The document discusses biosimilars and biopharmaceuticals. It defines biopharmaceuticals as pharmaceuticals produced through biotechnology methods, including recombinant DNA technology and products extracted from biological sources. Biosimilars are similar but not identical copies of biopharmaceuticals whose patents have expired. Unlike generics, biosimilars cannot be proven bioequivalent due to inherent variability in biological manufacturing processes. Biosimilars undergo a rigorous approval process involving comparability exercises to demonstrate similarity in quality, safety and efficacy to the reference product.

1. Biosimilars: assets and
sustainability, between
regulation and information
Final Project Work, March 2016
Master in Pharmaceutical Marketing & Management
Alma laboris S.r.l.
Author: Jacopo Sacquegno

2. Index
1.1 What are biopharmaceuticals?
1.1.1 Some definitions and general features
1.1.2 Notable differences with traditional drugs
1.2 What are biosimilars?
1.2.1 Comparing generics and biosimilars
1.3 How are biosimilars authorized?
1.3.1 Bioequivalence and regulatory needs;
1.3.2 Interchangeability and substitutability for biosimilars;
1. A SCIENTIFIC APPROACH

3. 1.1 What are biopharmaceuticals?
 «Broad Biotech»
Pharmaceuticals that are biological in nature and manufactured by
biotechnology methods. This includes both products manufactured by
recombinant DNA technology (e.g., monoclonal antibodies and
recombinant proteins; involving genetic engineering) and products
naturally present in living organisms and extracted (e.g., proteins
and vaccines derived from non-engineered organisms as well as
blood/plasma-derived products)
1.1.1 some definitions and examples
 «New Biotech»
Only those pharmaceuticals biological in
nature and manufactured using genetic
engineering (hence, it includes only
biological products such as monoclonal
antibodies and recombinant proteins).
• Been around for over 200 years;
• Revenues reaching about 160$bn/yr

4. “
”
“Any virus, therapeutic serum, toxin, antitoxin or analogous product
applicable to the prevention, treatment or cure of diseases or injuries of
man” (FDA)
“A medicinal product manufactured with one or more of the following
biotechnological techniques: recombinant DNA techniques, controlled
gene expression and antibody methods” (EMA)
“A product, the active substance of which is a biological substance. A
biological substance is a substance that is produced by or extracted from
a biological source […]” (AIFA)
Definitions by some regulatory authorities…

5.  RECEPTOR CONSTRUCTS (fusion proteins), usually based on a naturally-
occurring receptor fused to the immunoglobulin frame through DNA
recombinant techniques. In this case, the receptor provides the construct with
detailed specificity, whereas the immunoglobulin-structure imparts stability
and other useful features in terms of pharmacology.
 Biosynthetically produced substances that are (nearly) identical to the body’s own key signalling
proteins, including:
 Hormones, chemicals transfer information and instructions between cells in animals and
plants (INSULIN, GLUCAGON, GROWTH HORMONE, GONADOTROPINS);
 Cytokines, hormone-like molecules that can control reactions between cells (INTERFERON,
INTERLEUKINS, ERYTHROPOIETIN);
 Enzymes, complex proteins that catalyse organic reactions (INSULIN, GLUCAGON, GROWTH
HORMONE, GONADOTROPINS);
 Various blood factor, involved in coagulation (FACTOR VIII, FACTOR IX) and thrombolysis
(TISSUE PLASMINOGEN ACTIVATOR);
 MONOCLONAL ANTIBODIES. These are antibodies produced by using
hybridoma technology (i.e. hybridizing antibody-producing spleen cells with
immortalized cells) or other methods that allow to obtain antibodies made
by identical immune cells all clones of an identical parent cells and bind the
same target, in contrast to polyclonal antibodies which are made from
several different immune cells. When used as biopharmaceuticals, they are
designated with the stem -mab.

6. Technology Mechanism of
action
Indications
1. Adalimumab
(Humira®)
Monoclonal antibody TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
psoriasis, ulcerative colitis, Crohn's disease
2. Etanercept
(Enbrel®)
Recombinant human TNF-
receptor fusion protein
TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis
3. Infliximab
(Remicade®)
Monoclonal antibody TNF antagonist Rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis,
psoriasis, ulcerative colitis, Crohn's disease
4. Insulin glargine
(Lantus®)
Recombinant insulin Insulin analogue Diabetes
5. Rituximab
(Rituxan®, MabThera®)
Monoclonal antibody CD20 binding and B-cell
elimination
Many lymphomas, leukemias, transplant rejection and autoimmune
disorders.
6. Bevacizumab
(Avastin®)
Monoclonal antibody VEGF-A antagonist Colorectal, lung, breast, renal and brain cancer; several eye disease.
7. Trastuzumab
(Herceptin®)
Monoclonal antibody HER2/neu receptor
antagonist
Breast cancer
8. Pegfilgrastim
(Neulasta®)
PEGylated form of the
Granulocyte colony stimulating
factor (GCSF)
Stimulates neutrophils blood
concentration
Fight infections in patients undergoing chemotherapy.
9. Ranibizumab
(Lucentis®)
Monoclonal antibody fragment VEGF-A antagonist Age-related web macular degeneration
10. Erythropoietin alfa
(Epogen®, Procrit®,
Eprex®, ESPO®)
Recombinant human
erythropoetin
EPO analogue Anemia from chronic kidney disease, chemotherapy-induced anemia in
patients with cancer, Crohn's disease and ulcerative colitis and
myelodysplasia from the treatment of cancer
Top-10 biologic active substances for global sales in 2014

7. 1.1.2 Notable differences with traditional drugs
Traditional drugs Biopharmaceuticals
Size Tens or hundreds of Da Hundreds of thousands of Da
Complexity Relatively simple Much more complex
Origins Standardized organic reactions Living Organisms
Stability Stable Not so stable
Production Synthesis is relatively cheap, can be standardised and
is easily replicable.
Synthesis is expensive and hardly reproducible
(“product is the process”); purification is not
standardisable.
Treatment Used to treat “traditional” diseases. Used to treat otherwise untreatable pathologies.
Adverse effects Predictable. Possible immunogenicity.

8. MCBs are under trade secret,
hence no MCB is equal to the
other and this influences the
final product. Cell banks are
constantly examined in order
to avoid contamination from
external agents.
After scaling up in increasingly bigger
volumes, culture is collected, active
principle is extracted and goes through
several steps of purification before being
ready.
The whole process is
much more complex and
expensive than what is
usually required for
traditional drugs. The
complexity of the process
makes the final product
totally dependent from
each step. The same
molecule obtained by
two different companies
can be different at the
end of the manufacturing
process (e.g. in its
tridimensional structure
and post-translational
modifications), leading to
significant alterations in
terms of effectiveness
and safety. Even
different batches of the
same product display a
certain degree of
variability.
After culture, the resulting product-
producing cells are generally aliquoted and
frozen, creating identical and ready to use
“MASTER CELL BANKS” (MCB) that can be
indefinitely preserved.
Each “master cell bank” is
then thawed and used up to
create aliquoted “WORKING
CELL BANKS” (WCB), which
functions as viable source of
cells for a production batch.
This system allows to ensure
an essentially indefinite
supply of the originally
developed production cells
for manufacturing purposes.
«The product is the process»

9. *Adverse effects
 A peculiar feature of biopharmaceuticals is their possible IMMUNOGENICITY, i.e. the
capacity of inducing an immune reaction. Once in the body, these recombinant
proteins can be recognized as “non-self” by the organism, which in response produces
anti-drug-antibodies (ADAs) inactivating the therapeutic effects of the treatment and,
in rare cases, inducing adverse effects. One example of this is the aplastic anemy that
was associated with a particular form of recombinant erythropoietin (Eprex®). The
prediction of the immunogenic potential of novel protein therapeutics is thus a
challenge in biotherapy.
*Molecular size
 Ibuprofen has only 13 carbon
atoms and a molecular weight of
about 206 Da;
 Simvastatin has 25 carbon atoms
for about 418 Da;
 Vancomycin has 66 carbon atoms
for about 1450 Da.
 Human growth hormone is a protein
with 191 amino acids and a
molecular weight of 22 kDa;
 Human erythropoietin is a
glycoprotein with 165 amino acids in
its mature form, weighing 34 kDa;
 Immunoglobulins have molecular
weights in the range of 150kDa;

10.  Biopharmaceuticals are designed to target precisely on a single structure
(protein, receptor, DNA sequence), increasing the effectiveness of the therapy
and reducing side effects at the same time.
 Biopharmaceuticals have had a profound impact on many medical fields,
primarily rheumatology and oncology, but also cardiology, dermatology,
gastroenterology, neurology and others, adding major therapeutic options for
the treatment of many diseases, including some for which no effective
therapies were available, and others where previously existing therapies were
clearly inadequate.
 Autoimmune diseases (e.g. rheumatoid arthritis, ankylosing spondylitis,
psoriatic arthritis).
 Many form of tumors (e.g. breast, renal, liver, lungs, brain, colorectal),
including lymphomas and leukemias.
 Chronic inflammatory diseases (e.g. Chron’s disease, ulcerative cholitis).
*Treatments

11. 1.2 What are biosimilars?
 The increasing development of sequencing technologies, molecular cloning
processes and in vitro biological production has allowed the production of
virtually any recombinant DNA-based biological substance for eventual
development of a drug. Monoclonal antibody technology combined with
recombinant DNA technology has paved the way for tailor-made and targeted
medicines. Gene- and cell-based therapies are emerging as new approaches.
 Since many of the first generation biopharmaceuticals have been developed
in the 80’s, they are getting close to their patent’s expiration date; for some
of them, this date is soon to come or has passed by already. This allows any
biotech company other than the original creator of the expired biological
product to develop and market the same product on its own. After years of
debate, these products have been defined “BIOSIMILAR MEDICINES” by the
EMA. The term clearly distinguish them from what generics (“bioequivalent”)
are with respect to traditional drugs.
1.2.1 Comparing generics and biosimilars

12. Generics Biosimilars
Structure Identical to the reference product. Most probably not identical.
Production Manufacturing process is highly standardized and
generally the same as the originator.
Manufacturing process can be different from the one
of the originator (possible patent).
Analysis Analytical techniques can demonstrate identity with
the originator.
Analytical techniques cannot fully characterize
complex molecules.
Contaminants Detectable and quantifiable. Different depending on the substrate/organism used.
Formulation Rarely influences bio-equivalency. May interfere with therapeutic effects.
Safety & Efficacy variations Minimal. Cannot be inferred without supporting clinical trials.

13.  Generic drugs are based on active
substances, which are bioequivalent to
another active substance already
authorized, with the same quali-
quantitative composition,
pharmaceutical form and therapeutic
indications. Mass spectrophotometry
and nuclear magnetic resonance can
safely identify the active substance
and detect contaminants;
manufacturing procedures, being highly
standardised, are generally the same
as those of the originator; different
excipients and final formulations have
minimal effects on the final safety and
efficacy of the drug.
 A biosimilar and its reference product, on the
other hand, are obtained through inevitably
different manufacturing processes, which is due
to the inherent variability of the biological
expression system and the manufacturing
process itself. Differences in the former
determine differences in the contaminants, and
replication of the latter can be even harder
because the originator’s producer can hold
patent rights on the production process
itself. Moreover, analytic techniques cannot
fully characterize complex biological
molecules, which makes them insufficient to
demonstrate that the biosimilar product is
equal to its originator. An alternative final
formulation can also alter the biosimilar’s
properties.

14. “
”
“the absence of a significant difference in the rate and extent to which the active
ingredient or active moiety in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when administered at the
same molar dose under similar conditions in an appropriately designed study.” (FDA)
“[bioequivalency occurs if two medicinal products are] pharmaceutically equivalent
or pharmaceutical alternatives and if their bioavailabilities after administration in
the same molar dose are similar to such a degree that their effects, with respect to
both efficacy and safety, will be essentially the same” (EMA)
“[bioequivalency occurs if two medicinal products], at the same dosage, present
blood concentration profiles depending on time so similar that it is improbable they
will have relevant differences in their efficacy and safety effects”. (AIFA)
Definitions by some regulatory authorities…
Biosimilars cannot be completely bioequivalent due to the batch-to-batch variability
and their intrinsic biological nature. They are only “highly similar”, considering
minor differences in clinically inactive components and no clinically meaningful
differences in terms of safety, purity and potency.

15.  In short, bioequivalent drugs must show the same absorption, the same upstream and
downstream blood levels, the same permanency in the blood circle and same excretion
time. These parameters define a drug’s BIOAVAILABILITY
The fraction of an administered
dose of unchanged drug that
reaches the systemic circulation
and it is described by the plasma
concentration time curve assessing
the rate and extent of absorption.
The area under the curve (AUC)
reflects the extent of exposure.
Cmax, the maximum plasma
concentration or peak exposure,
and the time to maximum plasma
concentration, tmax, are
pharmacokinetic parameters that
are influenced by absorption rate.
 Most small molecule drugs are accepted as bioequivalent if
their AUC and Cmax are within the range of a 90%
Confidence Interval of 0,8-1,25.

16.  Marketing authorization for
biopharmaceuticals is released by the EMA
through a Centralized Procedure.
 The COMMITTEE FOR MEDICINAL PRODUCTS
FOR HUMAN USE (CHMP) writes the
EUROPEAN PUBLIC ASSESSMENT REPORT
(EPAR), published on the EMA website, which
includes the motivation for the favourable
response to the authorization request and a
section about presentation requirements
(labelling, packaging, etc.).
 Attribution of a Community M.A. number.
 Registration in the Community Register of
Medicinal Products (available on the
European Commission website).
1.3 How biosimilars are approved?
1.3.1 Regulatory needs and marketing authorization

17.  EMA has been the first regulatory authority to
establish a specific set of rules for the approval
of biosimilar products. This legislative framework
later inspired several other countries (Australia,
Canada, Japan, Turkey, Singapore, South Africa,
Taiwan, the United States), as well as the World
Health Organization.
 The authorization procedure follows EMA
guidelines:
 General guidelines defining the concept of
biosimilars and establish general
requirements for authorization.
 Guidelines for biosimilars’ quality;
 Guidelines for preclinical and clinical studies;
 Guidelines specific for each biosimilar line
(e.g., monoclonal antibodies,
erythropoietins, GH, ecc.).

18. “COMPARABILITY EXERCISE” is the
name for the overall process
aiming to ensure that the quality,
safety and efficacy of a
biopharmaceutical produced by a
changed manufacturing process
overlap the originator’s ones. The
exact requirements of
Comparability Exercises are set by
the EMA (in Europe) or the FDA (in
the U.S.). A Comparability Exercise
consist of a series of stepwise
procedures starting with tests for
quality (physical-chemical and
biological comparability) and
proceeding with non-clinical and
clinical trials (evaluation of safety
and efficacy).
CTD modules Generic drugs Biosimilar drugs
Module 1:
Administrative informations Complete Complete
Module 2:
Summary of the next modules
Complete Complete
Module 3:
Product quality
Complete
Complete +
comparability exercise
Module 4:
Non-clinical reactions
Omissis / bibliographic
references
Preclinical tests results +
comparability exercise
Module 5:
Relations on clinical trials
Bioequivalence study
Clinical trials results +
comparability exercise
Requirements for the Common Technical Document (CTD)

19.  Step 1 - Quality comparability: this involves a thorough characterisation program comparing
the physicochemical and biological quality attributes, including the purity of the potential
biosimilar medicine as compared with the reference product.
 Step 2 - Non-clinical comparability: As is the case with any biopharmaceutical, proposed
biosimilars must undergo pre-clinical studies before trials in humans are conducted. Data for
biosimilars are usually obtained via an abbreviated program of in vitro tests or studies in
animals, as required by EU guidelines. The non-clinical studies usually comprise repeat dose
toxicity, pharmacokinetic and pharmacodynamic studies in an appropriate animal model,
together with local tolerance testing in some instances.
 Step 3 - Clinical comparability: A proposed biosimilar has to show that it is clinically
comparable to its reference biologic in terms of both efficacy and safety (phase I and III
clinical trials), including specific evaluation on immunogenicity. Specification of the clinical
information required takes into account existing comparability data, such as physicochemical
characteristics, receptor-binding assays and results from testing in animal models. The closer
the profiles of a biosimilar and reference products and the higher the similarity that has been
demonstrated through previous steps, the more an abbreviated clinical trial program can be
accepted by regulators.
Comparability exercise

20. 1.3.2 Interchangeability & substitability for
biosimilars
“An interchangeable pharmaceutical product is one which is therapeutically
equivalent to a comparator product and can be interchanged with the comparator in
clinical practice.” (WHO 300 technical report series, no. 937, 2006)
“Interchangeability refers to the medical practice of replacing one drug with another
equivalent one in a given clinical context on the initiative or with the agreement of
the prescribing physician.” (European Generic Medicines Association, EGA)
“Interchangeability refers to the medical practice of replacing one drug with another
that has the same benefit-risk profile and is expected to have the same clinical effect
in a given clinical context on the initiative or with the agreement of the prescribing
physician.” (EFPIA/EBE-EuropaBIO)

21. Limits in the interchangeability of biosimilars
1. Manufacturing Process: reference biopharmaceuticals and their
biosimilar are similar but not identical. Therefore, it cannot be
assumed that they are automatically interchangeable. The switch
must be carefully monitored.
2. Lack of phase II clinical trials aiming to identify proper dosage:
clinical trials for the originator are taken into account.
3. Extension of indication: once the biosimilar’s effectiveness has been
demonstrated for one indication, it gets extended to all others. In
onchology, this could result inadequate, especially for monoclonal
antibodies. Each new therapeutic indication should be tested with a
specific registration process.
4. Immunogenicity risk: undetectable differences between biosimilars
and originators could lead to unexpected immunogenicity.

22.  SUBSTITUTABILITY, on the other hand, refers to the practice of replacing a
drug with another drug, often at a lower cost for the Health Service or for the
patient, which has the same qualitative and quantitative composition of
active substances, the same pharmaceutical form and route of administration
and is bioequivalent to the reference medicine on the basis of appropriate
bioavailability studies. Automatic substitutability (of equivalents) by
pharmacists refers to the practice by which the pharmacist may, or must, in
accordance with national or local regulations, dispense a drug equivalent and
interchangeable instead of the prescribed medicine, without consulting the
prescriber. Finally, as regards substitutability, these differences should be
noted:
• primary substitutability refers to the medical practice of beginning a new
treatment with a biosimilar product (or an equivalent) rather than with
the originator reference product;
• secondary substitutability, on the other hand, refers to the medical
practice and/or of the pharmacist of modifying the treatment of a patient
already being treated with a biologic drug with its biosimilar.

23. 2.1 How is the biopharmaceutical market?
2.1.1 The present-day global scenario
2.1.2 The lead actors on the biopharma market
2.2 How does biosimilars impact the market?
2.2.1 The past and the present of biosimilars
2.2.2 The future of biosimilars
2.3 How is the biosimilar situation in Italy?
2.3.1 The AIFA and the regional heterogeneity;
2.3.2 Interchangeability and substitutability for biosimilars;
2. A MARKETING APPROACH

24. 2.1 How is the biopharmaceutical market?
2.1.1 The present-day global scenario
 Sales from biotechnology
products have grown from a
share of 14% in 2006 to 23% in
2014, and they are expected to
reach 27% of the global market
by 2020.
 Top-100 blockbuster drugs in 2006
comprehended only 21% biophar-
maceuticals; in 2014, this figure
has much increased reaching 44%.
 The forecast for 2020 see the
percentage to increase to 46%,
lower than the 52% predicted in
last year’s report (which would
have meant a reversal in the
major market share of top selling
drugs between biological and
conventional medicinal
products).

25.  Humira® (adalimumab)
was the single most
lucrative product in 2014
($12 billion).
 Humira® generated $35
billion sales over the
period 2010-2013.
 A total of 37 individual
biopharmaceuticals
recorded blockbuster
sales (>$ billion).
 Taken together, the top
ten generated $69.8
billion sales in 2013
(50% of total
biopharmaceutical
revenues)
In terms of target indications, the majority of antibody and antibody-like products target inflammatory
and/or autoimmune conditions (cumulative 2013 sales of $41bn) and cancer (2013 cumulative sales of
$26bn). Among nonantibody–based products, insulins are the next most lucrative product class, collectively
generating sales of $21.5bn in 2013.

26.  Number of biopharmaceuticals approved for
market:
a. Approvals in the US and EU for each year
from 2010 to 2013 period;
b. Approval numbers over the indicated
period.
 More than 250 biopharmaceutical products
licensed in both markets over the considered
period.
 In 2014, 150 biologics were marketed
worldwide and more than 370 were in the
pipeline.
 Product approvals as a percentage for each
class over the total, in the 2010-2014 period
and from 1982 to 2014 (cumulative).
 There has been a decrement in approval for
some classes (such as interferon and
interleukins) in the last period, likely
reflective of market saturation.
 Monoclonal antibodies, on the other hand,
have continuously grown in importance;
from about 10% of all approvals by the
end of the 1980s to 22% by 2014.

27.  Promising research into synthetic biology and continuing computer-related progress in
biotech areas: Many bioinformatics studies are carried out for gene sequencing, drug
discovering, searching new drug receptors and producing tailored drugs which act specifically
on the target.
 Unsatisfied therapeutic needs: biopharmaceuticals are the only known medications capable
of being used for the treatment of diseases and disorders toward which other therapies are
otherwise often ineffective.
 Vast research investments by major pharmaceuticals firms: many major Pharmaceutical
companies are going to augment their biological portfolio and they have greatly increased
their research investments or benefitted from their partnering or acquisition of biotechnology
companies.
 Major Pharmaceutical firms went or will go off patent: Many major conventional drugs,
including best-sellers like GSK’s Advair® (2010), Pfizer’s Lipitor® (2011), BMS’s Plavix® (2012),
Novartis’ Diovan® (2012) and AstraZeneca’s Nexium® (2014) have recently gone off patent, or
will do so in the near future, which means a significant boost to generic manufacturers that
quickly issues their own low-priced versions.
Reasons of this success

28. 2.1.2 The lead actors on the biopharma market

29.  Roche can count on three of the most important
anti-tumoral monoclonal antibody products in its
pipeline (Avastin®, Herceptin®, Rituxan®),
totalizing more than $20 billion revenues in 2014
taken all together.
 By 2014, Amgen had 12 approved biological
medicines. Among these, the largest selling product
lines were Neulasta® and Enbrel® (co-marketed
with Pfizer in the U.S.)
 Novo Nordisk, a diabetes specialist, manufactures
many recombinant insulin-based products (e.g.
Novolog®/Novorapid®, Levemir®,
Actrapid®/Novolin®).
 Sanofi has recently seen a slowdown in Lantus®
sales, but it has enforced partnerships with the
American biotechnology firm Regeneron to develop
and launch monoclonal antibodies; four specialities
are already at a critical stage.
 Originated in 2013 as a spin-off of Abbott
Laboratories, Abbvie owes most of its fortune to its
best-selling drug Humira® (almost 55% of total
revenue in 2014).

30. Mergers & Acquisitions
 Pfizer acquired Wyeth
Biotech in 2009.
 Producer of Enbrel®,
co-marketed with
Amgen.
 Roche acquired
Genentech in 2009
 Producer, among
others, of Avastin®,
Herceptin®, Rituxan®
and Lucentis®
...and also Sanofi + Genzyme ($20.1bn), the world third-largest biotechnology firm; Pfizer +
Hospira ($17bn), world's leading supplier of injectable drugs and infusion technologies; etc.
 Merck & Co. acquired
Schering-Plough in
2009.
 Producer of several
biologics, including
Remicade®
 A wave of acquisition by
Big Pharma toward
successful biotech
companies, in order to
acquire biologic expertise
and market.
 However, innovation in
biopharmaceuticals have
started to slow down
with respect to late
1990s (saturation for
therapeutic indication
and more restrictive
requests from regulatory
agencies may be the
cause)
 Entering biosimilar
market may be an
alternative way to create
value with biologic for
Big Pharma.

31. 2.2 How do biosimilars impact the market?
2.2.1 The past and the present of biosimilars
 March 23th, 2012: the Obama administration
passed The Biologics Price Competition and
Innovation Act (BPCI Act), an amendment to the
Public Health Service Act to create an abbreviated
approval pathway for biological products.
 July 24th, 2014: First biosimilar application to
FDA.
 August 8th, 2014: First monoclonal antibody
application to FDA.
 March 6th, 2015: Zarxio® by Sandoz is the first
biosimilar approved by FDA. Its reference product
is Amgen’s Filgrastim (originally licensed in 1991).
 July 1st, 2005: First biosimilar application to
EMA.
 April 12th, 2006: Omnitrope® (somatropin) by
Sandoz is the first biosimilar approved by EMA.
 2010: By the end of the year, 14 biosimilars
were approved in EU, establishing a market that
reached about $172 million.
 March 1st, 2012: First monoclonal antibody
application to EMA.
 September 10th, 2013: EMA authorizes sale of
Remisma® (biosimilar of Remicade) by Celltrion
Healthcare in the EU.
Timeline
In Europe In the U.S.

32. Drivers
 Growing pressure to reduce healthcare
expenditure in developed countries;
 Increase in the number of patients that
can afford prescription drugs in
developing markets;
 Various blockbuster biologics going off
patent;
 High prevalence of chronic diseases in
ageing population;
 Regulatory initiatives (e.g. the EMA
introduction of a licensing procedure; the
BPCI act decided by the American
government).
Restraints
 High initial investment in research and
development;
 Medical efficacy and patient safety.
 Stringent regulations in developed
economies to restrict investments.
COST
The average R&D investment for a
biopharmaceutical is $1.2bn. As a
consequence, for example,
Remicade costs almost $18.000 a
year; Herceptin costs up to $40.000
a year per patient. The BGMA
estimates that by 2020 biosimilars
could shave up to €33bn off drug
bills in eight EU countries.
TIME
It takes an average of 10-15 years
to develop and market a new
biopharmaceutical. Biosimilars may
benefit from shortened licensing
process and previous research
studies. In this way, their marketing
time is reduced to 7-8 years.

33.  After an initial burst of approvals
from 2006–2008, the EU approval
rate has slowed. This is hardly the
opening of the biosimilar’s
floodgate that someone predicted.
 Market penetration was slow,
although now biosimilar market in
the EU stays at around $360mn,
with global total sales reaching
about $676mn (0.4% of the
biological market) (IMS Health).
 On the positive side:
• by the end of 2012, 41% of EU
filgrastim market and 19% of
short-acting EPO market were
covered by biosimilars.
• Biosimilar prices in the EU have
an average 30% discount on the
product relative to their
originator.
• No unexpected safety issues
raised.
The European experience

34.  An increasing number of
markets is developing their
own biosimilar pathways,
either based on EMA or
WHO.
 Globally, by 2014 there
were 280 biosimilars in the
pipeline, and their clinical
trials is increasing by 20%
each year.
 Two big markets like Russia
and China have still to
develop their own pathway.
 As for biosimilar
manufacturing, India is the
third big player after EU
and the US.
 The Asia-pacific region is
the most promising market,
with many biosimilars
already in use. By 2020, it
will become the highest
revenue generating area.
© 2016 - William Reed Business Media SAS - All Rights Reserved

35.  Biopharma industry is in the middle of a
“patent cliff” in Europe and US, which
will put a market of more than $60bn
(considering only the top 10 selling
products) at risk.
 The most important patent expirations
in the EU for the next future are
represented by Neulasta® ($4.4bn)
and, even more remarkable, Humira®
($12bn).
 Biosimilars developers will be using
emerging markets with less intellectual
property protection to quickly enter
into established markets. Best example
for this is the Asia-Pacific Region:
• Collaboration between Mylan and
Biocon to commercialize biosimilar
of Herceptin® in India;
• Cadilla Healthcare launched in
India the first adalimumab
biosimilar under the name
Exemptia® in 2014.
2.2.2 The future of biosimilars © 2016 - William Reed Business Media SAS - All Rights Reserved

36.  The challenge for biosimilar manufacturers is not only to implement a proper manufacturing
process, but also to prove comparability through clinical trials in a cost-effective manner. The
high upfront costs needed, both to manufacture and to execute clinical trials will, therefore, act
as a strong barrier to entry into the biosimilars market regardless of the ”patent cliff”.
 The price drop for biosimilars will not be as pronounced as for generics, because companies
entering the market need to overcome these barriers yet still make a financial return (at date,
most biosimilars are sold at about 65%-85% of the originator’s price in the EU)
 The key capabilities necessary to entry and prevail into the biosimilar market can be identified in:
• Research and Development: financial resources for basic research and clinical trials.
• Manufacturing: access to specific biomanufacturing facilities.
• Supporting activities: such as legal expertise and global distribution channels.
• Marketing: scientific information and a global network of sales representatives.
• Lobbying: with regulatory bodies, KOLs and governments.

37. 2.3 How is the biosimilar situation in Italy?
2.3.1 Biosimilars impact on the Italian market
 Therapeutic proteins
(growth factors,
interleukins, interferons,
insulins, ecc.) cover
almost all volumes of
biopharmaceuticals used
in Italy and more than
half of the expenses.
 Monoclonal antibodies
represent only 5% of the
volumes, but this amount
translates into 42% of the
total expense for
biopharmaceuticals.
Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)

38. Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)

39.  By the end of 2013, 9 on 14
biosimilars approved by the
EMA were present on the
Italian market:
Omnitrope (somatropine) 29/10/07
Abseamed (EPOetin alfa) 03/11/08
Binocrit (EPOetin alfa) 29/10/07
Retacrit (EPOetin alfa) 03/11/08
Ratiograstim (filgrastim) 16/03/09
Tevagrastim (filgrastim) 01/11/09
Zarzio (filgrastim) 01/11/09
Nivestim (filgrastim) 08/06/10
Grastofil (filgrastim) 12/12/13
 Italian market share of biosimilars has steadily grown.
 Use of filgrastim biosimilars has become higher than
the reference product since 2012.
 EPO biosimilars has sensibly grown as well, while
somatropine remained more or less stable.
Cesbio Bocconi – secondo rapporto di ricerca sui farmaci biotech (2014)

40. 2.3.2 The AIFA and the regional heterogeneity
 To date, the EMA has not expressed an official opinion yet about biosimilars’
substitutability, leaving decisional and legislative autonomy on the matter to
national authorities.
 Recommendations suggest a precautionary approach:
 In Italy, the AIFA makes it clear that biological medicines and biosimilars cannot be
considered purely and simply the same as equivalent products, and thus excludes
the mutual automatic substitutive therapy.
“The decision about the choice of prescribing a particular drug to be
used, rather than reference biosimilar, must be entrusted to qualified
health workers” (Ref. EMEA/74562/2006 Rev.1)

41. Tuscany (Regional Resolution n.592/2010)
 In public purchase procedures for biosimilars,
composition, route of administration, therapeutic
indications and dosage must be indicated exclusively.
 In no circumstance substitution with drugs equal in
composition, pharmaceutical form and dosage
produced by a different pharmaceutical company is
allowed.
 Choice by the medical specialist to prescribe a drug
different from the one accepted by the public
purchase procedure must be motivated to the
people/person in charge of the institute of
reference.
 Further costs deriving from prescription of drugs
different from those object of the public procedure
cannot be charged on the Regional Health System.

42. Molise (Regional Decree n.5/2010)
 Biosimilar drugs must be used as first choice with
drug naïve patients, except for other therapeutic
indication and/or clinical judgement, which will be
object of a specific technical relation that must be
sent to the Therapeutic Regional Committee (CTR).
 In patients already treated with biopharmaceuticals,
it must be guaranteed the alternative use of a
biosimilar, except for other clinical judgement or
welfare complexity conditions, object of a specific
technical relation that must be sent to the
Therapeutic Regional Committee (CTR).
 Treatment with biopharmaceutical drug must be
guaranteed to the patient in case of therapeutic
inefficacy, non-sufficient therapeutic response or
manifested non-tolerance to the biosimilar.

43. Campania (Regional Decree n.34/2012)
(D.n.44/2010 – n.15/2009)
 All prescribing doctors, in the act of prescribing
biopharmaceuticals, must show a preference to
biosimilar drugs, with equal therapeutic indications
and route of administration. Prescribers will
motivate a different therapeutic choice with the
specific patient card, which must be attached to
the request and sent online, monthly, to the Nucleo
di controllo dell’appropriatezza.
 Patient card does not have to be filled for those
biopharmaceuticals of the same fifth level-ATC
category that got their price reduced with respect
to the one established at the release date of
Commissioner’s Decrees n.15 of 30/11/2009 and
n.44 of 14/07/2010, allowing achievement of the
expected 40% discount.
 Concerning naïve patients, with equal therapeutic
indication in the data sheet, the least expensive
biosimilar must be used.
 In case of documented therapeutic inefficacy
and/or non-tolerance, use of another
biopharmaceutical must be guaranteed.

44.  Lacking a national policy about biosimilar’s substitutability, every Italian region has expressed or
could express its own set of rules and measures, which can be discordant on the matter and put
the equality of the citizen’s right to healthcare over all national territory at risk.
 Tuscany, Molise and Campania are regions that have favoured biosimilar’s use, at least for naïve
patients. For those being already treated with a biopharmaceutical, the principle of therapeutic
continuity is generally held. Therapeutical switch toward a biosimilar must be carefully
evaluated and decided only with the consent of prescribing doctor.
 Nevertheless, for example, therapeutic continuity and personalization is more stressed in Tuscany’s
resolution, while Campania’s regulations aim primarily to cut expenses. These are two different
approaches that could probably lead to different guarantees for the citizens of the two regions.
Regions interested by resolutions on biosimilars and their relative number
over the course of the 2009-2012 period
Cesbio Bocconi – primo rapporto di ricerca sui farmaci biotech (2013)

45. (Re)defining biopharmaceutical (Rader, 2008; Nature)
Position paper of the Italian Society of Rheumatology on the Prescription of
Biosimilars (2015)
Generici e biosimilari visti dal farmacologo (Rossi, 2013; 3^ conferenza sui farmaci a
brevetto scaduto, Università di Napoli)
Farmaci biotecnologici e biosimilari - La rivoluzione dei biotech: dalle eritropoietine
agli anticorpi monoclonali in oncologia (AIOM, 2013)
World Preview 2015, Outlook to 2020 (EvaluatePharma, 2015)
Biosimilars: Company Strategies to Capture Value from the Biologics Market
(Fernandez & Hurtado, 2012; Pharmaceuticals)
Biopharmaceutical benchmarks (Walsh, 2014; Nature)
La diffusione dei farmaci biotecnologici, la loro costo-efficacia e i trend legati
all'associazione farmaco-test per biomarker (Centro di Ricerche sulla Gestione
dell’Assistenza Sanitaria e Sociale, Università Bocconi, 2014)
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