The new-india-biosimilar-guidelines

Christopher Ohly The New India Guidelines on Similar Biologics

The New India Guidelines
On Similar Biologics
Regulatory and Market Authorization Requirements

By, Christopher Ohly,
Partner, Schiff-Hardin.

October 8, 2012

Overview1

Biological products are any virus, therapeutic serum, toxin, antitoxin, vaccine, blood
component or derivative, allergenic product, protein (except any chemically
synthesized polypeptide) or analogous product applicable to the prevention, treatment
or cure of diseases or injuries of man.2 Biological products are generally produced using
a living system or organism, but increasingly may be synthesized using chemical and
computational techniques.3 While “small molecule” drugs have well-defined chemical
structures that can be readily and fully characterized, and are “are ideal for replication
as generics,”4 biological pharmaceutical products are not yet as readily replicable in
identical forms. Biological pharmaceutical products are usually large, complex
molecular structures, whose chemical composition and conformation are important to
activity, effectiveness and toxicity.

Biologic products are both therapeutically and economically important. In contrast to
other therapeutic agents, such as chemotherapies, biologic products, particularly
monoclonal antibodies, are highly selective, offering effective treatments against
dreaded diseases with fewer side effects.5 More than 150 “reference product” biologics
have been approved for marketing in the United States. There are more than 370
biopharmaceutical drug products and vaccines in clinical trials targeting more than 200
diseases including cancer, Alzheimer's disease, heart disease, multiple sclerosis, AIDS,
and arthritis.

Of the top 10 pharmaceutical products in 2011, by global sales, three (Humira, Enbrel
and Remicade) were biologics. 6 In 2010, the combined sales of the top 12 biologic
products in the U.S. approached $30 billion.7 Biologic products are expensive. In the
US in 2011, it was estimated that the average cost of a biologic product was $16,000 per
year, with the costs for biologic therapies for treatment of some cancers costing as much
as $10,000 a month.8 According to one prediction, by 2014, seven out of the top ten
best-selling drugs will be biologic drugs, with sales exceeding $50 billion.9 The trend

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will continue, with biologic products increasingly replacing “small molecule” products
as the largest generators of sales revenues, if not the preferred therapeutic method.

These market and therapeutic opportunities have led to development of “biosimilars,”
or “follow-on biologics,” which are produced by cellular means, not “identical” but
therapeutically equivalent (in safety and efficacy) to reference products, and, hopefully,
made and sold at substantially lower cost. Current U.S. law defines biosimilarity to mean
“that the biological product is highly similar to the reference product notwithstanding
minor differences in clinically inactive components” and that “there are no clinically
meaningful differences between the biological product and the reference product in terms
of the safety, purity, and potency of the product.”10

Biologics and Biosimilars in India

According to a 2010 report, more than 40 biologics are marketed in India, of which 25
are biosimilars manufactured in India, including insulin, epoetin, filgrastim,
streptokinase, and rituximab. Another 25 biosimilar products are in development.
The same report states that there “are more than 130 companies in the
biopharmaceutical market in India, but “only 7-10 companies are involved in the
manufacture of recombinant products.”11 Although, in the short term, some Indian
companies are reportedly targeting unregulated and “semi-regulated” markets,
including India itself, price advantages will lead to entry in highly regulated markets,
including the EU and United States.

At the same time, changes are coming in the Indian market, as larger pharmaceutical
and biologic manufacturers enter the growing Indian market, sometimes in competition
and sometimes in joint ventures (or mergers) with Indian pharmaceutical
manufacturers:

In 2001 India liberalized foreign direct investment (FDI) norms for the pharmaceutical
sector. As a result, 100% FDI was allowed through the 'automatic route' (without prior
permission) in pharmaceutical manufacturing (except in sectors using recombinant
DNA technology).

*****
In recent years there have been a number of high-profile MNC acquisitions of Indian
pharmaceutical companies, starting with the takeover of Matrix Laboratories by US
generic manufacturer Mylan Inc in 2006. This was followed by the Japanese corporation
Daiichi's acquisition of India's largest pharmaceutical company Ranbaxy. At times
MNCs offered purchase prices which were many times higher than the actual sales

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turnover of the acquired firms. For instance, Abbott paid $3.7 billion for Piramal
Healthcare, whose sales revenue was reported to be approximately $400 million. …
The same period witnessed a series of strategic alliances between MNCs and Indian
pharmaceutical companies. … Generally speaking, these strategic alliances take place in
any one of the following areas: research and development (R&D), marketing and
contract manufacturing. Of the three categories, the dominant form is in the field of
contract manufacturing.12

The impact of these market changes in India is uncertain, particularly as litigation over
patents covering important and expensive products, including biologics, works its way
through the Indian courts.13 Nevertheless, it is inevitable that Indian manufacturers will
enter the burgeoning global biosimilars market, and that foreign manufacturers will
continue to penetrate the growing Indian market for biologic drugs.14

India’s New Biosimilar Guidelines

On June 20, 2012, at the BIO2012 conference in Boston, India’s Department of
Biotechnology (DBT) and its Central Drugs Standard Control Organization (CDSC)
announced the release of final guidelines for approval of “similar biologics.”
The guidelines became publicly available on the Internet a short time later.
At BIO, DBT Secretary Maharaj Bhan stated,

“We don’t want the global and local industries to be in conflict all the time, there
needs to be a more harmonious relationship. It [the guidelines] will give a very clear
message to everyone...that the Indian regulatory system is capable of taking a scientific
view of things and not necessarily worrying about trivial advantage in one
direction or the other."15

India’s new guidelines describe a regulatory pathway for a similar biologic claiming to
be similar to an already authorized reference biologic. They address pre-market
regulatory requirements including the “comparability exercise” for quality, preclinical
and clinical studies and describe detailed post market regulatory requirements. They
also contain requirements relating to manufacturing processes and quality control.
These requirements are themselves similar in many respects to comparable regulatory
guidelines in the United States and the EU. 16 While harmonization is far from
complete, it appears that, at least in his area, science will dominate and bring different
regulatory systems into significant conformity.17

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Basic Principles

The Indian guidelines define a “similar biologic” as a “biological product/drug
produced by genetic engineering techniques and claimed to be ‘similar’ in terms of
safety, efficacy and quality to a reference biologic, which has been granted a marketing
authorization in India by DCGI on the basis of a complete dossier, and with a history of
safe use in India.” 18 This definition is not substantively different from definitions
offered in US and EU laws and regulations. Unlike US law, neither Indian nor EU
guidelines or law distinguish between a “biosimilar” and an “interchangeable” product,
leaving choice about therapeutic substitution of a biosimilar for a reference product to
physicians and their patients. Unlike US law, neither Indian nor EU law or regulations
provide any a period of market or data exclusivity to a biosimilar manufacturer that is
able to demonstrate that its product may be freely “switched” for a reference product in
any given patient,” without increasing “the risk of using the reference product without
such alternation or switch.”19

Analytical Studies

Like the “stepwise approach” taken in the US and EU, India has adopted a “sequential
approach” to its consideration of applications to market biosimilars.20

According to India’s biosimilar guidelines, “[s]imilar biologics are developed through
[a] sequential process to demonstrate the similarity by extensive characterization
studies revealing the molecular and quality attributes with regard to the reference
biologic.” 21 Through this stepwise approach, “extensive structural and functional
characterization of both the proposed product and the reference product” using advance
analytical techniques to identify and compare “physico-chemical and biological properties,
such as higher order structures and functional characteristics,” not only of “the drug
substance of a protein product, but also excipients and product- and process-related
impurities,” serves as the “foundation of a biosimilar development program.”22

The India Guidelines set forth specific and highly technical requirements for “routine
analytical tests” to be employed in a “comparability exercise,” including analytical
methods for determination of structural and physicochemical product properties,
biological activity, immunological properties, characterization of impurities, and
stability testing.23 Taking this sequential approach, the India Guidelines suggest that the
results of such analytical testing may reduce the potential requirement of human and
animal clinical testing of biosimilars candidates:

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Although the extent of testing of the similar biologic is likely to be less than that
required for the reference biologic, it is essential that the testing of the similar biologic
be sufficient to ensure that the product meets acceptable levels of safety, efficacy and
quality to ensure public health.

Generally, a reduction in data requirements is possible for preclinical and/or clinical
components of the development program by demonstration of comparability of product
(similarity to authorized reference biologic) and the consistency in production process, which
may vary depending on the characteristics of the already authorized reference
biologic.24

Correspondingly, the India Guidelines, like the US and EU guidances, leave ultimate
requirements to science, defined by discussions between product sponsors and
regulators.

Clinical Testing

Under US procedures, after evaluating results of analytical testing that characterizes
both the reference product and a proposed biosimilar, the FDA will then determine on a
case-by-case basis how much animal and clinical data are required and evaluate the
application based on the totality of the evidence. 25 Under the India Guidelines, some
information is provided about potential animal studies to be conducted with the
approval of India’s Institutional Animal Ethics Committee (IAEC), if such approval is
available. The guidelines clearly state that, when characterizing the “immunological
properties” of a proposed biosimilar product, “evaluation by animal studies should be
performed.”26

In case of in vivo toxicity studies, at least one repeat dose toxicity study in a relevant
species is required to be conducted. The duration of the study would be generally not
less than 28 days with 14 days recovery period. However the duration may vary
depending on the dosage and other parameters on case by case basis.

Regarding the animal models to be used, the applicant should provide the scientific
justification for the choice of animal model(s) based on the data available in scientific
literature. However if the relevant animal species is not available and has been
appropriately justified, the toxicity studies need to be undertaken in two species i.e. one
rodent and other non rodent species, as per the requirements of Schedule Y with due
permission from the RCGM.27

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Human clinical testing will ordinarily follow analytical and clinical testing.28 Under
the India Guidelines a biosimilars applicant must submit an application to conduct a
clinical trial in accordance with previously published CDSCO guidelines.29 Once such
an application is approved, a biosimilar sponsor will be required to conduct several
studies designed to establish comparative safety and efficacy in relevant patient
populations.30

Comparative pharmacokinetic studies should be conducted “in healthy volunteers or
patients to demonstrate the similarities in pharmacokinetic characteristics between
similar biologic and reference biologic on case to case basis.” Such PK
(pharmacokinetic) studies must be performed using dosages “within the therapeutic
dose range of reference biologic.” The India Guidelines continue:

A parallel arm design is more appropriate for biologics with a long half life or for
proteins for which formation of antibodies is likely or if study is being done in patients.
In case of short half life, cross over design may be considered with a scientific
justification.

*****

Multiple-dose, comparative, parallel arm steady state PK studies are required for a
similar biologic that is used in a multiple dose regimen, where markedly higher or
lower concentrations are expected at steady state than that expected from single dose
data PK measurements, and where time-dependence and dose-dependence of PK
parameters cannot be ruled out. 31

Similarly, the India Guidelines require human pharmacodynamic studies:

Comparative, parallel arm or cross-over, PD study in most relevant population (patients
or healthy volunteers) is required for detecting differences … If PD marker is available in
healthy volunteers, PD in healthy volunteers can be done. … The relationship between
dose/exposure, the relevant PD marker(s) and response/efficacy of the reference biologic
should be well established and used to justify the design. The acceptance ranges for the
demonstration of similarity in PD parameters should be predefined and appropriately
justified.32

Such PD studies are “recommended” when “the PD properties of the reference biologic
are well characterized with at least one PD marker being linked to the efficacy of the
molecule.”33

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The India Guidelines appear to mandate at least some additional human clinical trials “to
demonstrate the similarity in safety and efficacy profiles between the similar biologic
and reference biologic.” To establish similarity, “equivalence trials with equivalence
designs (requiring lower and upper comparability margins) are preferred.”34 Hence, in
India, unlike the US, it would seem to be possible, in some circumstances, to employ
non-inferiority tests to establish efficacy and aspects of safety in addition to
immunogenicity.35

As in the US and EU, assessment of adverse events occasioned by administration of a
biosimilar product is a critical component of human clinical testing. Hence, the India
Guidelines state that the “nature, severity and frequency of adverse events should be
compared between the similar biologic and reference biologic and should be based on
safety data from a sufficient number of patients treated for an acceptable period of
time.” These guidelines add that [e]fforts should be made to ensure that comparative
clinical studies have a sufficient number of patients treated for acceptable period of time
in order to allow detection of significant differences in safety between similar biologic
and reference biologic.”36

The India Guidelines add specific post-market surveillance requirements that seemingly
will augment or, perhaps, substitute for extensive pre-approval human clinical testing
requirements. First, the guidelines require institution of a post-approval Risk
Management Plan, designed to monitor and detect both known inherent safety concerns
and potential unknown safety signals that may arise from the similar biologics. Such a
risk management plan must be submitted along with a biosimilar sponsor’s Market
Authorization Application. 37 The Plan must include at least one non-comparative
post-marketing clinical study with focus on safety and immunogenicity, designed to
confirm that the similar biologic does not have any concerns with regards to the
therapeutic consequences of unwanted immunogenicity. However, the India Guidelines
provide, “[i]f immunogenicity is evaluated in clinical studies, it is not mandatory to
carryout additional non-comparative immunogenicity studies in post-marketing
studies.”38

The importance of shifting human clinical testing requirements to the speed of approval
of a biosimilar may be demonstrated by the experience of Dr. Reddy’s Laboratories
(DRL) in approval of its Reditux® (rituximab) biosimilar product. During the
November 2010 pre-guidance FDA hearing, a speaker for DRL reported that
pre-approval testing of DRL’s rituximab biosimilar required administration of the
proposed product to a mere 67 patients, with many more reported in post-market
surveillance. Post market surveillance did not show “a single case of immunogenic

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response in any patient,” with more than 1000 patients treated with DRL’s Reditux after
market approval, by the time of the presentation.39

Extrapolation

The FDA guidances indicate that data derived from a clinical study sufficient to
demonstrate safety, purity, and potency in an appropriate condition of use, potentially
may be extrapolated to allow the biosimilar to be licensed for one or more additional
indications for which the reference product is licensed. 40 For example, relying on
clinical testing of a Humira® or Remicade® biosimilars in patients with rheumatoid
arthritis, it may theoretically be possible to obtain licensing for sale and use of such
biosimilars in patients suffering from psoriasis or Crohn’s disease, which, like
rheumatoid arthritis, are thought to be conditions associated with inflammation caused
by the production of TNFα (tumor necrosis factor-α) in humans, without substantial or
any additional clinical testing.

The India Guidelines state that “[i]n case the reference biologic is used for more than one
indication, the efficacy and safety of the similar biologic has to be justified and if
necessary demonstrated separately for each of the claimed indications.” They add that
[j]ustification will depend on clinical experience, available literature data and whether
or not the same mechanism of action is involved in specific indications.” The guidelines
thus state that, in India, “extrapolation of the safety and efficacy data of a particular
clinical indication (for which clinical studies has been done) of a similar biologic to
other clinical indications may be possible,” if certain conditions are met. The list of
conditions for consideration of extrapolation is not as long as the list in US guidances,
but it is similar in content.

Reference Product

The India Guidelines define a “reference biologic” as “the comparator [used] for
head-to-head comparability studies with the similar biologic in order to show similarity
in terms of safety, efficacy and quality.” The definition requires that “[o]nly a product
that was licensed on the basis of a full registration dossier can serve as reference
biologic.” 41 Under the guidelines the reference biologic must be used in all
“comparability exercise[s] with respect to quality, preclinical and clinical
considerations.”42

Under the India Guidelines, the reference biologic “should be licensed in India and should
be innovator product.” It should be “licensed based on a full safety, efficacy and quality

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data.” Hence, “another similar biologic cannot be considered as a choice for reference
biologic.”43

While the reference biologic must be licensed in India and should be innovator product,44 it
is not necessary, under the India Guidelines for the reference product even to be sold or
marketed in India. 45 The India Guidelines may simply recognize that some foreign
manufactured biologic products are simply not yet available in India, if only for
economic reasons. The India Guidelines appear to permit use of foreign reference
biologic products in a comparability exercise, whether or not the reference product is
marketed or, under some circumstances, even licensed in India.46 The critical issue will
be whether Indian biosimilar developers and manufacturers are able to obtain sufficient
quantities of a foreign reference product to enable all of the required analytical, animal
and human clinical testing required by Indian regulators. While this seemingly has not
been an extraordinary impediment to date, legal developments may make acquisition of
reference product more difficult in the future.47

Manufacturing

The India Guidelines set forth a series of quality considerations applicable to
manufacturing of biosimilar products.48 Among other things, these guidelines state that
the “manufacturing process for similar biologic should be highly consistent and
robust.” 49 They set standards for cell lines used in the biosimilar manufacturing
process,50 as well as standards for fermentation and downstream process development,
analytical methods, product characterization, stability and specifications. 51 The
guidelines generally require that “three consecutive standardized batches which have
been used to demonstrate consistency of the manufacturing process should be used” in
the quality comparability study. 52 The guidelines mandate that “[h]ead-to-head
characterization studies are required to compare the similar biologic and the reference
biologic at both levels of drug substance and drug product,” adding that “[d]ifferences
… should be evaluated for their potential impact on safety and efficacy of the similar
biologic and additional characterization studies may be necessary.” 53 The India
Guidelines provide that such a “quality comparison … should employ state-of-the-art
analytical techniques, including the analytical methods that are sensitive enough to
detect the possibilities of changes to the product,” providing a list of routine analytical
tests to be included in the quality comparability exercise.54

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Concluding Comments

The India Guidelines represent a major step forward in establishing a rigorous,
science-based regime for approval of biosimilars pharmaceutical products, especially
for sale and therapeutic use in India. The guidelines mirror similar efforts in the US
and EU and, like those “regulated market” guidances, consciously rely upon other
guidance documents issued by the International Conference on Harmonization, with a
view toward encouraging the manufacture of safe and effective biologic products in
India, perhaps at lowered costs, to ensure access to life-saving drugs for many.

Like their counterparts in the US, EU and perhaps elsewhere, the India Guidelines will
contribute to harmonization efforts, perhaps ultimately resulting in a globally consistent
approach to biologic development and manufacture, reducing the need for redundant
clinical trials. The guidelines will likely also contribute enabling certainty to the efforts
of both Indian drug manufacturers and others who may enter the burgeoning Indian
market, that contemplate significant investment in research, manufacturing facilities,
and new means of product marketing.

All of this may well lead Indian manufacturers to become effective competitors in the
global market for biologic medicines, both as suppliers of biosimilar products and, soon
thereafter, of “biobetters” and innovative new medicines. That contribution to global
health, whether encumbered or unencumbered by disputes over exclusivities and
patent protection, will be welcomed by all.

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ANNEX 1: Other India Guidance Documents

According to the India Guidelines, similar biologics are regulated in India under the
Drugs and Cosmetics Act, 1940, the Drugs and Cosmetics Rules, 1945; Rules for the
manufacture of hazardous and genetically engineered organisms or cells, 1989 (Rules,
1989); and several additional guidelines, including:

Schedule Y: Requirements and Guidelines for Permission to Import and/or Manufacture
of New Drugs for Sale or to Undertake Clinical Trials.

Recombinant DNA Safety Guidelines, 1990

Guidelines for generating preclinical and clinical data for rDNA vaccines,
diagnostics and other biologicals, 1999

CDSCO guidance for industry, 2008, on Submission of Clinical Trial Application for
Evaluating Safety and Efficacy; Requirements for permission of New Drugs Approval;
Post approval changes in biological products: Quality, Safety and Efficacy Documents;
and Preparation of the Quality Information for Drug Submission for New Drug
Approval: Biotechnological/Biological Products

Guidelines and Handbook for Institutional Biosafety Committees (IBSCs), 2011

The India Guidelines state that, for “establishment and characterization of the cell banks,
the guidelines issued by the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use, i.e., ICH Q5A, Q5B
and Q5D.”

The guidelines add that “methods used to measure quality attributes for batch release,
stability studies and in-process controls should be validated in accordance with ICH Q2,
Q5C, Q6B.”

The India Guidelines provide that “[s]tability studies on drug substance and drug
product should be carried out using containers and conditions that are representative of
the actual storage containers and conditions, according to, e.g., ICH Q5C and WHO TRS
822,” and that [a]ssays should be calibrated against an international or national
reference standard, where available and appropriate. If no such standards are available,
an internal reference standard must be established under ICH guidelines.”

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The India Guidelines also cite other references as pertinent to consideration of biosimilars
marketing applications, including:

i. EMEA guideline on similar biological medicinal products containing
biotechnology derived proteins as active substance: non-clinical and
clinical issues. London, 2006 (CHMP/BMWP/42832)
ii. EMEA guideline on immunogenicity assessment of biotechnology-derived
therapeutic proteins London, 2007 (CHMP/BMWP/14327)
iii. ICH guideline on preclinical safety evaluation of biotechnology-derived
pharmaceuticals (S6), 1997
iv. Guideline for Safety Study of Biological Products, (KFDA, 2010)
v. World Health Organization (WHO) Guidelines on Evaluation of Similar
Biotherapeutic Products (SBP), 2009

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ANNEX 2: DRL Slide on Reditux Testing

1 The views, positions and opinions expressed in this article are those of the author
alone and do not necessarily reflect the views of any of the other partners in Schiff Hardin LLP,
or the views of any of the firm’s clients. Nothing in this article is intended to provide legal
advice. No attorney-client relationship is established by virtue of this article.

2 21 C.F.R. § 600.3(h).

3 “Synthetic biologics” may be said to be biologically based or inspired materials that
are newly designed and created from “scratch,” combining laboratory chemicals, typically with
computer assistance, to carry out novel tasks. See, e.g., What is Synthetic Biology?,
http://www.synbio project.org/topics/synbio101/definition/.

4 Rep. Anna Eshoo (D-Calif.), H.R. 1548 better than alternatives on new drug class,
http://thehill.com/special-reports/the-economy-of-healthcare-july-2009/49603-hr-1548-better-tha
n-alternatives-on-new-drug-class

5 See Mayo Clinic Staff, Monoclonal antibody drugs for cancer treatment: How they work,
http://www.mayoclinic.com/health/monoclonal-antibody/CA00082/METHOD=print (“In

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general, monoclonal antibody treatment carries fewer side effects than do traditional
chemotherapy treatments.”)

6 http://www.twnside.org.sg/title2/resurgence/2012/259/cover03.htm

A. Bourgoin (Thomson-Reuters), WHAT YOU NEED TO KNOW ABOUT THE
7

FOLLOW-ON BIOLOGIC MARKET IN THE U.S.: IMPLICATIONS, STRATEGIES, AND
IMPACT http://thomsonreuters.com/content/science/pdf/ls/newport-biologics.pdf, at 1.

8 Id.

9 http://www.fiercebiotech.com/pages/top-10-products-sales-2014;
http://www.evaluatepharma.com/Universal/View.aspx?type=Story&id=188700&sectionID=&isE
PVantage=yes. By 2014, it is projected that 7 of the top 10 selling pharmaceutical products will
be monoclonal antibodies (Avastin, Humira, Rituxan, Herceptin and Remicade) or recombinant
protein products (Enbrel, Lantus).

10 42 U.S.C. § 262(i)(2). US law (the “US Biologics Act”) also defines an
“interchangeable” product as a biosimilars product may be substituted for the reference
product without the intervention of the health care provider who prescribed the reference
product. 42 U.S.C. § 262(i)(3). For a product to be licensed as a “interchangeable” in the U.S.,
it must be demonstrated that it is biosimilar and that it “can be expected to produce the same
clinical result as the reference product in any given patient. For a biological product that is
administered more than once to an individual, it must also be shown that “the risk in terms of
safety or diminished efficacy of alternating or switching between use of the biological product
and the reference product is not greater than the risk of using the reference product without
such alternation or switch.” 42 U.S.C. § 262(k)(4).

11See The opportunity for India in the global biosimilars market (June 2010),
http://www.pharmaphorum.com/2010/06/21/the-opportunity-for-india-in-the-global-biosimilars
-market/

12 An unhealthy future for the Indian pharmaceutical industry?, http://www.twnside.org.
sg/title2/resurgence/2012/259/cover03.htm

13Id. (“out of 3,488 product patents issued from 2005 to March 2010, 3,079 were granted
to MNCs”). See, e.g., F. Hoffman-LaRoche et al. v. Cipla Ltd., CS (OS) No.89/2008 and C.C. 52/2008
(Delhi High Court September 7, 2012), http://lobis.nic.in/dhc/MAN/judgement/
10-09-2012/MAN07092012S892008.pdf

14 See McKinsey & Company, India Pharma 2020: Propelling Access and Acceptance,
Realizing Full Potential, at 20 (2012)(the “biologics market will also grow rapidly to become a $3
billion segment [of the Indian economy] by 2020.”) http://www.mckinsey.com/~/media/

14


mckinsey/dotcom/client_service/Pharma%20and%20Medical%20Products/PMP%20NEW/PDFs/
778886_India_Pharma_2020_Propelling_Access_and_Acceptance_Realising_True_Potential.aspx

15 http://www.in-pharmatechnologist.com/Regulatory-Safety/India-launches-
similar-biologics-guidelines-at-BIO2012

16 See, e.g., India’s New Biosimilar Guidelines and Their Relationship to the Rest of the World,
BioLawgics, July 16, 2012 http://www.biolawgics.com/fda-approval/guise-biogeneric-regulatory
pdfthe-indian-ministries/ (“The Indian Guidelines mirror the U.S. and European emphasis on
detailed structural and functional characterization of the proposed biosimilar in comparison to
the reference product. To earn reduced pre-clinical and clinical data requirements, there must be
no “significant differences in safety, efficacy and quality studies.”)

Until the new guidelines were promulgated, India’s regulatory regime for biologic
medicines, especially biosimilars, was less well defined. See DRUGS AND COSMETICS
(IIND AMENDMENT) RULES, 2005 (Schedule Y), http://cdsco.nic.in/html/schedule-y%20
(amended%20version-2005)%20original.htm.

The United States Food and Drug Administration issued three draft guidances in early
2012, to describe its proposed approach to approval of biosimilars. See Quality Considerations in
Demonstrating Biosimilarity to a Reference Protein Product (FDA Quality Considerations); Scientific
Considerations in Demonstrating Biosimilarity to a Reference Product (“FDA Scientific
Considerations”); and Biosimilars: Questions and Answers Regarding Implementation of the Biologics
Price Competition and Innovation Act of 2009 (FDA Q&A) (February 9, 2012),
http://www.fda.gov/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm290967.htm, http://www.fda.gov/Drugs/Development
ApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBi
ologicApplications/Biosimilars/default.htm, and https://collaboration.fda.gov/p13473376/
?launcher=false&fcsContent =true&pbMode=normal (webinar). Written and oral public
comments were received by the FDA before and after these guidances were issued. See
http://www.regulations.gov/#!docket Detail;D=FDA-2010-N-0477 (before), and
http://www.regulations.gov/#!docketDetail;D=FDA -2011-D-0618 (after). No date has been set
for issuance of the FDA’s final guidance documents.

The EMA issued its first Guideline on Similar Biologic Medicinal Products in 2005.
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500
003517.pdf. In 2012, the EMA issued a detailed Guideline on similar biological medicinal products
containing monoclonal antibodies – non-clinical and clinical issues. http://www.ema.europa.eu/
docs/en_GB/document_library/Scientific_guideline/2012/06/WC500128686.pdf. In November
2011, the EMA issued a Concept paper on the revision of the guideline on similar biological medicinal
product (the “overarching” guidelines). http://www.ema.europa.eu/docs/en_GB/document_
library/Scientific_guideline/2011/11/WC500117987.pdf. Comments on these new guidelines

15


were received by February 29, 2012. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c#Overarchingbiosim
ilarguidelines. See also http://www.in-pharmatechnologist.com/Regulatory-Safety/EMA-
will-accept-reference-meds-made-outside-Europe-under-biosimilars-guidelines

17 See India Calls for Science-Based Regulation for Biotech, The Hindu Business Line, October
1, 2012, http://www.thehindubusinessline.com/industry-and-economy/article3954041.ece.

18 Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in
India, at 29, http://cdsco.nic.in/Bio%20Similar%20Guideline.pdf (“India Guidelines”). Obversely,
the India Guidelines provide: “Identification of any significant differences in safety, efficacy and
quality studies would [require] more extensive preclinical and clinical evaluation and the product
will not qualify as a similar biologic.” In the United States, significant improvements in efficacy will
likely disqualify a proposed biosimilar product from consideration under abbreviated
procedures established under the US Biologics Act and the FDA’s recent guidances.

The FDA guidances state that “clinical studies should be designed such that they can
demonstrate that the proposed product has neither decreased nor increased activity compared
to the reference product.” They add that [d]ecreased activity ordinarily would preclude
licensure of a proposed product,” and that [i]ncreased activity might be associated with more
adverse effects, or might suggest that the proposed product should be treated as an entirely
different product with superior efficacy, in which case the appropriate licensure pathway would
be section 351(a) of the PHS Act [BLA].” FDA Scientific Considerations at 17.

It is less clear whether such “biobetters” may still qualify for consideration as
“biosimilars” under the India Guidelines.

Relevant to this article, the guidelines also define a “comparability exercise” as
“Comparison of a similar biologic with a reference biologic with the goal to establish similarity
in safety, efficacy and quality.” Id., at 26. They define a drug product as a “pharmaceutical
product type that contains a drug substance, generally in association with excipients,” and a
drug substance as the “active pharmaceutical ingredient and associated molecules that may be
subsequently formulated, with excipients, to produce the drug product,” including the desired
product, product-related substances, and product, process-related impurities, and other
components such as buffers. Id., at 26 – 27.

19 42 U.S.C. § 262(k)(4).

20 The FDA Scientific Considerations, see Note 16, supra, note: “The purpose of a biosimilar
development program is to support a demonstration of biosimilarity between a proposed
product and a reference product including an assessment of the effects of any observed
differences between the products, but not to independently establish the safety and

16


effectiveness of the proposed product. FDA recommends that sponsors use a stepwise approach
to developing the data and information needed to support a demonstration of biosimilarity. At
each step, the sponsor should evaluate the extent to which there is residual uncertainty about
the biosimilarity of the proposed product and identify next steps to try to address that
uncertainty.” Id., at 7.

21 India Guidelines at 4.

22 FDA Scientific Considerations at 5, 7. As set forth in the US guidances, a biosimilar
sponsor must first “extensively characterize the proposed product and reference product with
state-of-the-art technology as the foundation for a demonstration of biosimilarity.” The
guidance sets forth the FDA’s expectation that “the expression construct for a proposed product
will encode the same primary amino acid sequence as the reference product. Minor
modifications will not affect safety and effectiveness may be justified and should be explained
by the sponsor.”

23 India Guidelines at 8 – 10, 35 – 42 (Annexure 2). Test requirements are in some ways
described, albeit in basic terms, in greater detail in the India Guidelines than in the FDA’s
guidances. For example, with respect to physicochemical and biological characterization of
antibodies, the India Guidelines set forth eleven requirements for physicochemical
characterization (e.g., “Purity on HPLC (RP, SEC, IEX)/MALDI (To check if preparation is free of
any impurities).”) and four requirements for biological characterization (e.g., “Neutralizing
activity in actual target host cell (at least one highly prevalent Indian variant/isolate should be
used) (To compare activity of similar biologic with reference biologic in the target cell).”) Id., at
41- 42 (Annexure 2D).

The FDA guidances do not contain product specific requirements, although such biosimilar
product guidelines are statutorily authorized and may be promulgated in the future. See, e.g.,
FDA, Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human
Use, http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceCompliance
RegulatoryInformation/OtherRecommendationsforManufacturers/UCM153182.pdf. The EU
has already issued several biosimilar product specific guidance documents. See, e.g., EMA,
Guideline on non-clinical and clinical development of similar biological medicinal products containing
recombinant erythropoietins (Revision), http://www.ema.europa.eu/docs/en_GB/
document_library/Scientific_guideline/2010/04/WC500089474.pdf. See also EMA,
Product-specific biosimilar guidelines, http://www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c#Productspecificbios
imilarguidelines.

24India Guidelines at 7. Similarly, the FDA Scientific Considerations note that “[s]uch a
strategy may further reduce the possibility of undetected structural differences between the

17


products and lead to a more selective and targeted approach to animal and/or clinical
testing.” Id., at 7.

25 The FDA Scientific Considerations state that pharmacologic activity of protein products
can be evaluated by in vitro and/or in vivo functional assays, including, but are not limited to,
bioassays, biological assays, binding assays, and enzyme kinetics. They add that animal toxicity
data will be considered useful when uncertainties remain about the safety of the biosimilar
product and need to be addressed before initiation of clinical studies in humans. They state
that animal toxicity studies will generally not be regarded as useful “if there is no animal
species that can provide pharmacologically relevant data for the protein product (i.e., no species
in which the biologic activity of the protein product mimics the human response …).”

26 India Guidelines at 10. The India Guidelines state that “Antibody response to the similar
biologic should be compared to that generated by the reference biologic in suitable animal
model. The test serum samples should be tested for reaction to host cell proteins. … For
evaluating immune toxicity of the similar biologic under study, the results of local tolerance
(part of repeat dose or stand-alone test) should be analyzed …” Id., at 17.

27 India Guidelines at 14 - 17. Compare FDA Scientific Considerations at 10 – 12.

28 In the US, the FDA has said, “In general, the clinical program for a [biosimilar]
application must include a clinical study or studies (including an assessment of immunogenicity
and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate
conditions of use for which the reference product is licensed and intended to be used and for
which licensure is sought for the biological product … The scope and magnitude of clinical
studies will depend on the extent of residual uncertainty about the biosimilarity of the two
products after conducting structural and functional characterization and possible animal
studies. … Lessening the number or narrowing the scope of any of these types of clinical studies
(i.e., human PK, PD, clinical immunogenicity, or clinical safety and effectiveness) should be
scientifically justified by the sponsor.” FDA Scientific Considerations at 12.


30 India Guidelines at 20 (“Information to establish comparative safety and efficacy in
relevant patient population is mandatory for all similar biologics.”)

31 India Guidelines at 18 - 19. The guidelines state: “Appropriate rationale for dose
selection should be provided. The route of administration should be the one where the
sensitivity to detect differences is the largest. Sample size should have statistical rationale …”
Compare FDA Scientific Guidance at 13 (“… both PK and PD studies (where there is a relevant
PD measure) generally will be expected to establish biosimilarity, unless a sponsor can
scientifically justify that an element is unnecessary. … Sponsors should provide a scientific

18


justification for the selection of the human PK and PD study population (e.g., patients
versus healthy subjects) and parameters … ”)


33 Id.

34 Id. at 20. The India Guidelines provide that confirmatory clinical safety and efficacy
study requirement can be waived if all of the following conditions are met, but cannot be waived
if there is no reliable and validated PD marker:

“i. Structural and functional comparability of similar biologic and reference
biologic can be characterized to a high degree of confidence by physicochemical and in
vitro techniques
ii. The similar biologic is comparable to reference biologic in all preclinical
evaluations conducted
iii. PK/PD study has demonstrated comparability and has preferentially been
done in an in-patient setting with safety measurement (including immunogenicity) for
adequate period justified by the applicant and efficacy measurements
iv. A comprehensive post-marketing risk management plan has been presented
that will gather additional safety data with a specific emphasis on gathering
immunogenicity data.”

India Guidelines at 21.

35 Under the proposed US FDA guidances and the US Biologics Act, it appears that
bioequivalence must be established for efficacy and aspects of safety other than immunogenicity.
The US guidance documents indicate that two-sided clinical studies will generally be necessary to
establish that there are no other clinically meaningful differences between the biosimilar and the
reference product. They state that “at least one clinical study that includes a comparison of the
immunogenicity of the biosimilar product to that of the reference product will generally be
expected.” The FDA guidances add, however, that generally it will only be “important to
demonstrate that the immunogenicity of the proposed product is not increased, so a one-sided
(non-inferiority) design will ordinarily be adequate to compare clinical immunogenicity of the
proposed product and reference product.” Hence, under the proposed FDA guidances,
improved (bio-superior) immunogenicity will not preclude approval as a biosimilar. However,
as noted above, superior efficacy (biobetter) will, in all probability, require submission of a full
Biologics License Application (BLA), rather than an abbreviated application under the US
Biologics Act.

The EU recently issued a concept paper that recognizes the need to tackle the issue of
“biobetters” and the related clinical testing requirement issue, i.e., whether a two-sided

19


equivalency test must be conducted, or a simpler non-inferiority test will suffice, even for a
demonstration of efficacy. See EMA, Concept paper on the revision of the guideline on similar
biological medicinal products containing biotechnology derived proteins as active substance: non-clinical
and clinical issues, at 3 (September 2011), http://www.ema.europa.eu/docs/en_GB/document_
library/Scientific_guideline/2011/10/WC500115611.pdf. See also S. Chow, et. al., Scientific factors
for assessing biosimilarity and drug interchangeability of follow-on biologics, Biosimilars 2011:1 13–26
(2011), www.dovepress.com/getfile.php?fileID=10321.

Under the India Guidelines, if “non-inferiority trials are required they must be clearly
justified and applicants are advised to consult with CDSCO prior to study initiation. Sample
sizes should have statistical rationale and comparability limits should be defined and justified
prior to conducting the study.” India Guidelines at 20 (emphasis added).


37India Guidelines at 23. The Risk Management Plan must include, among other
things, a Pharmacovigilance Plan designed to evaluate the clinical safety in all the
approved indications in the post-marketing phase, including requirements for
submission of periodic safety update reports (PSURs), every six months for the first two
years after approval of the similar biologic and annually for the subsequent two years.

India Guidelines at 23 – 24. See FDA Scientific Considerations at 20 – 21 (noting
38

that “robust post-marketing safety monitoring is an important component in ensuring
the safety and effectiveness of biological products, including biosimilar therapeutic
protein products, taking into account particular safety or effectiveness concerns
associated with the use of the reference product and its class.”) See also 42 U.S.C. §
262(k)(4)(C) (REMS requirements for “interchangeables”).

39See Transcript of FDA Hearing, November 3, 2010, at 70.
http://www.regulations.gov/#!documentDetail;D=FDA -2010-N-0477-0012. The slide
referenced in DRL’s testimony, apparently no longer available on the Regulations.gov website is
depicted in Annex 2, below.

40See FDA Q&A at 9 – 10. According to this guidance, scientific justification for such
extrapolation must be based on several factors, including a product’s mechanism of action, the
target/receptor(s) for each relevant activity/function of the product, the binding,
dose/concentration response, and pattern of molecular signaling upon engagement of
target/receptor(s), the relationship between product structure and target/receptor interactions,
the location and expression of the target/receptor(s), “PK and bio-distribution of the product in
different patient populations; PD measures may provide important information on the MOA,”
differences in expected toxicities in each condition of use and patient population, and “[a]ny

20


other factor that may affect the safety or effectiveness of the product in each indication and
patient population for which licensure is sought.” Id.

41 India Guidelines at 28. Similarly, the guidelines define an “innovator product” as “[a]
medicine which has been licensed by the national regulatory authorities on the basis of a full
registration dossier; i.e., the approved indication(s) for use were granted on the basis of full
safety, efficacy and quality data.” Id. In both definitions, the use of the phrase ”full dossier” is
critical and dispositive. The definition suggests that another biosimilar cannot be a “reference
biologic” unless it has been licensed on the basis of full human clinical testing.

In the US, the Biologics Act defines a “reference product” as “the single biological
product licensed under subsection (a) [a full Biologics License Application] against which a
biological product is evaluated in an application …” 42 U.S.C. § 262(i)(4).


43 Id.

44 Among other things, the guidelines also require that the reference biologic be
maintained throughout the life cycle of the product, for purposes of further comparison. Id.
This seems requirement seems to recognize that there may be differences between an initial
reference product and later versions that may have “drifted” in some characteristic away from
the initial product. Use of a single reference standard may also avoid enlargement of the scope
of bioequivalency in any one or more specific characteristics and thus somewhat narrow the
ranges within which a biosimilar product sponsor will be able to demonstrate comparability.
See Note 39, supra.

45 The India Guidelines provide that “[i]n case the reference biologic is not marketed in
India, the reference biologic should have been licensed and widely marketed for 4 years post
approval in innovator jurisdiction in a country with well-established regulatory framework. In
case no medicine or only palliative therapy is available or in national healthcare emergency, this
period of 4 years may be reduced or waived off.” Id¸ at 5.

46 The EU recently issued a statement “that it intends to accept batches of reference
medicinal products sourced from outside the EEA in certain pre-clinical and clinical studies for
the comparability exercise.” Under this approach, “it will be the applicant's responsibility to
establish that the batches sourced outside the EEA is representative of the reference medicinal
product authorised in the EEA through an extensive analytical comparison.”
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/q_and_a/q_and_a_detail_0001
25.jsp&mid=WC0b01ac0580533e0c.

21


The US Biologics Act requires comparison of a proposed biosimilar to a single reference
product, 42 U.S.C. § 262(k)(5)(A). Like the India Guidelines, the US Biologics Act requires that
the reference product be “licensed under” US laws governing Biologic License Applications, 42
U.S.C. § 262(i)(4)(defining a “reference product” and referring to 42 U.S.C. § 262(a)). See also
FDA Q&A, at 7 (non-US licensed reference product may be used as comparator under some
circumstances, with “bridging” studies); and FDA Quality Considerations at 9 (commenting on
the potential use of data obtained in foreign analytical, animal and clinical studies, comparing a
proposed biosimilar product to a reference product not licensed in the US).

47In the United States, a lawsuit has been recently commenced by a manufacturer
seeking a declaratory judgment against two generic manufacturers, to enforce the
manufacturer’s right to choose with whom it does business and to declare that the
manufacturer has no duty or obligation to provide samples of its patented product to the
generic competitors. See Actelion Pharmaceuticals, et al. v. Apotex, Inc., et al., Civil No. 1:
12-cv-05743-NLH-AMD (D.N.J. September 14, 2012).

48In the US, each facility at which a biosimilars product may be manufactured must be
inspected and licensed by the FDA before marketing of a product made at that facility will be
permitted. See, e.g., US Biologics Act, 42 U.S.C. §§ 262(a)(1)(c)(ii), 262(k)(2)(A)(i)(V), 262(k)(3)(B).

The FDA Quality Considerations provide “guidance on analytical studies that may be
relevant to assessing whether the proposed biosimilar protein product and a reference product
are highly similar, which is part of the biosimilarity assessment.” Id., at 4. In part, these
guidances describe the “complete and thorough chemistry, manufacturing and controls (CMC)
section that provides the necessary and appropriate information (e.g., characterization,
adventitious agent safety, process controls, and specifications) for the product to be adequately
reviewed.” Id., at 4 – 5.

The FDA Quality Considerations document contemplates that the CMC submission in a
biosimilar application will include, in addition to other data, the same CMC information
required in a BLA. See, e.g., Guidance for Industry for the Submission of Chemistry, Manufacturing,
and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal
Antibody Product for In Vivo Use (issued jointly by CDER and CBER, August 1996).

Among other things, the FDA Quality Considerations guidance states that “[a]
comprehensive understanding of all steps in the manufacturing process for the proposed
biosimilar product should be established during product development.” It adds that
“[c]haracterization tests, process controls, and specifications that will emerge from information
gained during process development must be specific for the proposed biosimilar product and
manufacturing process.” And, it states that “[t]he use of Quality-by-Design approaches to
pharmaceutical development, along with quality risk management and effective quality
systems, will facilitate the consistent manufacturing of a high-quality product.”

22


The FDA Quality Considerations also provides guidance about impurities, drug product
stability, reference product standards and other issues relating to biosimilar products in both
laboratory and manufacturing level scales.


50 Id. (“If the host cell line used for the production of reference biologic is disclosed, it is
desired to use the same cell line as the reference biologic. Alternatively any cell line that is
adequately characterized and appropriate for intended use can be used to develop a similar
biologic, with appropriate justification in order to minimize the potential for significant changes
in critical quality attributes of the product and to avoid introduction of certain types of process
related impurities that could impact clinical outcomes and immunogenicity. For the
establishment and characterization of the cell banks, the guidelines issued by the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals
for Human Use (referred to as ICH) viz. Q5A4, Q5B5 and Q5D6 should be referred for guidance.”

51Id., at 7. The guidelines list forms that used in connection the approval process, and
include requirements for data retention. Id., at 25.

52 Id., at 11.

53 Id., at 11.

54 Id., at 11 - 12. See also Annexure-2 (2A-2D).

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