Biosimilar DevelopmentOur “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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Biosimilars @ US FDA: Current state57 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• Other documents• Purple book• Draft guidance Naming, labeling• Planned guidance Statistical approaches to analytical similarity • Planned guidance Interchangeability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, 13:17336 % 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.

Zarzio® (EU) & Zarxio® (US)

EP2006

Zarzio®

Zarxio®

US‐NeupogenEU‐Neupogen

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Highly similarInterchangeable? Highly similar

Highly similar

Extrapolation of indications; easier Extrapolation of indications; difficult

Finger-print like similarity; statistical confidence

Products and Trade-marks of Sandoz

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

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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/

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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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, 2015Amgen, 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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First Biosimilar Medicine Launches; Price Disappoints Those Hoping For Deeper DiscountForbes | 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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‘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) •

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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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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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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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 = BioequivalenceTE = Therapeutic equivalence

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Our “generic” paradigm: Interchangeability with confidence

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Pharmaceutical Equivalence

Bio-equivalence

Practices > Confidence

Therapeutic Equivalence

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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“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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“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

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.

Characterization by 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

Equivalence of starting materials and basic

chemistry.

Equivalence of structural signatures for polymerization,

depolymerization, and purification.

Equivalence of physicochemical properties.

Equivalence of biological and 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)

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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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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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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