This document discusses biosimilars and their regulation. It begins with a brief history of biotechnology and biopharmaceuticals. It then defines biosimilars as similar but not generic versions of biologic drugs whose patents have expired. The document outlines key differences between biosimilars and generic drugs, including their larger and more complex molecular structures. It also discusses concerns regarding biosimilar efficacy, safety, interchangeability, and pharmacovigilance. Finally, it provides an overview of regulatory frameworks for biosimilars in various regions like the EU, US, India, and WHO guidelines.
Definition of biopharmaceuticals and biosimilars, Steps involved in manufacturing biopharmaceuticals, Points of differences between Biosimilars and Chemical Generics, Related issues with biosimilars
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
Biosimilar a biological drug evaluation includes the biopharmaceutical families, the difference between small molecules and bio-pharmaceutical products, the regulatory requirements for biosimilars and the fact about biosimilars and biologic / bio pharmaceuticals the competent authorities and the key component of successful pharmacovigilane programs
Pharmacovigilance Risk Management for BiosimilarsCovance
This paper focuses on pharmacovigilance (PV) and risk management for biosimilars, the issues and challenges faced in monitoring their safety and possible solutions.
Definition of biopharmaceuticals and biosimilars, Steps involved in manufacturing biopharmaceuticals, Points of differences between Biosimilars and Chemical Generics, Related issues with biosimilars
Bioavailability and Bioequivalence StudiesPranav Sopory
BA and BE studies.
Seminar presented in All India Institute of Medical Sciences (AIIMS - New Delhi).
Focus in Pharmacokinetic parameters (Cmax, AUC)
Single dose PK study, Steady state PK study, Modified drug release PK study, In vivo mechanisms, invitro mechanisms, Pharmacodynamic Study, Comparatice Clinical Trials. Biowavers and Biosimilimars.
Reference: CDSCO guideline, USFDA guideline, ICH guidelines
Biosimilar a biological drug evaluation includes the biopharmaceutical families, the difference between small molecules and bio-pharmaceutical products, the regulatory requirements for biosimilars and the fact about biosimilars and biologic / bio pharmaceuticals the competent authorities and the key component of successful pharmacovigilane programs
Pharmacovigilance Risk Management for BiosimilarsCovance
This paper focuses on pharmacovigilance (PV) and risk management for biosimilars, the issues and challenges faced in monitoring their safety and possible solutions.
The present slide focuses on the applications and different uses of biosimilars along with the basic difference in between biosimilars and bioequivalence.
Hi all, with the rigorous secondary research for almost one month helped me to understand basic things about biosimilars and made me do this presentation. Hope u will appreciate it while going through it. thanks.
If anyone in need of this presentation, pls.put ur emial ID in comment box. will be sharing. and please share your thoughts about the presentation. i will be more thankful.
An introductory presentation (ppt) on biosimilars and guidelines related to their approval along with the challenges faced by biosimilar industries in India.
Dialogue with Canada’s leading regulatory and assessment experts: Health Canada Bureau of Biologics and Genetic Therapies (BGTD) and Canadian Agency for Drugs and Technologies in Health (CADTH)
Date: June 29, 2016
Time: 1:00pm to 3:00pm EST
Functional Overview of the Biotechnology IndustrythinkBiotech
Comprehensive introductory presentation on the business of biotechnology describing legal, commercial, scientific, and regulatory foundations; used in biotech MBA programs.
The Roman Empire A Historical Colossus.pdfkaushalkr1407
The Roman Empire, a vast and enduring power, stands as one of history's most remarkable civilizations, leaving an indelible imprint on the world. It emerged from the Roman Republic, transitioning into an imperial powerhouse under the leadership of Augustus Caesar in 27 BCE. This transformation marked the beginning of an era defined by unprecedented territorial expansion, architectural marvels, and profound cultural influence.
The empire's roots lie in the city of Rome, founded, according to legend, by Romulus in 753 BCE. Over centuries, Rome evolved from a small settlement to a formidable republic, characterized by a complex political system with elected officials and checks on power. However, internal strife, class conflicts, and military ambitions paved the way for the end of the Republic. Julius Caesar’s dictatorship and subsequent assassination in 44 BCE created a power vacuum, leading to a civil war. Octavian, later Augustus, emerged victorious, heralding the Roman Empire’s birth.
Under Augustus, the empire experienced the Pax Romana, a 200-year period of relative peace and stability. Augustus reformed the military, established efficient administrative systems, and initiated grand construction projects. The empire's borders expanded, encompassing territories from Britain to Egypt and from Spain to the Euphrates. Roman legions, renowned for their discipline and engineering prowess, secured and maintained these vast territories, building roads, fortifications, and cities that facilitated control and integration.
The Roman Empire’s society was hierarchical, with a rigid class system. At the top were the patricians, wealthy elites who held significant political power. Below them were the plebeians, free citizens with limited political influence, and the vast numbers of slaves who formed the backbone of the economy. The family unit was central, governed by the paterfamilias, the male head who held absolute authority.
Culturally, the Romans were eclectic, absorbing and adapting elements from the civilizations they encountered, particularly the Greeks. Roman art, literature, and philosophy reflected this synthesis, creating a rich cultural tapestry. Latin, the Roman language, became the lingua franca of the Western world, influencing numerous modern languages.
Roman architecture and engineering achievements were monumental. They perfected the arch, vault, and dome, constructing enduring structures like the Colosseum, Pantheon, and aqueducts. These engineering marvels not only showcased Roman ingenuity but also served practical purposes, from public entertainment to water supply.
Synthetic Fiber Construction in lab .pptxPavel ( NSTU)
Synthetic fiber production is a fascinating and complex field that blends chemistry, engineering, and environmental science. By understanding these aspects, students can gain a comprehensive view of synthetic fiber production, its impact on society and the environment, and the potential for future innovations. Synthetic fibers play a crucial role in modern society, impacting various aspects of daily life, industry, and the environment. ynthetic fibers are integral to modern life, offering a range of benefits from cost-effectiveness and versatility to innovative applications and performance characteristics. While they pose environmental challenges, ongoing research and development aim to create more sustainable and eco-friendly alternatives. Understanding the importance of synthetic fibers helps in appreciating their role in the economy, industry, and daily life, while also emphasizing the need for sustainable practices and innovation.
This is a presentation by Dada Robert in a Your Skill Boost masterclass organised by the Excellence Foundation for South Sudan (EFSS) on Saturday, the 25th and Sunday, the 26th of May 2024.
He discussed the concept of quality improvement, emphasizing its applicability to various aspects of life, including personal, project, and program improvements. He defined quality as doing the right thing at the right time in the right way to achieve the best possible results and discussed the concept of the "gap" between what we know and what we do, and how this gap represents the areas we need to improve. He explained the scientific approach to quality improvement, which involves systematic performance analysis, testing and learning, and implementing change ideas. He also highlighted the importance of client focus and a team approach to quality improvement.
2024.06.01 Introducing a competency framework for languag learning materials ...Sandy Millin
http://sandymillin.wordpress.com/iateflwebinar2024
Published classroom materials form the basis of syllabuses, drive teacher professional development, and have a potentially huge influence on learners, teachers and education systems. All teachers also create their own materials, whether a few sentences on a blackboard, a highly-structured fully-realised online course, or anything in between. Despite this, the knowledge and skills needed to create effective language learning materials are rarely part of teacher training, and are mostly learnt by trial and error.
Knowledge and skills frameworks, generally called competency frameworks, for ELT teachers, trainers and managers have existed for a few years now. However, until I created one for my MA dissertation, there wasn’t one drawing together what we need to know and do to be able to effectively produce language learning materials.
This webinar will introduce you to my framework, highlighting the key competencies I identified from my research. It will also show how anybody involved in language teaching (any language, not just English!), teacher training, managing schools or developing language learning materials can benefit from using the framework.
Welcome to TechSoup New Member Orientation and Q&A (May 2024).pdfTechSoup
In this webinar you will learn how your organization can access TechSoup's wide variety of product discount and donation programs. From hardware to software, we'll give you a tour of the tools available to help your nonprofit with productivity, collaboration, financial management, donor tracking, security, and more.
Read| The latest issue of The Challenger is here! We are thrilled to announce that our school paper has qualified for the NATIONAL SCHOOLS PRESS CONFERENCE (NSPC) 2024. Thank you for your unwavering support and trust. Dive into the stories that made us stand out!
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
6.
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?
Editor's Notes
30% 40%
Leachate is any liquid that, in passing through matter, extracts solutes, suspended solids or any other component of the material through which it has passed.
Leachate is any liquid that, in passing through matter, extracts solutes, suspended solids or any other component of the material through which it has passed.
Lack of validation and standardization of methods for detection of immunogenicity further implies the necessity for robust pharmacovigilance
guidelines issued by the International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use (referred to as ICH)
Streptokinase
Eg: FSH
test substance, vehicle, plasma / serum, tissues, paraffin blocks, microscopeslides, documents, electronic material etc
test substance, vehicle, plasma / serum, tissues, paraffin blocks, microscopeslides, documents, electronic material etc
test substance, vehicle, plasma / serum, tissues, paraffin blocks, microscopeslides, documents, electronic material etc