte, 2018) ............................................. 37
Table 6: Development of Business strategy of biosimilars in the MENA region Framework .......... 50
Table 8: Adaptation of Business Models for Biosimilars in the MENA Region................................ 53
v
GLOSSARY
GDP Per Capita According to Investopedia, Per capita gross domestic product (GDP)
is a metric of GDP per person. That means the GDP is divided over
the number of populations. GDP is an indicator of prosperity and
the wealth of the country and its economic growth.
Extrapolation Concerns the extension of an indication to another, or a population

to another referring to safety and efficacity data from clinical trials
studies
Health Technology Analytic frameworks based on clinical and cost-effectiveness

Assessment (HTA) analysis. HTA serves as a decision-making tool to evaluate the
factors that can affect health technology and the indirect and
unintended consequences of accepting or refusing health
interferants.
Interchangeability Two medicines are interchangeable if the administration of one or

another does not imply a clinical alteration or any significant safety
issue. The interchangeability is not automatic between the
originator and its biosimilar. The clinical practice of changing an
interchangeable medicine is called a switch.
Pharmacovigilance Activities that survey and prevent the adverse events (AEs) of the
drug products to control the safety of any medicine during the
approval and after the commercialisation. Increasing number or
gravity of AEs can lead to medicine withdrawal.
CAGR According to Investopedia, the Compound Annual Growth Rate is

geometric to estimate the return on investment and evaluate the
proportional growth of the business from year to year from this
investment
Post-marketing After the approval of the product by the regulatory affairs, all the
safety study marketed drug products are controlled by Post-marketing studies
for the identification of AEs or lack of effectiveness, the
quantification of the hazardous events, and the enhancement of
vi
the good use of the products through the risk management plans
to preserve the safety and the quality of the drug product.
Substitution The replacement of a drug product by another similar or

bioequivalent product by the pharmacist. In general, this practice
concerns the substitution of the reference drug by its generic or
biosimilar. If the pharmacist changes the product without referring
to the doctor according to the regulation, we talk about the
automatic or systematic substitution.
Biotechnology The transfer of tools and “Know-How” from drug discovery to

Transfer product development until the commercialisation. It also concerns
the process by which the third party or clients will exploit this
technology outside of the original environment, space or context.
Spillover effect In economy, it describes how events apparently unrelated can

impact one nation or another. For example, what the impact of ISIS
in Libya on price inflation in Italy
vii
Acknowledgement
I dedicate this work to my lovely country Tunisia that raised on me the passion of the
discovery and curiosity,
I would thank Dr Stuart Allen for his unlimited support and dedication along this academic
year and during the dissertation process,
For my parents: Zohra & Lazhar that I left behind waiting for my glorified return,
For my beautiful sisters, Rihab, Hiba & Isra, your smiles and your small disputes had cheered
my heart and my mind,
For my soulmate, your encouragement words had lightened my loneliness days, and your
perseverance had inspired my thoughts,
For Yvette, Jeanette, Layth and Amanda, your laughter soothed my long journey
To everyone that helped me implicitly or explicitly to fulfil this work, thank you!
I am very grateful to Chevening and the University Warwick scholarship for allowing me to
be part of an exciting international experience.
viii
ABSTRACT
Biosimilars seemed to be an attractive solution to overcome the cost challenge and
increase health access. After the expiry of biological originator patent, the manufacturer
will develop a biosimilar with comparable quality, efficacy and safety as the biological
originator. The adoption of biosimilars was slow outside of Europe despite the considerable
cost saving, that raises questions about the probable reticence reasons regarding
biosimilars acceptance and the efficiency of the current strategies to support biosimilars.
This research highlights the reasons behind the limited acceptance of biosimilars in the
Middle East & North Africa (MENA) region by examining the regulation, pricing strategy and
physician perception toward biosimilars through three case studies in Tunisia, Egypt and
Gulf Cooperation Council (GCC). The comparison with the European experience in the
discussion had identified eventual gaps in guideline harmonisation, health coverage and
the Business Model. This research had concluded that biosimilars uptake is remarkably
mitigated across the MENA region. The equivocal or absent guidelines, the socioeconomic
divergence, the stakeholders’ resistance are the principal obstacles behind the incapability
of the region to follow the European experience.
The enhancement of biosimilars success will be possible only if the national institutions
refocus their priorities on drawing more strict regulation and reviewing the reimbursement
systems. The manufacturer should consider improving their reliability through
accreditations, and the cooperation with biosimilars experts. Moreover, the awareness
reinforcement of the health professional is the ultimate step toward the concretisation of
biosimilars uptake improvement. Overall, the heterogeneity and disparity complicate the
investment in MENA countries. In result, biosimilars entry expects a significant return on
investment. Among the countries of the region, GCC seemed to be the most attractive
market to the branded biosimilars. However, most MENA countries are encouraging the
domestic biosimilars industry. Finally, the whole region is aware of the biosimilars
importance, whereas, the adoption of biosimilars is intertwined mainly on the willingness
of policymakers.
ix
TABLE OF COTENTS
1. BACKGROUND........................................................................................2
2. INTRODUCTION ......................................................................................3
2.1. DEFINITION OF BIOLOGICAL MEDICINES .......................................................................... 3

2.2. DEFINITION OF BIOSIMILARS .......................................................................................... 5
2.3. THE GLOBAL BIOSIMILAR MARKET .................................................................................. 8
2.4. BIOSIMILARS LANDSCAPE IN EUROPE ............................................................................ 10
2.5. BIOSIMILAR LANDSCAPE IN THE MIDDLE EAST AND NORTH AFRICA REGION ................... 13
2.5.1. DEFINING MENA REGION ......................................................................................................... 13
2.5.2. BIOSIMILAR LANDSCAPE ..................................................................................................... 14
3. RESEARCH QUESTION ........................................................................... 15
4. METHODS ............................................................................................ 16
4.1. CASE STUDIES ............................................................................................................... 16

4.2. PUBLISHED SURVEYS .................................................................................................... 17
4.3. BUSINESS REVIEW ........................................................................................................ 17
5. FINDINGS ............................................................................................. 18
5.1. CASE STUDIES ............................................................................................................... 18

5.1.1. CASE STUDY 1: ENOXAPARIN BIOSIMILARS IN TUNISIA ....................................................... 18
5.1.2. CASE STUDY 2: ERYTHROPOETIN IN EGYPT.......................................................................... 22
5.1.3. CASE STUDY 3: INSULIN BIOSIMILARS IN GCC ...................................................................... 26
5.2. SURVEYS FOR PHYSICIAN UPTAKE ................................................................................. 29
5.3. BIOSIMILAR BUSINESS STRATEGY IN MENA REGION....................................................... 30
5.3.1. MARKET RESEARCH ............................................................................................................. 30
5.3.2. ACTUAL BUSINESS MODEL .................................................................................................. 38
6. DISCUSSION ......................................................................................... 39
6.1. DISCUSSION OF CASE STUDIES ...................................................................................... 39

6.1.1. REGULATION ....................................................................................................................... 39
6.1.2. MANUFACTURING ............................................................................................................... 44
6.1.3. PRICING ............................................................................................................................... 45
6.2. DISCUSSION OF SURVEYS RESULTS ................................................................................ 47
6.3. BUSINESS STRATEGY DISCUSSION & RECOMMENDATIONS ............................................ 49
x
6.3.1. BUSINESS FRAMEWORK ...................................................................................................... 49

6.3.2. BUSINESS MODEL ................................................................................................................ 51
6.3.3. IMPLEMENTATION .............................................................................................................. 55
7. CONCLUSION & FURTHER CONSIDERATIONS ........................................ 58
8. APPENDIX ............................................................................................ 60
8.1. BIOSIMILAR GUIDELINES MAPPING ............................................................................... 60

8.2. BIOSIMILARS REQUIREMENTS FRAMEWORK ................................................................. 65
8.3. METHODOLOGY OF ACCESS EVALUATION TO BIOSIMILARS IN MENA REGION ................. 75
8.4. BIOSIMILAR ACCESS WORLDWIDE (DELOITTE MAPPING) ............................................... 77
9. REFERENCES ......................................................................................... 78
xi
1. BACKGROUND
Innovation in drug discovery has changed the treatment approach from classic inhibition
or inducing of the substrate to a more sophisticated mechanism of actions. Biologics
enabled scientists to understand the pathology in deepness and suggested therapies that
imitate the machinery of the human body and other micro-organisms. Unlikely to small
molecules, biologics offered a highly specific therapeutic action with limited Adverse Events
(AEs)(Morrow and Felcone, 2004). The biologics gave the hope to most rebel, rare and
orphan diseases that remained uncurable for centuries , thanks to innovative technologies
like genetic engineering. Given the advanced Research& Development, the long years of
testing and high technology input, the cost of the biological drug can go over $1,2 billion
(Boat, 2010) that should be paid back at the expense of patients. Therefore, biologics
overturned the traditional therapeutic era but at a high price.
Following the generics experience, drug makers had shifted their attention to the
biosimilars industry as a cheaper alternative to biologics. Despite stakeholder’s uncertainty,
introducing biosimilars to the therapeutic arsenal beside to biologics and small molecules
is an undisputable advantage to therapy choices diversification in the treatment of most
complicated diseases. IQVIA consulting expects that the competition between biosimilars
and their biologics will reduce the spending on biologics by 10% to 30% ($50 billion to $78
billion) between 2018 and 2022 (IQVIA, 2018). The growing interest in biosimilars in Europe
has also attracted the less developed countries to join the trend. As illustrated in Figure 1,
China and India have the richest pipelines and the highest number of biosimilars.
China 269
India 257
United States 187
South Korea 109
Russia 97
switzerland 57
Argentina 48
Japan 45
Brazil 37
0 50 100 150 200 250 300
Biosimilars Number
Figure 1: Number of biosimilars in development by country in 2017(IQVIA, 2018a)
2
The emerging countries are probably the most concerned by developing an alternative
industry regarding the economic and demographic pressure to enable the access to the
health in large, various and heterogeneous countries like China and India(IQVIA, 2018a).
In an emerging market like the Middle East& North Africa (MENA), The uptake of
biosimilars had incited many doubts about their regulation scrutiny, cost-saving and safety.
Therefore, the gap of expertise and policies should be questioned to assess the actual
situation and explore the best strategy to thrive biosimilars growth. This research will
describe and evaluate the biosimilars experience in the MENA countries as an example of
an emerging market in comparison with the European experience.
2
2. INTRODUCTION
2.1. DEFINITION OF BIOLOGICAL MEDICINES

Biological medicines are issued from the living organisms or using organisms as bio-
platform to produce the active substance (AS) via recombinant DNA or any other gene
engineering methods. Biological medicines are also designed by “Biological Medicinal
Products” or “Biopharmaceuticals”. They can be polysaccharides, proteins or nucleic acids
or a combination of all. Blood derivatives, vaccines, proteins, Tissue, gene therapy cells,
allergic extracts and recombinant technology products are examples of biological products,
as shown in Figure 2 (Declerck, 2012).
Blood derivatives
Vaccines
Proteins
Biologic products
Tissue engineered products
Cellular & Gene Therapy
Allergic Extracts
Products manufactured using recombinant technology (proteins, e.g.

insulin and antibodies)
Figure 2: Definition of Biological Medicines (Declerck, 2012)
The complexity and variation of biologics structure are due to diversity of the expression
systems such as mammalian cells, Bacteria or yeast where the AS can be exposed to post-
translational modifications mainly glycosylation, phosphorylation, N-acetylation,
Methylation, S-nitrosylation, Ubiquitination proteolysis and lipidation(ThermoFisher,
2019). Those modifications are responsible for the intrinsic molecular heterogeneity and
the proteome complexity. As demonstrated in Figure 3, a genome of 20 to 25 thousand
3
genes is transcribed via alternative promoters to obtain approximately 100000 different

transcripts. After the post-translational modifications, more than a million proteins are
obtained, starting from only one genome (ThermoFisher, 2019).
Figure 3: The possible variations during the protein synthesis from one genome (ThermoFisher, 2019)
The variation inter-batches are the major challenge in the biopharmaceutical industry. Any
modification in the media, extraction, purification process, storage and transport will affect
the drug product quality and stability. In contrast with the small molecule’s medicines, the
analytical characterisation of proteins is not obvious for a clear identification of the drug
product during its development. In the absence of producible and consistent
physicochemical technics, the combination with in vivo tests are needed to fully understand
the protein structure (Cohen et al., 2018), (Gutka et al., 2018). Additionally, the interaction
of the protein with its external environment influences the biological activity and safety of
the finished drug products. Hence, events like denaturation, misfolding, oxidation,
degradation, aggregation and inactivation cannot be easily predictable or avoided
comparing to the small molecule medicines(Kresse, 2009). The major differences between
the small molecule medicines and biological medicines are described in the Table 1
4
Table 1: The main differences between biological medicine and small molecule medicine (Gutka et al.,
2018)
Chemical Medicine Biological Medicine
Produced by chemical synthesis Produced by living cell cultures
Predictable and controlled The process from substance drug to product drug is
process not producible
Low molecular weight High molecular weight
Well-defined structure Complex structure
Mostly process-independent Any process variation affects the structure and the
activity of the protein
Completely characterised A combination of different technologies is needed

for the characterisation
Stable Fragile, specific storage conditions are required
Highly susceptible to the environment variation
Mostly non-immunogenic Immunogenicity is the principal safety issue
Produces by one batch At least three batches
Contamination can be detected Contamination is hard to remove.
Easy to purify Purification is a long process
Systematic therapeutic activity Targeted biological activity
2.2. DEFINITION OF BIOSIMILARS
Biosimilars are biological products, highly similar to an approved originator biological

product. The comparability exercise between the biosimilar and its originator (or Reference
Medicinal Product (RMP)) is the only regulatory way to prove the bio-similarity between
two biologics. To be biosimilar to an originator, the structure, quality, efficacity, safety and
purity must be comparable to its RMP through a stepwise process regulation (Declerck et
al., 2017). Biosimilar has the same amino acid sequence as the originator. However, it is
5
produced with different process using the same or different micro-organism’s machinery.
At the end of the process, the biosimilar should have the same mechanism of action,
dosage, strength and administration route as its RMP. Given the complexity of biological
medicine, any variation between the biosimilar and its RMP in any level of the
comparability studies should be justified to affect the biosimilarity to its originator albeit
the variations (EMA, 2017).
Like the originator, biosimilars can eventually express a variation enter-batches as

illustrated in Figure 4. In fact, the most common post-translational modification is
glycosylation represented in yellow in Figure 4. Attached to the same amino acids
represented by circles, glucose chain length can vary from batch to batch without leading
to a major impact on the biological activity. An important modification in glycosylation can
affect the immunogenicity of the new biological medicine. Thus, it is imperative to compare
the biosimilar to its originator for the approval and not to another biosimilar of the same
originator. Once approved, it is the manufacturer responsibility to respect the synthesis
process, used for the biosimilar approval. If the manufacturing process is modified, the
manufacturer should follow the local regulations to ensure the quality of its biosimilar.
Biosimilar is also called bio-better when it shows an improved efficacy or safety compared
to the originator or presents a better usage convenience like an adapted administration
route or a reduced posology (Academy of Managed Care Pharmacy, 2017). The originator
manufacturer can use biobetters as a tactic to keep the market exclusivity although the
patent expiry of its originator product. Roche, for example, obtained a biobetter Marketing
Authorisation (MA) for the development of the subcutaneous formulation of Herceptin just
before of Herceptin intravenous patent expiry, its originator product (Anour, 2014).
Figure 4: potential variations inter-batches (EMA, 2017)
6
Although that the biosimilar is an “intended copy” of its originator, some differences are spotted
in Table 2 (Cohen et al., 2018), (EMA, 2017).
Table 2: Some highlighted differences between a biosimilar and the originator (EMA, 2017)
Biological originator (RMP) Biosimilar medicine

No prior information about efficacity and Using the RMP records of safety and efficacy
safety tested on patients
The comparability studies concern the A comprehensive comparability exercise
manufacturing process changes and clinical against the RMP
trials to show at least the Non-inferiority
against an existing treatment/placebo
Full Pre-clinical studies (Toxicology & The Clinical and Preclinical studies are
pharmacology) determined according to the outcome of the
quality. If more differences are highlighted in
the quality comparability exercise, more
clinical and non-clinical studies should be
done against the RMP
The clinical trials are always required. They The clinical trials are not automatically
demonstrate the efficacy and safety against an required in certain conditions. The objective
existing therapy or placebo of clinical trials is to demonstrate the
comparability of clinical effect between the
biosimilar and its RMP
The Endpoints in clinical trials are standard Using more sensitive endpoints to detect the
and known (Long-term outcomes) impact of the minimal variation between a
biosimilar and its RMP on the patients (more
sensitive biomarkers are needed)
Safety and efficacity trials conclude the Comparability studies between biosimilars
risk/benefit outcomes and its RMP define the risk/benefit ratio.
More safety and immunogenicity studies are
needed
Clinical trials are the biggest task to do in Quality exercise against RMP is the principal
originator approval part for the biosimilar approval.
7
2.3. THE GLOBAL BIOSIMILAR MARKET
Business analysts’ reports expect a rapid expansion of the biologics market comparing to
the chemical medicines. Biosimilars sales will reach a 614 % growth between 2015 and
2020, according to Arlys’s business report versus 109% in Originator’s biologics. Europe is
leading the market of biosimilars by owning more than 80 % of the global market against
less than 5% in the USA, the most attractive pharmaceutical industry in the world(Figure 5)
(Arlys consulting, 2017).
Biologics& Biosimilars Sales

% of Global Market 2017
100
80
60
40
20
0
USA All others Japan Europe
Biologics Biosimilars
Figure 5: Sales and market share growth of biosimilars worldwide (Arlys consulting, 2017), (IMS, 2016).
The Institute for Healthcare Informatics (IMS) deems that the biologics will present 28% of
the global pharmaceutical market in 2020, corresponding to USD 390 billion(IMS, 2016).
Given the healthcare access improvement and the cost optimisation strategies, the
biosimilars market is expected to achieve USD 25 billion in 2020 (Arlys consulting, 2017).
The uptake of biosimilars is very mitigated around the world. In the USA, the biologics
market is estimated by 59% of the global biological market against 22% in Europe.
Conversely, the USA lags behind Europe in biosimilars uptake; it sits at only 2 % of global
biosimilars market against 87% in Europe and 7 % in Japan (Figure 5)(Brennan, 2018).
Although the USA is the most profitable market in the pharmaceutical industry in general,
biosimilar manufacturers face a rigid regulation of biosimilars with no clear government
willingness to encourage the biosimilar industry. (Blackstone and Joseph, 2013). In the
emerging countries, biosimilars sales are accelerating to reach a CAGR growth at 30.9% in
2020, a superior growth than Europe ( at 30.2% CAGR) and North America (at 29.9% CAGR)
(GlobeNewswire, 2018).
8
Overall, the capital of investment needed for biosimilar development can be between $250
and $ 500 million which makes the investment in biosimilars a risky decision specially when
the originator’s manufacturers secure their market exclusivity or extend their patents and
consequently that delays or freezes the biosimilars entry following the patent cliff
(Blackstone and Joseph, 2013).
However, biosimilars regained the attention of payers because of the concerns about the
increased expenditure in health. After a slow adoption of biosimilars in the USA compared
to Europe, Food and Drug Administration (FDA) has launched the interchangeability
guideline, In May 2019 to support the uptake of biosimilars in the USA and globally(FDA,
2019). According to the database of clinicaltrial.gov, Nineteen originator’s biologics lost
their patents between 2013 and 2019 mainly in haematology and oncology areas which
allowed to manufacturers to develop biosimilars for the most breakthrough therapies as
Adalimumab, Infliximab, Etanercept and Insulin Glargine as illustrated in Figure 6 (IMS,
2016).
Figure 6: Patents cliff of biological originators in Europe and the US between 2013 &2019 (Huml, 2018).
As mentioned above, the growth of the biologics market is a future opportunity to

biosimilars drug-makers. IMS predicts 18 new entries of biosimilars in the next ten years
9
(2020-2030) as presented in Figure 7 (2026 is the last available patent expiry). Ranibizumab
with the highest profitability is the future potential biosimilars entry.
Figure 7: Biosimilars pipelines in Europe and the US between 2020 and 2030 (Huml, 2018)
2.4. BIOSIMILARS LANDSCAPE IN EUROPE
Since the European Medicines Agency (EMA) has published the first biosimilar guideline in
2005, Europe had attested a growing number of biosimilars. Sandoz’s somatotropin
biosimilar Omnitrope® was the first approved biosimilar in 2006. (EMA, 2017). Since then,
approximately 60 biosimilars has been licensed in Europe (REINKE, 2017). The Committee
for Medicinal Products for Human Use (CHMP) has elaborated the biosimilars guideline
under the responsibility of EMA that served later as a reference model to global guidance
issued by WHO in 2009 and for national guidelines worldwide (Fitch Solutions, 2018).
In the first version of European guideline development, EMA had proposed general
guidance covered an overarching, quality, Non-clinical and Clinical requirements for all
biosimilars as shown in Figure 8. Later, the growing interest on biosimilars and the
bourgeoning need of more specified guidelines that respond better to the identified gaps
amid practical experience, specific products data requirements have been added to the
general section in 2005(EMA, 2018). Figure 8 summarises the EMA guideline topics showing
that all biosimilars should respect the overarching, quality, Non-clinical and clinical
10
requirements. Additional requirements are mentioned in the annexes of Non-clinical and

clinical section for recombinant human erythropoietin, Recombinant human G-CSF,
Recombinant human Insulin, recombinant human growth hormone, Interferons (INF alfa &
Beta) Low-Molecular-Weight Heparins, recombinant follicle-stimulating hormone and
Monoclonal antibodies (see Appendix 9.1. BIOSIMILAR GUIDELINES MAPPING).
General: all biosimilars

Individual requirements
Figure 8: EMA biosimilars guideline summary (EMA, 2018)
For the MA grant, the biosimilar manufacturer should present a dossier to the competent
agencies containing five sections as schematised in Figure 9. The registration of the
reference medicine and the biosimilar is stepwise. Both reference and biosimilar medicines
should go through four sections: pharmaceutical quality studies, Non-clinical studies,
clinical studies and risk management plan, as shown in Figure 9.
In the originator case, the clinical studies should be extensive and cover Safety, efficacy,
Pharmacokinetics, Pharmacodynamics and immunogenicity versus placebo or prior
therapy. In biosimilar case, EMA guideline requires a ‘comparability exercise’ between the
biosimilar and its RMP. Therefore, the first important step is the comparative qualities
11
studies. If during this section, the quality analysis had concluded that biosimilar and its RMP
are very similar, the comparative non- clinical (preclinical) and clinical studies are alleviated
or not needed in some cases (EMA, 2018). Finally, the applicant should perform a
pharmacovigilance program, including a risk management plan and Periodic Safety Update
Reports (PSURs) during the biosimilar lifecycle. Because of safety issues, the manufacturer
must follow and trace AEs during the early phase of comparability studies until the post-
marketing phase (EMA, 2018).
Figure 9: The difference of requirements between the Reference Medicinal Product and its biosimilar (EMA,
2018)
The European market of biosimilars is leading the way globally by US$ 2,934.6 Million of
sales in 2018 and with expected growth at CAGR of 24.9% between 2019-2024 to reach
US$ 11,663.1 Million of revenues by 2024. The use of biosimilars in the EU5 countries
(France, Germany, Italy, Spain, United Kingdom) permitted to save more than €10 billion
between 2016 and 2020 according to IQVIA (IQVIA, 2018b).
Until 2018, at least 15 International Non-proprietary Names (INN) are commercialised as

biosimilars. Figure 9 showed the first biosimilars commercialised in Europe per INN.
Somatotropin was the first biologic originator to lose its exclusivity, and Mvasi® was the
first biosimilar brand of Bevacizumab introduced to the European market in 2018
(IQVIA,2018b).
12
Figure 10: Biosimilars approvals after the first European guideline (IQVIA, 2018b)
Biosimilars have improved access to the biological therapy for more than 400 million
patient days in EU5, given the supportive incentive of the biosimilars adoption by
policymakers (McKinsey, 2018). Nevertheless, the accelerating demand for biosimilars is
not identical among the Europe countries due to the supply chains specificity and
stakeholder’s acceptance.
The local policymakers had encouraged the use of biosimilars through national tenders
with single winners, leading to considerable discounts (IQVIA, 2018b). Sweden and
Germany have also adopted biosimilar to contain health expenditures(Grabowski et al.,
2014). Nonetheless, France, Italy and the UK were slow adopters until recently (Goldsmith
et al., 2018). According to the Medicines Optimisation Dashboard, The steady adoption of
biosimilars in the UK enabled the NHS to save £210 million in 2017/2018(NHS, 2018).
2.5. BIOSIMILAR LANDSCAPE IN THE MIDDLE EAST AND NORTH AFRICA REGION
2.5.1. Defining MENA region
According to the world bank data, the Middle East and North Africa (MENA) region covers
Morocco, Algeria, Tunisia, Libya, Egypt, Palestine, Israel , Lebanon, Syria, Irak, Bahrain,
Qatar , Kingdom of Saudi Arabia (KSA), United Arab Emirates (UAE), Jordan, Kuwait, Oman,
Iran, Yemen, Djibouti and Malta (World bank, 2013). However, other organisations have
13
different definitions of the region and include or exclude countries like Ethiopia, Sudan,
Turkey, Cyprus (Chen, 2019). Only UAE, KSA, Qatar, Kuwait, Oman and Bahrain are part of
the Gulf Cooperation Council (GCC) with harmonised and united policies.
2.5.2. BIOSIMILAR LANDSCAPE
According to Market Data Forecast report, the biosimilars market in MENA region was
valued at $0.37 billion in 2016, and it is projected to reach $1.63 billion by 2021 at CAGR of
32% (Clarivate, 2019). The increasing demand for biologics, in general, is due to the shift in
demographics and socio-economics improvement in some countries. Given the ageing
population, increasing NCD prevalence and the development of purchasing power, the
health challenges became comparable to those in Western countries(Fitch Solutions,
2018). However, the biosimilars market can be more profitable thanks to the enormous
opportunities inside. In fact, the population growth in MENA is one of the fastest in the
world, offering an untapped market with a diluted competitive environment (Mueller,
2014).
Unfortunately, few challenges are hampering the biosimilars uptake in the region. The
regulation disparity between the MENA countries hinders the investors from entirely
benefiting from the potential opportunities and slowing down the entry of the biosimilars
into the market. Despite the recent reforms, misconceptions and ambiguity around
regulations raised the doubt about the quality of licensed biosimilars. Despite that some
MENA countries had already adopted national guidelines for biosimilars, the real
implementation is still limited and very few biosimilars were approved referring to the
national pathways(The economist, 2015).
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3. RESEARCH QUESTION
Regarding the regulation discrepancies across the MENA region and the inconsistency of data, this
research aims to present an overview of the main challenges for biosimilars adoption in the MENA
region
Therefore, this project will identify the possible responses to this question: What MENA countries
can improve to address the local challenges and thrive a supportive environment to biosimilars
uptake referring to the European experience in biosimilars?
To answer this question, a comparative analysis of market access elements (regulation, pricing, and
prescriber’s acceptance) was conducted to create regulatory frameworks that facilitate the data
research and the comparison across MENA region.
In addition, business analysis is performed to identify the improvement areas and build a contextual
business plan for the enhancement of biosimilars entry and competitivity in the region.
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4. METHODS
4.1. CASE STUDIES
In order to identify and evaluate the biosimilars uptake in the MENA region, cross-
reference research is performed. None of the peer-reviewed scientific literature had
mentioned an update of the totality of biosimilar guidelines across the MENA region.
Hence, a classic literature review will not be enough to establish regulation and business
frameworks. An extensive Internet hand searching through the official organisational and
governmental websites using keywords like’ biosimilar guideline’, MENA, FDA, EMA, ICH,
DPM, EDA, SFDA, JDFA, CDSCO, WHO, MOH was the primary method to build a general
overview of regulation landscapes in the region in comparison with Europe.
To zoom in, more specific research is fulfilled through three case studies to prescribe and
discuss the market access to three biosimilars: Enoxaparin, Erythropoietin and Insulin in
Tunisia, Egypt and GCC respectively. The mentioned biosimilars are locally produced in
domestic manufacturers. The chosen countries present three models with diversified
economic, political and legal environmental settings also with different expertise levels in
the biopharmaceutical industry. The imported biosimilars have certain specificities which
are also discussed along with the finding and the discussion sections.
To carry out the case studies comparison, data is directly and individually collected from
the governmental, National agencies, and Non-Profit-Organisation websites (Namely,
WHO, INEAS, World Bank).
An in-depth reading of guidelines permitted the identification and the extractions of the
general requirements related to the comparability exercises, interchangeability,
extrapolation and manufacturing process. Therefore, any specificity or divergence between
the national guidelines and the European guideline are addressed in this review.
At the end of the analysis of the individual guidelines, a non-exhaustive guidelines list and
requirements mapping are presented in the Appendix to roadmap the biosimilars
regulations in the World(WHO), Tunisia, Egypt and GCC (including KSA, UAE, Qatar), USA,
Europe, India, Lebanon, Algeria, Morocco, Jordan and Turkey. Therefore, a comprehensive
overview of the biosimilar guideline requirements is highlighted in key countries of the
region.
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4.2. PUBLISHED SURVEYS
To evaluate the perception of the HealthCare Professionals (HCP) toward biosimilars, a

discussion of three published surveys was explored.
The first survey entitled “Perception of haematologists and oncologists about the
biosimilars: A prospective Tunisian study based on a survey” was published in the ‘Journal
of Oncology Pharmacy Practice’ in May 2019. The published survey targeted 150
oncologists and haematologist in public and private sector around Tunisia using a
prospective questionnaire including 15 questions and aims to evaluate the knowledge and
the attitude of physicians toward the biosimilars in Tunisia (Hadoussa et al., 2019). The
second survey was conducted during the Pan Arab Oncology Meeting in 2015 and published
in Springer Plus as “Review and results of a survey about biosimilars prescription and
challenges in the Middle East and North Africa region”. The regional survey contained 14
questions and targeted 150 physicians in different specialities and pharmacists. The aim of
the survey was the evaluation of the knowledge and the factors influencing the biosimilars
prescription (Farhat et al., 2016). The European Society for Medical Oncology (ESMO) has
developed the third survey using an online platform (SurveyMonkey) including 19
questions to assess the current understanding and comfort of use of biosimilars among 480
oncologists (Giuliani et al., 2019).
4.3. BUSINESS REVIEW
A business review is fulfilled referring to proposed frameworks in Europe by well-known

pharma consultancy firms: Deloitte, McKinsey, IQVIA and EY for the evaluation of the actual
business strategy and the proposition of a new roadmap to improve the biosimilars
penetration in MENA region referring to the European experience.
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5. FINDINGS
5.1. CASE STUDIES
5.1.1. CASE STUDY 1: ENOXAPARIN BIOSIMILARS IN TUNISIA
BACKGROUND
Enoxaparin is a Low Molecular Weight Heparin (LMWH). Compared to the unfractionated
heparin, LMWH has better bioavailability, a longer half-life, a lower incidence of heparin-
induced thrombocytopenia (HIT), and less monitoring points (Mourier et al., 2016). The first
LMWH was approved in 1993 as Lovenox® or Clexane® (Jupalli and Iqbal, 2019) for the
prevention and the treatment of venous thromboembolism by the activation of
antithrombin that inhibits mainly factors Xa and IIa (Mourier et al., 2016). The global market
of heparin is estimated by USD 9,98 billion in 2017, and it is expected to grow at a CAGR of
6,2 % between 2018 and 2023 (Zion Market Research, 2018). In Tunisia, two enoxaparin
‘generics’ (Enoxa®, Enoxamed®) have been marketed besides the originator Lovenox®
(DPM, 2019).
REGULATION (DPM, 2018)

The first edition of biosimilars guideline in Tunisia was published in July 2018 by the
“Direction de la Pharmacie et du Medicament” (DPM) which is responsible for the
procurement, Control and Approval of drugs in Tunisia (DPM, 2018). This guideline
referred to WHO, EMA and ICH and benchmarked with the Egyptian and Jordanian
guidances.
The guideline indicates that the comparability exercise between the Reference Medicinal
Product (RMP) and its biosimilar is a stepwise process. Once the quality comparability to
RMP is proven, nonclinical (preclinical) and clinical studies can be pursued. The quality
exercise in biosimilar registration is quite important. The applicant should extend the
comparability quality tests to avoid unnecessary, expensive and time consuming
preclinical and clinical studies, (EMA, 2017). The Tunisian guideline didn’t require specific
analytic tests during the quality exercise. However, it invites the applicant to refer to
EMA and ICH (International Conference on Harmonisation) guidelines for more details.
Lovenox®, the originator biological medicine was the first enoxaparin introduced in
Tunisia in 1990 (Khlif et al., 2015). In 2007, Enoxa® was the first domestic biosimilar of
Lovenox® (by Medis Laboratories, Tunisia). The second biosimilar of Lovenox was
18
Enoxamed® ( by Unimed, Tunisia) approved in 2015 (DPM, 2019). Both of biosimilars

were approved as ‘bio-generics’ or ‘intended copies’ before the implementation of a
national guideline of biosimilars (Kresse, 2009). In fact, the registration of the “copies”
of Enoxaparin followed the generic pathway rather than the pathway of biosimilars as
described in EMA guidance. In Tunisia, every five years, all pharmaceutical companies
are called to renew their applications for MA. If biosimilars/bio-generic were approved
before the actual Biosimilars guideline, the companies should present their
pharmacovigilance program, risk management plan and any report in relation with the
safety and tolerability of the questioned biosimilar/bio-generic to renew the license
(DPM, 2018). Enoxamed® and Enoxa® were registered as biological generics before the
publication of the national guideline. For the MA renewal, no further studies are
required, and only safety reports should be submitted, which leads to a bigger debate
about the transparency and the efficiency of the pharmacovigilance system. To prove
their alignment to the current Tunisian biosimilar guideline and to defend the quality of
their ‘biosimilars’, the Tunisian manufacturers of Enoxamed® and Enoxa® had fulfilled
voluntarily clinical and non-clinical studies versus the innovator Lovenox®
(ClinicalTrials.gov, 2019a) (Kobbi et al., 2017) (Sassi et al., 2016). The results of
comparability of the both “biologic generics” seemed reassuring. However, the
population size, inclusion criteria and the trial protocol of the studies should be carefully
assessed as no local recommendations of clinical trials in the actual Tunisian biosimilar
guideline(DPM, 2018). It is worth to mention that even the FDA doesn’t consider LMNH
as biological medicines but as a semi-synthetic drug. Hence, the generic pathway for
Enoxaparin is followed in the USA rather than biosimilars approach (Imberti et al., 2017).
‘Interchangeability’ is a critical concept in biosimiliraty which means that biosimilar is

equivalent to the originator since they lead to a same clinical activity that makes them
switchable for the same indication whenever the prescriber decides that for his patient
(Kurki et al., 2017). In the Tunisian guideline, interchangeability is assessed case by case.
However, physicians in public health centres are limited by hospital tenders that changed
every two years. In this case, the switch depends on the availability of drugs on the
Tenders more than the physician/patient preference (Merimi, 2018). In summary, The
Tunisian biosimilars guideline has followed WHO and EMA guidance but with more vague
information about the manufacturing process, clinical trials protocol and schedule. Other
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requirements about the RMP, comparability test, extrapolation and substitution are
mentioned in the Appendix (9.2. Biosimilars Requirements Framework)
MANUFACTURING
The heparins are polysaccharides, called glycosaminoglycans (Fu et al., 2016). Extracted
from different animal species and organs. The fractioning of heparin result on a new
therapeutic class named LMWH with less AEs. Enoxaparin, the most prescribed LMWH is
obtained by esterification and alkaline depolymerisation (Guan et al., 2016) to form shorter
polysaccharides chain. Like the heparin, Enoxaparin has the same biological activity (Ingle
and Agarwal, 2014). First developed by Dr Johnson in mid-1970 by isolating LMWH from
heparin using gel filtration(Lever, 2012). Later, Sanofi separated Enoxaparin by alkaline
treatment of the benzyl ester of heparin. The enzymatic cleavage is also described as
another patented biosynthesis of LMNH (Ingle and Agarwal, 2014). Figure 11 depicts a
flowsheet of general LMNH production initiated with the extraction of Heparin from Hog
tissues and mucosa through a protease treatment. Then, the heparin will undergo a
chemical depolymerisation followed by filtration and desalt to obtain Enoxaparin. If the
Heparin goes through an enzymatic depolymerisation, Tinzaparin is the finished product
(Fu et al., 2016). Because of the intellectual propriety, the manufacturing process of the
biologic originator is protected, and it is quasi impossible to make a copy due to the
complexity of the biologic structure and the process itself (O’Callaghan et al., 2019).
Figure 11: An example of manufacturing flowsheet of LMWH (Enoxaparin) (Fu et al., 2016)
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PRICING STRATEGY
Health expenditure control is always a political priority due to the expanding need for
healthcare services. According to World Bank, the Domestic general government health
expenditure (% of current health expenditure) is valued 56,5% and an Out-of-pocket
expense (% of current health expenditure) of 39,9% in 2016 (World Bank, 2019).
Tunisia has a remarkable system of procurement and pricing control strategy. The Central
Pharmacy of Tunisia, a Ministry of health affiliate, is the unique payer of imported
medicines. Moreover, the ‘Institut de Pasteur’ is the only institute responsible for biological
products procurement (i.e. Vaccines, Allergen). The monopoly of purchasing enabled the
Ministry of Health(MOH) to ensure the stability of prices and to absorb the inflation rate
(WHO, 2003). The centralisation of purchasing and the monopoly strengthen the
negotiation power and reduce the margin gain of secondary payers and distributors. Hence,
the Central Pharmacy ensures the availability, accessibility and quality of the medicines in
Tunisia against counterfeit products too.
For biosimilars, Enoxa® has reported the tender call with the highest discount among the
Tender list. In private sector Lovenox®, Enoxa® and Enoxamed® are reimbursed on the
base of the cheapest product, Enoxamed® in this case with 39.5% of discount (Table 3).
Table 3: Enoxaparin Biosimilars cost saving compared to the originator (Lovenox) in Tunisia (PCT, 2019)
Product Price Discount /RMP

Lovenox® 4000UI Anti-Xa Sol.Inj. Bt 2 Ser/0,4ml 18.476 TD -
Enoxa® 4000UI Anti-Xa Sol.Inj. Bt 2 Ser/0,4ml 12.335 TD 33%
Eoxamed® 4000UI Anti-Xa Sol.Inj. Bt 2 Ser/0,4ml 11.160 TD 39.5%
TD= Tunisian Dinar (1TD= 0,28 Pound sterling)
Both local biosimilars present a saving of more than 30 % comparing to the RMP. The
medicines prices are defined by a Reference Pricing (RP) which based on price negotiation
referring to benchmark prices (WHO, 2013). In the small molecule drugs, Ayadi
demonstrates that the reduction of the originator price is relative to the competition
between the available generics and their numbers. A new generic in the market will induce
a decrease of 9,8% of originator price. A second generic of the same originator will cause a
4,1% reduction of the average cost of generics. Overall, the originator is more affected in
price reduction (-12,3 %) than generics (-1,3 %) in each new generic entry (Ayadi, 2009).
21
According to the DPM requirements, the applicant for the imported biosimilars must
attach a cost-effectiveness study with the registration dossier, which is not the case with
the local biosimilars. To implement a long-term saving cost strategy, the MOH started
health assessment technology program. In cooperation with an international expert (the
International Network of Agencies for Health Technology Assessment (INAHTA)), National
Authority for Assessment and Accreditation (INEAS) was launched for the promotion of the
cost-effectiveness studies throughout the life cycle of the product to help the policymakers
in their decisions. HTA program reflects the government incentive in improving the quality
of local biosimilars. Meanwhile, non-cost effectiveness studies to assess the local
biosimilars Enoxa® and Enoxamed® comparing to the Lovenox®.
5.1.2. CASE STUDY 2: ERYTHROPOETIN IN EGYPT
BACKGROUND
By 1893, Friedrich Miescher was the first scientist to notice the implication of
Erythropoietin (Epo) in hypoxia. In 1977, the first purified human Epo was prepared by
Goldwasser after 15 years of experimenting. This preparation enabled the configuration of
DNA probes to be used later as a matrix for the molecular cloning of the identified gene
(Bunn, 2013).
Epo is an amino acid glycoprotein hormone synthesised in response to hypoxia by renal

interstitial cells leading the production of red cells. Hence, Epo is indicated for patients
suffering from anaemia associated with chronic renal failure (Kamyar, 2017)
The first generation of recombinant human epoetin (rhEpo)or Epoetin alpha was marketed
for the first time by Amgen as Epogen® in USA for the US dialysis market (Figure 12).
Following a license agreement with Johnson & Johnson (J&J), Procrit® is commercialised by
J&J for US non-dialysis market and under Eprex® name for the dialysis and dialysis market
worldwide (Kamyar, 2017).
22
Figure 12: Same Biological Medicine of EPO with different names in the various markets(Kamyar, 2017)
In 2007, Binocrit® was the first biosimilar introduced to the European market by Sandoz
referring to EMA biosimilars guidelines. The global erythropoietin drugs market size was
valued at USD 7.4 billion in 2016 and is expected to witness an increase at CAGR of 11.5%
between 2018-2025(Grand Review Research, 2017).
REGULATION (EDA, 2019a)

In 2014, the Egyptian Drug Authority (EDA) had published the first 23 pages guideline for
biosimilars in coordination with Central Administration for Pharmaceutical Affairs and the
National Organization for Research & Control of Biologics (EDA, 2015).
All the requirements concerning the comparability exercise of biosimilars had referred to
ICH, WHO, EMA and the Indian guidelines(GaBi, 2013) as shown in the Appendix (9.2.
Biosimilars Requirements Framework).
The Egyptian guideline takes into consideration the complexity of the quality comparability
and the variation of the manufacturing process. Thus, EDA defined two pathways for
standalone and Biosimilars routes, as described in Figure 13. If the comparability exercise
concludes that the differences between the candidate biosimilar and RMP are meaningful,
the applicant should follow the standalone pathway that demands complete product
development (EDA, 2019a). In the biosimilar pathway, the applicant should present a CMC
and comparability exercises dossier.
23
EGYPTIAN GUIDELINES OF BIOSIMILARS
STAND-ALONE
BIOSIMILAR PATHWAY
PATHWAY
Reduced preclinical Complete product

Complete product Comparability and clinical development
CMC developemt quality excercise comparabilities (quality, preclinical,
studies clinical)
Figure 13: General requirements of Biosimilars in the Egypt guideline(EDA, 2019a)
The guidelines also defined different requirements and registration workflows for the
imported and domestic biosimilars. If the biosimilar is locally manufactured, specific needs
of each following case:
a) The development of final biosimilar product from AS to the finished product

occurred in a local manufacturer
b) The finished product is manufactured from an imported AS
c) An imported Final bulk is filled locally in unitary products
Because of the importance of manufacturing process, EDA requires a separate evaluation

of AS (or drug substance) and drug product either if both are developed in the same
manufactory or not. The manufacturer of the drug product (finished product) must always
provide the local regulatory authority with the master file of AS. In the absence of
biotechnology transfer guideline, EDA requires a complete assessment report of any minor
manufacturing process variation that may affect the clinical activity in addition to the
mentioned requirements in the biosimilars pathway.
MANUFACTURING
The most described manufacturing process in literature is genetic engineering. It consists
of the identification and isolation of the gene responsible for erythropoietin synthesis to
be introduced into CHO cells. Epo is produced and then purified to obtain the final active
form (Kamyar, 2017). All the manufactured Epo are similar to the endogenous
erythropoietin but with different glycosylation patterns (Covic and Abraham, 2015). Until
2019, Only South Egypt Drug Industries Company (SEDICO) and Egyptian International
Pharmaceutical Industries Co. – EIPICO are manufacturing Erythropoietin locally as
24
Epoetin® and Epoform®. Generally, the active substance is imported in bulk as raw material
from China (Ebied et al., 2014). The market of Erythropoietin is dominated by biosimilars
imported from China (Shandong Kexing Bioproducts Co., Ltd, SHENYANG SUNSHINE
PHARMACEUTICAL CO., Ltd, North China Pharmaceuticals group) and UAE (Julphar
pharma) (EDA, 2019a).
PRICING STRATEGY
Egypt has the highest patient out pocket rates (61,99%) one of the highest in the region.
Additionally, the Domestic general government health expenditure (% of current health
expenditure) is 29,30%.
A pricing decree (499/2012) has set a RP that defined medicines prices in Egypt in
comparison with a reference list (ICH countries, e.g. Canada) (Farag, 2013). The biosimilars
price should be at least 30% cheaper in Egypt If the same biosimilar is manufactured in one
of ICH counties. If the biosimilar is manufactured in non-ICH countries (e.g. Egypt), it should
be at least discounted at 35 %. In the two cases, the proposed price of the biosimilar should
not exceed its price in its origin country or in any other country where the same biosimilar
is marketed. For the locally manufactured biosimilars, Epoetin® and Epoform® offer a cost
saving of more than 50 % against the originator Eprex® (Table 4).
Table 4: Epoetin biosimilars cost saving in Egypt (EDA, 2019a)
Brand Name Company Price (EGP) Discount rate

EPREX® 4000I.U/vial J&J 266 -
EPOETIN® 4000 IU/ vial SEDICO (Egypt) 115 56%
EPOFORM® 4000I.U/vial EIPICO (Egypt) 130 51%
EGP= Egyptian Pound (1EGP=0,049 Pound sterling)
Officially, two dominant pricing forms are used in Egypt: ERP for the patented drugs and
the tenders for the off-patented medications. Although the combination of different
strategies, the reimbursement system is very defected due to the internal economic and
politic crises after the Arab springs(Kanavos et al., 2018). Egypt has not yet adopted an
official HTA approach. However, EDA provides the service of pharmacoeconomic overview
to enable policymakers to conduct economic studies in oncology for health expenditures
optimisation (EDA, 2019b). There is no cost-effectiveness studies For Epoetin® and
Epoform® until now.
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5.1.3. CASE STUDY 3: INSULIN BIOSIMILARS in GCC
BACKGROUND
The insulin is non-glycosylated, disulphide-bonded heterodimer protein. First time

discovered by Sir Frederick G Banting in 1921 and one year later, the insulin was used for
the first time in diabetes patients (Diabetes UK, 2017). Insulin is a protein with a well-
defined primary, secondary and third structure. Recombinant technology has advanced the
bioprocessing of insulin in the last century. The expiration of the top seller’s insulin is a
considerable opportunity for the biosimilars market. Lantus® (insulin glargine), Sanofi’s one
of the best-selling products was unpatented in 2015, Humalog® (insulin lispro) in 2013 and
Novorapid® (Insulin Aspartate) in 2017 (Huml, 2018).
The global insulin market is estimated by USD 25.7 billion in 2019, where MENA is one of
the top growing insulin markets (Figure 14) . The global sales of Human Insulin are expected
to reach a growth at CAGR of 4.93% between 2019–2024 (Mordor Intelligence, 2018).
Among GCC countries, Saudi insulin pharma has a value of $6.7 billion in 2016, and it is
expected to grow at GACR of 10% to reach $9 billion by 2020(SA.GOV, 2019).
AFR: Africa, MENA: Middle East & North Africa, NAC: North America &Caribbean, SACA: South & Central America, SEA:
South East Asia, WP: Western Pacific Region
Figure 14: the prevalence of diabetes worldwide between 2017 and 2045(Cho et al., 2018)
26
REGULATION
The Saudi national regulatory bodies Saudi Food Drug Authority (SFDA) is responsible for
assuring the safety, efficacy, and quality of human medicines in KSA and considered as a
guideline reference for the rest of GCC states. Although the literature reports that SFDA
published a complete guideline of biosimilars in 2010, the last updated guidance in SFDA
official website covers only quality chapter that became active only after 2017 (SFDA,
2017).
The Executive Board of the Health Ministers’ Council for the GCC States has also issued a
centralised biosimilars guideline in 2016 but without being implemented (Gulf Health
Council, 2016). The GCC guideline will be the most elaborated one in the region, including
general specific requirements for individual biosimilars such as Insulin (Gulf Health Council,
2016). GCC has also followed EMA and ICH guidelines in term of comparability exercise. An
expanded explanation of methods concerning quality, non-clinical and clinical studies is the
main strength of GCC guideline. For more guidance, the EDA guideline has listed specific
requirements to overcome eventual process variations. This guideline also highlighted a
non-exhaustive list of possible changes that might lead to additional tests and clinical
studies to prove the comparability to RMP. Besides the general guideline that covered the
comparability testing, extrapolation conditions, interchangeability and pharmacovigilance
requirements (see Appendix 9.2. Biosimilars Requirements Framework). GCC guideline is
the only guideline in the MENA region to mention specific requirements for individual
biosimilars (Insulin, Interferon, Erythropoietin, Monoclonal Antibodies, Granulocyte Colony
Simulating factors).
MANUFACTURING
The process is the product. Any deviation in the process implies a different outcome. In
insulin production, the choice of the production platform (i.e., bacteria or yeast) is a crucial
step because it defines the finished product (Kuhlmann and Schmidt, 2014). Figure 15
describes a general example of insulin synthesis. After the identification of DNA source, the
targeted gene sequence coding for insulin production is inserted in the vector. The transfer
of DNA vector into the host cell will enable the gene to use the cell machinery to produce
the insulin protein. For larger-scale production, the growth media will be transferred to
27
bigger bioreactor with suitable conditions. Insulin will be recovered through filtration or
centrifugation followed by purification to obtain a purified bulk drug.
Figure 15: An example of Insulin bioprocessing reference(Kuhlmann and Schmidt, 2014)
In the Gulf countries, the in-house manufacturing contributes only by 25% of the total
pharmaceutical market (WHO, 2007) and 5% of local production is produced under a
license agreement with brand manufacturers (Al-Abbadi, 2009). However, AUE has
developed a strong R&D for new medicine discovery (WHO, 2011b) with an expanding
export capacity (WHO, 2007).
AUE becomes the only country in the region fulfilling a positive pharmaceutical trade
balance (BMI, 2017). Julphar an Emirati biotech pharma is the unique manufacturer in
MENA to produce locally raw material for Insulin biosimilars (Julphar, 2019). In 2019,
Julphar has finished clinical trials in Germany for its biosimilar Insulin 30/70 versus the
28
originator Huminsulin® (ClinicalTrials.gov, 2019b). Julphar was the first pharmaceutical

company in MENA to peruse clinical trials according to the EMA biosimilar guidelines, under
the absence of current national biosimilars guideline (Julphar, 2019).
PRICING STRATEGY
GCC has comprehensive health coverage, and Qatar has the most significant Domestic
general government health expenditure (% of current health expenditure) estimated at
81,63% and the lowest out-of-pocket expenditure (% of current health expenditure) at
8,55% in 2016 (World Bank, 2019). The most used pricing model in GCC is ERP. The price is
determined against the reference list prices, the country of origin price and the same family
products price in GCC (WHO, 2013). In KSA, the reference country of GCC, a full dossier
should be provided to competent authorities with a certificate of price indicating factory
price, Wholesaler in the country of origin, Retail price, the exportation cost, and list of
prices of the biosimilar in thirty countries (Alhomaidan, 2016).
Some countries of GCC (Kuwait and Oman) follow the mark-ups in the supply chain as the
second pricing model for medicines, where the authority can control the margin within the
distribution channels and supply chains(WHO, 2013).
5.2. SURVEYS FOR PHYSICIAN UPTAKE
Physician, pharmacist and patient’s acceptance is one vital factor to determine the uptake
of biosimilars. In the MENA region, physicians, unlike pharmacists and patients, play a
primordial role in the treatment decision. It is essential then to evaluate his attitude
towards biosimilars. For this objective, three published surveys are used, a local survey in
Tunisia (Hadoussa et al., 2019), a regional survey in MENA Region (Farhat et al., 2016)and
a European survey (Giuliani et al., 2019). The choice of oncologist and haematologist aligns
with the previously discussed biosimilars (Enoxaparin and Epoetin). The Tunisian survey
contained 15 questions distributed to 150 specialists (57% oncologists, 43%
haematologists). 71% of physicians were able to differentiate between a biosimilar and a
generic drug definition, 22% are familiar with biosimilars, but only 3,7 % of the respondents
are well informed about biosimilars (Hadoussa et al., 2019). In the MENA survey, 117
specialists (50 % oncologists and 16 % haematologists) participated in 14 questions survey.
65.8% of physicians “had knowledge about biosimilars” (Farhat et al., 2016). In the ESMO
29
survey, among 393 (92% oncologists) who responded to the 19 questions survey, 79,2% of
the respondents have a general average to high knowledge of the biosimilars.
In the Tunisian survey, 69,16% of physicians prefer to prescribe biosimilars case by case
against 48% of the respondents used biosimilars in the MENA region. However, only 49%
of oncologists in the European survey are using biosimilars versus 63,6 % of haematologists.
52, 3% of the Tunisia survey’s participants were in favour of justified substitution and
interchangeability. Unlikely, only 30 % of the respondents in ESMO were familiar with the
interchangeability definition. 26,5% of MENA survey participants believe that the price is
an advantage to increase the access to the treatment compared to 38,3% of the participant
in the Tunisian survey. In the three published surveys, physicians prefer using biosimilars
that have been approved in Europe and the USA. 86.7% of prescribers in ESMO express
their interest to learn more about the biosimilars against 96% of participants in Tunisia
survey.
5.3. BIOSIMILAR BUSINESS STRATEGY IN MENA REGION
Biosimilars experience is relatively new in the MENA region that will need to more
aggressive marketing to gain more market share. The existing biosimilars in MENA
countries, proving stakeholders and drug makers willingness to improve the biosimilars
business in the MENA region. A deep understanding of the market specificity is as
important as all the previously discussed elements.
5.3.1. MARKET RESEARCH
Before starting the biosimilar business, the manufacturer should analyse where to play to
create an adequate business plan. A complete analysis of internal company characteristics
and its interactivity with the external environment will create a unique value to targeted
stakeholders through defensible competitive advantages. Thus, a Strength-Weakness-
Opportunity-Threat (SWOT), Porter’s Five Forces and PESTEL analysis are explored to
corticate the market and assess the actual business model.
PESTLE ANALYSIS
PESTLE analysis (P for Political, E for Economic, S for Social, T for Technological, L for Legal
and E for Environmental) is a strategic framework that permits the comprehension of the
30
environment and the assessment of the risks/ benefits for a better decision making. The
goals, the vision and strategy of biosimilars business should be inspired and related to the
PESTLE analysis of the MENA region.
POLITICAL
The political landscape in MENA is unstable with revolutionary and counterrevolutionary

dynamics. The first Arab spring revolution started in Tunisia in 2011 to expand over other
Arab countries as Egypt, Libya, Syria. Expect the Monarchical countries (Jordan, Morocco
and Gulf Cooperation Council (GCC)); the region is suffering from civil wars (Iraq, Libya,
Syria, and Yemen), persistent conflict (Israel/Palestine) and terrorism (ISIS). Among the
countries of the region, only Tunisia and Lebanon are adapting democratic models that is
still venerable and fragile to the chaos relapse. Thus, political uncertainty is not offering the
ideal circumstances to the self-generated growth and external investment attractiveness.
In the health sector, the population ageing, the growth of NCD prevalence and lifestyle-
related diseases may present an attractive market for biosimilars. Nevertheless, the region
suffers from the limited equal access to the health because of socio-economic disparity
across the region and inside the country itself. The Universe Health Coverage (UHC) reform
is a governmental priority to restrict patient the out-of-pocket expenditure and face the
surge of healthcare services need (The economist, 2015). In addition, most healthcare
policymakers encourage the privatisation of the health system to alleviate the health
budget burden. Therefore, private health facilities and insurance scheme are developing at
the expanse of low-income patients. Several health policies are reforming to control the
health cost and to ensure equal access to healthcare services in spite of the lack of
transparency and high rate of corruption (Zurich insurance group, 2014).
ECONOMIC
The economic situation in the MENA region is dramatically heterogenous. Three groups can
be considered (World Bank, 2018): 1-GCC countries are High-Income Countries (HIC), a
wealth related to energy resources (oil, gas); 2- Iraq, Algeria and Libya are resource-rich
countries, but they are classified as Low-Middle-Income Countries (LMIC); 3-Egypt, Jordan,
Lebanon, Morocco, Tunisia, Syria, Yemen and Turkey are LMIC. Figure 16 illustrates the
economic wealth by country related to the number of populations in the vertical axe and
31
the Gross Domestic Product (GDP) adjusted for Purchasing Power Parity (PPP) in the
horizontal axe, two indicators showing the economic dynamics. If PPP and GDP are high,
the economy is favourable for investments. According to the analysis of 15 countries, as
illustrated in Figure 16, Yemen has the weakest economy in contrast to Qatar, the
wealthiest country of the region(Zurich insurance group, 2014).
Figure 16: MENA Countries wealth estimated according to GDP per capita (US dollars) adjusted for
purchasing power parity (PPP) (Zurich insurance group, 2014)
Regarding the oil depletion, most MENA region is aiming to diversify their economy for
more sustainability and long-term development through encouraging the external
investments in the area (Yazbeck et al., 2017). Figure 17 presents a world bank ranking of
the MENA countries based on how much comfortable an investor can launch a business.
UAE figures as the easiest place to do business, followed by Turkey and Morocco. Algeria,
Iraq and Yemen are at the bottom of the ranking system.
In health economics, the report of Fairness and Accountability showed that MENA
countries spend only 8 % of their budget in healthcare system compared to 17 % in OECD
countries between 2013 and 2018. The out of pocket expenses is 40 % of total health
expenditures in MENA countries versus 14 % in OECD countries (World Bank, 2013). UCH
is also heterogeneous and varies between 30% and 88% across MENA countries (Kanavos
et al., 2018). Therefore, patients tend to neglect their healthcare needs.
32
EASE OF DOING BUSINES RANKING

UAE 11
43
MOROCCO 60
62
OMAN 78
80
Countries
QATAR 83
92
KUWAIT 97
104
EGYPT 120
128
ALGERIA 157
171
YEMEN 187
0 20 40 60 80 100 120 140 160 180 200
Ranking
Figure 17: How much easy to do business in the MENA region ? (World Bank, 2018)
SOCIAL
The demographic landscape in MENA is diverse. In countries like Tunisia, the population is
ageing. However, In Egypt, the youth population is growing and demanding new job
markets. Youth unemployment is estimated by 25% in the MENA region, the highest rate
globally, against only 5.3% in OECD countries between 2015 and 2018. Therefore, a clear
need to develop new industries to absorb the unemployed labour is expressed in the
region.
TECHNOLOGICAL
Digitisation and e-commerce had flourished in the MENA region with many initiatives to
support the start-ups and small enterprises. Although few countries of the MENA region
had a very sophisticated developed industry (nuclear industry, for example), the
pharmaceutical industry has been expanding the last century. The technology Transfer was
one of the solutions to strengthen the expertise of the region in many sectors. In the
biotech industry, some countries like Jordan, Turkey, Egypt and Tunisia had published a
general regulation of technology transfer to regulate the biosimilars manufacturing and
ensure the quality of biosimilars wherever it is produced(JFDA, 2015), (Mueller, 2014).
ENVIRONMENTAL
According to the International Finance Corporation (IFC), 29 countries in the MENA region
are classified among 100 countries the most polluted in the world. In addition, the
33
electricity sector in MNEA is considered one of the least environmentally friendly in the
world where Yemen, Lebanon, Iraq, Kuwait, KSA, and Syria are the countries with minimal
renewable energy use (Cheraghlou, 2012). Regarding the depletion of petroleum and the
fluctuation of the oil prices, MENA countries become more aware of the necessity of energy
diversification .Compelled by this motivation, KSA, for example, had pledged to get 10% of
their energy from sustainable sources by 2020 (Hochstrasser, 2015).
LEGAL
Many MENA countries are part of different free trade agreements (FTAs). Egypt, GCC,
Jordan, Morocco, Tunisia, Turkey, Yemen are members of the World Trade Organisation
(WTO). Jordan and Turkey had recently signed FTA with the U.S to penetrate the American
market. Tunisia and Morocco are related to Europe through European Union Agreements.
All those agreements exercise the pressure on the local governments to set stringent rules
concerning product registration, data exclusivity, and Intellectual property. The
discrepancies in the product patent laws and the violation of Intellectual property are the
key are of concerns in the MENA region(Krishnan, 2010).
SWOT ANALYSIS
Although the regulation challenges, SWOT analysis showed that the MENA is a potential
Market in Biosimilars business. Early entry is an attractive option to local and multinational
companies to an untapped market in its way to maturity.
34
• Less expensive compared to the innovator with a comparable quality

• Biosimilar can be a Biobetter with improved efficacy comparing to
innovator
• Biosimilars can be developed in the same industry as the innovator
S (Novartis). Thus, a garanted quality
• Biosimilars can be introduced faster and easier to the local market (fast
track approval with only confirmatory efficacy studies )
• Biosimilar can be the only option in a specific market where the
originator is not patented or commercialised
• Intercheangibility and Switch status are unclear.
• Variablity interbatchs
• The cost fo the treatment is high comparing to standard treatments
• No long-term safety studies
W • Not a real copy
• Very high technology products comparing to generics
• For Mab biosimilars , their manipulation required trained physicians and
dedicated health centers
• Storage constraints
• Aging population and the health expiduture growth

• The Local regulations are encouraging the Biosimilars
• Developing new regulations in almot all the region
• Increased awarness about the similarity of Biosimilars to original
bioproducts
O • Going forward proving the interchangeabilty : the medical swith from
Originator to Biosimilars will be possible
• Acquisation of new market in developing countries that are sensible to
lower prices
• Governments adopt cost saving strategies
• Pattents cliff
• Partnership with local manufacturers
• The adoption of Biosimilars is very variable among the MENA countries.

Qatar is not encouraging Biosimilars Market. However, Morocco is
importing and producing biosimilars without a local regulation.
• limited knowldge of biosimilars restricts the biosimilars prescription by
physicians
• The high cost of biosimilars comparing to generics
T • Small market with no centralised process
• Absence or equivocal regulations
• The economic and the politic instability: Arab spring, civil wars
• Limited access to high technology and digitization
• limited pharmaceutical infrastructure: local facilities cannot support the
Biosimilars technolgy (limited technology transfer)
Figure 18: SWOT analysis of Biosimilar market in the MENA region(WHO, 2015a), (Clarivate, 2019), (World Bank, 2019)
35
Porter’s Five forces

Porter’s Five forces analysis will explore the entry attractiveness to MENA market through
analysing four parameters: Suppliers availability, Barriers to entry, substitution and Buyers
uptake.
•Few suppliers •No regulation in some MENA

•Switching from supplier to countries
another supplier can affect •Biosimilars are registred as
negatively the biosimilar Generics : Less studies
quality. Switching cost is high •Patents
• Suppliers should be •High Capital, High Tech
approved by the local agency •Economy of scale
•Governmental pressure Barrier to •Limited competitors
Suppliers entry
•Monopoly of procurement in power HIGH •
(Tunisia ) Mitigated
Low Competitive Rivalry: depends on the

country and if the biosimilar is local or imported
Substitute Buyers power

Power ( from
Innovator to LOW
Biosimilar)
•Interchangeability is unclear
•Automatic substitution not LOW •Limited health insurance
allowed in majortity of MENA •Biosimilars are expensive
countries •Patient are not involved in
•Switch from innovator to treatment decision
Biosimilar is not preferable
Figure 19: Porter's Five Forces analysis of biosimilar market attractivity in MENA region
Porter’s five forces show that the entry barriers are mitigated. Even though the competition
is not intense and most of the countries don’t require local clinical research, the market is
not totally attractive for the external companies because of the absence of stringent
regulation were the patents of the international drug-makers can be infringed. However,
the entry can be interesting to carry on phase IV studies (post-marketing phase) to collect
enough data of the biosimilar and enter later to more regulated areas with an established
record of efficacity and safety data (Asharpe, 2012). The international manufacturer ‘Dr
Reddy’, for example, had launched several biosimilars in Turkey ahead entering US market
to reinforce its position in a very competitive environment (Hernandez, 2013), (Blackstone
and Joseph, 2013). For the local companies, the entry risk is mitigated too. Even though the
36
policymakers encourage the domestic biotech pharma, the capital of investment, the high
technology and the lack of expertise discourage local investors.
Cross countries Biosimilar Market Access analysis

The collected data from the guideline’s framework and the market research of MENA
permitted to summarise a Market Access mapping of the MENA region in Table 5. The
criteria of the assessment included the world bank classification, Healthcare Access
&Quality Index(HAQ), HTA and Interchangeability regulation. are fully described in the
Appendix.
The mapping analyses showed the market access of more than seven countries in MENA
region with the different economic and political environment (Morocco, Algeria, Tunisia,
Jordan, Egypt, Turkey, Lebanon, GCC countries). UK and India used as a comparison
model.
Table 5: MENA Market Access Mapping inspired by (Deloitte, 2018)
Affordable Regulatory Payer Prescriber Patient Biosimilars

Variable
access Environment advocacy acceptance acceptance availability
Algeria Medium Ongoing Low Low Low Low
Morocco Poor Ongoing Low Low Medium Medium
Tunisia Poor Established Medium Low Low Medium
Egypt Poor Established Medium Low Low Low
GCC High Established Low Low Low Low
Lebanon Medium Ongoing Low Low Low Medium

Jordan Medium Established Low Low Low Low
Turkey High Established High Low Low Low
UK High Established High Medium Medium Medium
India Poor Established High Medium Medium High
For new entry, the mapped access in Table 5 permits to identify three categories of MENA
countries:
37
First category: future potential (Algeria): Algeria presents acceptable affordability with
a limited number of biosimilars in the market, which can be explained by the absence of
local regulation. (Clarivate, 2018).
Second Category: Immediate opportunistic entry (TURKEY, GCC): Although some

Biosimilar companies have been invested in GCC countries and Turkey, the actual number
of biosimilars is still limited compared to the need of the market. Many workshops and
conferences are held in those countries to enhance guideline implementation and engage
stakeholders (GaBi, 2019).
Third Category: competitive market (Tunisia, Morocco, Lebanon, Jordan, Egypt): The
competitiveness is due to limited market volume (Tunisia, Lebanon, Jordan) and/or to the
actual number of marketed biosimilars (Morocco, Egypt).
5.3.2. ACTUAL BUSINESS MODEL
Most licensed biosimilars were imported or produced locally following agreements

between multinational biotech companies and local manufacturers. In some countries like
Algeria, foreigner companies must establish their facilities locally to operate and
commercialise their medicines (WHO, 2003). For the imported biosimilars, the
international industry will choose to operate directly or through a third-party agency to
commercialise its products. Despite the effort to respect the specificity of the individual
culture in MENA, multinational companies didn’t fully succeed in taking advantage of the
MENA potential opportunities because of “one fits all” Business Model although the
obvious market heterogeneity (EY, 2014).
The most common and useful Business Model, followed by the local pharma companies to
commercialise their products is price-volume trade-off (McKinsey, 2018). In Tunisia for
example, the cheapest generics (or biosimilars) will be the base of reimbursement in the
private sector and the tender winner in the public healthcare sector (Ayadi, 2009) to target
the broadest range of patients
38
6. DISCUSSION
6.1. DISCUSSION OF CASE STUDIES

6.1.1. REGULATION
Among the three studied countries, Egypt was the first North African country to publish an
official guideline for biosimilars. However, GCC countries published in 2016 a centralised
guideline that is not officially implemented yet. Overall, the three guidelines were similar since
they refer to the WHO and European guidelines. All described guidelines are stepwise process
and require Quality comparability, nonclinical and clinical studies followed by safety studies
of the biosimilars issued from DNA recombination (Figure 20). Overall, GCC seemed to be the
clearest and the most developed guideline compared to the Tunisian and the Egyptian
regulation. Only GCC guideline has expanded specific regulation for individual biosimilars like
insulin and interferons. However, the Tunisian and the Egyptian guidelines advised the
applicants to refer to WHO, EMA and ICH guidelines for the individual biosimilars. The GCC
was the most specific and elaborated guidelines compared to the Egyptian and the Tunisian
guideline. (EDA, 2015); (Gulf Health Council, 2016), (DPM, 2018). For example, In the GCC
guideline, more information is mentioned about the design of clinical trials, the population
size and endpoints selection. In addition, GCC dedicated a separate section for the
manufacturing process variations where it specified the requirements following the
manufacturing process change during the comparability exercises and before or after the
approval, which was briefly mentioned in the EDA guideline and quasi absent in the Tunisian
guideline. On the other hand, EDA guideline seemed to give more importance toward the
additional requirements of the local and the imported biosimilars aside. Tunisia, to a lesser
extent, defines the registration procedure of biosimilars with or without technology transfer
but none of that information is mentioned in the GCC guideline. Numerous similarity and
divergence are identified along with the three guidelines in the comparative framework in
Appendix concerning RMP, interchangeability, extrapolation, labelling and
pharmacovigilance. However, the regulations are constantly evolving with the introduction of
new concepts and technologies leading to controversial definitions or identifications of terms
like of biosimilarity, interchangeability, reference product to be more adaptative to the needs
of the local market. For example, Both Tunisia and Egypt follow the European definition of
“Biosimilar”; however, AUE follows the American definition “Follow on Biologics (FOB)”.
Nevertheless, all the discussed guidelines agree on the interdiction of the automatic
substitution. Although the similarity, the harmonisation of regulation across the MENA
countries is not one of the strengths of the region. Dr Derbyshire thinks that the alignment
has many advantages like the reduction of manufacturing cost, clinical trials number and
facilitation of the commercialisation of the biosimilars with fewer boundaries (Derbyshire,
2014). The lack of harmonization could be explained by its impossibility in very diverse context
or the absence of a political will or maybe both. The three discussed case studies showed the
flexibility of the requirements to let understand the existence of different incentives toward
biosimilars locally produced. Both Egypt and Tunisia are encouraging the local industries by
dealing with biosimilars in a case by case approach mainly in the extrapolation, giving a room
for the individual interpretation like the case of clinical trials requirements. Despite the clarity
of GCC guideline, gulf countries didn’t activate their guidelines and continue to import
originator products and branded biosimilars(Gulf Health Council, 2016) despite the high cost.
For sure the regulation of biosimilars in the MENA region is the principal obstacle for
biosimilars adoption. Between vague guidelines supporting misleading interpretations and
existing guidelines without real implementation, the manufacturer in gulf countries, Tunisia
and Egypt face a regulation gap leading to unanswered questions, doubt and inconsistency
about the quality of biosimilars in the region.
Individual Overarching
guidelines guideline
RMP Biosimilarity
GCC Comparability
Selection concept
Preclinical Clinical GCC,Tunisia,

Quality Tunisia,Egypt
studies studies Egypt
GCC,Egypt, Physicochemical Manufacturi

In vitro In vivo
Tunisia caracterisation ng porcess
GCC,Egypt, GCC, GCC, Egypt,

GCC
Tunisia Egypt,Tunisia Tunisia
Figure 20: Comparison of Tunisia, GCC and Egypt biosimilars guidelines (EDA, 2015), (Gulf Health Council,
2016) (DPM, 2018)
40
Other than GCC, no harmonised regulatory pathways among the MENA countries. Iran,
Turkey, Jordan, Irak, Lebanon, Egypt, Saudi Arabia an Tunisia have succeeded to disclose
national guidelines for biosimilars that resemble at the certain extent the EMA and/or WHO
biosimilar regulatory pathways (Fitch Solutions, 2018). The rest of MENA countries continue
to approve the “biological generics” under the absence of biosimilars guidelines (Morocco,
Algeria) which incite doubts about the quality and the safety of the licensed products in those
unregulated countries. The Jordanian experience, however, is another exciting model in the
region. Jordan was among the first countries that adopted EMA biosimilars guideline in 2008
and promulgated its national guideline in 2015(JFDA, 2015). In 2013, Jordan exported $Int722
million in pharmaceuticals (Azevêdo, 2013), leading the Arab world in the pharmaceutical
sector (Haqaish et al., 2017). Recently, the international Jordanian company Hikma has agreed
with Celltrion a global pioneer for the infliximab biosimilar production in Jordan(GaBi, 2018)
which reflects the quality and the reliability of Jordanian biotechnology.
The MENA region experience in biosimilars is still in its infancy despite the efforts to follow
the successful European experience. Europe was the first to encourage and regulate the
biosimilars market (Derbyshire, 2014) and then becomes the model to follow. The first version
of EMA guideline was similar to those published in Tunisia and Egypt as it contains quality,
preclinical and clinical requirements. As soon as biosimilars gained more interest, EMA has
updated its guideline several times to face more practical inquiries (Dahal, 2014). No doubt
that the European guideline is the most detailed, given the relevant experience and
accumulated records (EMA, 2017). The biosimilars approved outside of Europe may not have
the same rigorous comparability requirements as the European biosimilars hence a
questioned quality (GaBi, 2015). Unexpectedly, MENA is not the only region where the uptake
of the biosimilar is a country-specific incentive. Europe has for sure the largest biosimilars
market share compared to MENA, but some European countries were more conservative than
the others. Figure 21 highlighted the Norwegian experience in comparison with the rest of the
European countries. Norway with the highest growth in Europe, increased the biosimilars sales
volumes (Dark green) at CAGR of 22 % starting from 2014, followed by Denmark whereas Italy
was the last adopter of biosimilars by only 2% of sales growth (IQVIA, 2018b).
41
Figure 21: the evolution of Biosimilars uptake in Europe(IQVIA, 2018b)
The variation of the biosimilar adoption in Europe is probably due to the healthcare system
difference. Denmark and Norway have a strong UHC compared to Italy, where the health
system also relies on the private sector(Thomson et al., 2016). Besides, the stakeholders'
scepticism can be another reason for slow biosimilars adoption (Blackstone and Joseph, 2013).
It could be unfair to compare the adoption of biosimilars in the MENA region to the European
experience due to the massive difference of socio-economic and political environment. Plus,
the disparity between the MENA countries is the primary barrier (see PESTLE Analysis) to
centralise the regulation process and replicate the European regulatory experience.
India is an interesting model that shows the successful incarnation of the European experience
in developing countries. Although the socio-economic challenges, Indian biotechnology
becomes the leader in biosimilars industry worldwide. Unlike the big pharma, Indian
biotechnology has entered to unregulated and under-regulated market like MENA to build a
biosimilar capital that enables the Indian biotech to develop their expertise and expand their
market share. Except for GCC, the MENA countries have on common with India the struggle
for equal health access among the middle- and low-income patients (World bank, 2013). The
similarly of the context makes India a more realistic model for the comparison instead of
42
Europe (Gautam, 2017). So, How India did differently than MENA that contributes to its
leadership with seventy approved biosimilars until 2017 (McKinsey, 2018) and a pipeline of
257 biosimilars(Figure 1)(IQVIA, 2018a) ?.
Before 2012, the India market was not attractive, although the vast potential market for
multinational companies given the uncertainty of the return on investment (McKinsey, 2018).
To improve the quality, the national agency Central Drugs Standard Control Organisation
(CDSCO) has published biosimilars guideline in line with the European and global requirements
in 2012(Rathore, 2012). In the beginning, despite quality improvement efforts, the Indian
biotech companies succeeded to expand only in less regulated markets (e.g. MENA) (Gautam,
2017). In the last few years, the regulation of biosimilars in India had gained significant steps
to maturity. The accumulated records of safety and efficacy in the emerging countries where
the Indian biosimilars were commercialised enabled India to access to the most competitive
market. Dr Reddy’s and Biocon are examples of the Indian biotech companies that expanded
internationally and established partnership strategy with key biotech pharma around the
world (IAPO, 2013). In conclusion, the difference with the MENA region resides on
-The policy-makers decision to enhance the local biosimilars industry, which is not always the
case in the MENA region,
-the early entry to the biosimilars market contributed to build accumulated expertise and take
advantage of the untapped market, especially the huge Indian market.
- Manufacturing and technology development are the main qualities of the Indian industry,
starting from imitation to mastering and competing with the international industries.
- Effective implementation of national guidelines inspired by the European one and the
continuous update to respond better to the new technology and the market demand.
- Adapting a visionary Business Model to expand its market in the emerging region, a market
neglected by the big pharma.
43
Learning from the Indian scenario, the MENA countries should be able to learn how to refocus
on the internal market with its enormous opportunities to mature the biotechnology
experience and then expand to similar markets (like Africa).
To summarise, the regulatory pathway of biosimilars in the MENA region is immature,

suggesting different country-specific incentives. The local health agencies clearly express the
willingness to support biosimilars as a cost-saving alternative. However, it may be more
important that policymakers focus their efforts on providing the local patient with high-quality
biosimilars to support the sustainability of the cost-effectiveness in the long-term.
6.1.2. MANUFACTURING
In the whole MENA region, no domestic manufacturer is fully producing biosimilars. The local
biotech companies import the drug substance and finish the process to obtain the drug
product. Generally, it stops at filling the bulk into unitary packaging as the discussed example
of EPO manufacturing in SEDICO, Egypt. For a more complicated process, usually licensing,
and subcontracting with experienced industries are more common production forms in the
MENA region. In GCC, domestic production was not one of the region strengths (WHO, 2007).
According to Alsaddique, 90% of commercialised medicines are imported (Alsaddique, 2017).
While in Tunisia, domestic pharmaceutical production is esteemed by 47% (Oxford Business,
2016) and around 82 % in Egypt (Wanis, 2015). The local high output doesn’t reflect
necessarily the local ability to support biosimilars manufacturing as much international
biotech prefer to establish their own facilities to produce locally for cheap labours and other
preferential advantages. Few are among the MENA companies that succeed to agree with
global biotechnology companies given the adequate infrastructure for the technology transfer
namely Hikma, the Jordanian biotech company (GaBi, 2018). Only the international
accreditations and certification of the process like Good Manufacturing Process (GMP)
transform the MENA region pharmaceutical industry into an interactive and eligible partner
to the international companies (Malhotra, 2011).
Intellectual property and data exclusivity are significant challenges for drug-makers. Unlikely
to the small molecule generics, reverse engineering is incapable of recreating the same
process as the reference product (Kirchhoff et al., 2017). Therefore, extensive testing should
44
be performed to survey safety, efficacy and immunogenicity profile along the manufacturing
process from the substance drug to the product drug to avoid batch to batch variation (Halabi
et al., 2018). In Europe and India, where the optimisation of the process is a priority for higher
quality, many attempts to make the bioprocessing more predictable are running. Quality by
Design (QbD) and Process analytical technology (PAT) are two technologies that MENA
countries can experiment as solutions for biosimilars bioprocessing. Lathore describes QbD as
a systematic approach recommended by ICHQ8 guidelines to assure the quality and to assess
risks (Rathore, 2016). Jentzsch has also suggested (PAT) as a practical framework using data
analysis, analytic technologies and algorithms to increase the understanding and the control
of the process for optimal quality(Jenzsch et al., 2018).
The MENA region must strengthen the manufacturing process to improve the quality of the
inhouse biosimilars. It is indisputable that the quality of local biosimilars is doubtable mainly
for non-conformity of the manufacturing to the international accreditations, the lack of
expertise and the nonchalance of health decision-makers regarding manufacturing
regulations. Unfortunately, the biotech industry is still behind despite the restructuration
efforts. Regulations, technology and expertise reinforcement will be the success keys of a
high-quality biosimilars industry in the region.
6.1.3. PRICING
Among the three discussed countries in previous case studies, patient in Egypt has the highest
Out-of-pocket expenditure (61,99 % of current health expenditure) (world bank, 2016)
comparing to Tunisia (39,9%) and GCC (Qatar=8,55%).
Apart from reviewing the coverage system, the policymakers implemented differential
advantages to reduce the health expenditure by encouraging the local production of
biosimilars. GCC has a comprehensive UHC, and most of the health services are free of charge
(Alhomaidan, 2016). Nevertheless, the policymakers started to understand the importance of
expenditure optimisation, taking into consideration the fragility of their economy due to the
oil price fluctuation and the macro-economic dynamicity of this region. As a result, most GCC
countries had adopted the EPR model and had unified medicines prices across GCC (Kanavos
et al., 2018). On the other hand, Tunisia and Egypt have suffered from the depreciation of
45
their local currency because of the political and economic shift after the Arab spring where
the medicines importation costs heavily to both countries. Hence, “discriminative” practices
against imported medicines were the best strategy to force multinational companies to install
or subcontract locally. Both of Tunisia and Egypt use the tendering system in the public
healthcare system where generally the winning offered the lowest price. In Egypt, the
imported medicine will be forced to provide discount against the cheapest local drug in the
tender list. Otherwise, the imported medicine will lose the tender(Wanis, 2015). The
healthcare system in Egypt relies more on the private sector, which explains the high rate of
the patient out of pocket. In Tunisia, the prices of imported medicine are quite stable because
of the importation centralisation strategy (WHO, 2003).
A report published in LSE consulting assumes that External Reference Pricing (ERP)is the most
popular pricing policy in the MENA region, particularly in the private sector. In contrast with
Internal Reference Pricing, EPR aims to minimise the health cost by benchmarking to the
lowest prices in the reference list (Kanavos et al., 2018). In this pricing model, the new product
(biosimilar or generic) will be automatically cheaper than the same INN product in the market
(Reference, Biosimilar, generic) and its entry will induce an additional discount of those
commercialised products automatically. (Alhomaidan, 2016). On the other hand, Health
Action International (HAI) and WHO think that Mark-up supply chain is the most used pricing
model in low and middle LMICs countries like Tunisia, Syria in private and the public sectors
(WHO, 2015b), (HAI, 2019).
Whatever the pricing system (ERP or Mark-up or tender), the advantage of those strategies is
ensuring access to medicines with monitored prices. Unfortunately, the discussed systems are
not perfect. In the Tender model, if one treatment option is available in hospitals and the
physician prefers to prescribe a different treatment, the patient will pay the medicine from
his pocket (Deloitte, 2018). Considering the spillover effects, the ERP system discourages the
multinational industries from entering a market with low prices as they will be forced to
present lower prices globally. Hence the local market in the MENA region will be restricted to
generics and biosimilars with questionable quality since no international company will accept
to enter at a lower price (Kanavos et al., 2018). The mark up of supply chain, in another side,
will accentuate the disparity between cities and rural zones because no distribution channels
46
will be interested in reaching remote areas with the same margin as in the city (HAI, 2019). In
Europe, the most successful pricing model was attributed to the Norwegian experience
(Moorkens et al., 2017). Thanks to a single one winning tender strategy, Remimsa® the
biosimilar of Remicade® gained the Norwegian tender by discounting its price up to 69%
(Asharpe, 2012). This model is only viable when the healthcare system is predominantly
public. The single winning tender model has been criticised since it restricts the physician’s
decision and excludes the competitor from the market during the tender contract (IQVIA,
2018b).
What can MENA really learn from the European experience is the implementation of Health
Assessment Technology. In the majority of MENA countries, no official HTA system is
operating. The Tunisian MOH has officially established an HTA program in collaboration with
an international expert (INEAS, 2019). Egypt didn’t adopt the HTA system explicitly, but it
carried out cost-effectiveness studies under the Egyptian Health Ministry (EDA, 2019b). GCC
didn’t yet explore this option; however, Jordan has introduced a pilot experience of HTA
system in one of its royal hospitals King Hussein Cancer Centre (Rabayah et al., 2018). India
and Turkey had adopted several years ago HTA system to enhance the quality perception and
attractiveness of its market (See Appendix Methodology of access evaluation).
Overall, many MENA countries are combining two or three pricing systems to respond
appropriately to internal divergences in purchasing capacity and reimbursement coverage.
The shift from the public to the private sector will affect the biosimilars adoption negatively
and accentuate the out of pocket rate in the next years in the absence of efficient
reimbursement systems.
6.2. DISCUSSION OF SURVEYS RESULTS
Considering the lack of publications regarding biosimilars acceptance, the survey provides
useful data on the role of stakeholders in biosimilars adoption. Although the difference of
sample size (140, 117, 393 participants) and content of the questionnaire (15,14,19 questions)
in Tunisia, the Middle East and Europe respectively, most doctors express their general
knowledge of the biosimilars 71%, 65.8% and 79.2%. In Tunisia, only 3,7% of responders
believe they have an in-depth understanding of biosimilars. However, in the ESMO survey,
47
79,2% of respondents describe their knowledge by average to high. No objective comparison

can be made as the assessment criteria of the ‘biosimilar knowledge’ level is not defined in
the three published surveys. Both surveys in MENA and Europe showed a comparable uptake
rate of the biosimilars (48% versus 49%). Even Europe has more experience with biosimilars;
the acceptance of the physicians is still modest. That can be suggesting the inefficacy of
current educational programs or the existence of more profound objections behind the
indifference of the prescribers like negative feedback. In Tunisia and MENA region, only 25
% to 30 % of the physicians think that price is a strong motivation to prescribe local or
imported biosimilars; and doctors trust more the imported biosimilars approved by the EMA
and FDA (Hadoussa et al., 2019). (Farhat et al., 2016). Although, the inefficiency of the
reimbursement coverage and the high out of pocket, the MENA prescribers still prefer a
biosimilar with a higher quality regardless of the price. That can be explained by the lack of
clinical and cost-effectiveness data of local biosimilar compared to an imported biosimilar with
a registered and traceable efficacy and safety data. Meanwhile, the price issue is not even
mentioned in the European survey , probably because of the excellent healthcare coverage in
Europe. In the MENA region, Tunisia seemed to be more open to biosimilars experience in
comparison with the rest of MENA countries (mentioned in the survey) with higher rate of
knowledge 71 % versus 68% plus the expressed interest in biosimilars training.
The brand trust hinders the biosimilar adoption, despite the cost-saving benefit. According to
the survey results, the physicians are more concerned about the quality than the price. The
lack of highly regulated clinical trials and transparent pharmacovigilance program is tarnishing
the local biosimilars reputation. The lack of knowledge and the conservatism can also explain
the reluctance of the prescribers(Fitch Solutions, 2018). Therefore, intensive training, a
targeted marketing campaign and more implicative strategies may increase the biosimilar
uptake in the MENA region. A successful business strategy will imply KOLs in their marketing
campaigns. The exchange of positive clinical experiences and involving in product
development can be benefic to biosimilar experience. The third part of the discussion will
propose practical solutions to the previously discusses elements.
48
6.3. BUSINESS STRATEGY DISCUSSION & RECOMMENDATIONS
The previous market research has demonstrated the weakness of the actual business plan
adopted in the MENA. More importantly, it showed how the local market is fragmented in a
diverse socio-economic context, with no harmonised regulations or common vision. Given the
risks of the investment in an uncertain market, the entry to the MENA market remains
challenging. Due to the above considerations, the investor will demand a bigger return
regarding the investment risk. Therefore, a well-considered business strategy is a way to take
advantages from the region without falling in its pitfalls.
The actual business model didn’t seem to refer to a well-studied strategy with a clear vision
and identified objectives. As the market is fragmented, the business strategy should be
fragmented to respond better to the need of each market. Currently, the adjustment of
strategy is not considered seriously by the multinational industries. The manufacturer must
set realistic targets that align with the profitability (short term objectives), sustainability (long-
term objectives) and a win-win relationship with the local stakeholders and authorities (long-
term objectives). Hence, this section will recommend a more adaptative business plan that
considers all the previously discussed elements.
6.3.1. BUSINESS FRAMEWORK
To create a MENA business framework, a set of questions about the identification and the
implementation of the business strategy is presented in Table 6 (Deloitte, 2018).
This not-exhaustive questions list will help the applicant to identify its roadmap in each
market. The questions focus on the analysis of the market specificity to identify the existent
gaps and adapt a model respecting the need of the market. The applicant should identify the
tactics that go with the legal and economic context and choose the adequate tools for a viable
model. The Business strategy should be SMARTER ( Specific, Measurable, Action-oriented ,
Realistic, Timed, Evaluated and Reviewed) and hence, this framework is not fixed but dynamic.
49
Table 6: Development of Business strategy of biosimilars in the MENA region Framework(Deloitte, 2018)
BUSINESS STRATEGY IMPLEMENTATION
MARKET RESEARCH BUSINESS MODEL TOOLS BUSINESS TACTICS
Where to invest? How to profit? -What capabilities to develop? -What the best tactics?
-What is the potential of each -What are the opportunities and -What resources to use? (subcontracting, licensing?)
market? (SWOT analysis) risks in this market?
-What distribution channels to -What are the timeline and
-What Therapeutic area to focus -What can this business offer to use Milestones of the Biosimilar
according to a specific market? stakeholders and clients? business?
What is the need of each buyer and What are the competitive
supplier in this segment? advantages of this business?
-What is the most suitable model for

each market?
What is the right pricing model?
50
6.3.2. BUSINESS MODEL
Decisive Diagram
In-depth market research (SWOT, PESTLE, PORTER’S FORCES) allowed to decorticate the
complexity of MENA market, but before fixing the definitive Business Model, some questions
should be considered to define principal strategy axes. Here, a proposition of decisive diagram
(Figure 22) to brainstorm challenges and solutions. Three key endpoints have been concluded
from the previous market analysis for the international and domestics biosimilars: Regulation,
Expertise and Public Relations (PR) are the main factors conditioning the growth of the
biosimilars in the area.
Business Model (BM) options
To concretise the decisional algorithm (Figure 22)and the strategic framework (Table 7),
three BM inspired by the European experience can be applied in the MENA region.The
proposed BM is based on three major criteria 1).Pricing ; 2).Brand Notoriety ; 3).Patient
Focus
51
Regulations Imported Biosimilars Understand the specificity of regulatory

context in the individual markets: Tailor the application
For imported biosimilars:
can applicant use a global Decide if the existing data in similar contexts can be supportive
approach in an individual
Get in contact with local authorities directly through dedicated
market if NO national
services
guidance? No
Interact with local consultancy firm
For locally manufactured
biosimilars: is there any Locally Manufactured Biosimilars: obtention of international
clear local guideline? certifications to improve processing quality
Cooperate with government to elaborate national guidelines
Don’t content with generic status, individual initiative to prove

Yes
similarity in the absence of guidance
Expertise Considering license or subcontracting to gain expertise
Do we have the right Regional/ international workshops participation

expertise to develop a
good quality Collaborate the local research institute and contribute to university
No research funding
Biosimilar?
Are we scarifying Obtention of international certifications of GMP, International

quality while focusing training, expertise exchange in the region
on cost saving? Optimizing the Bioprocessing, developing economical viable plants,
mastering the approval schema and marketing researching can save
money, time and preserve the quality of the products
Yes Total adhesion and respect of the guidelines
Marketing Research: Choose the market where the innovator has a

PR limited access
Is patient,
Physician, payer No Stakeholders engagement plans
adopt our Centralize all efforts around patients
biosimilar
Explore physicians’ motivations and needs: international or national
consensus, Clinical trials in local context, personal experience,
affordability, data in similar contexts, personal affinity
Yes Payer motivations: the willingness of the government to encourage

local industry (Foreigners companies should think of licensing or
establishing of a local facility). Tenders, Cost-effectiveness studies,
-Marketing/Commercial support according to HTAs implication.
the specificity of each market
Patient: the implication of patient in decision making? Price
-Educational support to maximize the safety sensitivity, pathology awareness, Trust in the local healthcare
follow up system
-Implement Business Intelligence to limit the

market-share of competitors
-Build the trust!
Figure 22: Decisional Algorithm of biosimilars Business Strategy in the MENA region inspired from (Dahal,
2014)
52
Table 7: Adaptation of Business Models for Biosimilars in the MENA Region inspired from (Deloitte, 2018), (McKinsey, 2018)
Price-to-volume model (Pricing Brand Notoriety Patient focus approach (Implicative

Business
approach) Business Model)
Model
-Reducing the margin of selling prices The branded product is a secure option for Relies on the physicians and patient uptake
Principle
due to a limited affordability the countries where the counterfeit is -Involving local KOLs
-It is more suitable for local common -Raise awareness
manufacturers. -Branded products are equivalent to a -Suitable for imported medicines, either
-It concerns the biosimilars first high quality Branded or No Branded Biosimilars.
generation with enough records It more suitable to multinational pharma -Local companies should provide quality
with originators/biosimilars portfolio proves first.
(Novartis)
Suitable to price-sensitive countries - Price-insensitive Countries (GCC, UK) Suitable to countries where patient out-of-
Can be
with non-established insurance and -Countries with no Biosimilars regulation: pocket is high
applied in
high out-of-pocket Algeria -Where patients are involved in treatment
Tunisia, Morocco, Yemen, Egypt Countries with counterfeit issues: Africa, decision
Asia (Turkey) -Where doctors are the significant deciders
(MENA-India)
53
1. PRICE TO VOLUME MODEL: LOWER MARGIN, HIGHER VOLUME
In the majority of MENA region, price is the main barrier to access to biosimilars. With
incomplete reimbursement and the high out-of-pocket rates, patients are incapable of
affording their treatment. The in-house biotech companies can benefit from the lower cost of
labour and several government initiatives to encourage the local industries to build a lower-
priced biosimilar portfolio.
The multinational biotech companies face high pressure from the local government to reduce
prices. Some big pharma like Roche adopted a differential pricing system to enter different
affordability segments in Egypt (Roche, 2018). Roche has agreed with the Egyptian
government to package and distribute locally Pegferon®, the second brand of Pegasys® the
same medicine commercialised in Europe with a higher price. Pegferon® enabled the
government to save and facilitate access to 160,000 patients for chronic hepatitis C treatment
(Roche, 2018). Roche also has benefited from this program. A $10 million investment in
hepatitis C portfolio in Egypt leaded to sales growth of nine times the first investment within
five years (McKinsey, 2019).
2. BRAND NOTORIETY MODEL
The multinational companies are in continuous racing to enhance their reputation and
strengthen their relationship with stakeholders. Participating in public projects in low- and
middle-income countries in an attempt to improve their ranking in the Access to Medicine
Index was one of the business strategies to strengthen their brand image worldwide(Hogerzeil
et al., 2018). Consequently, in emerging countries where the quality of local biosimilars is
questionable, the reputation and the commitment of multinational in improving health access
is a guarantee to a better biosimilar quality. In GCC, for example, the willingness to pay for
branded biosimilars is even higher than the developed countries. Enhancing the reputation
should be a priority of the domestic companies if interested in the gulf market.
3. IMPLICATIVE BUSINESS MODEL
It seems that the implicative model is the most suitable for most MENA countries referring to
the market analysis and the survey results above. In the MENA region, physicians play an
important advocacy role in health access decisions. In biosimilars case, it is the physician who
54
decides the interchangeability between innovator and biosimilar as mentioned in the

discussed guidelines. (EDA, 2015),(Gulf Health Council, 2016), (DPM, 2018). Although the
patient is not directly involved in the treatment in MENA countries, the treatment affordability
is crucial in the doctor’s decision.
The discussed surveys showed a restricted adoption of physicians either because they are not
familiar with biosimilars or sceptical of the biosimilar quality. Hence, the physician reluctance
is translated by a few prescription rates. To raise awareness, educational programs,
workshops and specific training should be considered by the biosimilar companies to highlight
the clinical comparability and assist the healthcare professionals (HCPs) through a risk
management program. Bringing stakeholders inside the marketing plan will enhance the trust
and guide the company to more targeted tactics. Among the tools that can be displayed in the
model is the digital and the clinical trials. Digital will play a considerable role in physician and
KOLs engagement. Smartphone, webinar, Artificial Intelligence, sponsored mobile clinics are
examples of educational platforms that have been used successfully in developed countries
(Deloitte, 2018). However, Biosimilar companies should wisely choose the right tools for each
market, considering the current infrastructure. For the quality concerns, including patients
from MENA region in the clinical trials can be a strategic initiative to ensure the implication of
local HCP in the studies and prove the safety and the efficacy of the biosimilars in regional
settings.
Higher patient awareness will also have a positive impact on biosimilars uptake. Working with
patient advocacy groups and national non-profit organisation is the efficient option to inform
the patient of the long-term benefits of biosimilars and their comparability to branded
medicines with lower out-of-Pocket rate. The conceived educational materials must be simple
and comprehended by most patients under the requirements of the local regulations
(Deloitte, 2018).
6.3.3. IMPLEMENTATION
1. Partnership and Joint venture
The multinational industries must heed the partnership strategies in response to the risks/
opportunities ratio. The collaboration with local biotech companies and the government is
55
imperative to gain knowledge of the local guidelines, reimbursement systems, commercial

landscape for a long-lasting relationship with the local policymakers and KOLs.
Algeria, for example, attributes MA to international biosimilars only if the foreigner company
considers building facilities and produces domestically (Oxford Business, 2015). Such
technology transfer will induce a price reduction of up to 60 % and contribute to the economic
viability and pharma sustainability (WHO, 2011). A similar experience in Egypt has conciliated
interest in local manufacturing. Collaboration and joint venture with the early adaptor of
biosimilars in emerging countries (China, India, Korea, Cuba, Argentina) were supported by
the Egyptian government to develop local manufacturing. Free lands, pricing advantages over
the imported biosimilars, interest-free loans, and subsidises efficient practices to complicate
the importation and refocus on the inhouse production. (Farag, 2013).
2. Expertise & Data
The commercialisation of biosimilars in the MENA market is a relatively new business. The
local manufacturers are still incapable of proving the quality of their biosimilars because of
the absence of stringent regulations. In addition, the manufacturing process of biosimilars is
highly complex and delicate. International certifications as Good Manufacturing
Practice (GMP) are primordial to align with international standards. (Fitch Solutions, 2018) and
to be recognised locally and regionally.
An important challenge in the MENA region is the lack of reliable data and records. The
accessibility to a transparent database will open ways to better traceability. In this context,
creating a regional platform and regulation harmonisation will be beneficial to biosimilar
uptake. Meanwhile, the implementation of clinical trial protocols to obtain real-world results
and foundation of pharmacovigilance programs confirm the commitment of the area toward
the quality assurance of their biosimilars.
In the biotechnology field, building the bridge between research and business leaders to the
concretisation of biologics and biosimilars products. The complementarity between
universities and the biotech pharma contributes significantly to the expertise reinforcement.
Europe is the best example of the synergy between academia and business through creating
research centres excellence, funding awards, investing in start-ups and PhD funding. Building
56
complementarity will encourage innovation and the creativity of skilled people and keep them
from leaving their countries.
3. Patient-assistance programs
It is common for the multinational companies to offer patient assistance program. Knowing
that access to reimbursement system is complicated in most MENA countries, the patient is
not able to pay for its chronical disease and ends to abandon his treatment. Patient assistance
programs can offer discounts or contributes to cost. Novartis used this scheme to enable some
patients access to Gleevec. The patient will pay for the initial treatment, and then Novartis
participates in the next cycles. This scheme permitted to reach more patients by offering a
differential service to increase the compliance to Gleevec and restrict by consequence the
switch to another competitor. Introduction of this program in local companies agenda will
increase the market share in the long-term and improve their image by focusing on the
patient benefit that will be translated to a sustainable sales growth (McKinsey, 2019)
4. Health Assessment Technology
HTA is a critical step to assess the added value of biosimilars in short and the long run and
ensure the sustainability of the healthcare system. The cost-effectiveness studies are an
efficient tool to remodel the policymakers' decision about accepting or refusing of biosimilar
approval. Therefore, International and local companies must incite and help the local
institutions to restore a legal framework (e.g. guidelines, HTA, national consensus) to support
a favourable environment for biosimilars implementation in the MENA region. Under the
absence of HTA in some countries, international organisation (mainly WHO) elaborates
workshops and training sessions to exchange experiences with the experts to establish HTA.
Meanwhile, a clear gap in decision tools needs to be addressed. In the absence of the
governmental initiative, private HTA firms can play a crucial role to spread the sustainability
mindset
57
7. CONCLUSION & FURTHER CONSIDERATIONS

The success of the European experience in the improvement of patient quality life and the
control of health expenditure triggered the interest of MENA policymakers who were
incapable of facing the increasing need for health access.
This research showed the disparity and the heterogeneity of MENA countries in term of
market access to biosimilars. GCC had the most favourable infrastructure and resources for
biosimilars entry. However, the local biosimilars guideline was not actively implemented since
the stakeholders prefer branded products. In another side, Egypt was the first country in North
Africa to implement a biosimilar national guidance. Regarding the size of the Egyptian
population and healthcare reforms projects, Egypt will be a potential source market of
biosimilars in the future. Tunisia was the last to adopt a national guideline. Despite the
insignificant volume of its market, Tunisia was known as the entry gate to its neighbourhood
(Algeria, Libya and Africa).
Although the European guideline has inspired most MENA countries, the biosimilars adoption
is still limited, given the lack of expertise, inefficient health coverage and stakeholder’s
resistance. Therefore, the enhancement of biosimilars adoption depends on several factors
that go beyond regulation only. The MENA region can learn more from the European
experience. This research has revealed the next recommendations respecting the European
experience
• Establish more stringent biosimilars guidelines.

• Restrict the ‘Bio-generic copies’ approvals.
• Harmonise the regulations in the countries with similar settings (For example, The
North African union (Algeria, Tunisia, Morocco).
• Implement a Real-world-data incentive and local clinical studies to prove efficacy,
safety and quality in regional settings and participate the local stakeholders in clinical
monitoring
• Raise awareness among HCPs about biosimilars to improve the patients and HCP
acceptance.
• combine pricing systems to offer a preferential and competitive environment.
• Follow tender market experience (Namely: NHS experience in the UK).
58
• Foster agreements and partnership with recognised biotech industries will permit the
transfer of the technology and the know-how.
However, the replication of the European experience can be challenging due to the current
and critical economic, politic and social gap between the two regions. The experience in
pharmaging countries like BRICS (Brazil, Russia, India, China and South Africa) can be more
suitable to copy.
This research aimed to also build a guideline mapping and regulations framework (In
Appendix) of the non-exhaustive list of MENA countries (Tunisia, Morocco, Algeria, Egypt,
Jordan, Lebanon, Qatar, UAE, KSA. Nevertheless, the growing biosimilars market in countries
like Iran, Ethiopia and Israel (the appurtenance to MENA region is questioned) were not
mentioned in the comparative analysis. So, further research can be conducted in this area to
benefit from the successful models in the same environment. Considering the
underdeveloped regulatory landscape, intellectual property remains a controversial topic in
the MENA region. Extensive research on the impact of the new agreements with WTO and
European union on biosimilars/generics approvals should be considered. The harmonisation
of the guidelines was proposed as a solution in this research; however, it is essential to explore
its feasibility and its impact across MENA comparing to the European model in further
discussions.
Overall, the landscape of biosimilars in the MENA region is in its infancy, and it is expected to
mature slowly. The focus on the internal development and the cooperation with Europe and
pharmaging countries will have a positive impact on biosimilars uptake in the future.
59
8. APPENDIX
8.1. BIOSIMILAR GUIDELINES MAPPING
60
REGION Regulatory body Biosimilar terminology Official guideline Issue date Product-Specific Guidelines Issue date Link
(General)
Global WHO Similar Biotherapeutic Yes (ENGLISH) 2009 Yes (1) 2016 https://www.who.int/biologicals/
biotherapeutics/similar_biothera
Products (SBP) peutic_products/en/
World Health well-established and Monoclonal antibodies as
Organisation well-characterized Similar Biotherapeutic
biotherapeutic products
products such as
recombinant DNA-
derived therapeutic
proteins.
USA FDA Follow on Biologics FOB Yes 2015 Yes May 2019 https://www.fda.gov/vaccines-
blood-biologics/general-
biologics-guidances/biosimilars-
Food and Drug 4 guidance Interchangeability guidances
Administration guidelines
EUROPE EMA Biosimilars Yes (English) 2005 Yes (8) https://www.ema.europa.eu/en/
human-regulatory/research-
development/scientific-
Similar biological Feb 2006 guidelines/multidisciplinary/mult
idisciplinary-
medicinal products biosimilar#Overarching%20biosi
containing milar%20guidelines
biotechnology-
derived proteins as
active substance
Similar medicinal products https://www.ema.europa.eu/en/

biosimilar-medicinal-products-
containing recombinant containing-recombinant-
granulocyte-colony granulocyte-colony-stimulating-
factor-annex
stimulating factor (Annex)
61
REGION Regulatory body Biosimilar terminology Official guideline Issue date Product-Specific Guidelines Issue date Link
(General)
Similar biological medicinal Sep 2013 https://www.ema.europa.eu/en/
similar-biological-medicinal-
products containing products-containing-interferon-
interferon beta beta
Similar biological medicinal June 2017 https://www.ema.europa.eu/en/

non-clinical-clinical-
products containing low- development-similar-biological-
molecular-weight heparins medicinal-products-containing-
low-molecular
products containing development-similar-biological-
recombinant human insulin medicinal-products-containing-
recombinant-human
and insulin analogues
Similar biological medicinal Dec 2012 https://www.ema.europa.eu/en/
products containing products-containing-monoclonal-
monoclonal antibodies antibodies-non-clinical-clinical-
issues
Similar biological medicinal Jan 2019 https://www.ema.europa.eu/en/
products containing products-containing-
recombinant recombinant-erythropoietins
erythropoietin
products containing products-containing-
recombinant follicle- recombinant-follicle-stimulating-
hormone
stimulating hormone
Similar medicinal products Jan 2019 https://www.ema.europa.eu/en/
similar-medicinal-products-
containing somatropin containing-somatropin-annex-
guideline-similar-biological-
medicinal
62
REGION Regulatory body Biosimilar Official guideline Issue date Product-Specific Guidelines Issue date Link
terminology
(General)
similar biological medicinal Under https://www.ema.europa.eu/en/

products containing revision development-similar-biological-
recombinant interferon medicinal-products-containing-
recombinant
alpha or pegylated (First
recombinant interferon version
alpha 08/2009)
TUNISIA DPM Biosimilars/ Similar Yes (French) July 2018 No http://www.dpm.tn/images/pdf/

guide_biosimilaires.pdf
Biological product
Direction de la pharmacie (SBP)
et des médicaments
EGYPT EDA Biosimilars Yes (English) Sep 2014 NO
Egyptian Drug Follows EU guidelines

Administration
JORDAN JFDA Biosimilars, similar Yes (Arabic &English) NO http://www.jfda.jo/EchoBusV3.0

/SystemAssets/PDF/AR/LawsAnd
biological medicinal Regulation/Drug/RegisterSection
Jordan Food and Drug product /10_303.pdf
Administration
TURKEY Turkish Medicines and Similar Yes, Turkish August NO https://www.titck.gov.tr/mevzua
t/biyobenzer-tibbi-urunler-
Medical Devices Agency Biotherapeutic (published Draft) 2008 hakkinda-kilavuzu-taslagi-
(TMMDA) Product (Rahalkar et al., 2018) 27122018173016
MOROC DPM(Direction de la Biosimilars On going NO
CO pharmacie et des
médicaments)
63
REGION Regulatory body Biosimilar Official guideline Issue date Product-Specific Guidelines Issue date Link
terminology
ALGERIA Agence Nationale des Biosimilars On going NO
Produits Pharmaceutiques
LEBANO Minister of Public Health Similar Biological Yes Oct 2009 No https://www.moph.gov.lb/en/Dy
namicPages/index/3/6917/guida
N Medicinal products nce-and-list-of-requirements-for-
(WHO guideline registration-of-biosimilars-
products
adoption)
SAUDIA SFDA Biosimilars Partially Aug 2017 No https://www.sfda.gov.sa/ar/drug
/resources/DocLib2/Guideline-
ARABIA
on-biosimilar-products.pdf
* Saudi Food and Drug (Quality)
Authority
QATAR* Ministry of Public Health: No
Pharmacy and Drug Control
Department
UAE* Supreme Committee for Similar biological Ongoing The first 2016 http://www.ghc.sa/en-
Drug Registration medicinal products version, us/Pages/modawanat.a
= Follow-on-protein Centralised not Yes, spx
Procedure guidelines implemen
Biosimilars ted yet Not implemented yet
(2016)
India Department of Similar biologics Yes Dec 2012 No https://cdsco.gov.in/opencms/ex

port/sites/CDSCO_WEB/Pdf-
Biotechnology documents/biologicals/CDSCO-
Revised DBT2016.pdf
& Central Drugs Standard 2016
Control Organization
CDSCO
*GCC countries aim to produce a harmonised Biosimilar guideline which is under-development although Saudi Arabia has already its guideline that contains only the
quality requirements. Clinical and non-Clinical studies are not mentioned.
64
8.2. BIOSIMILARS REQUIREMENTS FRAMEWORK

Part 1=(WHO, UK LEBANON, INDIA, TUNISIA, EGYPT, JORDAN, GCC)
Criteria United Kingdom (EMA) WHO Lebanon India

Reference Medicinal -EEA authorized product -Also, called Reference biotherapeutic -The used RMP should be registered -RMP should be an innovator
Product products RBP, following a full dossier. and approved in India
-A single reference medicinal following a complete dossier
(RMP) product throughout the - The dose and administration route of
comparability programme for the biosimilar throughout the - If the RMP is not registered
quality, safety and efficacy studies validation is defined by the RMP and marketed in India, it
should be approved in an ICH
-The possibility of referring to a -The similarity exercise is a head-to- country
Non-EEA authorized product in vivo head comparison between the
non-clinical and clinical studies candidate biosimilar and the RMP -The same RMB is used in the
comparability exercise
-RMP should be authorised by a - The same RMP should be used during (quality, Non-clinical and
regulatory authority with similar the exercise clinical)
scientific and regulatory standards
as EMA (e.g. ICH countries). - The RMP should be licensed & - An approved biosimilar
marketed for a suitable duration cannot be RMP
(without precision) with enough data
RMP can be imported if not
- A single RMP must be used in the marketed in India
similarity exercise (quality, efficacy,
safety) The use of imported RMP does
not imply the approval of that
- A biosimilar can’t be considered as RMP in India
RMP
65
- The RMP should have enough data in
the countries with a well-established

biologics regulation to be used in other
countries where the same RMP is not
yet registered or marketed
The use of RMP doesn’t imply its

approval if it is not registered yet in that
country
Quality -Analytic issues Manufacturing process Comparability process (Quality, -Analytic testing follows ICH
efficacy, safety) is totally based on Guidelines (Q2, Q5C, Q6B)
-Physicochemical issues Characterization WHO guidelines
-Characterization of the final
-Biological activity - Physicochemical issues product follows the
- Potency pharmacopoeia and ICH Q6B
-Immunochemical issues - Immunochemical issues
- Purification issues -Structural and
-Impurity issue physicochemical testing
Specification issues (biologic activities,
-Specification according to ICH Q6B immunological, contaminant
Analytical techniques issues testing)
Stability issues -Specifications according to

ICH Q6B
-Stability according to ICH,

WHO
66
Non-clinical In vitro studies In vitro studies Comparability process (Quality, - The clinical data should be
efficacy, safety) is totally based on addressed to the “Review
(preclinical) data Binding, Signal transduction and Receptor binding, cell-based assays WHO guidelines Committee on Genetic
functional activity/viability studies Manipulation” (RCGM)
In vivo studies In vivo studies -Preclinical studies
PK and/or PD and/or safety -Biology activity, PD studies if they are PK Studies

necessary
in vitro: binding
-Toxicity studies at least one single dose proprieties
toxicity study + Repeated dose toxicity
dose in vivo: PD, biological
activity
Toxicology testing (single

dose & repeated dose
studies)
-Immunology trials
Clinical data Pharmacokinetic studies (PK) -According to ICH Q5E Comparability process (Quality, -PK studies
efficacy, safety) is totally based on
Pharmacodynamic studies (PD) - PK studies (single dose PK studies) WHO guidelines -PD studies
Efficacy trials -PD studies -Safety studies
Clinical safety -Efficacy studies (study design depends

on the biological product)
67
-Safety: define the pre-licensing short

term side effects
-Immunogenicity: even though the

similarity between RMB and the
candidate biosimilar was proven only
by confirmatory
pharmacokinetic/pharmacodynamic
studies, Immunogenicity studies are
compulsory
Post-marketing The risk management plan is -Safety specification and Not specified -Submission of periodic PSURs
safety required pharmacovigilance plan should be for the PV plans
provided with the Marketing
Pharmacovigilance system in Authorisation application - Submission of Adverse
accordance with current EU Reaction Drug reports
legislation and pharmacovigilance - The pharmacovigilance plan can
guidelines is required follow ICH E2E -Phase IV studies (Post-
marketing studies)
-in five years after the marketing - Once marketed, it is the responsibility
authorisation approval, biosimilar of the National Regulation Agency to
(like any new product) should show survey the periodic post-marketing
the black triangle (more monitoring reports from the manufacturer
of PV), and any side effect must be
addressed via the yellow card
scheme
Extrapolations Yes, when Biosimilar is comparable Yes, under certain conditions. If not, Possible under certain conditions Yes, it is based on quality, Non-
to its the manufacturer should present more mentioned in the Lebanese guideline Clinical and clinical
68
clinical data to support the comparability and literature

extrapolation request data
Interchangeability Case by case. According to a Not specified Case by Case, referring to clinical Not specified (Rahalkar et al.,
decision of the Clinician and the evidence and physician responsibility 2018)
patient
Automatic Not allowed Not specified Not allowed Not specified (Rahalkar et al.,
substitution 2018)
(Pharmacy level
substitution)
Labelling Name brand and batch number The biosimilars should be clearly The biosimilar should be clearly Not specified
should be clearly cited (NICE, 2019) identified by its brand name. The name identified by a unique brand name and
of INN INN referring to WHO policy
(http://www.who.int/medicines/servic
es/inn/innquidance/en/index.html),Ba The name of biosimilar and its RMP
tch number must be mentioned for should be mentioned in the label with
traceability an explanation note of what is a
biosimilar product
69
Biosimilars requirements framework (Part2= Tunisia, GCC, Egypt, Jordan)
Criteria Tunisia GCC Egypt Jordan

Reference -RMP should be registered in -Innovator, approved in EMEA, -A single reference medicinal product -The same RMP with
Medicinal Tunisia preferably registered in KSA throughout the comparability identified Brand name,
Product programme for quality, safety and dosage, pharmaceutical
-A single reference medicinal -The same RMP is used during
efficacy studies form, the formulation is
(RMP) product throughout the the manufacturing and
used in the comparability
comparability programme for biosimilars development -An approved biosimilar cannot be
test (Quality, Efficacy and
quality, safety and efficacy studies reference product
Safety studies)
-The test of comparability is
- If RMP is not registered in exercised on the active -RMP should be either marketed in
-Public domain information
Tunisia, RMP should be registered substance and final product Egypt or in a reference country for at
cannot be used as
and commercialised in the least 2 years at the time of
reference (pharmacopoeia
-The name of the brand,
European Union, UK, Switzerland, submission and 4 years at time of
monograph)
USA, Canada, Australia and Japan acquiring registration license
strength, form and formulation
-RMP should be approved
of RMP should be identified
-If the RMP is not registered or - The Biosimilar candidate should
in reference countries in
before the comparability
available in Tunisia, a signed have the same dosage,
European Union, USA,
exercise
importation Authorisation
Canada and /or Jordan
request should be presented to
Tunisian Central Pharmacy
70

same form, same administration A single RMP is used along
route as the RMP with comparability tests
(Quality, Non-Clinical and
clinical studies
Quality Biosimilar candidate should have -Specifications -The manufacturing process

the same pharmaceutical form, Characterization of the structure and should follow ICH
Defined according to GCC
same dosage, same conformation guidelines
administration mode as RMB -Specifications (Physicochemical
and ICH Q6B.
-JFDA should approve
properties, Potency, Purification,
manufacturer of biosimilars
-Analytic characterisation -Stability (ICH guidelines)
-Characterisation
-Suitability and validation
considerations
-Physicochemical comparison -Physicochemical
properties: ICHQ6B
-Immunochemical proprieties - Potency:
-Immunochemical
- assessment of Biological
proprieties
activity referring to the
-Purification
International Pharmacopoeia
requirements
71
-Heterogeneity studies -Specifications

consideration
-Purity, Impurity, contaminant
-Stability (ICHQ5C and
Q1A(R2) guidelines)
Non-clinical -Biological activity (in vitro and In Vitro studies In Vitro studies
trails In vivo studies)
Follows WHO recommendations Pharmacodynamic Studies Binding studies
-PK and metabolism testing
1)In vitro studies In vivo studies In Vivo studies
-Efficacity and safety testing
2)In vivo studies (if needed) Pharmacodynamic/Toxicological/ Animal PK studies
-Immunogenicity testing Immunogenicity Studies
Repeat dose toxicity
-Preclinical testing: (ICH topic studies, safety studies
S6 guidelines)
Toxicity studies
-Local tolerance testing
-Single-dose toxicity testing
72

-Repeated dose toxicity testing
-Reproductive performance
-Genotoxicity testing
-Carcinogenicity studies
Clinical Trials Follows WHO recommendations -Clinical comparability (PK follow ICH guidelines PK studies
studies, PD studies)
adhere to the national Head to head comparative studies PD studies
requirements of clinical -Clinical efficacity studies with RMP
Comparative clinical trial vs
experiments
Study design based on ICH E10 PK studies RMB is required (a Head to
http://www.dpm.tn/index.php/es
head, randomised,
sai-clinique/reglementation
-Clinical safety studies ICHE10 PD studies
preferably double-blind,
parallel groups trial), should
-Immunogenicity Efficacy studies
follow ICHE10
demonstration
Safety studies
-Clinical safety and
The final formulation should be immunogenicity trial
evaluated clinically according ICHE1
73

Post- Risks management plan required - Risk management program -Product pharmacovigilance -Risk management plan
marketing or PV Plan accordance with
Pharmacovigilance reporting Plan according to the Egyptian -Pharmacovigilance plan
safety current GCC procedures and
according to «Guideline on good Pharmacovigilance centre (EPVC)
guidelines and ICH Q9 is
-Periodic Update Safety
pharmacovigilance practices for guidelines is required
required
Reports (PUSR)
Arab countries»
-Post Marketing risk management
http://www.jfda.jo/EchoBusV3.0/ https://www.dha.gov.ae/Docu
plan is required
SystemAssets/PDF/AR/PharmVigil ments/HRD/UAE%20MOH%20
ance/TheGoodPharmacovigilance GVP%20Guidlines%202017.pd
Practicev2.pdf f
Extrapolations Yes, Follows WHO guidelines Yes, clinical studies are Yes, with certain conditions Allowed under specific
required case by case conditions
Interchangeab Case by case depends on the Case by case, a decision of the Not specified Case by Case depends on a
ility National consensus, biosimilars physician and the patient qualified health
profile, pathology and patient professional opinion
Automatic Not allowed Not allowed Not allowed Not allowed
substitution
Labelling NOT SPECIFIED Brand name +INN+ Company Not specified Specified for
name + inside leaflet including pharmacovigilance
the name of RMP & SPC traceability
74
8.3. METHODOLOGY OF ACCESS EVALUATION TO BIOSIMILARS IN MENA REGION

Variable Affordable Payer advocacy Patient Biosimilars
acceptance 5 * availability 6 **
World Bank Access to Healthcare assessment Regulation

classification healthcare (HAQ technology (HTA) 3 Interchangeability 4
1 INDEX)(Fullman et
al., 2018) 2
Algeria UMIC 58 No Not interchangeable 30,88 12 (3+9)
Morocco LMIC 57,6 Ongoing Not specified 48,62 65 (EZZARAD, 2018)
collecting national health
insurance data.(WHO, 2015b)
Tunisia LMIC 69,4 Yes Case by case 39,90 30 (17+13)
http://www.inahta.org/members/i
nasante/
Egypt LMIC 58 ON GOING Not specified 61,99 39
(PHARMAECONOMIC UNIT)
http://www.eda.mohp.gov.eg/Arti
cles.aspx?id=165
UAE HIC 70,3 No Case by case 18,57 40
Qatar HIC 81,7 No Not specified 8,55 0
Saudi HIC 77,1 No Not specified 14,34 16
Arabia
Lebanon UMIC 85,6 On going Case by case 32,14 30
https://www.moph.gov.lb/en/Dyn
amicPages/index/3/6917/guidance
-and-list-of-requirements-for-
registration-of-biosimilars-
products#/en/Pages/3/2275/medic
al-technology
Jordan UMIC 70,2 PARTIALLY Case by case 27,98 17
75
Variable Affordable Payer advocacy Patient Biosimilars

acceptance 5 * availability 6 **
World Bank Access to Healthcare assessment Regulation
classification healthcare (HAQ technology (HTA) 3 Interchangeability 4
1 INDEX)(Fullman et
al., 2018) 2
HTA at the King Hussein Cancer

Centre (KHCC)
(Rabayah et al., 2018)
Turkey UMIC 74,4 YES Case by case 16,47 38 (13+25)

http://tusside.tubitak.gov.tr/sit (Frost & Sullivan,
es/images/ko_-htapolicy.pdf 2016)
India LMIC 41,2 YES Case by case 64,58 68 (GaBi, 2017)
https://dhr.gov.in/health-
technology-assessment-
department-health-research-
dhr
United HIC 78 YES Case by case 15,2 53 (NHS, 2019)
Kingdom https://www.nihr.ac.uk/explore
-nihr/funding-
programmes/health-
technology-assessment.htm
1-financial and physical ability to produce and market biosimilars; 2- presence of a clear pathway and regulations; 3- Engagement of payers in favour of
Biosimilars; 4- Willingness of prescribing or switching from reference drug to biosimilars; 5-Patient awareness about Biosimilars; 6- Number of biosimilars
in the market (Deloitte, 2018)
*Is proportionally opposite to Out-of-pocket expenditure (% of current health expenditure)(world bank, 2016)
**Considering biosimilars with different dosage of brands. The number of biosimilars takes into consideration only Insulin, Filgrastim, Epoetin,
Somatropin, Rituximab, Enoxaparin, Etanercept, Infliximab, Bevacizumab, Trastuzumab, Interferon alfa, Interferon B, Adalimumab. Biosimilars of Toxins,
allergens are not explored because of lack of exhaustive database in all the official drug websites
The HAQ Index and individual causes are reported on a scale of 0–100, with 0 representing the worst levels observed from 1990 to 2016, and 100
reflecting the best during that time. HAQ Index=Healthcare Access and Quality Index(Fullman et al., 2018).
76
8.4. BIOSIMILAR ACCESS WORLDWIDE (DELOITTE MAPPING)
Variables Affordable Regulatory Payer Prescriber Patient Biosimilars

access 1 Environment 2 advocacy 3 adoption 4 acceptance 5 availability 6
DEVELOPED
USA Large access In Development Low Low Low 0 -5

EU Large access Established High Medium Medium >10
JAPAN Large access Established Medium Low Low >10
DEVELOPING
BRICS BRAZIL Poor access Established High Medium Medium 0-5
RUSSIA Fragmented In development Low Low Medium 0-5
INDIA Poor access Established Low Medium Medium >10
CHINA Poor access In development Medium Medium Low 0-5
SOUTH AFRICA Poor access Established High High Medium 0-5
MIST MEXICO Fragmented Established High Low Medium 0-5
INDONESIA Poor access No Medium Medium Low 0-5
SOUTH KOREA Fragmented Established High High Medium >10
TURKEY Poor access Established Low Medium Medium 6-10
77
9. REFERENCES
Academy of Managed Care Pharmacy, 2017. What Is a Biobetter? Biosimilars Resource Center. URL
https://www.biosimilarsresourcecenter.org/faq/what-is-a-biobetter/ (accessed 9.4.19).
Alhomaidan, A.M., 2016. Pricing of biosimilars in Saudi Arabia - GaBI Journal 5, 27–9.
https://doi.org/10.5639/gabij.2016.0501.007
Alsaddique, A., 2017. Future of the pharmaceutical industry in the GCC countries. Integr Mol Med 4.
https://doi.org/10.15761/IMM.1000296
Anour, R., 2014. Biosimilars versus ‘biobetters’—a regulator’s perspective. GaBI J 3, 166–167.
Arlys consulting, 2017. Market_Access_Biosimilars_Arlys_Whitepaper_March2017.pdf.
Asharpe, R., 2012. Biosimilars 2012 – what does the current landscape look like? [WWW Document].
Pharmaphorum. URL https://pharmaphorum.com/views-and-analysis/biosimilars_2012_-
_what_does_the_current_landscape_look_like/ (accessed 8.19.19).
Ayadi, I., 2009. these ines ayadi.pdf (Doctorate Thesis). University of Dauphine Paris, Sfax.
Azevêdo, R., 2013. International Trade Statistics 2013. World Trade Organization 208.
Blackstone, E.A., Joseph, P.F., 2013. The Economics of Biosimilars. Am Health Drug Benefits 6, 469–
478.
Boat, T.F., 2010. Development of New Therapeutic Drugs and Biologics for Rare Diseases. National
Academies Press (US).
Brennan, Z., 2018. Unpacking an NEJM Perspective on the Lackluster Biosimilar Uptake in the US.
Regulatory Focus.
Bunn, H.F., 2013. Erythropoietin. Cold Spring Harb Perspect Med 3.
https://doi.org/10.1101/cshperspect.a011619
Chen, J., 2019. Middle East and North Africa (MENA) [WWW Document]. Investopedia. URL
https://www.investopedia.com/terms/m/middle-east-and-north-africa-mena.asp (accessed
9.5.19).
Cheraghlou, A.M., 2012. The case for solar power in the Middle East and North Africa. World Bank
Blogs. URL http://blogs.worldbank.org/arabvoices/case-solar-power-middle-east-and-north-
africa (accessed 9.12.19).
Cho, N.H., Shaw, J.E., Karuranga, S., Huang, Y., da Rocha Fernandes, J.D., Ohlrogge, A.W., Malanda,
B., 2018. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and
projections for 2045. Diabetes Research and Clinical Practice 138, 271–281.
https://doi.org/10.1016/j.diabres.2018.02.023
Clarivate, A., 2019. Rivaling some BRIC countries, Middle East-North Africa region is a growing market
[WWW Document]. BioWorld. URL http://www.bioworld.com/content/rivaling-some-bric-
countries-middle-east-north-africa-region-growing-market (accessed 9.6.19).
Clarivate, A., 2018. Algeria, Morocco and Tunisia changing their regulatory landscape? Cortellis. URL
https://clarivate.com/cortellis/blog/algeria-morocco-tunisia-changing-regulatory-landscape/
(accessed 9.13.19).
ClinicalTrials.gov, 2019a. Comparison of Thromboembolic Events in Patients Undergoing
Thromboprophylactic Treatment With ENOXA® vs Lovenox® - No Study Results Posted -
ClinicalTrials.gov [WWW Document]. URL
https://clinicaltrials.gov/ct2/show/results/NCT02444572 (accessed 8.22.19).
ClinicalTrials.gov, 2019b. Pharmacokinetic (PK) Bioequivalence and Pharmacodynamics (PD) of
Julphar Insulin 30/70 and Huminsulin® Profil III - Full Text View - ClinicalTrials.gov [WWW
Document]. URL https://clinicaltrials.gov/ct2/show/NCT02631928 (accessed 8.21.19).
Cohen, H.P., Blauvelt, A., Rifkin, R.M., Danese, S., Gokhale, S.B., Woollett, G., 2018. Switching
Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes.
Drugs 78, 463–478. https://doi.org/10.1007/s40265-018-0881-y
78
Covic, A., Abraham, I., 2015. State-of-the-art biosimilar erythropoietins in the management of renal
anemia: lessons learned from Europe and implications for US nephrologists. Int Urol Nephrol
47, 1529–1539. https://doi.org/10.1007/s11255-015-1042-9
Dahal, D., 2014. to biosimilar development & commercialization 12.
Declerck, J.P., 2012. Biologicals and biosimilars: science and implications - GaBI Journal [WWW
Document]. URL http://gabi-journal.net/biologicals-and-biosimilars-a-review-of-the-science-
and-its-implications.html (accessed 9.3.19).
Declerck, P., Danesi, R., Petersel, D., Jacobs, I., 2017. The Language of Biosimilars: Clarification,
Definitions, and Regulatory Aspects. Drugs 77, 671–677. https://doi.org/10.1007/s40265-
017-0717-1
Deloitte, healthcare consulting, 2018. Winning with biosimilars: Opportunities in global markets |
Deloitte | Life Sciences & Health Care.
Derbyshire, M., 2014. Comparison of biosimilars guidelines - GaBI Journal. GaBi.
Diabetes UK, 2017. First use of insulin in treatment of diabetes on this day in 1922 [WWW
Document]. Diabetes UK. URL
https://www.diabetes.org.uk/about_us/news_landing_page/first-use-of-insulin-in-
treatment-of-diabetes-88-years-ago-today (accessed 8.26.19).
DPM, 2019. MMS par classe thérapeutique [WWW Document]. URL
http://www.dpm.tn/index.php/medicaments-a-usage-humain/mms-par-classe-
therapeutique (accessed 8.11.19).
DPM, 2018. Autres Guides [WWW Document]. Biosimilars registration guideline in Tunisia. URL
http://www.dpm.tn/index.php/medicament/humain/guide-de-bioequivalence2 (accessed
7.31.19).
Ebied, W.M., Ahmed, H.A., Elbarbry, F.A., 2014. Production and analysis of a biosimilar erythropoietin
in Egypt [WWW Document]. Biosimilars. https://doi.org/10.2147/BS.S60038
EDA, 2019a. .:: EDA - Egyptian Drug Authority ::. [WWW Document]. URL
http://www.eda.mohp.gov.eg/Articles.aspx?id=165 (accessed 8.22.19).
EDA, 2019b. .:: EDA - Egyptian Drug Authority ::. [WWW Document]. Pharmacoecnomic unit. URL
EDA, 2015. .:: EDA - Egyptian Drug Authority ::. [WWW Document]. Services. URL
EMA, 2018. Biosimilar medicines: Overview [WWW Document]. European Medicines Agency. URL
https://www.ema.europa.eu/en/human-regulatory/overview/biosimilar-medicines-overview
(accessed 9.8.19).
EMA, 2017. Biosimilars in the EU, Information guide for healthcare professionals.
EY, 2014. Commercial excellence in pharma 3.0 12.
EZZARAD, S., 2018. MÉDICAMENTS BIOLOGIQUES : SPÉCIFICITÉS ET APPLICATIONS EN ONCOLOGIE.
UNIVERSITE MOHAMMED V DE RABAT FACULTE DE MEDECINE ET DE PHARMACIE, Maroc.
Farag, M.A.A., 2013. A Thesis Submitted to the Public Policy and Administration Department in
partial fulfillment of the requirements for the degree of Master of Public Policy. The
American University in Cairo School of Global Affairs and Public Policy, EGYPT.
Farhat, F., Othman, A., el Karak, F., Kattan, J., 2016. Review and results of a survey about biosimilars
prescription and challenges in the Middle East and North Africa region. SpringerPlus 5, 2113.
https://doi.org/10.1186/s40064-016-3779-8
FDA, 2019. Biosimilars Guidances. FDA.
Fitch Solutions, 2018. Long-Term Growth Potential For Biosimilar Manufacturers In MENA [WWW
Document]. URL http://www.fitchsolutions.com/corporates/healthcare-pharma/long-term-
growth-potential-biosimilar-manufacturers-mena-19-12-2018 (accessed 8.17.19).
Frost & Sullivan, 2016. An Outlook on Biotech Pharmaceuticals Market in Turkey. Frost & Sullivan.
URL https://ww2.frost.com/frost-perspectives/outlook-biotech-pharmaceuticals-market-
turkey/ (accessed 8.5.19).
79
Fu, L., Suflita, M., Linhardt, R.J., 2016. Bioengineered heparins and heparan sulfates. Advanced Drug
Delivery Reviews, Extracellular Matrix (ECM) and ECM-like materials: Therapeutic Tools and
Targets in Cancer Treatment 97, 237–249. https://doi.org/10.1016/j.addr.2015.11.002
Fullman, N., Yearwood, J., Abay, S.M., Abbafati, C., Wyper, G.M.A., Yano, Y., Yimer, N.B., Yin, P., Yip,
P., Yonemoto, N., Zaidi, Z., Zaki, M.E.S., Zenebe, Z.M., Zhou, M., Zuhlke, L.J., Murray, C.J.L.,
2018. Measuring performance on the Healthcare Access and Quality Index for 195 countries
and territories and selected subnational locations: a systematic analysis from the Global
Burden of Disease Study 2016. The Lancet 391, 2236–2271. https://doi.org/10.1016/S0140-
6736(18)30994-2
GaBi, 2019. biosimilars - GaBI Journal [WWW Document]. Generic and Biosimilars Iniative Journal.
URL http://gabi-journal.net/?s=biosimilars (accessed 9.13.19).
GaBi, 2018. Biosimilar deals for Hikma and Lupin / Pharma News / Home - GaBI Online - Generics and
Biosimilars Initiative [WWW Document]. URL http://gabionline.net/Pharma-News/Biosimilar-
deals-for-Hikma-and-Lupin (accessed 8.22.19).
GaBi, 2017. ‘Similar biologics’ approved and marketed in India / General / Biosimilars / Home - GaBI
Online - Generics and Biosimilars Initiative.
GaBi, 2015. Development of biosimilars for rheumatoid arthritis - GaBI Journal. GaBi, generics and
biosimilars initiative.
GaBi, 2013. Egypt issues draft guidelines for biosimilars / Guidelines / Home - GaBI Online - Generics
and Biosimilars Initiative.
Gautam, A., 2017. Market watch: Strategies for biosimilars in emerging markets. Nature Reviews
Drug Discovery 16, 520–521. https://doi.org/10.1038/nrd.2017.113
Giuliani, R., Tabernero, J., Cardoso, F., McGregor, K.H., Vyas, M., de Vries, E.G.E., 2019. Knowledge
and use of biosimilars in oncology: a survey by the European Society for Medical Oncology.
ESMO Open 4, e000460. https://doi.org/10.1136/esmoopen-2018-000460
GlobeNewswire, 2018. Biosimilars Market To See 305% Annual Growth Through 2022. Biosimilar
Development. URL https://www.biosimilardevelopment.com/doc/biosimilars-market-to-see-
annual-growth-through-0001 (accessed 9.5.19).
Goldsmith, D., Dellanna, F., Schiestl, M., Krendyukov, A., Combe, C., 2018. Epoetin Biosimilars in the
Treatment of Renal Anemia: What Have We Learned from a Decade of European Experience?
Clin Drug Investig 38, 481–490. https://doi.org/10.1007/s40261-018-0637-1
Grabowski, H., Guha, R., Salgado, M., 2014. Biosimilar competition: lessons from Europe. Nature
Reviews Drug Discovery 13, 99–100. https://doi.org/10.1038/nrd4210
Grand Review Research, 2017. Erythropoietin (EPO) Drug Market Size | Industry Report, 2018-2025
(market research), pharmaceuticals.
Guan, Y., Xu, X., Liu, X., Sheng, A., Jin, L., Linhardt, R.J., Chi, L., 2016. Comparison of Low-Molecular-
Weight Heparins Prepared From Bovine Lung Heparin and Porcine Intestine Heparin. J Pharm
Sci 105, 1843–1850. https://doi.org/10.1016/j.xphs.2016.03.037
Gulf Health Council, 2016. GCCGuidelinesonbiosimilars_v11.pdf.
Gutka, H.J., Yang, H., Kakar, S. (Eds.), 2018. Biosimilars: regulatory, clinical, and biopharmaceutical
development, AAPS Advances in the Pharmaceutical Sciences Series. Springer, Cham.
Hadoussa, S., Bouhlel, M., Soussi, M.A., Drira, C., Hadoussa, M., Khrouf, M.R., 2019. Perception of
hematologists and oncologists about the biosimilars: A prospective Tunisian study based on a
survey. J Oncol Pharm Pract 1078155219848817.
https://doi.org/10.1177/1078155219848817
HAI, 2019. Working Paper 3: The Regulation of Mark-ups in the Pharmaceutical Supply Chain [WWW
Document]. Health Action International. URL https://haiweb.org/publication/working-paper-
3-the-regulation-of-mark-ups-in-the-pharmaceutical-supply-chain/ (accessed 8.27.19).
Halabi, H., Al Zahrani, Z., Al Swailem, R., Husain, W., Al Rayes, H., Al Osaimi, H., El Dershaby, Y.,
Ahmed, H.M., Mounir, M., Omair, M.A., 2018. Biosimilars in Rheumatic Diseases: Regulatory
Guidelines, Efficacy and Safety Implications in Saudi Arabia. The Open Rheumatology Journal
12. https://doi.org/10.2174/1874312901812010313
80
Haqaish, W.S.A., Obeidat, H., Patel, P., Walker, S., 2017. The Jordan Food and Drug Administration:
Comparison of its Registration Process with Australia, Canada, Saudi Arabia and Singapore.
Pharmaceut Med 31, 21–30. https://doi.org/10.1007/s40290-016-0172-4
Hernandez, R., 2013. Implications of Biosimilar Use: A Market Perspective. Specialty Pharmacy Times.
Hogerzeil, H., Frost-Helt, S., Griego, F., Hill, S., Massey, A., 2018. EXPERT REVIEW COMMITTEE 80.
Huml, R.A., 2018. Trends in Biosimilars: Innovative Approaches to Expediting Development [WWW
Document]. URL https://www.raps.org/news-and-articles/news-articles/2018/6/trends-in-
biosimilars-innovative-approaches-to-ex (accessed 9.3.19).
IAPO, 2013. Briefing Paper on Biological and Biosimilar Medicines.
Imberti, D., Marietta, M., Polo Friz, H., Cimminiello, C., 2017. The introduction of biosimilars of low
molecular weight heparins in Europe: a critical review and reappraisal endorsed by the Italian
Society for Haemostasis and Thrombosis (SISET) and the Italian Society for Angiology and
Vascular Medicine (SIAPAV). Thrombosis Journal 15, 13. https://doi.org/10.1186/s12959-
017-0136-2
IMS, 2016. delivering-on-the-potential-of-biosimilar-medicines.pdf.
INEAS, 2019. INAHTA [WWW Document]. URL www.inahta.org (accessed 8.22.19).
Ingle, R.G., Agarwal, A.S., 2014. A world of low molecular weight heparins (LMWHs) enoxaparin as a
promising moiety—A review. Carbohydrate Polymers 106, 148–153.
https://doi.org/10.1016/j.carbpol.2014.01.100
IQVIA, 2018a. 2018 and Beyond: Outlook and Turning Points. IQVIA.
IQVIA, 2018b. Advancing Biosimilar Sustainability in Europe. IQVIA.
Jenzsch, M., Bell, C., Buziol, S., Kepert, F., Wegele, H., Hakemeyer, C., 2018. Trends in Process
Analytical Technology: Present State in Bioprocessing. Adv. Biochem. Eng. Biotechnol. 165,
211–252. https://doi.org/10.1007/10_2017_18
JFDA, 2015. Biosimilars (guideline). JFDA, Jordan.
Julphar, 2019. Overview [WWW Document]. URL http://www.julphardiabetes.net/Overview.htm
(accessed 8.21.19).
Julphar, pharma, 2019. API [WWW Document]. URL http://www.julphardiabetes.net/API.htm
(accessed 8.21.19).
Jupalli, A., Iqbal, A.M., 2019. Enoxaparin, in: StatPearls. StatPearls Publishing, Treasure Island (FL).
Kamyar, K.Z., 2017. History of Erythropoiesis-Stimulating Agents, the Development of Biosimilars,
and the Future of Anemia Treatment in Nephrology. Am J Nephrol 45, 235–247.
https://doi.org/10.1159/000455387
Kanavos, P., Tzouma, V., Fontrier, A.-M., Kamphuis, B., Parkin, G.C., Saleh, S., 2018. Pharmaceutical
pricing and reimbursement in the Middle East and North Africa region. business andc
onsultancy 154.
Khlif, J., Tkhayet, S.B., Ghorbel, M.B., Fradi, I., 2015. TUNISIA : TOWARD A DRAFT GUIDELINE ON
BIOSIMILARS IN 2016 ! Presented at the MENA Regulatory Conference on Bioequivalence,
Biowaivers, Bioanalysis and Dissolution, Amman, p. 45.
Kirchhoff, C.F., Wang, X.M., Conlon, H.D., Anderson, S., Ryan, A.M., Bose, A., 2017. Biosimilars: Key
regulatory considerations and similarity assessment tools. Biotechnol Bioeng 114, 2696–
2705. https://doi.org/10.1002/bit.26438
Kobbi, Z., Kraiem, H., Benlasfar, Z., Marouani, A., Massoud, T., Boubaker, S., Bouhaouala-Zahar, B.,
Fenina, N., 2017. Comparative subcutaneous repeated toxicity study of enoxaparin products
in rats. Regulatory Toxicology and Pharmacology 84, 9–17.
https://doi.org/10.1016/j.yrtph.2016.12.003
Kresse, G.-B., 2009. Biosimilars – Science, status, and strategic perspective. European Journal of
Pharmaceutics and Biopharmaceutics 72, 479–486.
https://doi.org/10.1016/j.ejpb.2009.02.014
Krishnan, A., 2010. Middle East North Africa Pharmaceutical Market - In Transition [WWW
Document]. Pharma IQ. URL https://www.pharma-iq.com/market-access/articles/middle-
east-north-africa-pharmaceutical-market-in (accessed 9.7.19).
81
Kuhlmann, M.K., Schmidt, A., 2014. Production and manufacturing of biosimilar insulins: implications
for patients, physicians, and health care systems [WWW Document]. Biosimilars.
https://doi.org/10.2147/BS.S36043
Kurki, P., van Aerts, L., Wolff-Holz, E., Giezen, T., Skibeli, V., Weise, M., 2017. Interchangeability of
Biosimilars: A European Perspective. BioDrugs 31, 83–91. https://doi.org/10.1007/s40259-
017-0210-0
Lever, R., 2012. Heparin: A Century of Progress. Handbook of Experimental Pharmacology |
SpringerLink.
Malhotra, H., 2011. Biosimilars and non-innovator biotherapeutics in India: An overview of the
current situation. Biologicals, Evaluation of Similar Biotherapeutic products: Scientific and
Regulatory Challenges 39, 321–324. https://doi.org/10.1016/j.biologicals.2011.06.018
McKinsey, C., 2019. Biologics and biosimilars in emerging markets | McKinsey [WWW Document].
What’s next for biosimilars in emerging markets? URL
https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-
insights/whats-next-for-biosimilars-in-emerging-markets (accessed 7.29.19).
McKinsey, P.& M. products, 2018. The biosimilars market: Five things you need to know | McKinsey
[WWW Document]. Our Insights. URL
https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-
insights/five-things-to-know-about-biosimilars-right-now (accessed 7.2.19).
Merimi, Z., 2018. Algeria, Morocco and Tunisia changing their regulatory landscape? Clarivate.
Moorkens, E., Vulto, A.G., Huys, I., Dylst, P., Godman, B., Keuerleber, S., Claus, B., Dimitrova, M.,
Petrova, G., Sović-Brkičić, L., Slabý, J., Šebesta, R., Laius, O., Karr, A., Beck, M., Martikainen,
J.E., Selke, G.W., Spillane, S., McCullagh, L., Trifirò, G., Bonanno, P.V., Mack, A., Fogele, A.,
Viksna, A., Władysiuk, M., Mota-Filipe, H., Meshkov, D., Kalaba, M., Bedrač, S.M., Fürst, J.,
Zara, C., Skiöld, P., Magnússon, E., Simoens, S., 2017. Policies for biosimilar uptake in Europe:
An overview. PLOS ONE 12, e0190147. https://doi.org/10.1371/journal.pone.0190147
Mordor Intelligence, 2018. Human Insulin Market | Growth, Trends and Forecast (2019 - 2024),
Industry reports. Mordor Intelligence, North America.
Morrow, T., Felcone, L.H., 2004. Defining the difference: What Makes Biologics Unique. Biotechnol
Healthc 1, 24–29.
Mueller, L.L., 2014. A Report from the “Biosimilars and Biotech: MENA Conference” in Istanbul,
Turkey: Part 1. Presented at the Biosimilars and Biotech: MENA Conference, Newstex LLC,
Turkey.
NHS, 2019. what-is-a-biosimilar-medicine-guide-v2.pdf. United Kingdom.
NHS, 2018. CSUs_TrustsBiosimilarsUptakeSurveyApril2018.pdf (governmental report). NHS, UK.
NICE, 2019. biosimilar-medicines-58757954414533.pdf.
O’Callaghan, J., Barry, S.P., Bermingham, M., Morris, J.M., Griffin, B.T., 2019. Regulation of biosimilar
medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol 75,
1–11. https://doi.org/10.1007/s00228-018-2542-1
Oxford Business, 2016. Tunisian pharmaceutical industry is looking to export more. Oxford Business
Group. URL https://oxfordbusinessgroup.com/analysis/good-shape-local-pharmaceutical-
industry-looking-export-more (accessed 8.27.19).
Oxford Business, 2015. Cap sur la production pharmaceutique en Algérie [WWW Document]. Oxford
Business Group. URL https://oxfordbusinessgroup.com/news/cap-sur-la-production-
pharmaceutique-en-alg%C3%A9rie (accessed 9.13.19).
PCT, 2019. Medicaments Humain [WWW Document]. la pharmacie centrale en Tunisie. URL
http://www.phct.com.tn/index.php/medicaments-humain (accessed 9.16.19).
Rabayah, A.A.A., Froukh, R.F.A., Sawalha, R.D., 2018. A capacity-building programme in health
technology assessment for hospital pharmacists in a low- to middle-income country. Journal
of Pharmaceutical Health Services Research 9, 275–280. https://doi.org/10.1111/jphs.12241
82
Rahalkar, H., Cetintas, H.C., Salek, S., 2018. Quality, Non-clinical and Clinical Considerations for
Biosimilar Monoclonal Antibody Development: EU, WHO, USA, Canada, and BRICS-TM
Regulatory Guidelines. Front Pharmacol 9. https://doi.org/10.3389/fphar.2018.01079
Rathore, A., 2016. Quality by Design (QbD)-Based Process Development for Purification of a
Biotherapeutic. Trends in Biotechnology 34, 358–370.
https://doi.org/10.1016/j.tibtech.2016.01.003
Rathore, A., 2012. Guidelines on Similar Biologics: Regulatory Requirements for Marketing
Authorization in India. PDA Journal of Pharmaceutical Science and Technology 66, 393–393.
https://doi.org/10.5731/pdajpst.2012.00886
Roche, 2018. Improving access to hepatitis treatment in Egypt [WWW Document]. sustainability. URL
https://www.roche.com/sustainability/access-to-healthcare/hepatitis-egypt.htm (accessed
8.20.19).
SA.GOV, 2019. Overview [WWW Document]. NICDP. URL /en/clusters/pharmaceutical-
biotech/overview/ (accessed 8.16.19).
Sassi, M., Beltaief, K., Haouala, H., Kraiem, S., Kammoun, Samir, Maatoug, F., Jeridi, G., Hassine, M.,
Methammem, M., Nciri, I., Kammoun, Sofiane, Zilli, M., Kortas, M., Grissa, M.H., Elalamy, I.,
M, W.B., Nouira, S., 2016. Comparability of “Enoxamed” a Tunisian Generic Enoxaparin with
the Originator Product: Non-clinical and Clinical Studies. Journal of Bioequivalence &
Bioavailability 8, 249–253. https://doi.org/10.4172/jbb.1000304
SFDA, 2017. Guideline-on-biosimilar-products.pdf.
The economist, 2015. Health Care Middle East and North Africa [WWW Document]. The Economist
Events. URL https://events.economist.com/events-conferences/emea/health-care-middle-
east-north-africa/ (accessed 7.26.19).
ThermoFisher, 2019. Overview of Post-Translational Modification - UK [WWW Document]. URL
https://www.thermofisher.com/uk/en/home/life-science/protein-biology/protein-biology-
learning-center/protein-biology-resource-library/pierce-protein-methods/overview-post-
translational-modification.html (accessed 9.4.19).
Thomson, S., Evetovits, T., Cylus, J., Jakab, M., 2016. Research article: Monitoring financial protection
to assess progress towards universal health coverage in Europe 2, 10.
Wanis, H., 2015. Pharmaceutical Pricing in Egypt, in: Babar, Z.-U.-D. (Ed.), Pharmaceutical Prices in
the 21st Century. Springer International Publishing, Cham, pp. 59–78.
https://doi.org/10.1007/978-3-319-12169-7_4
WHO, 2015a. WHO | Health in 2015: from MDGs to SDGs [WWW Document]. WHO. URL
http://www.who.int/gho/publications/mdgs-sdgs/en/ (accessed 7.26.19).
WHO, 2015b. Final_meeting_report_Approach_for_using_HTA..pdf.
WHO, 2013. Evidence summary 4 – Use of external reference pricing. World Health Organization.
WHO, 2011. WHO Guidelines on Transfer of Technology in Pharmaceutical Manufacturing. WHO
Technical Report Series, No. 961, 2011, Annex 7 [WWW Document]. Essential Medicines and
Health Products Information Portal. URL
http://apps.who.int/medicinedocs/en/m/abstract/Js18677en/ (accessed 9.13.19).
WHO, 2003. Maîtrise des coûts des médicaments importés - Etude de cas: Tunisie - Série
réglementation pharmaceutique, No. 10: LA CENTRALISATION DE L’IMPORTATION: Les
aspects opérationnels de l’importation des médicaments (N.10), Série réglementation
pharmaceutique. World Health Organization resource.
World Bank, 2019. Out-of-pocket expenditure (% of current health expenditure) | Data [WWW
Document]. URL https://data.worldbank.org/indicator/SH.XPD.OOPC.CH.ZS (accessed
9.11.19).
World Bank, 2018. Rankings [WWW Document]. World Bank. URL
https://www.doingbusiness.org/en/rankings (accessed 9.6.19).
world bank, 2016. Out-of-pocket expenditure (% of current health expenditure) | Data [WWW
Document]. World Health Organization Global Health Expenditure database. URL
https://data.worldbank.org/indicator/SH.XPD.OOPC.CH.ZS (accessed 8.22.19).
83
World bank, 2013. Middle East and North Africa Health Strategy (2013-2018) (Text/HTML).
World Bank, 2013. Fairness and Accountability : Engaging in Health Systems in the Middle East and
North Africa, Open Knowldge Repository. Wold Bank, Washington, DC.
Yazbeck, A.S., Rabie, T.S., Pande, A., 2017. Health Sector Reform in the Middle East and North Africa:
Prospects and Experiences. Health Systems & Reform 3, 1–6.
https://doi.org/10.1080/23288604.2016.1272984
Zion Market Research, 2018. Global Heparin Market Expected to Reach USD 10,929.51 Million by
2023 [WWW Document]. Global Heparin Market. URL
https://www.zionmarketresearch.com/news/heparin-market (accessed 9.11.19).
Zurich insurance group, 2014. The role of insurance in the Middle East and North Africa [WWW
Document]. Zurich Insurance Group Ltd. URL
https://www.zurich.com/en/knowledge/articles/2014/05/the-role-of-insurance-in-the-
middle-east-and-north-africa (accessed 7.26.19).
84
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Evaluation of biosimilars landscape in the MENA region: what lessons can be

Thesis · September 2019

The user has requested enhancement of the downloaded file.

School of Life Sciences

Dissertation submitted for the degree of MSc in Biotechnology, Bioprocessing and

September 20, 2019

EVALUATION OF BIOSIMILARS LANDSCAPE IN THE MENA REGION: WHAT LESSONS CAN

Student ID number: 1893269

Supervisor: Dr Stuart Allen

Word count: 14810

AEs: Adverse Events ........................................................................................................................... 1

ERP: External Reference Pricing ....................................................................................................... 25

INAHTA: International Network of Agencies for Health Technology Assessment ........................... 22

MOH: Ministry Of Health ................................................................................................................. 21

UHC: Universe Health Coverage....................................................................................................... 31

Figure 1: Number of biosimilars in development by country in 2017 ................................................2

Extrapolation Concerns the extension of an indication to another, or a population

Health Technology Analytic frameworks based on clinical and cost-effectiveness

Interchangeability Two medicines are interchangeable if the administration of one or

CAGR According to Investopedia, the Compound Annual Growth Rate is

Substitution The replacement of a drug product by another similar or

Biotechnology The transfer of tools and “Know-How” from drug discovery to

Spillover effect In economy, it describes how events apparently unrelated can

2.1. DEFINITION OF BIOLOGICAL MEDICINES .......................................................................... 3

3. RESEARCH QUESTION ........................................................................... 15

4.1. CASE STUDIES ............................................................................................................... 16

5.1. CASE STUDIES ............................................................................................................... 18

6.1. DISCUSSION OF CASE STUDIES ...................................................................................... 39

6.3.1. BUSINESS FRAMEWORK ...................................................................................................... 49

7. CONCLUSION & FURTHER CONSIDERATIONS ........................................ 58

8.1. BIOSIMILAR GUIDELINES MAPPING ............................................................................... 60

0 50 100 150 200 250 300

Figure 1: Number of biosimilars in development by country in 2017(IQVIA, 2018a)

2.1. DEFINITION OF BIOLOGICAL MEDICINES

Tissue engineered products

Cellular & Gene Therapy

Products manufactured using recombinant technology (proteins, e.g.

Figure 2: Definition of Biological Medicines (Declerck, 2012)

genes is transcribed via alternative promoters to obtain approximately 100000 different

Chemical Medicine Biological Medicine

Produced by chemical synthesis Produced by living cell cultures

Low molecular weight High molecular weight

Well-defined structure Complex structure

Completely characterised A combination of different technologies is needed

Stable Fragile, specific storage conditions are required

Highly susceptible to the environment variation

Mostly non-immunogenic Immunogenicity is the principal safety issue

Produces by one batch At least three batches

Contamination can be detected Contamination is hard to remove.

Easy to purify Purification is a long process

Systematic therapeutic activity Targeted biological activity

2.2. DEFINITION OF BIOSIMILARS

Biosimilars are biological products, highly similar to an approved originator biological

Like the originator, biosimilars can eventually express a variation enter-batches as

Figure 4: potential variations inter-batches (EMA, 2017)

Biological originator (RMP) Biosimilar medicine

2.3. THE GLOBAL BIOSIMILAR MARKET