Sharing my learning in dealing with complexity and uncertainty and shed some light on: (a) Understanding the ‘biosimilar paradox’ (b) Accelerating our “QbD” Journey – focusing on ‘from Generics to Biosimilars’ (c) In preparing this talk, collect my thoughts to help NIPTE consider ways for developing its program on Biosimilars to help the Nation improve assurance of quality with confidence and lower costs (D) Invite the audience to get to know NIPTE and provide us ways to collaborate with industry

1. Biosimilar Development
Our “QbD” Journey from Generics to Biosimilars
Ajaz S. Hussain, Ph.D.
The National Institute of Pharmaceutical Technology & Education, Inc.
& Insight Advice and Solutions LLC.
Celebrating 54 Years
September 25, 2015, Basking Ridge, NJ
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2. Biosimilars @ US FDA: Current state
57 products in review, 16 reference products
• New Review paradigm; totality of evidence – putting analytics first
• Advisory committee process (Zarxio®; ‘totality of evidence’ making the case to clinicians poses challenges)
• Final Guidance documents
• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (2012)
• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (2012)
• Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
(2012)
• Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (2013)
• Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (2014)
• Other documents
• Purple book
• Draft guidance Naming, labeling
• Planned guidance Statistical approaches to analytical similarity
• Planned guidance Interchangeability
• Building confidence – education?
• 30 years of Generics; still we have confidence challenges
• How will we build confidence in ‘biosimilars’?
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generics are for minor but
not serious illnesses;… and
poor people are forced to
‘settle’ for generics.
What do people really think of generic medicines? A systematic review and
critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:173
36 % of the patients reported negative
experiences after medication substitution
89 % of pharmacists reported receiving
patient complaints regarding use of generic
medicine, although 64 % suggested that this
was due to a nocebo effect
Only 50.2 % of the surveyed pharmacists
agreed that all products that were
approved as generic equivalents can be
considered therapeutically equivalent.
Just 6 % of pharmacists considered
that dry powder inhalers were
interchangeable.
While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains,
particularly within the patient and, to a lesser extent, physician groups.
Nearly half the patients stated they would
refuse generic substitution when it became
available if this was just to save the health
authority money.
Generic medicines were
considered to be poor quality and
treated with suspicion.

4. Zarzio® (EU) & Zarxio® (US)
EP2006
Zarzio®
Zarxio®
US‐NeupogenEU‐Neupogen
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Highly similar
Interchangeable?Highly similar
Highly similar
Extrapolation of indications; easier Extrapolation of indications; difficult
Finger-print like similarity; statistical confidence
Products and Trade-marks of Sandoz

5. This talk: My objectives
• To share my learning in dealing with complexity and uncertainty and
shed some light on
• Understanding the ‘biosimilar paradox’
• Accelerating our “QbD” Journey – focusing on ‘from Generics to Biosimilars’
• In preparing this talk, collect my thoughts to help NIPTE consider ways for
developing its program on Biosimilars to help the Nation improve assurance
of quality with confidence and lower costs
• Invite the audience to get to know NIPTE and provide us ways to collaborate
with industry
9/24/2015 ajaz@nipte.org 5

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A unique, non-profit consortium of pharmaceutical
science and engineering programs across 14 major
research universities. Lowering cost & enhancing
confidence……
Biosimilars Group
Analytical Comparison of Parent and
Follow-On Biologics to Aid Biosimilars
Regulatory Guidelines Development
•Lead: Anna Schwendeman
•Institution: University of Michigan
Physiochemical and Biological
Evaluations of Different IgG1Fc
Glycoforms as a Model of Biosimilar
Comparability Analysis
•Lead: Thomas Tolbert
•Institution: University of Kansas
http://www.nipte.org/

7. My viewpoints and interests
Viewpoints
• US FDA
• SUPACs, BCS,….PAT, QbD, Integrations of
Office of Biotechnology within CDER
• Sandoz
• Omnitrope®, Binocrit®, Zarzio®, generic
enoxaparin, generic glatiramer acetate
• Philip Morris International
• Plant based vaccines and modified-risk
tobacco products
• Reconnecting with India
• Wockhardt and current advisory practice
in India – Culture of Pharmaceutical
Quality
Interests
• NIPTE consider ways for developing its
program on Biosimilars to help the
Nation improve assurance of quality
with confidence and lower costs
• Insight Advice and Solutions LLC.,
Allocated time filled-up; not accepting
new clients until the end of 2016
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8. In the news; past few days
Sept. 24, 2015
Novartis in biosimilar push to cut US drug prices: The introduction of
biosimilar drugs in the US, which kicked off this month with Novartis’s version
of an Amgen blockbuster, hands healthcare payers a new weapon against
rising drug prices.
Sept. 23, 2015
Amgen, Allergan Biosimilar Lung-Cancer Therapy Shows Positive Results: ABP
215 is being developed as a biosimilar to Roche’s Avastin
Sept. 22, 2015
Lack of regulatory clarity dominates US biosimilar debates post Zarxio®:
Sandoz has reiterated its call for US FDA guidance on biosimilar
interchangeability arguing that the lack of clarity makes it hard to gauge what
impact switching rules will have on pricing.
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9. First Biosimilar Medicine Launches; Price
Disappoints Those Hoping For Deeper Discount
Forbes | Opinion Sept. 15, 2015
Chart using 2014 data. Retrieved from Rand Corporation, September 14, 2015.
“..could reduce spending on biologics in the United
States by $44 billion over the next decade..”
Chart using 2013 data. Retrieved from Express Scripts, September 14, 2015.
Another biosimilar is coming along that could
actually cost taxpayers a higher price!!!
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10. ‘Biosimilar Paradox’
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http://invivoblog.blogspot.com/2007/08/are-these-large-molecule-twins.html
•Not Similar; Similar; Highly Similar;
Highly similar; fingerprint-like
similarity ; Interchangeable
•Barriers to Market Entry -
Commercial Success Disappointing
•(Will) there will be significant
savings for the U.S. Medicare and
Medicaid programs?
•US is not Europe! Zarzio® (EU) &
Zarxio® (US)•

11. Biosimilar Paradox: EU
Aug., 10 2007
• But despite Europe's pioneering regulatory pathway for biosimilars, and
reluctant grunts of acceptance from originator companies, most of which have
realized that it’s pointless and counterproductive to keep resisting the
biosimilar movement, the going’s tough, according to Ajaz Hussain, Sandoz’s VP
and Global Head of Biopharmaceutical Development.
• One might expect a drug that sells at a 20-30% discount—he did confirm this
much--to fly off the shelves, given all the fuss around Amgen’s monopoly over
EPO supply…..and the noise that most European governments and US payors
are making about drug costs. But education and perception are blocking
widespread uptake….
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12. Biosimilar Paradox: Promises & Perils
Steep discounts help biotech drug copies gain ground in Europe: Biosimilar antibody drug prices fall faster
than expected ( Sept. 23, 2015, Reuters). But US is not Europe! Zarzio® (EU) & Zarxio® (US)
There will be significant savings for the U.S. Medicare and Medicaid programs? CBO estimates savings
of ~$25 billion between 2013 and 2020. How to build confidence, cost savings, and commercial success?
Assessing Valuation Risk of Big Pharma Companies: Forbes | Investing (Sept. 21, 2015)
J&J’s Remicade Revenues May
See Significant Decline
Merck May Actually Be Well
Off In The Near Term
Pfizer Seems To Have Upside
Possibility
Bristol-Myers Squibb’s Risk Lies
A Few Years Ahead
Roche Might Be Vulnerable,
But Will Fiercely Defend
Barriers to Market Entry: It takes 7 to 8 years to develop a biosimilar, at a cost of between $100 million and
$250 million: Commercial Success (Currently) Disappointing
?
?
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13. FDA's Woodcock to Senators: Need to First Get the
Science Right on Biosimilars
• Sept., 17 2015
• "We have to get the science right. We can't have problems with the first biosimilars
out of the block"
• One of the most important parts of launching a robust US biosimilar market and
setting up the regulations to support it is to make sure the scientific framework is
"bulletproof”
• Key issues remaining - FDA guidance on interchangeability and the difficulties behind
developing, naming and labeling
• "We've laid out a plan of education campaigns and still need to determine what
people need to know“
• It's a complicated issue so we have a menu of educational activities for the next
several years“
• Does this mean the EU didn’t get its “science right”? No!
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14. Essentially taken for granted  paying attention is the critical factor.........
To understand this Paradox: Understand our
“QbD” Journey from Generics to Biosimilars
The Hatch-Waxman Act of 1984:
Successfully contained the cost
of small-molecule drugs; based
on the [PE + BE = TE] paradigm
[PE + BE = TE] paradigm
struggles to deal with
complexity; including
Complex Generics
The Biologics Price
Competition &
Innovation Act
2009: pathway for
Biosimilars;
recognizing the
complexity; a high
bar!
PE = Pharmaceutical equivalence:
BE = Bioequivalence
TE = Therapeutic equivalence
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15. Our “generic” paradigm:
Interchangeability with confidence
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Pharmaceutical
Equivalence
Bio-equivalence
Practices >
Confidence
Therapeutic
Equivalence

16. Generic paradigm has been tested and
“knocked on its head”
• “It still is solid” but in need for attention – particularly in the realm of
complex generics
• “Knocks on the head”
• Generic Drug Scandal
• Failures to detect obvious errors/flaws
• Recent failures and manufacturing challenges
• Tested – numerous prospective studies to assess therapeutic
equivalence
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17. “Knocks on the head” erode confidence and
increase nocebo effects!
• “Knocks on the head” have occurred
• When we failed to appreciate a systems approach to development, review, process
validation, and inspections (GLP/GCP/CGMPs)
• When we ignored to ask the ‘right question’ and in the ‘right sequence’
• When we did not question assumptions we take for granted
• Most of these relate to Pharmaceutical Equivalence
• PE = dosage form (irrespective of color, shape, mechanism of release,….);
• A clear liquid in a bottle is a “solution”: e.g., cyclosporine micro emulsion, and low-
permeability excipients (e.g., sorbitol)
• Consider current examples….ER failures and AB to BX downgrades
• Our incorrect thinking – “BE is the pivotal evidence”; instead of integrating PE,BE,
Practices – as in a system
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18. “Pharmaceutical Equivalence” that is the
‘Elephant in the Dark’
• Q1/Q2
• Q1/Q2/Q3, ……
• Today … Color, Shape,…..moving towards same mechanism of release?
• Today we are back to “subjectXformulation” interaction – once again in
healthy subjects?
• Isn't this just an assumption? Which, politely, is not a part of “our elephant” but
what comes out of it when we don’t pay attention to PE!
• We lack consensus on a set of principles to integrate across multiple,
orthogonal, analytical characterization tools for physical attributes and
physical performance (e.g., size, shape, charge, flow, plume, …)
• This is a “billion dollar” opportunity; but only for certain companies
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Ajaz Hussain. Reducing technical and regulatory uncertainty in biosimilar development (2014)
Value of extensive
analytical characterization
Leveraging variability to
reduce uncertainty
in interchangeability

20. The “how” is very difficult because of “culture”
and “mind-set”
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Characterization of
Brand Copaxone
Thorough understanding of
reference listed drug
(Copaxone) required.
Review available scientific,
patent, and regulatory
literature on Copaxone.
Characterizationby more
than 60 physicochemical,
biological, and immunological
methods.
Multiple lots (up to 50 for
some attributes) were
studied over several years
probing the range and
diversity of the commercial
lots, as well as evaluating the
effects of lot aging.
Four-Point Criteria for
Demonstration of
Equivalence of
Glatopa and Copaxone
Equivalenceof starting
materials and basic
chemistry.
Equivalenceof structural
signatures for polymerization,
depolymerization, and
purification.
Equivalenceof
physicochemicalproperties.
Equivalenceof biologicaland
immunological properties.
Example: Equivalence considerations for Glatopa® and Copaxone®
http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf (accessed 16 September 2015)

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Ajaz Hussain. Reducing technical and regulatory uncertainty in biosimilar development (2014)

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Residual uncertainty; perhaps reserved for
uncertainty in extrapolation to some indications
Ajaz Hussain. Reducing technical and regulatory uncertainty in biosimilar development (2014)

23. Biosimilar: Totality of Evidence
• New Review Paradigm – meeting format
• Focus first on analytical characterization and comparability
• Totality of evidence evolves – based on residual uncertainty
• Is this a better – formalized- approach than for complex generics?
• For Complex Generics OGD has been willing to meet with sponsors more
often
• However, time for complex generic approval is very protracted
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24. Complex Generics & Biosimilars: What we need?
• Put R back in R&D & recognize It is a “complex” product and process!
• Invest smartly in analytics, mathematics & statistics, and large sample sizes; and
in systems/integrative thinking and data integration
• Get to know the RLD – multiple lots; open the door with large sample size
• Build capability to justify measured RLD variability is relevant to development of
the proposed generic/biosimilar
• Exquisite regulatory communication strategy
• This is not a ‘complicated process’ for which typical “good practices” will work
seamlessly (e.g., typical project management approach); this is a complex process
– with multiple interactions and “emergent properties”
• Treat it as it is - a complex process and plan; anticipate and address “emergent
issues” - in technical, regulatory and legal dimensions; at a certain point be
prepared for stakeholder (payers, patient groups,..) communications
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25. NIPTE: The Nation Needs
• Seamless scientific logic bridging different legal and regulatory
pathways
• Accelerate achieving consensus on a set of generalizable principles for
integrating information across multiple, orthogonal, analytical
characterization tools for chemical, biological and physical attributes; to
predict product performance, and estimate and describe residual uncertainty
• Consider categories such as peptides (synthetic and recombinant) as a bridge
between Generics and Biosimilars to achieve a ‘seamless scientific logic’
• The Nation needs the scientific & regulatory community to achieve
this quickly – so that efforts to educate to build confidence, in the
health care community and with patients, can begin
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