The New India Biosimilar Guidelines

Christopher Ohly The New India Guidelines on Similar Biologics

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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


14

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

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).

11 See 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

13 Id. (“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/


15

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


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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


17

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.

24 India 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


18

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


19

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


20

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).


37 India 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.

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

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”).

39 See 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.

40 See 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


21

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.


22

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).

47 In 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).

48 In 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.”


23

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.”

51 Id., 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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