The document discusses generics and biosimilars. It provides background on the Hatch-Waxman Act which established the abbreviated new drug application process for generic small molecule drugs. It also discusses the Biologics Price Competition and Innovation Act which created an abbreviated licensure pathway for biosimilar biologics. The manufacturing of biologics is more complex than small molecules due to production in living cells, and biosimilars are highly similar but not identical copies. Clinical trials are required to demonstrate biosimilarity in terms of safety and efficacy.

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2. Flow of thoughts for the day
Generics & Biosimilars
Generic Act
Generics
Biologics R&D
Need for biosimilars
Affordability Act
Goal post
Interchangeability
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3. Generics
&
Biosimilars
Every secret starts small..
By Kamalasundar
Moderated by Dr.Ravichandra
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4. ‘ANDA’ !
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8. Innovator
product
Provision for ‘ANDA’
hatching
by
Hatch Wax-man !
Generic
product
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9. “Generic Act”
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10. • 1984 Drug Price Competition and Patent Term Restoration Act
(Hatch‐Waxman Act)
• Hatch‐Waxman balanced the originator‐molecule
manufacturers meaningful period of patent protection to
recover development costs with public expectation of less
expensive alternatives
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11. Abbreviated New Drug Application
• section 505(j) FDCA
• established through the 1984 Hatch-Waxman Amendments
• generic drug program for “small molecule” drugs
• active ingredient is small in size and chemical origin
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12. Small molecule generics
‐ identical copies made
‐ approximately 50 simple tests to demonstrate identity,
strength, quality, potency, purity
‐ fully characterized
‐ stable
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13. - scientifically demonstrate that generic product is
bioequivalent
- in healthy volunteers  measure bioavailability of generic
drug  comparative to the innovator drug
- deliver same amount of active ingredients into human
bloodstream in same amount of time using the same route of
administration as innovator drug
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14. Wealth is Health ?
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15. “ Bigger - Better - Deal ”
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16. Biologic
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17. Biologic R&D
Vs
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18. 01 Modifying the selected cell
• Biologic medicines are made in living organisms by
genetically engineering DNA.
DNA is inserted into living cells, such as bacteria, yeast or
cultured animal cells, to code for the production of a
particular protein.
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19. 02 Growing a cell line from
modified cell
• The most effective cell line is selected for expansion.
During selection, the cells that can produce the biologic most
effectively are identified.
This cell line is unique to each manufacturer and is the source
of all future products.
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20. 03
Growing a large number of
cells from the cell line to produce
the desired protein
• The unique cell line is grown in bioreactors and carefully
monitored.
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21. 04
• Separating the protein from the cells through filtration or
centrifugation
• Purifying the collected protein through chromatography
• Purified bulk drug  characterisation and stability
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22. Manufacturing process
Modify host cells
(bacteria,
mammalian ) to
produce
recombinant
proteins
Extract, refold,
purify
to generate drug
substance
Formulate to
stable finished
drug product
(vial, syringe,
cartridge)
Grow cells
under controlled
conditions in
bioreactor
.
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23. • Biological ‐ manufacturer must ensure product consistency,
quality, and purity by ensuring that the manufacturing process
remains substantially the same over time.
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24. • Manufacturing and quality control issues can impact patient
safety and result in a loss of confidence in the quality of
biologics.
• They can also cause product recalls and drug shortages, which
can have profound effects on patients, treatment practices
and overall confidence in biologics.
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25. • A biologic medicine typically has around 250 in-process tests
during manufacturing, compared with around 50 tests for a
small molecule, to demonstrate safety and equivalent efficacy
and to ensure safe, reliable production of therapies for
patients.
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26. • With expanding demand for good-quality biologics comes
challenge of bearing with healthcare expenditure.
• Regulated introduction of generic biologics into market can
increase access to much needed biologic medicines and
reduce costs.
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27. Block
Buster
Biologic
Biologics Trade Name
Rituximab Rituxar
Adalimumab Humira
Insulin aspart Novolog
Bevacizumab Avastin
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28. Exclusivity
• application for follow-on biologic may not be submitted until
4 years after the date of first licensure of the reference
product.
• application for follow-on biologic may not be approved until
12 years after the date of first licensure of reference
product.
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29. Big B
falls off the
Patent cliff and
breaks
its crown!
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30. Catch me if u can !
The complexity of biologics precludes identical copies and hence
making generic biologic is impossible.
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31. Highly similar yet not the same…
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33. “Affordable Act”
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34. Rules of the New Game
• Public Health Service Act (PHS Act)
• Biologics Price Competition and Innovation Act (BPCI Act)
• an abbreviated licensure pathway section 351(k)
• Affordable Care Act, signed into law by President Obama on
March 23, 2010
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35. “ Twin pyramids ”
Purification process
development
Bioprocess development
Recombinant cell line development
Drug product
development
PK/PD
Preclinical
Biological
characterization
Physicochemical
characterization
Clinical
Process
development
Analytics
Confirmation
of
biosimilarity
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36. “ Biosimilar Goalpost ”
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37. Originator manufacturing process changes are the basis for
biosimilarity goal posts.
Reference product
2005 process
Reference product
2010 process
Biosimilar
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39. Totality of Evidence Approach
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40. Made in India Insulin
• Bowing to the stringent criteria required by the EU,
India-based Marvel Life Sciences officially notified the
Committee for Medicinal Products for Human Use (CHMP)
of EMA in December 2007, that it would withdraw its
applications for marketing authorisations for their
biosimilar human insulins, as they were unable to meet the
standards for comparability set by the CHMP.
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41. • This ‘Marvel insulin episode’ is critical from an Indian
perspective as ‘alternative’ biological insulin continue to flood
the Indian market, despite the fact that in the EU has not yet
approved a biosimilar insulin.
• ‘Similar biologics guidelines’  15 September 2012
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43. Non-clinical data
Should include pharmacodynamic, pharmacokinetic and comparative repeat-dose;
toxicity studies in a relevant species
Quality
All aspects of quality and heterogeneity should be assessed including
head-to-head comparisons with the reference product
Reference product
The reference product should be authorized in the country or another country with good regulations
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44. Pharmacovigilance and risk management
A pharmacovigilance plan is required when an application is submitted
Clinical studies
Required to demonstrate similar safety and efficacy. Immunogenicity should
always be investigated in humans before authorization
Non-clinical data
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45. ADR
• Incidence of pure red cell aplasia following a minor change in
the packaging process of epoetin alfa (erythropoietin, EPO)
made the world sit up and look at biopharmaceutical products
with more caution.
• It also prompted drug regulatory authorities to establish strict
guidelines for evaluating biopharmaceuticals and biosimilar
products.
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46. Naming, tracking and tracing medicines
• Currently, the International Nonproprietary Name (INN) for a
new biosimilar may be the same as that of the original
biologic medicine.
• In such a case, with INN (without a distinguishable name),
when prescribing a biologic medicine, the treating physician
may not know precisely which medicine a pharmacist gave
the patient.
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47. Interchangeability
• An application for interchangeability can be concurrent or
subsequent to the application for a biosimilar product under
351(k) of the BPCIA.
FDA criteria
• The biologic product should be biosimilar to the reference
biologic product
• It can be expected to produce the same clinical results as the
reference product in any given patient.
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48. • For a biological product that is administered more than once
to an individual, the risk in terms of safety or diminished
efficacy of alternating or switching between use of the
biological product and the reference product should not be
greater than the risk of using the reference product without
such alternation or switch.
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50. Unfair field
dominated by
Big players !
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51. protein protein
Protein
(no sugars)
Monoclonal
antibody
~150 kDa
Glycoprotein
(with sugars)
MammalianBacteria, Yeast
calcitonin
~3.5 kDa
epoetin
~30 kDa
somatropin
~22 kDa
Peptide
filgrastim
~19 kDa
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52. Thank you
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53. Bibliography
• www.FDA.gov
• www.amgen.com
• www.sandoz.com
• Images from Internet
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