This document discusses biological agents and their role in medicine. It defines biological products and biosimilars, and describes how biosimilars differ from original biologics in their manufacturing process and ability to be replicated exactly. The document outlines regulatory guidelines for biosimilars from agencies like EMA and FDA. Biosimilars can expand access to biologic treatments for diseases like rheumatoid arthritis and have potential cost savings compared to originator biologics. Safety monitoring is important due to concerns like immunogenicity.

1. BIOLOGICAL AGENTS AND IT ROLE IN
CURRENT ERA AND FUTURE ROLE

2. BIOLOGICAL AGENTS
 Biological agents are produced in a living system like a
microorganism, plant or an animal cell by harnessing rDNA.
 The end product is a protein directed against a specific gene or
another protein which is highly specific for its function and target
antigen.
 The introduction of biological such as erythropoietin, insulin,
growth hormones and anti-cytokine therapies brought a new
era in modern medicine and transformed the treatment of many
chronic diseases.
 The first biologic approved was humulin in 1982 by USFDA.

3. DEFINITIONS
 BIOLOGICAL PRODUCT: Medical products are made from a variety of
natural sources using biotechnology methods and other cutting edge
technologies and are intended to prevent or treat diseases and medical
conditions.
 BIOSIMILAR(EMA): A biosimilar is biological medicinal product that
contains a version of the active substance of an already authorized original
biological medicinal product. It demonstrates similarity to the reference
product in terms of quality characteristics, biological activity, safety and
efficacy.
 BIOSIMILAR(INDIA): A biological product/drug produced by genetic
engineering techniques and claimed to be similar in terms of safety,
efficacy, and quality to a reference biological.

4. BIOLOGICS AND SMALL
MOLECULE DRUG
 Active substances can be divided into small and large molecule
drugs.
 Small molecule drugs(SMDs) are stable, inorganic molecules with
a low molecular weight, typically manufactured by chemical
synthesis and can be fully characterized.
 Large molecular drugs/Biologics are 200-1000 times the size of
SMD made in living organism by rDNA or by controlled gene
expression methods. They are vulnerable to degradation in GI tract
thus given parenterally

5. HOW ARE BIOLOGICAL DRUGS
MANUFACTURED?

6. WORLDWIDE SCENARIO
 Biologics are one of the top selling drugs worldwide but the major
drawback of this drug has been its exorbitant cost, which makes it
unaffordable and inaccessible to many patients, especially in
developing countries where a large number of people are poor and
the concept of health insurance is at its nascent stage.
 But the silver lining is that once the innovator company loses their
intellectual property right and patent protection after a stipulated
period, it opens the window of opportunities for companies evince
an interest in manufacturing similar products, which cost less, and
at that time, it is known as biosimilar or similar biologic

7. GENERICS BIOSIMILARS
They have active ingredients whose
chemical and therapeutic characteristics
are identical to the reference products
in terms of dosage, strength, route of
administration, quality, safety, efficacy
and intended use.
The same standards of generic drugs
cannot be applied to biosimilars as there
are many differences
Regulatory agencies generally approve
applications of generic drug
manufacturers requiring only
demonstration of bioequivelance to
reference products in terms of
pharmacokinetics parameters and
bioavailability.
Biosimilar cannot be made an exact
replica of reference biological due to:
1- Complex structure.
2- Complex manufacturing process and
heterogenecity.
3- Characterisation.
4-Effect of external conditions

8. BIOSIMILARS VS BIOLOGICS
DEVELOPMENTAL PATHWAY

9. HOW BIOSIMILARS DIFFER
FROM ORIGINAL OR INNOVATOR
BIOLOGICS

10. DIFFERENCE BETWEEN
BIOLOGIC AND BIOSIMILAR

11. DIFFERENCE BETWEEN
BIOLOGIC AND BIOSIMILAR

12. ADVANTAGES
Biologics have benefitted the patients with rheumatologic
diseases, inflammatory bowel disease, malignant
conditions, dermatological conditions, and other
connective tissue disorders by halting the disease
progression, alleviating the symptoms, and improving the
quality of life.

13. SAFETY AND
IMMUNOGENICITY
 Immunogenecity is an important safety concern for biosimilars.
 Immune reactions may lead to inactivation of drugs and thus
limiting its efficacy and affecting its safety leading to adverse
effects.
 Factors affecting immunogenicity include:
1- Product-Related factors
2- Route of administration
3- Patient Factors
4- Eprex episode.

14. REGULATORY GUIDELINES
BY EMA
1-Guidelines on similar biological medicinal product.
2- Guidance on similar medicinal products containing
recombinant human insulin.
3- Guidelines on nonclinical and clinical development of
similar biological medicinal products containing LMWH
4- Guideline on similar biological medicinal products
containing recombinant FSH.
The first biosimilar, Omnitrope (a recombinant human growth was),
was approved in Europe by the European Medicines Agency (EMA)
in 2006

15. UNITED STATES FOOD AND DRUG
ADMINISTRATION(USFDA):
 BPCIA was passed in 2010 which created an abbreviated licensure pathway
for biological products shown to be biosimilar or interchangeable with FDA.
 FDA issued three draft guidance documents in 2012 on biosimilar products
addressing scientific and quality considerations and recommending a step-
wise approach to demonstrate biosimilarity.
 As per guidelines the biosimilar manufacturers will have to conduct animal
toxicology studies, pre-approval clinical trials, and potentially postmarketting
safety studies.
The first biosimilar approved by FDA was Zarxio(Filgrastim-sndz) in march
2015.
The latest one to be approved was pegfilgrastim-jmdb in June 2018 to
reduce the risk of infection following myelosuppressive chemotherapy

16. INDIAN REGULATORY GUIDELINES
FOR BIOSIMILARS:
 The first biosimilar was approved and marketed in India in
2000 for hepatitis B, although no specific guideline was
available at that time for the development and marketing
of biosimilar in India
 In July 2012 guidelines on similar biologics: Regulatory
requirements for marketing authorization in India was
introduced.
 It outlines an simple abridged procedure for evaluation in
similar biologics. (Guideline revised in 2016)

17. INDIAN REGULATORY GUIDELINES
FOR BIOSIMILARS:
 These guidelines address the regulation of manufacturing
process as well as quality, safety, and efficacy of similar
biologics.
 It also addresses the pre- and post-marketing regulatory
requirements for similar biologics.
 The demonstration of similarity depends upon detailed
and comprehensive product characterisations, preclinical
and clinical studies carried out in comparison with a
reference biological.

18. CDSCO has made it
essential for the
biopharmaceutical
company to conduct a
Phase IV study with a
minimum of 200
patients within 2 years
of getting approval for
marketing

19. RECENT ADVANCEMENT BY
INDIA
 Recently, an Indian biopharmaceutical company got the
USFDA’s nod for marketing its novel biologic. Herceptin
(active drug is trastuzumab) was the first biologic to be
approved by FDA, which is used in certain breast and
stomach cancer.
 This was also the first similar biologics manufactured by
an Indian company, which received approval to market in
the United States

21. INDIAN SCENARIO
 India has a robust growth in biosimilar drugs development.
 Biosimilar products being marketed currently include erythropoietin,
human growth hormone, recombinant human insulin, G-CSF,
interferon, etanercept, infliximab, rituximab and adalimumab.
 Developing a biosimilar is far more expensive than manufacturing
generic both in terms of time and cost.
 For development of a biological it is estimated that a biosimilar can
cost 20-40% less than their reference product.
 This reduction is marginal compared to generics of SMDs where the
reduction is as large as 70-80-%.

22. BIOSIMILARS APPROVED IN INDIA

23. BIOLOGICS IN
RHEUMATOLOGY

24. ROLE IN RA
 Biologics are typically reserved for people whose
arthritis has not responded adequately to traditional
disease-modifying anti rheumatic drugs (DMARDs)
 Biologics are usually given by Injection or IV
 Biologics require a strict follow-up schedule
 All biologics increase risk of infection.
 Patients should be screened for tuberculosis and other
infections before starting a biologic.

25. HOW DO BIOLOGICS TREAT
RHEUMATOID ARTHRITIS
 They inhibit specific components of the immune system that
play pivotal roles in inflammation.
 Biologics are used to treat moderate to severe rheumatoid
arthritis that has not responded adequately to other
treatments.
 Slow down the progression of rheumatoid arthritis when 1st
line drugs have failed.
 Aggressive treatment is known to help prevent long-term
disability from RA.

26. Anti-TNF agents
 Biologics, and specifically the anti-TNF biologics, can have a
very rapid onset of action: same day.
 Radiographic efficacy of the anti-TNF agents exceeded
expectations.
 Anti-TNF agents, and biologics in general, are surprisingly
well tolerated and relatively safe.
 Biologics have a well-defined and specific mechanism Of
action

30. BIOSIMILAR AGENTS USED IN
RHEUMATOLOGY IN INDIA

32. ADVERSE EFFECTS
 Infusion related reactions : Dyspnoea , chest pain ,
headache, high blood pressure, dizziness, rash, flushing,
hypotension or a “tickle in the throat.”
 Serious Infections: Tuberculosis and sepsis
 Malignancy : Lymphoma, Solid Tumors
 OTHERS:
Optic neuritis, Increase LFT, Severe allergic reaction,
Numbness and Tingling
 Pregnancy: stop before 3 months
 No live vaccines should be given

34. TOXICITY

35. HEAD TO HEAD
COMPARATIVE TRIALS

36. Comparison of the effects of tocilizumab
monotherapy and adalimumab in combination
with methotrexate on bone erosion repair
in rheumatoid arthritis.
Ann Rheum Dis. 2019 May 29. pii: annrheumdis-2018-214894.
TOC monotherapy achieves more pronounced
repair of existing bone erosions than ADA/MTX

37. Head-to-head comparison of subcutaneous
abatacept versus adalimumab for rheumatoid
arthritis: two-year efficacy and safety findings
from AMPLE trial.
Ann Rheum Dis. 2014 Jan;73(1):86-94
Subcutaneous abatacept and adalimumab were
similarly efficacious based on clinical, functional
and radiographic outcomes. Overall, AE frequency
was similar in both groups

38. Tofacitinib or adalimumab versus placebo:
patient-reported outcomes from OPAL Broaden-a
phase III study of active psoriatic arthritis in
patients with an inadequate response to
conventional synthetic disease-modifying
antirheumatic drugs.
RMD Open. 2019 Jan 11;5(1):e000806
Responses and adverse events were similar

40. BIOLOGICS IN PSORIATIC
ARTHRITIS

42. SYSTEMIC LUPUS
ERYTHMATOSUS

43. FUTURE PERSPECTIVE
 Many companies will have their patent expire in the
forthcoming year, which will open the window of opportunity
for other biopharmaceutical companies to explore the
possibility of development of biosimilar products.
 Every year, regulatory agencies are granting approval of
various similar biologics for the treatment of many cancerous
and noncancerous diseases.
 India has firmly established itself as a global player as a maker
of similar biologics.

44. FUTURE PERSPECTIVE
 Indian biosimilar market was approximately US$300
million in 2015. The domestic sales are close to US$250
million and growing at a compound annual growth rate
of 14%.

45. CONCLUSION
 Biosimilars offers the promise of more accessible to biological
products to patients suffering from chronic disease.
 High degree of variability among the biological products,
quality issues and safety issues such as immunogenicity call
for careful selection.
 Physicians and health care profesionals need comprehensive
information on biosimilars with awareness about critical
aspects of biosimilars such as safety, interchangeability,
tracking and substitution.