February 7, 2017 Many of today’s important medications are biological products made from living organisms, manufactured through biotechnology, derived from natural sources, or produced synthetically. Biosimilars are a type of biological product approved by FDA on the basis of being highly similar to an already approved biological reference product. This panel of experts discussed the current state of biosimilars in the healthcare ecosystem and what comes next from a technical and legal perspective. Topics included how the next generation of biosimilars could improve patient access to standard-of-care therapies, the concept of “biobetters,” economic and intellectual property considerations, and policy approaches to support existing and future biosimilars. Learn more on our website: http://petrieflom.law.harvard.edu/events/details/looking-forward

1. Draft Presentation
Biosimilars & BioBetters— The Differences Between
Both and the Two Very Different FDA Regulatory
Pathways
Jennifer L DiGiacinto, PharmD
February 7, 2017
Harvard Law School

2. Overview
• Biosimilars & BioBetters Definitions
• Current State of Biosimilars
• Concept of BioBetters
• Differences between Biosimilars and BioBetters
Development
• Regulatory Pathways for Biosimilars & BioBetters
• Cost and Development Time
• FDA Guidance
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3. Definition Biosimilar
• Biosimilars-are products that are “highly similar” to the biologic reference
product(s) regarding quality, biological activity, safety, and efficacy.
– The Biologics Price Competition and Innovation Act of 2009 (BCPI Act)
signed into law March 23, 2010
 BPCI Act creates an abbreviated licensure pathway for biological
products shown to be “highly similar” to and/or “interchangeable” to
an FDA licensed reference product
– Biosimilars are not generics – due to complex nature and produced in
living systems it can never duplicate the originator
 do not follow the same regulatory pathway as a generic 351(k) vs.
505(j) (generic / ANDA)
– Perceived to be a lower business risk vs original biologic
– Follows stringent legal and regulatory pathways across the globe
– No exclusivity granted for “highly similar” status / 1 year Exclusivity
granted for “interchangeability” status
– Approval across all indications for the Reference Biologic is possible
– Must wait for the Innovator’s patent to expire prior to submitting to FDA
for approval
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4. Definition-Biobetter
• BioBetter-is a biological that has been structurally and/or functionally
altered to achieve an improved or different clinical performance (eg,
altered structure, compared to an already approved biologic product)
 Chemical modification (PEGylation, Glycosylation), New Formulation
(novel ROA, modified released)
 Longer half-life, less immunogenic, better efficacy, better safety, less
frequent dosing, better purity, longer shelf-life, etc.
– Term “biobetter” surfaced in context to Biologics Price Competition
and Innovation Act (BCPI Act 2010-”Biosimilars Act”)
– Given the stringent regulatory requirements of highly similar and
interchangeability required for a biosimilar, Sponsors turned their
interest to biobetters.
– 351(a) –BLA same as the originator regulatory pathway
– Perceived to be a lower business risk vs original biologic
– Exclusivity (eg, 12 years) and Patentable
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5. Current State of Biosimilars
• US Biosimilars (2010) start was sluggish due to the stringent pathway
and; whereas, Europe had much more traction earlier on (2005)
– To date, 4 biosimilars (filgrastim (2015), infliximab (April 2016), etanercept
(August 2016) and adalimumab (September 2016) have been approved
by FDA (“as highly similar” but not “interchangeable”; whereas, Europe
currently has 20 biosimilar products approved (since 2005).
 Biosimilar which is approved as “highly similar” to reference product and
shown to have no meaningful clinical differences
 Interchangeable Biosimilar-in addition to meeting the biosimilarity, is expected
to produce the same clinical result as the reference product in any given
patient
 Highly similar = “B” rating vs “I” rating for “interchangeable” in the Purple
Book
• Early on major hurdle to US biosimilars is no real pathway or clarity of
how to obtain “interchangeable” status—consider to be the golden egg-
which requires a higher bar of evidence, more studies and was not clearly
defined how to obtain by FDA.
– US clinicians expressed concerns on how to determine if a product will be
interchangeable
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6. Current State of Biosimilars, Continued
• FDA just released a new draft Guidance for
Industry-- Interchangeable Biosimilar
Products-
• An interchangeable product is expected
to produce the same clinical result as
the reference product in any given
patient.
• Sponsor must demonstrate if the
product is administered more than once
to an individual, the safety and efficacy
risks of alternating or switching between
the use of the biosimilar product and the
reference product is not greater than the
risk of using only the reference product.
• FDA expects clinical data to
demonstrate this in all of the reference
product’s licensed conditions of use
• “Switching Studies”-outlined in guidance
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7. Current State of Biosimilars, Continued
– US current Biosimilar market is finally coming to existence
and signs of future potential; however, still some
uncertainties:
– Key issues and drivers:
 More originator biologics coming off patents=more opportunity
for biosimilars
o 2009-2019 $50B of the market value of biologics will come off
patent
o 100B of the market value of biologics will come off patent by 2020
 US pricing will play a role in biosimilars success
 Solidifying the policy and regulatory environment that will
expedite the development
 Education to the clinicians, patients, payers, and policy makers
as to the safety and efficacy of biosimilars
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8. Concept of BioBetter
– 2007 “BioBetter” coined by CEO (G.V. Prasad) of Dr.
Reddy’s Laboratories at a bioinvestor’s conference
– Not actually a new concept
 Pegylation of existing molecules is well-known method for
extending the half-life of a biologic molecule
 Results into a reduced dosing schedule for the patient
(improvement of QOL)
 First pegylatyed version of the interferon alfa (Pegasys®) was
approved by EMA in 2002, but wasn’t until 2007 the term
“biobetter” was coined.
– BioBetter –development most important element is defining
“better than” vs. a Biosimilar trying to achieve highly similar
and/or interchangeable is the most important development
goal
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9. Concept of BioBetter, Continued
– Biobetter refers to a recombinant protein drug which is in the same
class as an existing original biologic (Innovator) but is not identical and
has a different active compound when compared to the Innovator
 It is improved or an upgraded version of the innovator with no
structural limitations and may include molecular/chemical
modifications
– Biobetter aims for the same target as the innovator, but has a longer
activity duration and usually at lower doses with fewer adverse effects
– Biobetters are like new drugs and must be developed like a new BLA-
well-defined pathway
– Biobetters do not have to wait until a patent expires for the Innovator;
may obtain a patent or data exclusivity (up to 12 years) based on their
innovative properties, and will command a premium price
 Can only be marketed for the approved indication
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10. Differences between Biosimilars and BioBetters
Development
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H Gorham, The Value of BioBetters, 2016

11. Regulatory Pathways for Biosimilar
Biosimilar Regulatory Pathway 351(k)
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E. Olech 2016

12. Regulatory Pathways for Biosimilar
• Under the BCPI Act-
– The FDA interpretation is a biologic is first approved as a biosimilar that is
“highly similar” to the Reference product and may (or may not) then be
determined to be “interchangeable” to the Reference product
 Approvals are made on a “case by case” decision looking at the “totality” of the
package
– NEW FDA Guidance to Industry: Demonstrating Interchangeability with a
Reference Product (Jan 2017):
– D
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13. Regulatory Pathways for BioBetters
• 351(a)-Traditional BLA
– Longer and more
expensive clinical trials –
must follow new-drug
approval pathway
• How much better?
– Must be significantly better
to gain acceptance over
established reference
product or biosimilars
thereof. Large clinical trials
likely needed to prove
clinical superiority over
reference product
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14. Costs and Development Time
• Innovator Biologic: BLA
– 10-15 years to develop
– R&D Costs: $1.3-$2.6B /Failures into account $5B
• Biosimilar:
• 8-10 years to develop
• $100-$200M
– Celltrion invested $112M of Remsima, a biosimilar to
Remicade
• Monoclonal antibody biosimilar (Mab) >> $250M
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15. FDA Guidance for Biosimilars
• 8 FDA Guidances to Industry for Biosimilars
– Focus on therapeutic protein products
– Discusses general scientific principles
– Outlines a stepwise approach to generating data and the
evaluation of residual uncertainty at each step
– Introduces the “totality-of-the-evidence” approach
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm
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16. FDA Guidance for Biosimilars
• Biosimilar Initial Advisory Meeting
– General discussion regarding feasibility of licensure of particular product
under PHS Act
• BPD Type 1 Meeting
– Dispute resolution, clinical holds, SPA, important safety issue
– Type 1 Meetings should be scheduled within 30 days of the date of the written
request
• BPD Type 2 Meeting
– Specific Issue: study design/endpoints and can involve review of substantive
data
• BPD Type 3 Meeting
– In-depth data review and advice meeting-extensive data package
 Analytical similarity data / future proposed clinical trials
• BPD Type 4 Meeting
– Discuss the format and content of Biosimilar biological product application
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Outlined in FDA Guidance to Industry: Formal Meetings Between the FDA and Biosimilar Biological Sponsors or Applicants

17. FDA Guidance for BioBetters
• Meetings and guidance would follow standard practice
for new BLAs
– Type A Meetings- a meeting requested to help an
otherwise stalled product development program to proceed
 Dispute resolution, clinical holds, SPA
 Type A Meetings should be scheduled within 30 days of the
date of the written request
– Type B Meetings—
 PIND, EOP1, EOP2, Pre-Phase3, Pre-BLA
o Occur within 60 days of FDA written receipt of a meeting
request
– Type C Meetings
 Any other meeting that does not fall under Type A or Type B
o Occurs 75 days of FDA receipt of written request
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Outlined in FDA Guidance to Industry: Formal Meetings Between the FDA and Sponsors or Applicants

18. Proprietary and Confidential 18

19. Proprietary and Confidential 19
Backup Slides

20. Biosimilars vs BioBetters
• Biotechnology Information Institute reports:
– 21 Biosimilars and 12 Biobetters for Herceptin currently
companies are woraing on
– 21 Biosimilars and 13 Biobetters for Rituxan
• A new Biosimilar will enjoy a large market for a short
period of time—until next new Biosimilar approved or
BioBetter is approved
• A new “highly similar” Biosimilar does not receive the
180 day exclusivity period a ANDA product receives
upon approval (Hatch-Waxman Act)
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21. Biosimilars vs BioBetters
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Table from Bill Stohl, Janssen, IBC Biopharm Prod Week, 29 Feb 2012, SD, CA