Biological Drugs: Challenges to Access

Amit Sengupta

TWN
Third World Network
Biological Drugs: Challenges to Access
is published by
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© Amit Sengupta 2018

Cover design: Lim Jee Yuan

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ISBN: 978-967-0747-26-2
Contents

1. The Growing Therapeutic and Commercial Importance 1

of Biologics
2. How Biological Drugs Differ from Small Molecule Drugs 5

3. Recombinant Technologies in the Manufacture of 8

Biological Drugs
4. Renewed Interest in Biological Medicines 11
5. Why Are Biologics and Biosimilars So Expensive? 15
6. Biosimilars vs Generics of SMDs: Different Treatment 18
by Regulators
7. Technological Barriers to Manufacture of Biosimilars 20
8. Barriers Related to Intellectual Property Rights and 22
Data Exclusivity
9. The Evolving Regulatory Landscape for Approval 26
of Biosimilars
10. How Necessary Are Present Requirements to Establish 33
Similarity?
11. Uptake of Biosimilars in Clinical Practice: Interchangeability 34
and INN
12. Conclusions 37
 Chapter One

The Growing Therapeutic and Commercial

Importance of Biologics

BIOLOGICAL drugs (commonly referred to as ‘biologics’ or

‘biopharmaceuticals’) are drugs produced through biological processes.
They currently target diseases which, hitherto, had very limited or no
available treatment options – including several types of cancers, autoim-
mune diseases and other non-communicable diseases. These drugs are
different because they are produced in living cells. Biologics are larger in
size and more complex than the ‘small molecule drugs’ (SMDs) manu-
factured using chemical synthesis processes. Biologics have several po-
tential advantages as they can, theoretically, be tailored to hit specific
‘targets’ in the human body.

The global list of top-selling drugs is increasingly populated by biologics

(see Table 1). Revenues being generated by biological drugs are huge: the
projected global sales of the top-selling biologic, AbbVie’s Humira
(adalimumab) – a drug used to treat autoimmune disorders such as rheu-
matoid arthritis – in 2018 are US$20 billion, equal to about two-thirds of
the entire pharmaceutical market in India in 2017.

The penetration of biological drugs in standard treatment practices is still

comparatively lower than SMDs, due to their high costs, treatments being
currently available for only a limited number of diseases and the need for
a developed health system to supervise treatment with biologics. How-
ever, in some therapeutic areas treatment with biologics is already quite
significant, especially in high-income countries. An estimated 19% of
rheumatoid arthritis (the disease area where use of biologics has been the

1
highest) patients in Europe were accessing biologics in 2010.1 In 2014,
there were 3.1 million patients in the US being treated with one of seven
top-selling biologics available in the country.2 In 2015, the World Health
Organization (WHO) included two new biological drugs for cancer treat-
ment, trastuzumab and rituximab, in its list of Essential Medicines.3 The
list already contained two older biologics – pegylated interferon alfa (2a
or 2b) and filgrastim.

The fastest-growing segment of the market for biological drugs – the re-
combinant glycosylated proteins segment – is projected to grow annually
at 25% by 2018. Within this, the monoclonal antibody segment alone will
have an estimated compounded annual growth rate of 41.9% from 2013
to 2018. The US market is clearly driving the growth of biologics – be-
tween 2013 and 2014, spending on specialty drugs, including biologics,
increased by 32.4%, while spending on SMDs increased by just 6.8%.
Sales in the US account for over half of revenues generated by the sale of
biologics.4 By 2016, eight of the 10 top-selling drugs in the US market
were biologics.5

1
Laires, Pedro A et al. (2013) Patient’s Access to Healthcare and Treatment in Rheu-
matoid Arthritis: The Views of Stakeholders in Portugal. BMC Musculoskeletal Dis-
orders 14 (2013): 279, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849024/
2
The Biosimilars Council (2017) Biosimilars in the United States: Providing More
Patients Greater Access to Lifesaving Medicines. Available at: http://
biosimilarscouncil.org/wp-content/uploads/2017/09/Biosimilars-Council-Patient-
Access-Study-090917.pdf
3
Malik, Monica et al. (2016) Biosimilars in Low- and Middle-Income Markets: A
Case Study of India and Russia. 26 May 2016, https://am.asco.org/biosimilars-low-
and-middle-income-markets-case-study-india-and-russia
4
____________ (2013) Generating value in generics: Finding the next five years of
growth. McKinsey and Company, May 2013, http://www.mckinsey.com
5
____________ (2016) The economic impact of biosimilars in the US. 29 July 2016,
http://www.gabionline.net/Biosimilars/Research/The-economic-impact-of-
biosimilars-in-the-US

2
The anticipated percentage growth rate of biologic and biosimilar mar-
kets far exceeds that of the more established SMD markets. The biologics
market is set to increase its total market share from 16.6% in 2015 to
22.2% in 2021.6

The growing commercial importance of biological drugs is also evident

from the rise in patenting activity related to these drugs. In 2009, biologi-
cal drugs accounted for 60% of the patents filed by the top 10 pharmaceu-
tical companies.7 Abbott had as much as 80% of the patent filings be-
tween 2007 and 2009 focused on biologics.8 Recent interest in biological
drugs is also driven by the fact that several top-selling biologics have
gone or will go off-patent between 2013 and 2018. These include block-
busters such as Rituxan/MabThera, Remicade, Herceptin, Humira, Avastin,
Synagis, Erbitux and Lucentis.

While many of the discoveries of new biological drugs continue to origi-

nate in specialized biotech companies, the drugs are increasingly being
developed by leading multinational pharmaceutical companies (hereafter
referred to as ‘Big Pharma’) which had traditionally concentrated on de-
velopment of SMDs. In recent years many traditional pharmaceutical com-
panies have entered the market for biological drugs, often through acqui-
sitions of smaller biotech companies. Currently biologics contribute sig-
nificantly to the revenues of Big Pharma. They accounted for 22% of the
Big Pharma companies’ sales in 2013, and this is projected to rise to 32%

6
Results Healthcare (2017) Pharma & Biotech 2017, Review of outsourced manufac-
turing. http://resultshealthcare.com/wp-content/uploads/2017/01/Results-
Healthcare_Pharma-Biotech-2017-Review-of-outsourced-
manufacturing_Whitepaper.pdf
7
Jack, A (2012) Fall in number of patents filed by big pharma. Financial Times, 18
March 2012, https://www.ft.com/content/0912c0ea-70f9-11e1-a7f1-00144feab49a
8
Philippidis, Alex (2012) Higher percentage of large molecules compared to small
molecules makes it to market. Genetic Intelligence and Biotechnology News, 9 April
2012, http://www.genengnews.com/keywordsandtools/print/3/26751/

3
 Table 1: Top 10 best-selling drugs in 2015 and the share of biologics9

Drug Company Ingredient Indication Biologic 2015

sales
(million
US$)
Humira AbbVie Adalimumab Autoimmune YES 14,012
disorders
Harvoni Gilead Ledipasvir + sofosbuvir Hepatitis C NO 13,864
Rituxan Roche Rituximab Non-Hodgkin’s YES 7,327
lymphoma
Lantus Sanofi Insulin glargine Diabetes YES 7,088
Avastin Roche Bevacizumab Various cancers YES 6,951
Herceptin Roche Trastuzumab Breast cancer YES 6,799
Remicade Johnson & Infliximab Autoimmune YES 6,561
Johnson disorders
Prevnar Pfizer Streptococcus Vaccine YES* 6,245
pneumoniae vaccine
Januvia/ Merck Sitagliptin Diabetes NO 6,014
Janumet
Revlimid Celgene Lenalidomide Multiple NO 5,801
myeloma
* While vaccine manufacture is through a biological process, it doesn’t involve
recombinant technology (see below)

by 2023. Some of the leading companies poised to benefit from growing

sales of biological drugs include Abbott, Roche, Bristol-Myers Squibb,
Merck, Eli Lilly and Sanofi.10

9
____________ (2016) FirstWord Lists: The 100 best selling pharmaceutical brands.
https://www.firstwordpharma.com/node/1375342
10
____________ (2015) Pharmaceuticals: Going large. The Economist, http://
www.economist.com/node/21637387/print

4
 Chapter Two

How Biological Drugs Differ from Small

Molecule Drugs

BIOLOGICAL products include a wide range of products such as vac-

cines, blood and blood components, allergenics, somatic cells, gene
therapy, tissues and recombinant therapeutic proteins. Biologics can be
composed of sugars, proteins or nucleic acids or complex combinations
of these substances, or may be living entities such as cells and tissues.
Biologics are isolated from a variety of natural sources – human, animal
or microorganism – and may be produced by biotechnology methods and
other new technologies.11

Biologics can be produced through: a) biological processes that do not

involve the creation of a new cell (to produce the product), or b) recombi-
nant technology (see Box 1). The major innovation of the last two de-
cades, leading to renewed interest in the promise of biological products,
has been propelled by the development of recombinant technology. It must
be remembered, though, that biological drugs had been produced before
recombinant technologies became available, including, for example, vac-
cines and antibiotics such as penicillin. However, in this paper we are
limiting our analysis largely to biological drugs developed through re-
combinant technologies.

Biological drugs differ in many ways from SMDs. Biologics are extremely
sensitive to the manufacturing process and the starting material. As the
starting material is a living cell in the case of new biological products that

11
US Food and Drug Administration (2016) What Are ‘Biologics’ Questions and An-
swers. http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsand
Tobacco/CBER/ucm133077.htm

5
use recombinant technology, it is impossible to have exactly similar start-
ing cells. Moreover, very small changes in the manufacturing process can
bring about changes in the final product. It is impossible for a company
producing a follow-on biological product to completely replicate a large,
complicated biomolecule, since it doesn’t have access to the specific
methods and conditions that the original company had in synthesizing
and characterizing the compound.12 This has implications for the devel-
opment and manufacture of follow-on products. Here it may be noted,
however, that even in the case of the original product, there are variations
in the product between batches and even within the same batch. Current
analytical methods cannot fully predict the structural properties of a bio-
logical drug (called ‘characterization’) though the body’s immune system
can detect alterations in products missed by analytical methods. This is
however changing rapidly as more sophisticated methods of analysis are
developed, and it is possible now to almost fully characterize the large
complex molecules of which biologics are composed.

The relative uncertainty about the structural characteristics of biologics

has led to a reluctance to refer to follow-on products of biologics – that is,
similar biologics manufactured by someone other than the originator com-
pany – as generics. The biologics industry has introduced the notion that
since it is impossible to manufacture an exact replica, follow-on products
should be called biosimilars and not generics or bio-generics. Many see
this as a ploy to restrict the use of follow-on products by creating doubts
in the minds of regulators and prescribers.

The complexity of the manufacturing process for biologics is several or-

ders of magnitude higher than that for SMDs. Conventional pharmaceuti-
cal agents are small-molecule chemicals with a defined molecular weight
typically between 100 and 1,000 Da. In contrast, biologics are large, com-
plex and heterogeneous proteins with more variable molecular weights,

12
Stembridge, Bob (2015) Unique solutions to biosimilar patenting. http://
ip.thomsonreuters.com/sites/default/files/m/Thomson-Article-TPL.pdf

6
commonly ranging from 18,000 to 145,000 Da.13 Further, biological drugs
have high immunogenicity – that is, their ability to produce an immune
response in the body is of a much higher order than SMDs. This places
limitations on the use of biologics in settings where patients cannot be
adequately supervised while on biological medicines. Biological medi-
cines come in the form of injectables, further limiting access to these in
resource-poor healthcare systems.

Table 2: Differences between biologics and small molecule drugs

Characteristic Small molecule drugs Biological drugs
Size of molecule Small Large
Drug production By chemical synthesis By genetic engineering
methods
Produced in cell lines
Product Well characterized Difficult to characterize
characterization the product as they tend to
be produced as diverse
mixture of molecules which
are very slightly different
from one another
Purification, Easy to purify Lengthy and complex
contamination Contamination can be purification process
possibility generally avoided, High possibility of
is easily detectable contamination, detection is
and often removable harder and removal is
often impossible
Laboratory analysis Easily analyzed with Current physico-chemical
routine laboratory tests analytical methods or
bioassays cannot detect
all product variations
Susceptibility to Not affected by Highly susceptible to the
environmental or environmental changes or slightest changes in the
process changes any changes in the steps of environment, cell strains or the
the production process, manufacturing process, hence
hence the product is more it remains the most essential
important than the process aspect of manufacturing
Immunogenicity Low immunogenicity Generally immunogenic

13
Schellekens, Huub (2009) Biosimilar therapeutics – what do we need to consider?.
NDT Plus (2009) 2 [Suppl 1]: i27-i36; doi: 10.1093/ndtplus/sfn177

7
 Chapter Three

Recombinant Technologies in the Manufacture of

Biological Drugs

Box 1: What are recombinant technologies?

Biotechnology involves biological processes that have been manipu-
lated or modified in some way through modern science. A major indus-
trial application of biotechnology is in the development and prepara-
tion of biological medicinal products using genetically engineered bac-
teria, yeast, fungi, cells or even whole animals and plants. Some of
these biological medicines were originally extracted from tissues and
secretions, often of human origin and in relatively small amounts. With
the advent of recombinant DNA technology, the preparation of large
amounts of highly purified and characterized materials became pos-
sible, including products intentionally modified by pegylation (treat-
ment of a complex biomolecule with polyethylene glycol to stabilize it)
or changes in DNA sequences, fundamentally changing the manner in
which biological substances like these were produced and standard-
ized.14

In the case of drugs developed through recombinant technologies, there

were two waves of biologic drug discoveries: recombinant versions of
human endogenous molecules (i.e., hormones and enzymes found inside
the human body) were developed in the 1980s; and more complex prod-
ucts, such as monoclonal antibodies, in the late 1990s.15

14
World Health Organization (2016) Biotherapeutic Products. http://www.who.int/
biologicals/biotherapeutics/biotherapeutic-products/en/
15
Calo-Fernandez, Bruno and Juan Leonardo Martinez-Hurtado (2012) Biosimilars:
Company Strategies to Capture Value from the Biologics Market. Pharmaceuticals
2012, 5: 1393-1408; doi:10.3390/ph5121393

8
Recombinant biological products include: a) recombinant non-glycosylated
proteins; b) recombinant glycosylated proteins; and c) recombinant pep-
tides. Recombinant non-glycosylated proteins include insulin, granulo-
cyte colony-stimulating factor (G-CSF), interferons and human growth
hormone; recombinant glycosylated proteins include erythropoietin, mono-
clonal antibodies and follitropin; and recombinant peptides include calci-
tonin and glucagon. Of these, the new generation of drugs for cancer and
autoimmune diseases comprises those that are characterized as mono-
clonal antibodies (the convention for such drugs is to use an International
Non-proprietary Name (INN) ending in the three letters ‘mab’).

Table 3: Classification of recombinant biological products16

Non-glycosylated proteins Insulin, interferons, granulocyte colony-stimulating
factor (G-CSF), human growth hormone

Peptides Calcitonin, glucagon

Glycosylated proteins Erythropoietin, follitropin,

monoclonal antibodies

16
Biosimilars Market Product (2013) http://www.prnewswire.com/news-releases/
biosimilars-market-product-recombinant-non-glycosylated-proteins-insulin-
filgrastim-somatropin-glycosylated-monoclonal-antibodies-erythropoietin-peptides-
glucagon-calcitonin—application-oncology-blood-disorders-233468431.html

9
 Box 2: What are monoclonal antibodies?
Monoclonal antibodies, or MAbs, are laboratory-produced antibodies
that bind to specific antigens expressed by cells, such as a protein that
is present on the surface of cancer cells but is absent from (or expressed
at lower levels by) normal cells.

To create MAbs, researchers inject mice with an antigen from human

cells. They then harvest the antibody-producing cells from the mice
and individually fuse them with a myeloma cell (cancerous B cell) to
produce a fusion cell known as a hybridoma. Each hybridoma then
divides to produce identical daughter cells or clones – hence the term
‘monoclonal’ – and antibodies secreted by different clones are tested to
identify the antibodies that bind most strongly to the antigen. Large
quantities of antibodies can be produced by these immortal hybridoma
cells. Because mouse antibodies can themselves elicit an immune re-
sponse in humans, which would reduce their effectiveness, mouse anti-
bodies are often ‘humanized’ by replacing as much of the mouse por-
tion of the antibody as possible with human portions. This is done
through genetic engineering.17

17
NIH National Cancer Institute (nd) Biological Therapies for Cancer. https://
www.cancer.gov/about-cancer/treatment/types/immunotherapy/bio-therapies-fact-
sheet

10
 Chapter Four

Renewed Interest in Biological Medicines

THERE is, at present, renewed interest in the biologics market, and as a

consequence biotech companies are attracting large amounts of funding.
According to a PricewaterhouseCoopers (PwC) and National Venture
Capital Association (NVCA) report, over US$2.1 billion was invested in
biotech companies in the US in the second quarter of 2015. Four of the
five quarters up till then were among the top record-setting quarters for
the past 10 years in magnitude of venture capital funding being made
available to biotech companies.

When more capital is channelled into a particular area as compared with

historical norms, questions around bubbles and over-funding get raised.
The question that may be asked is whether there is a funding and valua-
tion bubble in the biotech sector. The growing pool of capital available
today could dissipate quickly if market sentiment turns against the biotech
sector.18

The question is valid if one scans the history of the promise of the biotech
revolution. Delivery on the promise of biotechnology has been slow and
previous failures would suggest the need for caution. The last time the
biotech industry was able to garner current levels of funding was around
2000, when companies promised, and investors believed, that genomics,
particularly after the decoding of the human DNA sequence, would revo-

18
Booth, B (2015) The Venture Funding Boom in Biotech: A Few Things It’s Not.
Forbes, 23 July 2015, http://www.forbes.com/sites/brucebooth/2015/07/23/the-ven-
ture-funding-boom-in-biotech-a-few-things-its-not/#4db49959439c

11
lutionize drug discovery. However, biotech stock prices eventually col-
lapsed when genomics did not yield the promised bonanza.19

The current enthusiasm around biotech drugs needs to be tempered by the

knowledge that we are yet to see biological drugs that have truly revolu-
tionized therapy in many areas. Most available therapies utilizing bio-
logical drugs are clustered around autoimmune disorders such as rheuma-
toid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis
and psoriasis, and around some forms of cancer. In the former case (au-
toimmune disorders), while treated patients have seen significant improve-
ment in quality of life, the new biologic-based treatments do not target
life-threatening diseases of an immediate nature. Cancer therapies avail-
able in the form of biologics are yet to provide dramatic results – rather,
in most cases they effect an incremental increase in survival rates. In fact,
in the recent past, it is small molecule drugs such as imatinib (for chronic
myeloid leukaemia) and sofosbuvir (for hepatitis C) that have provided
dramatic therapeutic breakthroughs.

An associated issue is that of the cost of biologics, including of follow-on

versions (called ‘biosimilars’ or ‘biogenerics’). The US market (and to a
certain extent the EU market) is fuelling the growth of the biologics sec-
tor, but the ability of even these markets to sustain the growth of such
high-cost therapies is uncertain unless new breakthrough drugs become
available.

This is not to suggest that the predicted growth of the biologics (and
biosimilars) market is a mirage or a funding-induced bubble, but to predi-
cate future projections on a bigger realization of the promise of biotech-
nology towards promoting better outcomes in a larger range of diseases.

The current optimism around the biotech sector is being driven by two
factors. As mentioned above, the fastest-growing segment of the biologics
market is the recombinant glycosylated proteins segment – projected to

19
Pollack, A (2015) Riding High, Biotech Firms Remain Wary. New York Times, 18
January 2015, http://www.nytimes.com/2015/01/19/technology/riding-high-biotech-
firms-remain-wary.html?_r=0

12
grow annually at 25% by 2018. One of the drivers of this growth, it is
projected, is the investment by drug manufacturers in developing biosimilar
versions of monoclonal antibodies (over 50 biosimilars of monoclonal
antibodies are in the pipeline). This interest is further strengthened as
patents on many top-selling biological drugs have expired or are set to
expire soon. Other fast-growing products (other than monoclonal anti-
bodies) include follitropin (to treat infertility) and erythropoietin (espe-
cially useful in treating anaemia secondary to chronic kidney failure).
Optimism around biological drugs is also being fuelled by the high prices
commanded by the top-selling drugs.

Big Pharma was not involved in and did not benefit from the success of
innovative biotech companies in the late 1990s, but the pharmaceutical
giants have recently acquired some of those successful biotech compa-
nies to shore up their capabilities in the biotech sector. The mega-mergers
of Pfizer and Wyeth, Roche and Genentech, and Merck and Schering-
Plough are examples of recent acquisitions by Big Pharma. However, the
rate of introduction of new biologics has slowed from the peaks in the
late 1990s. One reason for this deceleration is that innovative biotech
companies had patented and developed products saturating the currently
available approved indications, and regulatory agencies require new prod-
ucts to show better efficacy than the existing ones.

The slowdown in introduction of new biologics is driving interest in

biosimilars. Big Pharma, which missed the bus earlier, is now entering
the biosimilars market. This is an attractive option for Big Pharma, given
that a number of biologic blockbusters have lost or are soon to lose mar-
ket exclusivity. Top biotech innovator companies are also entering the
biosimilars market. For example, Amgen, the largest biologics manufac-
turing company globally, signed a deal in July 2016 with Japanese firm
Daiichi through which Amgen secured an exclusive agreement to com-
mercialize nine biosimilars in Japan.20 Earlier in 2016, Amgen had an-

20
____________ (2016) Amgen and Daiichi Sankyo Announce Agreement to Com-
mercialize Biosimilars in Japan. 13 July 2016, http://www.amgen.com/media/news-
releases/2016/07/amgen-and-daiichi-sankyo-announce-agreement-to-commercialize-
biosimilars-in-japan/

13
nounced plans to launch in the US its biosimilar version of AbbVie’s
Humira (adalimumab), the world’s biggest blockbuster drug.21

Established innovative biotech companies fund their research and devel-

opment (R&D) operations through the revenues obtained from their bio-
logic blockbusters, the majority of which were patented during the wave
of biologic drug discoveries of the late 1990s. The strategic decisions of
mega generics companies and Big Pharma to enter the biosimilars market
are therefore a real threat to the survival of innovative biotech compa-
nies.22

Companies such as Teva, Sandoz and Hospira, the largest generics com-
panies, are already commercializing biosimilar hormones, cytokines and
enzymes (e.g., insulin, EPO, interferon, G-CSF and imiglucerase). Among
monoclonal antibodies, the three most targeted products for biosimilars
are rituximab, infliximab and adalimumab due to their high worldwide
sales and approvals for multiple indications. Various key industry players
in the generics market have started working on the manufacturing and
clinical trials of MAbs. Bioexpress Therapeutic (Switzerland) has 16
biosimilar candidates of MAbs in the pipeline. Other major companies
that have invested in the production of MAbs are Gene Techno Science
(Japan), Celltrion (South Korea), Zydus Cadila (India), Biocon (India)
and Samsung Biologics (South Korea). Across countries, China and India
are considered attractive destinations for R&D outsourcing by foreign
biosimilar manufacturing companies that are looking to reduce their grow-
ing R&D costs and increase the number of drug applications and approv-
als.

21
Lawrence, S (2016) Amgen partners with Daiichi on biosimilars after positive FDA
panel. FierceBiotech, 14 July 2016, http://www.fiercebiotech.com/biotech/amgen-
partners-daiichi-biosimilars-after-positive-fda-panel
22
Calo-Fernandez, Bruno and Juan Leonardo Martinez-Hurtado (2012) Biosimilars:
Company Strategies to Capture Value from the Biologics Market. Pharmaceuticals
2012, 5: 1393-1408; doi:10.3390/ph5121393

14
 Chapter Five

Why Are Biologics and Biosimilars So Expensive?

UNLIKE in the case of SMDs where generic equivalents become avail-

able soon after the patents on these drugs expire (or in situations where
the patent is not recognized in a particular territory), there is no effective
competition in the market for biologics even in situations where the pat-
ents on the originator molecules have expired or are not granted. Contrib-
uting to this situation is what we described earlier – the complex struc-
tures of biologics and their dependence on relatively complex manufac-
turing processes involving living cells. This complexity introduces vari-
ous barriers to competition in the market. Thus, in addition to intellectual
property-related barriers (similar to what we see in the case of SMDs),
early introduction of biosimilars also faces technological and regulatory
barriers.

As a result, biologics are extremely expensive and consequently not eas-

ily accessible to patients, especially in low- and middle-income countries
(LMICs). For example, one vial of adalimumab (for the originator prod-
uct Humira from AbbVie) would cost about US$1,000 – almost equiva-
lent to the average annual wage in a low-income country. The high prices
of biological drugs place a major burden on the public health budget of
many LMICs which have introduced these drugs. For example, in 2015
biological drugs accounted for 35% of the pharmaceutical market in Co-
lombia. Similarly in Brazil, while biological drugs account for 4% by
volume of drugs distributed through its National Health System, they ac-
count for over half of the Ministry of Health’s expenditure on medicines.23
23
Barry, F (2015) Filgastrim biosimilar is first Latin copy biologic, says Brazil.
BioPharma Reporter, 24 November 2015, http://www.biopharma-reporter.com/Mar-
kets-Regulations/Filgrastim-biosimilar-is-first-Latin-copy-biologic-says-Brazil

15
The entry of biosimilars into the regulated markets of the EU and the US
has also been very slow; biosimilars in 2014 accounted for less than 0.5%
of the market for biological medicines.24

Even though biosimilar versions of many top-selling biological drugs are

now being produced by non-originator companies, there are various fac-
tors that limit access to these. Current regulatory regimes require clinical
trials to be done to establish that the biosimilar matches the potency, safety
and efficacy of the originator. This requirement, together with the costly
manufacturing processes, escalates the development costs for biosimilars.
The estimated cost for development of a biosimilar is between US$75-
250 million, one order of magnitude higher than the cost for generics.25

Importantly, unlike in the case of the small molecule generic industry,

many multinational pharmaceutical companies are entering the area of
bio-generic manufacture. The latter have a stake in keeping the prices of
biosimilars comparatively high, hence repeated industry-led assertions
that biosimilar introduction will lead to only a modest drop of 10-50% in
prices.26 While different estimates exist regarding the cost of developing
a biosimilar, the US Federal Trade Commission estimates the cost to be in
the range of US$100-200 million and development takes between 8-10
years (in contrast to 2-3 years for small molecule generics). The high
investment and risk involved, it is said, would depress costs by only 10-
35% compared with the cost of the originator biologic.27 These assertions
are however belied by other evidence – for example, the version of
adalimumab produced by India’s Zydus Cadila (Exemptia) led to an 80%

24
Dorey, Emma (2014) How the biologics landscape is evolving. The Pharmaceutical
Journal, 17 November 2014
25
Calo-Fernandez, Bruno and Juan Leonardo Martinez-Hurtado (2012) Biosimilars:
Company Strategies to Capture Value from the Biologics Market. Pharmaceuticals
2012, 5: 1393-1408; doi:10.3390/ph5121393
26
Mulcahy, AW, Z Predmore and S Mattke (nd) The Cost Savings Potential of Biosimilar
Drugs in the United States. Rand Corporation, https://www.rand.org/content/dam/
rand/pubs/perspectives/PE100/PE127/RAND_PE127.pdf
27
Dorey, Emma (2014) How the biologics landscape is evolving. The Pharmaceutical
Journal, 17 November 2014

16
price reduction.28 In Europe price drops in the range of 45-70% are al-
ready being seen in segments where there is competition from biosimilars.

Some analysts now say that the cost of developing a biosimilar is nearer
US$60 million. Of this, it is projected that US$7-15 million is the typical
cost of analyzing the originator molecule over a period of four years.
Steinar Madsen of the Norwegian Medicines Agency posits that the cost
of manufacture of a biologic is less than 10% of the market cost of the
drug. It is also being projected that regulatory regimes will, in the near
future, largely forgo the need to conduct expensive Phase III trials before
biosimilars are approved, thus drastically cutting the cost of development
of biosimilars.29

28
Press Trust of India (2014) Zydus Cadila launches biosimilar of AbbVie’s Humira in
India. Economic Times, 9 December 2014, http://articles.economictimes.indiatimes.
com/2014-12-09/news/56879703_1_rheumatoid-arthritis-first-biosimilar-humira
29
Stanton, Dan (2015) Number of biosimilar developers growing as costs plummet,
say CPhI experts. 21 October 2015, http://www.biopharma-reporter.com

17
 Chapter Six

Biosimilars vs Generics of SMDs: Different

Treatment by Regulators

EXPERIENCE with SMDs tells us that the introduction of generic drugs

(that is, copies of originator SMDs manufactured by non-originator com-
panies) produces competition in the market, depresses prices and enhances
access. A classic example is that of HIV medicines, the prices of which
saw a 97.5% drop in the early 2000s after the introduction of generics by
Indian companies. This has not happened in the case of biological drugs.
As we discussed earlier, the complex high molecular weight and three-
dimensional structures of biological drugs, their heterogeneity and de-
pendence on production in living cells make it difficult to make exact
copies.

Conventional generics are considered to be therapeutically equivalent to

a reference once pharmaceutical equivalence (i.e., identical active sub-
stances) and bioequivalence (i.e., comparable pharmacokinetics) have been
established. Generally, stringent clinical efficacy and safety studies are
not required. In contrast, as we discuss later, in the case of biosimilars
clinical trials to confirm safety and efficacy are demanded by regulatory
bodies before they are provided with marketing approval. It is argued that
the effects of a biological drug depend on its structural stability, and fac-
tors causing physical and chemical instability alter the three-dimensional
structure and folding pattern of proteins, which may lead to changes in
their immunogenic properties30 – thus adding a new layer of complexity
in testing for safety.

30
Undela, Krishna (2011) Biogenerics or Biosimilars: An overview of the current situ-
ation in India. International Journal of Medical and Pharmaceutical Sciences 1: 1-
10,https://www.researchgate.net/publication/236894615_Biogenerics_or_Biosimilar
s_An_overview_of_the_current_situation_in_India

18
Here, it needs to be underlined that all medicinal products developed
through biological processes do not pose the same level of complexity. In
fact, ‘similar’ versions of biological drugs have been in the market for
over five decades, for example in the case of penicillin, which is pro-
duced through fermentation technology. Likewise, vaccine manufacture
is now undertaken by a number of companies other than the originator
company. More recently, there have been several versions of human insu-
lin available in the market. The discussions below on the challenges to
biosimilar manufacture pertain to more recent biological drugs that use
recombinant technology, and especially to monoclonal antibodies. These
challenges are particularly relevant as the recent biologics of therapeutic
importance fall in this category.

19
 Chapter Seven

Technological Barriers to Manufacture of Biosimilars

A BIOSIMILAR has been defined as a biological medicine that has been

proven, through a regulatory process, to have a high similarity to a refer-
ence biological medicine (also referred to as the originator or original
biological medicine). A biosimilar’s primary amino acid sequence matches
that of the reference biological medicine with only minor differences in
clinically inactive components. Biosimilars are approved by regulatory
authorities to meet standards for similarity in quality, efficacy and safety
to the reference biological medicine.31

The manufacturing of biologics using recombinant technology requires

several stages of cell culture and purification, processes which are confi-
dential to the company developing the product. As it is not possible for
companies producing biosimilars to directly access this know-how, their
manufacturing process will differ from that of the originator, and the struc-
tural variability of the product may be more pronounced. For example,
different cell lines could alter the three-dimensional structure of the final
product. These alterations can, theoretically, lead to adverse consequences
for patient health, such as undesired immunogenic responses.32

31
International Union of Pure and Applied Chemistry (1997) Compendium of Chemi-
cal Terminology, 2nd edition. Cambridge Healthcare Institute
32
Calo-Fernandez, Bruno and Juan Leonardo Martinez-Hurtado (2012) Biosimilars:
Company Strategies to Capture Value from the Biologics Market. Pharmaceuticals
2012, 5: 1393-1408; doi:10.3390/ph5121393

20
It must be kept in mind, however, that all biological products are inher-
ently variable due to the fact that they are produced from living organ-
isms. This variability exists (even when the originator company manufac-
tures the drug) within batches, from batch to batch, and when production
processes are improved or changed or differ between manufacturers. Thus,
what is rarely acknowledged is that different batches of biologics from
innovator companies (branded biologics) also differ slightly.33

33
Welch, Anna Rose (2016) The Norwegian Biosimilar Phenomenon: From Biosimilar
to ‘Biogeneric’. Biosimilar Development, 26 July 2016, http://www.biosimilardevelop
ment.com/doc/the-norwegian-biosimilar-phenomenon-from-biosimilar-to-biogeneric-
0001

21
 Chapter Eight

Barriers Related to Intellectual Property Rights and

Data Exclusivity

BIOLOGICAL drugs are protected by patents (on both product and pro-
cess), trade secrets and data exclusivity. Unlike in the case of SMDs,
process patents can act as a major barrier to the introduction of biosimilars.
Due to the large-molecule nature of biologic products, product patent pro-
tection is often narrower than that for small molecule drugs. The signifi-
cant molecular size of biologic products makes it easier to ‘invent around’
an existing patent, thus narrowing the extent of coverage by a product
patent.34 Thus, process patents are proportionally more important.

Patents constitute the first-level barrier to the entry of biosimilars. Much

of the recent interest in biosimilar development is being driven by the fact
that several top-selling biologics have recently lost patent exclusivity or
are poised to lose it soon. The combined value in 2015 of eight top-sell-
ing biologics losing exclusivity protection from patents or other measures
between 2015 and 2020 in France, Germany, Italy, Spain and the UK, as
well as the US, was €42.3 billion.35 This includes one of the world’s big-
gest-selling drugs of all time, AbbVie’s Humira (adalimumab), which had
sales of €10.8 billion in five EU countries and the US, and which loses
exclusivity in the EU in 2018 and in the US in 2016. Similarly, Amgen
and Pfizer’s Enbrel (etanercept), which is used in the treatment of a num-
ber of chronic inflammatory conditions and which earned €6.9 billion in

34
Globerman, Steven (ed) (2016) Intellectual Property Rights and the Promotion of
Biologics, Medical Devices, and Trade in Pharmaceuticals. Fraser Institute, http://
www.fraserinstitute.org
35
Brennan, Zachary (2016) IMS: Biosimilars Could Save Up to $110B in EU, US
Through 2020. 29 March 2016, http://www.raps.org/Regulatory-Focus/News/2016/
03/29/24671/IMS-Biosimilars-Could-Save-Up-to-110B-in-EU-US-Through-2020/

22
the EU and the US, has lost exclusivity in the EU. Sanofi-Aventis’ diabe-
tes drug Lantus (insulin glargine), which had sales of €8.7 billion in the
EU and the US last year, lost exclusivity in the EU in 2014 and in the US
in 2015.36

Table 4: Patent expiry of top-selling biologics (global sales

>US$4.5 billion)37
Drug Ingredient Company Indication EU US
patent patent
expiry expiry

Humira Adalimumab AbbVie Autoimmune disorders 2018 2016

Lantus Insulin glargine Sanofi Diabetes 2014 2015
Enbrel Etanercept Amgen Autoimmune disorders 2015 2028
Remicade Infliximab Johnson Autoimmune disorders 2015 2018
& Johnson
MabThera Rituximab Roche Cancers; autoimmune Expired 2018
disorders
Avastin Bevacizumab Roche Cancers 2019 2019
Herceptin Trastuzumab Roche Breast cancer 2014 2019
Avonex/ Interferon Beta Biogen/ Multiple 2015 2016
Rebif -1A Pfizer sclerosis
Copaxone Glatirameracetate Teva Multiple sclerosis 2017 2014
Neulasta Pegfilgastrim Amgen Adjunct to cancer 2015 2015
chemotherapy
Lucentis Ranibizumab Genentech Macular degeneration 2016 2016

Concurrently, an estimated 30 companies are actively developing

biosimilars, particularly for infliximab, etanercept, rituximab and
adalimumab.38

However, even after originator biologics lose patent exclusivity, trade

secrets can continue to create barriers to the entry of biosimilars. Most
36
Ibid.
37
See: http://whocc.goeg.at/Downloads/Conference2015/Presentations/DI/
1030_strandI_Vulto.pdf
38
Ibid.

23
small molecule drugs can be easily manufactured once their chemical
structure is known. However, because of the complexity of producing
biologics, companies guard the specifics of their manufacturing and scale-
up methods as trade secrets. This forces biosimilar manufacturers to de-
velop their own methods of manufacture and subsequent validation (to
show similarity with the originator when applying for marketing approval),
often at great expense.39

Industry sources also assert that product and process patents are inad-
equate (or less effective as compared with the case of SMDs) in protect-
ing the intellectual property of the innovator firm’s safety and efficacy
data. Thus data exclusivity provisions are demanded to enhance protec-
tion for innovator drugs.40 Such provisions are ‘TRIPS-plus’, i.e., not re-
quired by the World Trade Organization’s Agreement on Trade-Related
Aspects of Intellectual Property Rights (TRIPS). The importance assigned
to data exclusivity provisions by innovator biotech companies was evi-
dent in the protracted negotiations on the issue during the discussions on
the Trans-Pacific Partnership (TPP) free trade agreement. The United
States (among others) bargained very hard for the introduction of a spe-
cial protection period of 12 years’ exclusivity for biologics,41 which was
opposed by Australia and New Zealand. The final agreement requires
countries to implement one of two options: (1) give eight years of market
exclusivity from the date the biologic is approved in the country con-
cerned; or (2) give five years of market exclusivity from the date the

39
Sherkow, Jacob S (2016) Protecting products versus platforms. http://
www.nature.com/bioent/2016/160401/full/bioe.2016.4.html
40
Lybecker, KM (2016) The Biologics Revolution in the production of drugs. Fraser
Institute, July 2016, https://www.fraserinstitute.org/sites/default/files/biologics-revo-
lution-in-the-production-of-drugs.pdf
41
Jackson, T and D Koedyk (2015) Piggy-backing to market? TPP negotiations bring
data exclusivity periods of biologics into public spotlight. Baldwins, 7 September
2015, https://www.baldwins.com/news/piggy-backing-to-market-tpp-negotiations-
bring-data-exclusivity-periods-of

24
biologic is approved in the country concerned and other measures to de-
liver a comparable market outcome. It is argued by a number of TPP gov-
ernments, such as Australia, New Zealand, Chile and Singapore, that the
provision does not require countries to grant more than five years of bio-
logic exclusivity.42

42
E.g., Australia: http://dfat.gov.au/trade/agreements/tpp/outcomes-documents/Pages/
outcomes-biologics.aspx; New Zealand: http://tpp.mfat.govt.nz/assets/docs/
TPP_factsheet_Intellectual-Property.PDF; Chile: https://ustr.gov/about-us/policy-
offices/press-office/speechestranscripts/2015/october/transcript-trans-pacific;
Singapore: https://www.politicopro.com/trade/story/2015/10/pro-trade-tppbiologics-
behsudi-059493.

25
 Chapter Nine

The Evolving Regulatory Landscape for Approval

of Biosimilars

WHILE the early introduction of cheaper biosimilars faces intellectual

property and technological hurdles, the regulatory barriers imposed by
regulatory agencies in different countries are currently the most signifi-
cant. WHO’s role in this has been less than facilitative and its conserva-
tive approach has had a chilling effect on the early introduction of
biosimilars.

Since the late 1990s, non-originator biological products have been known
by different names, viz., follow-on biologics, bio-generics, biosimilars,
etc. Generally speaking, these nomenclatures are closely linked to the
regulatory pathways followed for the approval of these products. Inter-
estingly, regulatory pathways for non-originator biological products were
recognized in many Asian countries (India, South Korea, etc.) as early as
the 1990s, that is, much before regulatory pathways existed in the EU and
the US. Thus non-originator biological products were available in coun-
tries such as India a decade or more before their entry into the European
market.

The regulatory pathway followed initially in Asian countries was differ-

ent from the biosimilar regulatory pathway broadly advocated by the In-
ternational Conference on Harmonization (ICH), a closed regulatory stan-
dard-setting body founded by drug regulatory authorities of the EU (Eu-
ropean Medicines Agency – EMA), Japan (Ministry of Health, Labour
and Welfare – JMHLW) and the US (Food and Drug Administration – US
FDA) and the originator pharmaceutical industry associations of those
countries (the European Federation of Pharmaceutical Industries’ Asso-
ciations – EFPIA; the Japan Pharmaceutical Manufacturers Association –

26
JPMA; and the Pharmaceutical Research and Manufacturers of America
– PhRMA). Positions that the ICH promotes are reflective of the interests
of originator companies.43

Biosimilars, including monoclonal antibodies, received regulatory ap-

proval in India and South Korea much before the developed-country mar-
kets. To date, India has approved more than 50 ‘similar biologic’ products
for its market. By contrast, the more stringent requirements of ICH-aligned
countries (mainly developed countries) have limited approvals so far. Till
2015 Australia had approved eight, Japan had approved seven and Canada
three.44 The EU had approved about 24, while the US approved its first
biosimilar for filgrastim in 2015. In June 2013, the first approval for a
biosimilar monoclonal antibody was granted in the EU for infliximab.45

The Indian guidelines for introduction of biosimilars were modified in

2012. Prior to 2012 the guidelines were less onerous on biosimilar manu-
facturers. See Table 5 for important divergences between the pre-2012
regulations in India and the WHO guidelines (see below). The 2012 guide-
lines in India were modelled on the then existing EMA guidelines and the
WHO guidelines,46 thus drastically reducing the divergences. The guide-
lines were further modified in 2016.47

43
Third World Network (2014) WHO: Alliance with industry raises concerns over medi-
cine regulation. TWN Info Service on Health Issues, 20 May 2014, http://
www.twn.my/title2/health.info/2014/hi140502.htm
44
Scott, Cheryl and S Anne Montgomery (2015) Biosimilars and Biobetters Offer Unique
Benefits – and Risks. 16 June 2015, http://www.bioprocessintl.com
45
Generics and Biosimilars Initiative (2018) Biosimilars approved in Europe. 2 Febru-
ary 2018, http://www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-
Europe
46
Ohly, C (2012) The New India Guidelines on Similar Biologics: Regulatory and
Market Authorization Requirements. Spicy IP, https://spicyip.com/2012/10/guest-post-
new-india-guidelines-on.html
47
Generics and Biosimilars Initiative (2017) India updates its similar biologics guide-
lines. http://www.gabionline.net/Guidelines/India-updates-its-similar-biologics-guide-
lines

27
 Table 5: Important divergences between pre-2012 Indian
guidelines and WHO guidelines48
Pre-2012 Indian guidelines WHO guidelines
Comparative PK/PD is not mandatory Comparative PK/PD is required
Comparative CT is not mandatory Comparative CT is required
Extrapolation to other indication can Extrapolation to other indication can
be obtained be approved only if the mode of action is
similar
Immunogenicity is not mandatory, Immunogenicity is mandatory
but expected
Notes: PK: pharmacokinetic; PD: pharmacodynamic; CT: clinical trials

WHO’s guidelines and resolution at the WHA

In 2009 the WHO Expert Committee on Biological Standardization

adopted Guidelines on Evaluation of Similar Biotherapeutic Products.
These guidelines drew heavily from the broad positions advocated by the
ICH and since then there has been a major push for the adoption in other
countries of biosimilar guidelines modelled on the ICH’s positions and
EU guidelines. (The EU guidelines have since been modified and are
now much less onerous (see below).) The 2009 WHO guidelines require
‘head to head’ comparability of the non-originator product with the origi-
nator product.

The principles underlying the approach to biosimilars included in the WHO

guidelines are:49
• Full quality dossier, including comparisons with original
• Limited preclinical dossier including pharmacokinetics comparison
with original
• Clinical similarity where hard clinical endpoint is not needed
• Extrapolation possible
• Post-marketing safety studies including immunogenicity.
48
Malhotra, H (2011) Biosimilars and non-innovator biotherapeutics in India: An over-
view of the current situation. Biologicals 39 (2011): 321-324, https://
www.ncbi.nlm.nih.gov/pubmed/21784652
49
See: http://bcn2012.europeanbioanalysisforum.eu/slides/day%202/ii%20biosimilars/
1_schellekens.pdf

28
Demonstration of similarity with the originator requires comparative clini-
cal trials with the originator. According to industry sources, a major pro-
portion of the biosimilar development cost arises as a result of the need to
purchase the originator product. Further, the burden of proof on similar-
ity also increases the duration of biosimilar development. These onerous
regulatory requirements delay introduction of biosimilars and prevent a
significant drop in prices when biosimilars are introduced. Thus regula-
tory requirements represent one of the most significant barriers to afford-
able access to biological products. Also, even with the smaller clinical
trials that are demanded by current regulations, biosimilar sponsors face
challenges in identifying clinical sites and investigators that understand
their unique development issues and can attract a sufficient number of
participants.50

The WHO guidelines have been criticized by analysts for their ‘similarity
proof requirement’: ‘Biosimilars regulatory guidance should be reviewed
in light not only of the scientific and regulatory experience gained over
time, but also of the needs and interests of national health systems and
pharmaceutical markets in low-resource countries. Stringent regulatory
authorities such as EMA have already begun to waive requirements for
comparability exercise at clinical level under appropriate circumstances.
This approach is supported by academic experts who claim that non-com-
parative clinical trials are sufficient for regulatory purposes, and who call
for pragmatic approaches focused primarily on the patients clinical out-
comes and on scientific principles, using the state-of-the-art tools.’51

Reflecting the concerns on non-availability of biological products at af-

fordable prices, WHO’s governing World Health Assembly (WHA) in
2014 adopted a resolution that urged member states ‘to work to ensure
that the introduction of new national regulations, where appropriate, does

50
Wechsler, J (2016) Biosimilar trials differ notably from innovator studies. http://
www.appliedclinicaltrialsonline.com/biosimilar-trials-differ-notably-innovator-studies
51
Milani, B and S Gaspani (2013) Pathway to affordable, quality based sources of
pegylated interferon alpha for treating Hepatitis C. Generics and Biosimilars Initia-
tive Journal, Volume 2, 2013, Issue 4, p. 194, http://apps.who.int/medicinedocs/docu-
ments/s21311en/s21311en.pdf

29
not constitute a barrier to access to quality, safe, efficacious and afford-
able biotherapeutic products, including similar biotherapeutic products’.52
The resolution further requested the WHO Director-General ‘to convene
WHO’s Expert Committee on Biological Standardization to update the
2009 guidelines, taking into account the technological advances for the
characterization of biotherapeutic products and considering national regu-
latory needs and capacities and to report on the update to the [WHO]
Executive Board’.

However, WHO does not seem to have followed the spirit of the WHA
resolution. Instead, it has, on its website, issued certain ‘clarifications’ in
the form of Q&As.53 Thus WHO has not actually updated its 2009 guide-
lines. It has issued several reports by its Expert Committee on Biological
Standardization which continue to strengthen the obligations of biosimilar
manufacturers laid out in the 2009 guidelines. A report by the expert com-
mittee issued in 2016 recommends reappraisal or re-registration of prod-
ucts introduced in situations where the WHO guidelines were not fol-
lowed.54 The 2016 report recommends, inter alia, that: ‘Attention should
be paid to any key differences between national requirements and the
WHO Guidelines – such as the lack of a head-to-head comparability exer-
cise for an SBP [similar biotherapeutic product]. The NRA [national regu-
latory authority] should provide manufacturers with a critical dataset for
the re-registration of such products. Changes in regulatory requirements
may be needed, as well as amendments to the legal framework of the
country concerned, to enable such new requirements to be implemented.’

52
World Health Organization (2014) Sixty Seventh World Health Assembly, Resolu-
tions and Decisions Annexes, p. 68, http://apps.who.int/gb/ebwha/pdf_files/WHA67-
REC1/A67_2014_REC1-en.pdf#page=25
53
See: http://www.who.int/biologicals/QA_for_SBPs_HK_12_Dec_2017_(2).pdf?ua=1
54
World Health Organization (2016) WHO Expert Committee on Biological Standard-
ization, sixty-sixth report. WHO technical report series No. 999, http://www.who.int/
biologicals/expert_committee/WHO_TRS_999_corrigenda_web.pdf

30
European guidelines

In October 2014 the EMA finalized new regulatory guidelines on

biosimilars in the EU.55 The guidelines update its October 2005 guide-
lines on biosimilarity (developed based on ICH standards), which offi-
cials said had become outdated. The new guidelines, it is claimed, would
clarify how companies can establish biosimilarity between their follow-
on biologic and the original biologic product approved by the EMA. The
guidelines also include a discussion regarding the ‘principles of estab-
lishing biosimilarity’. The EMA recommends a ‘stepwise approach’ meant
to build upon rigorous data at every stage of the evaluation process. The
EMA explains: ‘If the biosimilar comparability exercise indicates that
there are relevant differences between the intended biosimilar and the
reference medicinal product making it unlikely that biosimilarity will
eventually be established, a stand-alone development to support a full
Marketing Authorisation Application (MAA) should be considered in-
stead … Clinical data cannot be used to justify substantial differences in
quality attributes.’56 Essentially what this stepwise approach involves is
an assessment of similarity at every step. If, at any step, the divergence in
similarity is seen to be too large, the similar molecule will be treated as a
new molecule requiring submission of a full dossier.

US guidelines

At the end of March 2010 the United States enacted the Biologics Price
Competition and Innovation Act (BPCI). The BPCI defines a biosimilar
product as ‘(A) ... highly similar to the reference product notwithstanding
minor differences in clinically inactive components; and (B) ... no clini-
cally meaningful differences between the biological product and the ref-

55
The EMA guidelines can be accessed here: http://www.ema.europa.eu/ema/
index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01
ac058002958c
56
See: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2014/10/WC500176768.pdf

31
erence product in terms of the safety, purity, and potency of the prod-
uct’.57 As regards interchangeability between originator products and
biosimilars, the Act says that the interchangeable product must meet all
the same requirements as a reference product and in addition have the
same route of administration, dosage form and strength as the reference
product.58 In many states in the US, an interchangeable may be substi-
tuted for the reference product without the intervention of the healthcare
provider who prescribed the reference product, as this is governed by
state pharmacy laws. The US FDA states in this respect: ‘Once a biosimilar
has been approved by FDA, patients and health care providers can be
assured of the safety and effectiveness of the biosimilar, just as they would
for the reference product.’59

There are no fundamental differences between the EU and US guidelines

concerning the non-clinical and clinical testing strategies. However, ex-
trapolating immunogenicity data from one indication to another is allowed
in the US but not in the EU. The European Commission issued a directive
in 2012 requiring biological products to be identified by brand name and
not by INN. However, the US FDA is less precise in this context, saying
only that the naming and labelling of the drug should facilitate decision
making by the prescribing healthcare professional.60

57
Lemery, SJ, FJ Esteva and M Weise (2016) Biosimilars: Here and Now. Am Soc Clin
Oncol Educ Book 2016; 35: e151-e157; doi: 10.14694/EDBK_155954. https://
meetinglibrary.asco.org/record/50599/edbook#fulltext
58
See: https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalPro
ductsandTobacco/CDER/UCM606115.pdf
59
See:https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevel
opedandApproved/ApprovalApplications/TherapeuticBiologicApplications/
Biosimilars/ucm580430.htm#sub
60
Blank, Tobias (2013) Safety and toxicity of biosimilars – EU versus US regulation.
Generics and Biosimilars Initiative Journal 2013; 2(3): 144-150; doi: 10.5639/
gabij.2013.0203.039

32
 Chapter Ten

How Necessary Are Present Requirements to

Establish Similarity?

SEVERAL experts have argued that the merits and/or added value of the
comparability exercise are questionable as the comparison of quality char-
acteristics between the biosimilar and the reference product will always
show differences. It is further argued that there are also many reasons to
question the usefulness of comparative pharmacokinetic trials. ‘The as-
says to determine product levels are often too imprecise; the relation be-
tween pharmacokinetic parameters and clinical effect of biologics is un-
clear; the dose-response curve of therapeutic proteins is often bell-shaped
(meaning that widely differing protein levels have the same clinical ef-
fect); and the acceptance range for pharmacokinetics parameters between
biosimilar and reference product are difficult or impossible to predefine
and justify … Dropping the obligation to do the comparability exercise
will make it easier to develop more complex biosimilars, such as mono-
clonal antibodies (mAbs) and vaccines.’61 62

Moreover, the value of comparative clinical trials for showing clinical

equivalence of biosimilars that demonstrate a high degree of similarity in
physical, chemical, structural and biological characteristics with the origi-
nal product is increasingly being questioned, and advances in analytical
methods that provide robust non-clinical data should reduce the need for
extensive clinical comparison.63

61
Schellekens, H and E Moors (2010) Clinical comparability and European biosimilar
regulations. Nature Biotechnology 28: 28-31
62
Frapaise FX (2018) The End of Phase 3 Clinical Trials in Biosimilars Development?.
BioDrugs, August 2018
63
Schellekens, H et al. (2016) Safety and efficacy of biosimilars in oncology. The Lan-
cet, http://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(16)30374-6.pdf

33
 Chapter Eleven

Uptake of Biosimilars in Clinical Practice:

Interchangeability and INN

THE role of regulatory agencies is also critical in the uptake of biosimilars

in clinical practice. In the EU, different countries have differing approaches
to the issue of interchangeability between biologics and biosimilars. Most
EU member states do not explicitly authorize the substitution of biologicals
from different manufacturers, and a number have gone as far as banning
this practice.64 However, Norway has emerged as a leader in the introduc-
tion of biosimilars in the EU, led by Dr. Steinar Madsen of the Norwegian
Medicines Agency.

Europe saw the approval of Omnitrope, its first biosimilar, in 2006. Shortly
thereafter came the rise of what Madsen referred to as the ‘biosimilar
resistance’. EU countries encountered numerous claims that biosimilars
were inferior products and, therefore, that ‘switching’ (that is, interchange-
ability between higher-cost biologics and lower-cost biosimilars) should
not be permitted. However, Norway encouraged switching and the results
were often dramatic. In Norway the biosimilar infliximab (Remsima) has
a 92.9% market share (April 2016). Other Scandinavian countries have
followed suit; in Denmark, the biosimilar of infliximab has 96% of the
market, and in Finland 88%. In the absence of similar strategies in Swe-
den, biosimilars account for just 33.5% of the market.65

64
____________ (2015) Biosimilars and interchangeability. Generics and Biosimilars
Initiative, 13 November 2015, http://www.gabionline.net/Biosimilars/Research/
Biosimilars-and-interchangeability
65
Welch, Anna Rose (2016) The Norwegian Biosimilar Phenomenon: From Biosimilar
To ‘Biogeneric’. Biosimilar Development, 26 July 2016, http://www.biosimilardevelop
ment.com/doc/the-norwegian-biosimilar-phenomenon-from-biosimilar-to-biogeneric-
0001

34
Likewise in the US, a number of states have passed legislation that re-
quires a biosimilar to be deemed by the FDA to be interchangeable before
a pharmacist can automatically substitute a biosimilar for a biologic. No
interchangeable biosimilars have been approved in the US as yet.66

In 2015, the Australian regulatory authorities made the world’s first rec-
ommendation to allow clinicians and pharmacists the option of substitut-
ing expensive biologic medicines at the chemist’s if there is a cheaper
replacement or biosimilar available that has been determined by experts
to be a safe, equally effective treatment. The recommendation does not
require that pharmacists notify physicians or patients of a substitution,
nor does it specify that pharmacists must keep a log of the substitution.67

How biosimilars are named also has an impact on the willingness of phy-
sicians to switch between branded biologics and biosimilars. While in the
case of small molecule drugs generic equivalents are given the same INN
as the innovator drugs, there is no uniformity regarding this across vari-
ous regulatory regimes for biological products.

WHO’s INN Expert Group has proposed the use of a Biological Qualifier
(BQ), separate from the INN scheme, to identify the source of a biologi-
cal substance to ‘enable substances to be traced in different licensing sys-
tems, whether classified as “similar biological substances” or not’.68 Con-
sisting of four random consonants and an optional two-digit checksum,
the BQ is proposed as an identifier that follows the non-proprietary name
of each biologic and biosimilar product. This recommendation is in fact

66
Brennan, Zachary (2016) IMS: Biosimilars Could Save Up to $110B in EU, US
Through 2020. 29 March 2016, http://www.raps.org/Regulatory-Focus/News/2016/
03/29/24671/IMS-Biosimilars-Could-Save-Up-to-110B-in-EU-US-Through-2020/
67
Hernandez, R (2015) Australia Allows Pharmacy-Level Substitution of Biologics.
http://www.biopharminternational.com/australia-allows-pharmacy-level-substitution-
biologics
68
World Health Organization (2016) International Nonproprietary Names (INN) for
biological and biotechnological substances (a review). http://www.who.int/medicines/
services/inn/BioReview2016.pdf?ua=1

35
contrary to the recommendation of an informal consultation in 2006 con-
vened by WHO. This consultation recommended: ‘INNs should be based,
as now, on considerations of molecular characteristics and pharmacologi-
cal class. No specific process should be introduced for naming
biosimilars.’69

Biosimilar manufacturers argue that distinct names will impede the adop-
tion of biosimilars.70 Currently WHO has shelved the proposal on BQs,
but it could be resurrected at a later date at the behest of some WHO
member states which choose to side with industry.

The resistance towards substitution of innovator biologics with biosimilars,

including in the medical profession, stems from the notion that, given the
unique characteristics of biological drugs, copies in the form of biosimilars
simply will not be able to match the originator. However, some recent
research seems to suggest that biosimilars appear to be as good as the
originator biologics. A recent study reviewed data from 19 studies con-
ducted through April 2016, which compared biologic and biosimilar ver-
sions of tumour necrosis factor-alpha (TNF-α) inhibitors. These treat-
ments suppress the over-activity of the immune system in rheumatoid
arthritis, inflammatory bowel disease (such as Crohn’s disease) and pso-
riasis. They include well-known biologics – Amgen’s Enbrel, AbbVie’s
Humira, and Johnson & Johnson’s Remicade. The findings, published in
the Annals of Internal Medicine, suggest that the biosimilar forms of TNF-
α inhibitors are just as safe and effective as their biologic counterparts.71

69
See: http://www.who.int/medicines/services/inn/BiosimilarsINN_Report.pdf
70
Li, S and I Royzman (2016) Final WHO Biosimilar Naming Proposal Resembles
FDA Approach. Biologics Blog, 3 February 2016, https://www.biologicsblog.com/
final-who-biosimilars-naming-proposal-resembles-fda-approach
71
Guzowski, S (2016) How do biosimilars compare with brand-name biologics? http:/
/www.dddmag.com/article/2016/08/how-do-biosimilars-compare-brand-name-
biologics

36
 Chapter Twelve

Conclusions

THIS paper has discussed the ecosystem that informs access to biological
drugs, including biosimilars. The analysis carried out in the paper leads
us to the following conclusions and recommendations:

• The potential role of biological drugs in promoting real therapeutic

advances needs a deeper analysis. However, current evidence sug-
gests that they will play an increasingly major role in the future in
advancing therapeutic outcomes for several autoimmune and de-
generative diseases and in cancer treatment.
• Biological drugs are extremely expensive. Their high prices are a
reflection of protected monopolies in the biotech sector. Further,
unlike in the case of SMDs, the anticipated drop in prices after in-
troduction of biosimilars is conventionally pegged at only around
30%. There are no clear technical reasons why price drops cannot
be much sharper.
• Regulatory barriers (i.e., onerous requirements for regulatory ap-
proval) are key factors preventing introduction of cheaper follow-
on products of equivalent safety and efficacy. The current regula-
tory regimes and the underlying WHO guidelines are not in sync
with advances in the science of biological products. Insistence, by
regulatory agencies and in the WHO guidelines, on head-to-head
comparisons, including comparative pharmacokinetic studies, be-
tween innovator products and follow-ons is no longer justifiable.
Moreover, it is possible to obviate the need for expensive and diffi-
cult-to-design clinical trials given better techniques for character-
ization of follow-ons, which could be combined with animal stud-

37
 ies. Regulatory regimes and guidelines, including the WHO guide-
lines, need to be revised taking the above into account.
• Given monopolies enjoyed by innovator biologics and their very
high market prices, there appears to be little incentive available to
reduce the cost of manufacture of biological products through intro-
duction of more efficient technologies. On the other hand, the manu-
facturers of follow-on products appear better placed to introduce
more efficient and cheaper technologies.
• Intellectual property protection, just as in the case of SMDs, pro-
motes monopolies and prevents the early introduction of follow-on
biologics. Process patents and trade secrets are major barriers to the
introduction of biosimilars. In addition, the biotech industry is more
aggressive in demanding data exclusivity rules. All these act as lay-
ers of barriers to the early introduction of cheaper biosimilars.
• The proposed introduction of ‘Biological Qualifiers’ to be tagged
on to INNs for biosimilars is unjustified and WHO should not pur-
sue this proposal.
• It is necessary to harmonize rules and allow for interchangeability
between innovator products and biosimilars which have received
regulatory approval. This would make uptake of biosimilars in clini-
cal practice easier.

38