Dr. Kasim

1. BIOSIMILARS- THE FUTURE OF BIOLOGICAL DRUGS
A MOHAMED KASIM

2.  INTRODUCTION:
Biological agents are produced in a living system like a micro-organism, 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.
GENERIC DRUG: A generic drug is same as the brand name drug in dosage, safety,
strength, how it is taken, quality, performance and intended use.

4. BIOLOGICS AND SMALL MOLECULE DRUGS:
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.
Largemolecular 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. GENERICS AND BIOSIMILARS:
GENERICS:
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.
Regulatory agencies generally approve applications of generic drug
manufacturers requiring only demonstration of bioequivelance to reference
products in terms of pharmacokinetics parameters and bioavailability.

6. BIOSIMILARS:
The same standards of generic drugs cannot be applied to biosimilars as there are
many differences.
Two independently developed biologicals maybe bioequivalent yet not
pharmaceutically interchangeable in the absence of evidence gathered from clinical
studies.
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.

7. ADVANTAGES:
The biggest advantage is the accessibility of effective, affordable biologics to the
underserved patients suffering from chronic diseases.
VARIABILITY:
The complex manufacture process of biologics can introduce minor variations in the
end product that it affects its stability, safety, sfficacy and immunogenicity.
A study was carried out on 16 biosimilar brands covering three different biological :
recombinant C- GSF, Recombinant human C- GSF and rHuEPO.
It showed a lack of comparability between biosimilars and reference products and
significance difference in purity among biosimilars of C- GSF and erythropoietin.

8.  SAFETY INCLUDING 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.

9.  RECALL AND DRUG SHORTAGE:
The complex manufacturing process of a biosimilar may often lead to quality
concerns and batch-to-batch variation which may impact patient safety.
This may result in recall of some batches of the products and result in drug
shortages which can have significant disruption ins in treatment practices.
NAMING:
While conventional generic names have the same INN as the reference compound,
naming has become very difficult.
Effects of biosimilars may differ in patients and are often delayed and therefore it is
important to trace the effect of a biological in patients from safety point of view.

10.  NAMING:
While the conventional generic drug have the same INN as the reference compound
naming conventions have become complex.
Effects of biosimilars may differ in patients and are often delayed, therefore it is
important to trace the biological effect in patient in view of safety point of view.
Tracking the identity and traceability by INN in case of an undesirable effect may
create an unforeseen delays.
SUBSTITUTION AND INTERCHANGEABILITY:
Generic SMDs are considered interchangeable and easily substituted, biosimilars
cannot be considered interchangeable.
Interchangeability for biological cane be considered at two levels, one between the
biosimilars and the reference product and second between the two biosimilars of the
same reference product.

11. REGULATORY OUTLOOK OF BIOSIMILARS:
1- EUROPEAN MEDICAL AGENCY(EMA):
EMA was the first to establish the regulatory framework for approval of biosimilars
in 2005.
Omnitrope(Somatropin) was the first biosimilar approved by EMA in 2006.
It has issued overarching guidelines for demonstrating similarity between
biosimilars and reference product, followed by guidelines on quality, non-
clinical/clinical issues, with additional product specific guidelines for interferon
alpha, LMWH and monoclonal antibodies.
Safety assessment plan including postmarketting surveillance, pharmacovigilance
and risk management plans must be included in the data package submitted for
product approval.

12. RUGULATORY 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.

13. 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.
This pathway permits reliance on certain existing scientific knowledge about the
safety and effectiveness of the reference product.
The first biosimilar approved by FDA was Zarxio(Filgrastim-sndz) in march 2015.
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.

14. INDIAN REGULATORY GUIDELINES FOR BIOSIMILARS:
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.
The demonstration of similarity depends upon detailed and comprehensive
product characterisations, preclinical and clinical studies carried out in comparison
with a reference biological.

15. 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-%.

16. COMMON BIOSIMILARS AVAILABLE IN INDIA:
Epoetin alpha recombinant erythropoietin- Anemia, cancer and CKD
Etanercept- Ankylosing spondylitis, JIA, RA, Psoriais and psoriatic arthritis.
Filgrastim- Recombinant G-CSF- Neutropenia, hematopoietic SCT
Follitropin alpha(FSH)- female infertility
Recombinant human insulin- Diabetes mellitus
Recombinant human interferon alpha- Carcinoids, Hep-B&C, hairy cell, CML
Recombinant streptokinase- Arterial occlusion, DVT, PE
Recombinant rTPA- Myocardial infarction.
Rituximab Monoclonal Ab targeting CD20- Leukemia, Lymphoma, RA
Trastuzumab- RA
Adalimumab- Ankylosing spondylitis.
Teriparatide- Post-menopausal women with osteoporosis who are at risk for
fracture

17. 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.

18.  THANK YOU