1. Biosimilars
Dr. Kunal Chitnis
3rd Yr Resident
Dept of Pharmacology
T.N.M.C.
2nd Feb 2013

2.  Biotechnology is in some ways as old as human history
 Our ancestors harnessed living organisms to make bread,
curd, paneer & wine
 It was just during the early 20th century when the term
biotechnology came into use
 The term was coined in 1917 by Karl Ereky, a Hungarian
engineer & professor who described a technology based
on converting raw materials into a more useful product
 At that time, the newly categorized field was focused on
food production, addressing such issues as malnutrition
& famine
History of Biotechnology

3.  Field soon expanded its focus to medical uses, led by the
1940s introduction of penicillin made through a deep
fermentation process→ Greatly impacted countless lives
over a half-century ago
 Today, Biologic medicines are making significant impact
on the lives of patients with serious illnesses throughout
the world
 Hold promise to cure diseases like Cancers, Alzheimer’s,
Multiple sclerosis, Arthritis & Cardiovascular disorders

4. A standard definition of biotechnology was not reached
until the United Nations & World Health Organization
accepted the “1992 Convention on Biological Diversity”
& defined biotechnology as:
“Any technological application that uses biological
systems, living organisms or derivatives thereof, to make
or modify products & processes for specific use”

5. Biopharmaceutical
A drug created by means of biotechnology, especially
genetic engineering:
Primarily rDNA protein & Monoclonal antibody
 Typically derived from living organisms
(animal cells, bacteria, viruses & yeast)
 Include:
• Therapeutic proteins (cytokines, hormones & clotting
factors), Insulin, DNA vaccines, monoclonal antibodies
• New experimental modalities such as gene therapy,
stem cell therapy & RNA viruses

7. Biologic medicines are currently prescribed to
treat a wide variety of conditions, including:
• Blood conditions: leuko/neutro/pancytopenias
• Cancers: Colon & Breast Ca or NHL
• Immune system disorders: Rheumatoid arthritis,
Psoriasis & Crohn’s disease
• Neurological disorders: Multiple Sclerosis
 More than 400 biologics are in clinical trials
 These include therapies for cancers, Alzheimer’s
disease, heart disease, diabetes, HIV/AIDS &
Autoimmune disorders

8.  Represent a fast-growing segment of the
pharmaceutical market constituting:
• 32% of products in the development pipeline
• 7.5% of marketed products
• Expected to grow exponentially at more than 20% per year
• By 2016, seven of top ten pharma products worldwide will
be biologics
• Potential to reach up to 50% share in global
pharmaceutical market in the next few years

9. Develop host cell
 Identify the human DNA sequence for the desired protein
 Isolate the DNA sequence
 Select a vector to carry the gene
Insert the gene into the genome of a host
 Modification of cells→ “recombinant” technology
 The exact DNA sequence & type of host cell used will
significantly influence the characteristics of the product
Manufacturing of Biopharmaceuticals

10. Modifying the selected cell
Growing a cell line from the original modified cell
Growing a large number of cells from the cell line
Cultivating them to produce the desired protein
Separating the protein from the cells
Purifying the collected protein
Major steps involved

11. Differences in manufacture of
Conventional drugs & Biologics
 Small Molecule Drugs
 Low molecular weight drugs→ Made by adding &
mixing together known chemicals & reagents, in a series of
controlled & predictable chemical reactions
 Production techniques usually same as for Innovator
Product
 Production process is highly standardised
 Contaminants are consistent & quantifiable

12.  Biopharmaceuticals
 Strong relationship between manufacturing processes
of biopharmaceuticals & characteristics of the final product
 Manufacturing biologics is more complex
 A high level of precision is required → produce a
consistent product time after time

13. Even small changes in production
(Minor equipment/ Environmental variations)
Significant changes in
behaviour of the cells & changes in the protein
Alterations in the three-dimensional structure of the
Protein
Quantity of Acid–base variants & Glycosylation
Impact Safety & Effectiveness of biologic

14.  To assure high quality & consistency in final product,
production process requires a high level of monitoring &
testing throughout the process
 A biologic drug typically has around 250 in-process
tests during manufacturing, compared to around 50 tests
for small molecule drugs

15. Biosimilars
What are biosimilars?
Legally approved subsequent versions of innovator
biopharmaceutical products made by a different sponsor
following patent & exclusivity expiry of the innovator product
• Because of structural & manufacturing complexities,
these biological products are considered as similar,
but not generic equivalents of innovator biopharmaceuticals

16. Definitions & Interpretations of
Biosimilar Products
Term By Definition
SBP (Similar
Biologic
Product)
WHO Similar to an already licensed
reference biotherapeutic product in
terms of quality, safety & efficacy
FOB
(Follow-On
Biologic)
US-FDA Highly similar to the reference
product without clinically meaningful
differences in safety, purity and
potency
SEB
(Subsequent
Entry
Biologic)
Canada Drug that enters the market
subsequent to a version previously
authorized in Canada with
demonstrated similarity to a
reference biologic drug

17.  Based on these different definitions, there are three
determinants in the definition of the biosimilar product:
• It should be a biologic product
• the reference product should be an already licensed
biologic product
• the demonstration of high similarity in safety, quality &
efficacy is necessary
 Similarity should be demonstrated using a set of
comprehensive comparability exercises at the quality,
non-clinical & clinical level

18.  High unit cost of biologics has resulted in patients’
concerns about continued access to potentially
effective therapies
 Recently, the expiration of patents for a number of
blockbuster biologics has ushered in an era of the
subsequent production of biosimilar products
 Contribute to ↑ access to these products at an
affordable price

19. Global Scenario
 In 2010, sales of biologics reached $100 billion
worldwide with the top 12 biologics generating $30 billion
 By 2015, biologics responsible for $20 billion in annual
sales will go off patent
 Global market for biosimilars was $311 million in 2010 &
expected to increase to $2 billion-$2.5 billion in 2015

20. Indian Scenario
 India is one of the leading contributors in the world
biosimilar market
 Over 50 biopharmaceutical brands have got marketing
approval
 Potential to replicate success of Indian Generic Industry
 Imported Innovators market is estimated around
US$ 220 million

21.  India has inherited advantages of:
• Cost effective manufacturing
• Highly skilled, reasonably priced workforce
• Huge market
 Key benefit→ Reduce cost by 20-25%
For instance, European Generic Medicines Agency
estimated that biosimilars generated annual savings of
∼€ 1.4 billion in EU in 2009
 Owing to affordability and easy accessibility, established
good reputation among healthcare professionals

22. Cost Effectiveness of Biosimilars
Active
Substance
Trade Name Company Price
(INR)
Insulin Glargine
(100 IU x 1 mL x
10ml)
Lantus Sanofi Aventis 2530
Basalog Biocon 1475

23. Active
substance
Product
name
Launch date
in India
Company
Epoetin alfa Epofit/Erykine Aug 2005 Intas
Biopharma-
ceuticals
Darbopoetin
alfa
Cresp Aug 2010 Dr Reddy’s
Laboratories
Insulin
glargine
Basalog 2009 Biocon
Reteplase Mirel 2009 Reliance Life
Scienes
Rituximab Reditux Apr 2007 Dr Reddy’s
Laboratories
Few Biosimilars Approved in India

24. Problem Statement
 Biosimilars are not biological generics
 Unique molecules which are supported by only
limited clinical data at the time of approval
 Concerns regarding their efficacy, long-term safety
& immunogenicity

25. Generic drugs
 Chemically & therapeutically equivalent to the
branded, original, low molecular weight chemical drugs
whose patents have expired
 Identical to the original product
Most countries already have well-established scientific
standards & legal mechanisms for authorising generics

26. Approval of Generics
 In 1984, the US FDA was authorized to approve generic
drug products under the ‘Hatch-Waxman Act’
 When an innovator product is going off patent,
pharmaceutical companies file an abbreviated new
drug application (ANDA) for approval of generic copies
of Innovator Product (IP)
 According to FDA’s definition, the generic drug products
should be comparable to the reference drug product in:
dosage form, strength, route of administration, quality,
performance characteristics & intended use

27. Authorised on the basis of demonstrating that they
are the same in structure & bioequivalent to
approved product
 Requires evidence of comparable bioavailability →
Conduct of Bioequivalence studies
 Non-clinical & Clinical data are not usually required
 Recognised for some time that this paradigm will not
work for biologically derived drugs

28. Differences between chemical
generics & biosimilars
I. Heavier
 Unlike structurally well-defined, low molecular weight
chemical drugs, biopharmaceuticals are:
High molecular weight compounds with complex three-
dimensional structure
 For example, the molecular weight of Aspirin is 180 Da
whereas Interferon-β is 19,000 Da

29. II. Larger
 Typical biologic drug is 100 to 1000 times larger than
small molecule chemical drugs
 Possesses fragile three-dimensional structure as
compared to well-characterized one-dimensional
structure of chemical drug

30. III. Difficult to define structure
 Small Molecule drugs → easy to reproduce & specify
by mass spectroscopy & other techniques
 Lack of appropriate investigative tools to define
composite structure of large proteins

31. IV. Complex manufacturing processes
 Manufacturers of biosimilar products will not have
access to manufacturing process of innovator products→
Proprietary knowledge
 Impossible to accurately duplicate any protein product
 Different manufacturing processes use different cell lines,
protein sources & extraction & purification techniques
→ heterogeneity of biopharmaceuticals

32.  Versatile cell lines used to produce the proteins have an
impact on the gross structure of the protein
 Such alterations may significantly impact:
Receptor binding, Stability, Pharmacokinetics & Safety
Immunogenic potential of therapeutic proteins→
Unique safety issue→ Not observed with
chemical generics

33. Issues of concern with use of
biosimilars
I. Efficacy issues
 Differences between the bioactivity of the biosimilars &
their innovator products
Example 1:
• 11 epoetin alfa products from 4 different countries
(Korea, Argentina, China, India)
• Significant diversions from specification for in vivo bioactivity
• Ranged from 71-226%

34. • 5 products failed to fulfill their own specification
• Adequate hemoglobin monitoring→ variance in potency
may not be a critical issue
• Monoclonal antibody therapy for treating a transplant
rejection/cancer patient→ variability not acceptable

35. Example 2:
Study compared quality parameters (purity, content &
efficacy) of several biosimilar brands taken from the
Indian market & with those of the innovator drug products
 Carried out on 16 commercial brands covering 3 different
biopharmaceuticals:
pegylated G-CSF, G-CSF & erythropoietin
 Marked lack of comparability between biosimilars &
innovator products
 Significant difference in the level of purity was observed
among various brands of biosimilars as per European &
Indian Pharmacopoeia standards

36. II. Safety issues
 Concerns regarding immunogenicity
Example
• ↑ in no. of cases of Pure Red Cell Aplasia associated
with specific formulation of epoetin α
• Caused by the production of neutralizing antibodies
against endogenous epoetin

37. • Most of the cases in patients treated with Eprex→
biosimilar of epoetin α produced outside of the US
• Cause→ subtle changes in manufacturing process Eprex,
human albumin stabilizer was replaced by
polysorbate 80→ ↑ immunogenicity → formation of
epoetin-containing micelles by interacting with leachates
released by the uncoated rubber stoppers of prefilled
syringes

38. III. Pharmacovigilance
 Due to limited clinical database at the time of approval→
Vigorous pharmacovigilance required
 Immunogenicity is a unique safety issue
 Adverse drugs reactions monitoring data should be
exhaustive
 Type of adverse event & data about drug such as:
Proprietary name, International nonproprietary name
(INN) & dosage

39. IV.Substitution
 Allows dispensing of generic drugs in place of prescribed IP
 Rationale for generics→ Original drugs & their generics
are identical & have the same therapeutic effect
 Produce cost savings

40. Same substitution rules should not be applied:
 Decrease the safety of therapy or cause therapeutic
failure
 Uncontrolled substitution → confounds accurate
pharmacovigilance
 Adverse event emerges after switching from IP to its
biosimilar without documentation → event will not
be associated to a specific product or it will be ascribed to
a wrong product

41. V. Naming and labeling
 Generic adaptation of chemical medicines is assigned
the same name→ identical copies of the reference
products
 Biosimilars require unique INNs, as this would facilitate:
• Prescribing & dispensing of biopharmaceuticals
• Precise pharmacovigilance
 Need for Comprehensive labeling of biosimilars including
deviations from IP & unique safety & efficacy data
 Assist the physician & pharmacist in making informed
decisions

42. Status of Regulations for Biosimilars
Globally
 Strong need for regulations governing biosimilars
 Implementation of an abbreviated licensure pathway
for biological products presents challenges, given the
associated scientific & technical complexities
 European Union has regulations in place for quite some
time for approving biosimilars
 US & India have recently covered these under their
respective Acts by bringing in applicable guidelines for
their evaluation & overall regulation

43.  WHO Guidelines
Scientific basis for the evaluation & regulation of
biosimilars was discussed & agreement for
developing WHO Guidelines was reached at the first
‘WHO informal consultation on Regulatory evaluation
of Therapeutic Biological Medicinal Products’ held in
Geneva, 2007
 Published guidelines on Evaluation of Similar Biological
Products with detailed recommendations on clinical
development in October 2009

44.  Regulatory framework in EU
 Guidelines on similar biological products
containing biotechnology-derived proteins as active
substance were adopted by European Medicines Agency
(EMEA) in June 2006
 Issued product specific biosimilar guidelines
In European Union, the first patent on
biopharmaceuticals expired in 2001 & first biosimilar
medicine was approved by EMEA in 2006
 In 2010, the European biosimilars market generated
revenues of approximately $172 million

45.  Regulatory framework in US
 US FDA issued three draft guidance documents as
recent as 9th Feb 2012 on biosimilar product
development under Biologics Price Competition &
Innovation Act of 2009 (BPCI Act)
 Based on sponsors proving structural, composition &
clinical similarities with an approved Biologic
 Includes importance of extensive analytical, physico-
chemical & biological characterization in demonstrating
that proposed biosimilar product is highly similar to the
reference product not withstanding minor differences in
clinically inactive components

46. Regulatory framework in India
Similar biologics are regulated as per:
• The Drugs and Cosmetics Act, 1940
• The Drugs Cosmetics Rules, 1945
• Rules for the manufacture, use, import, export & storage
of hazardous microorganisms/genetically engineered
organisms or cells, 1989. Notified under the Environment
Protection Act

47. Apart from Central Drugs Standard Control Organization
(CDSCO), the office of Drug Controller General of India
(DCGI) two other competent authorities are involved in the
approval process
1. Review Committee on Genetic Manipulation(RCGM)
 Works under Department of Biotechnology (DBT)
Regulates import, export, carrying out research, preclinical
permission, No objection certificate for clinical trial (CT)

48. 2. Genetic Engineering Approval Committee (GEAC)
 Functions under the Department of Environment (DoE)
Statutory body for review & approval of activities
involving large scale use of genetically engineered
organisms & their products

49. Department of Biotechnology (DBT)
definition
“Biologics”
Substances produced by living cells used in the
treatment, diagnosis or prevention of diseases
“Similar Biological Product”
Biological product produced by genetic engineering
techniques & claimed to be similar in terms of quality,
safety & efficacy to a reference innovator product, which
has been granted a marketing authorization in India

50. Principles for development of Similar
Biologics
 Developed through sequential process
 To demonstrate the similarity by extensive
characterization studies revealing molecular & quality
attributes with regard to Reference Biologic (RB)
 The extent of testing of the Similar Biologic (SB)
is less than RB
 Ensure that the product meets acceptable levels of
safety, efficacy & quality to ensure public health

51.  In case Reference biologic used for more than one
indication→ efficacy & safety of similar biologic has to be
justified or if necessary demonstrated separately for each
of the claimed indications
 Justification will depend on:
• Clinical experience
• Available literature data
• Whether or not the same mechanism of action is involved
in specific indication

52. Selection of Reference Biologic (RB)
RB→ Authorized using complete dossier
 Rationale for the choice of RB provided by the
manufacturer in the submissions to the DBT & CDSCO
 Used in all the comparability exercise with respect to
quality, preclinical & clinical considerations.

53.  Following factors should be considered for selection of
the reference biologic:
• Licensed in India & should be Innovator Product
• Licensed based on a full safety, efficacy & quality data
• Another SB cannot be considered as RB

54. • In case RB not marketed in India:
Licensed & marketed for 4 years post approval in
innovator jurisdiction→ Country with well established
regulatory framework
• Period of 4 years may be reduced or waived→
- No medicine/ palliative therapy is available
- In national healthcare emergency
• Active substance, dosage form, strength & route of
administration of the SB→ same as that of RB

55. Manufacturing Process
 Should be highly consistent & robust
 If host cell line used for production of RB is disclosed,
use the same cell line
 Alternatively any cell line that is adequately characterized
& appropriate for intended use
 Applicant should submit a full quality dossier

56. Prerequisites before Conducting
Preclinical Studies
 At preclinical submission stage include a complete
description of:
1. Molecular Biology Considerations
• Details regarding host cell cultures, vectors, gene
sequences, promoters etc. used in the production
• Details of post‐translational modifications:
Glycosylation, oxidation, deamidation, phosphorylation

57. 2. Fermentation Process Development & Protein
Purification details should be provided
• A well-defined manufacturing process with its associated
process controls in accordance with Good Manufacturing
Practice (GMP)

58. 3. Product Characterization
• Physicochemical properties, biological activity,
immunochemical properties, purity (process & product
related impurities), contamination, strength & content
i. Structural and Physicochemical Properties:
Includes determination of primary & higher order
structure of the product

59. ii. Biological Activity:
Appropriate biological assays to characterize the activity &
establish the product’s mechanism of action
iii. Purity & Impurities:
Differences observed in the purity & impurity profiles →
Assess potential impact on safety & efficacy by conduct of
Preclinical & Clinical studies

60.  Apply more than one analytical procedure to evaluate the
same quality attribute
 Reference to acceptance limits for each test parameter
should be provided & justified based on the data from
sufficient lots of similar biologics.
Differences between SBP & RBP evaluated for
their potential impact on safety & efficacy→
Additional characterization studies may be necessary
 Submit the data generated along with the following to
RCGM for obtaining permission

61. Preclinical Studies
 Comparative in nature & designed to detect differences
 Study design depends on:
Therapeutic index, type & number of indications applied
 Conducted with the final formulation
 Dosage form, strength & route of administration should
be same as that of RB
 Approval:
• Prior to conduct of the studies statutory approvals from
respective Institutional Biosafety Committee (IBSC) &
Institutional Animal Ethics Committee (IAEC) be submitted

62. The following studies are required for preclinical
evaluation:
1. Pharmacodynamic Studies
i. In vitro studies:
 Comparability established by in vitro cell based bioassay
(e.g. cell proliferation assays or receptor binding assays)
ii. In vivo studies:
 Cases where in-vitro assays do not reflect the
pharmacodynamics, In vivo studies should be performed

63. 2. Toxicological Studies
 At least one repeat dose toxicity study in a relevant
species is required to be conducted
 Other toxicological (mutagenicity, carcinogenicity) studies
not generally required

64. Animal models to be used:
Scientific justification for the choice of animal model
 Relevant animal species is not available→ undertaken in
two species i.e. one rodent & other non rodent species
 Route of administration→ include only intended route
 Dose→ Calculated based on the therapeutic dose RB
 Three levels of doses (low, medium and high) →
Corresponding to 1X, 2X & 5X of human equivalent dose
 Schedule of administration→ therapeutic schedules

65. 3. Immune Responses in Animals
 Test serum samples tested for reaction to host cell proteins
 Immune complexes in targeted tissues by histopathology→
evaluating immune toxicity
 Clearance:
• Study reports cleared by respective IBSC before being
presented & cleared by RCGM for conducting appropriate
phase of clinical trial

66. Clinical Studies
Data Requirements for Clinical Trial Application
Applicant has to submit application for conduct of clinical
trial as per the CDSCO guidance for industry, 2008
I. Pharmacokinetic Studies
 Design should take following factors into consideration:
Half life, Linearity of PK parameters, Endogenous levels &
diurnal variations of SB, Conditions & diseases to be treated,
Route(s) of administration & Indications

67.  Standards to demonstrate bioequivalence should meet
the CDSCO Guideline for Bioavailability and
Bioequivalence studies
 Comparative pharmacokinetic (PK) studies →
Healthy volunteers or patients to demonstrate
similarities in pharmacokinetic characteristics
 If patient population is used for PK studies,
Phase III / PD study can be coupled in one study design

68. Appropriate design considerations can be combined
with adequate justification:
A. Single Dose Comparative PK Studies
 Dosage within the therapeutic dose range of RB
 Appropriate rationale for dose selection
 Parallel arm design→
• Biologics with a long half life or
• Proteins for which formation of antibodies is likely or
• Study is done in patients
 Cross over design→ Drugs with short half life

69. B. Multiple Dose Comparative PK Studies
 Biologic used in a multiple dose regimen
Markedly higher or lower concentrations are expected at
steady state than that expected from single dose data PK
measurements
 Time-dependence & dose-dependence of PK parameters
cannot be ruled out

70. II. Pharmacodynamic (PD) Studies
 Done in patients or healthy volunteers
If PD marker is available in healthy volunteers→
PD in healthy volunteers can be done
 At least one PD marker→ linked to efficacy of molecule
 Surrogate markers should be clinically validated
 PD studies combined with PK studies→
PK/PD relationship have to be characterized
 PD study can also be a part of Phase III clinical trial
wherever applicable

71. III. Confirmatory Safety & Efficacy Study
 Based on the comparability established during preclinical
& PK / PD studies
 Clinical trials
Comparative, parallel arm or cross-over
Sample sizes should have statistical rational

72.  To demonstrate the similarity in safety & efficacy
profiles, Equivalence trials with equivalence designs →
Require lower & upper comparability margins
 In the case of a non-inferiority trial, only the
lower margin is defined
 Nature, severity & frequency of Adverse events should
be compared

73.  Confirmatory clinical safety & efficacy study can be
waived if all the below mentioned conditions are met:
i. Structural & functional comparability characterized to a
high degree by physicochemical & in vitro techniques
ii. The SB is comparable to RB in all preclinical evaluations
iii. PK / PD study has demonstrated comparability & done in:
• in-patient setting
• safety measurement (including immunogenicity)
• for adequate period &
• with efficacy measurements

74. iv. Comprehensive post-marketing risk management plan→
Gather additional safety data →
Specific emphasis on gathering immunogenicity data
 Cannot be waived if there is no reliable & validated PD
marker

75. IV.Safety & Immunogenicity Data
 Comparative safety data based on adequate patient
exposure (numbers & time) with published data on RB
 Both pre-approval & post-approval assessment of safety
is desired
 Pre-approval safety assessment → Intended to provide
assurance of absence of any unexpected safety concerns

76. V. Extrapolation of Efficacy & Safety Data to
Other Indications
If following conditions are met:
• Similarity with respect to quality has been proven to RB
• Similarity with respect to preclinical assessment
• Clinical safety & efficacy is proven in one indication
• Mechanism of action is same for other clinical
indications
• Involved receptors are same for other clinical indications

77.  New indication not mentioned by innovator will be
covered by a separate application
VI. Market Authorization Application
 Submit application for market authorization as per
CDSCO guidance document for industry

78. Post-Market Data for Similar Biologics
The risk management plan should consist of the following:
A. Pharmacovigilance Plan
 Clinical studies done on SB prior to market authorization
are limited in nature→ Rare adverse events are unlikely
to be encountered
 Comprehensive Pharmacovigilance plan should be
prepared by manufacturer

79.  Periodic safety update reports (PSURs) submitted
every six months for the first two years after approval
 For subsequent two years the PSURs to be submitted
annually to DCGI office
B. Adverse Drug Reaction (ADR) Reporting
 All serious unexpected adverse reactions must be
reported to the licensing authority within 15 days of
initial receipt of the information by the applicant

80. C. Post Marketing Studies (PMS)
 Plan of PMS should be captured in Pharmacovigilance
plan & update on the studies should be submitted to the
CDSCO
 At least one non-comparative post-marketing clinical
study with focus on safety & immunogenicity should be
performed
 If immunogenicity is evaluated in clinical studies→
Not mandatory to carry out additional non-comparative
immunogenicity studies in PMS

81.  Assay methods should be validated & be able to
characterize antibody content & type (neutralizing/
cross reactivity) of antibodies formed
 Neutralizing antibodies→ their impact on the PK/PD
parameters, safety & efficacy assessed
D. Archiving of Data
 Applicant should archive all the data for a period of at
least five years after marketing approval
 Site & Material of archiving should be indicated

82. Conclusion
 Biotechnological medicines shall become an important
part of future healthcare landscape
 With patent expiration of innovator products,
biosimilars will increasingly become available
 Awareness of the deviations between biosimilars &
innovator products in terms of efficacy, safety &
immunogenicity is essential for proper prescription &
safety of the patients
 How similar is similar enough?