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 9/24/2015 [email protected]1
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Biosimilar DevelopmentOur “QbD” Journey from Generics to Biosimilars
Ajaz S. Hussain, Ph.D.
The National Institute of Pharmaceutical Technology & Education, Inc.
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• Other documents• Purple book• Draft guidance Naming, labeling• Planned guidance Statistical approaches to analytical similarity • Planned guidance Interchangeability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’?
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.
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
A unique, non-profit consortium of pharmaceutical science and engineering programs across 14 major research universities. Lowering cost & enhancing confidence……
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.
• 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….
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
“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,
“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
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)
• 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
• 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