New York
Washington
Seattle
INNOVATIVE STRATEGIES FOR NEW DRUG DEVELOPMENT
BIOBETTERS
Korea-Maryland, USA Bio Expo 2013
November 8, 2013
Brian J. Malkin, Partner (bmalkin@flhlaw.com)
Frommer Lawrence & Haug LLP
FDA Lawyers Blog
(http://www.fdalawyersblog.com)
KEY TOPICS
 Identifying opportunities to extend into the
marketplace.
 Resources necessary for the production of
biobetters.
 Assessing the risks and benefits of producing a
biobetter.
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WHAT IS A BIOBETTER?
 A biological product related to an already-approved
biological product but superior in one or more
product characteristics.
 The term “biobetter” became popular in the context
of the Biologics Price Competition and Innovation
Act (“the Biosimilars Act”).
 Faced with rigorous requirements for biosimilarity
and interchangeability in the Biosimilars Act, many
applicants have expressed interest in biobetters.
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WHY IS IT “BETTER”?
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Product characteristics targeted for improvement
Longer product half-life
Less frequent dosing
Lower likelihood of aggregation
Greater efficacy
Greater purity
Fewer adverse events
Streamlined manufacturing
Longer shelf-life
Easier administration/packaging improvements.
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LEGAL FRAMEWORK
 It does not appear that FDA would approve a “biobetter”
under the Biosimilars Act. A full BLA is likely required.
 The Biosimilars Act does not use the term “biobetter”.
 The Biosimilars Act authorizes FDA to approve biological
products that are “biosimilar” to an already-approved
biological product only under certain circumstances.
 “Biosimilar” is defined as
• “Highly similar to the reference product notwithstanding minor
differences in clinically inactive components.”
• “No clinically meaningful differences between the biological product
and the reference product in terms of safety, purity, and potency.”
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MODIFICATION STRATEGIES
Modification strategies include:
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Chemical modification
PEGylation
Glycosylation
New formulation
Controlled release
New routes of administration (e.g., transdermal, nasal)
New manufacturing process
Use of new cell platform.
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IDENTIFYING OPPORTUNITIES
Some areas of opportunity may include:
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Monoclonal antibodies
Glycoproteins
Vaccines
Protein hormones.
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IDENTIFYING OPPORTUNITIES (cont’d)
 Possible improvements to antibody products
 Further humanization
 Minimizing murine sequences and maximizing
human sequences
 Increased number of binding targets
 Bispecific antibodies
 Antibody-drug conjugates
 Links to cytotoxic drugs for targeting to cancer
cells
 Antibody fragments
 Smaller versions of full-size marketed antibodies
 May provide manufacturing advantages.
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IDENTIFYING OPPORTUNITIES (cont’d)
 Possible improvements to glycoprotein
products:
 PEGylation
 Altered glycosylation pattern
 Altered amino acid sequence
 Fusion with albumin or carrier protein
 Use of controlled release technology
 Improvements often focus on improving
half-life.
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IDENTIFYING OPPORTUNITIES (cont’d)
 Vaccines
 Switch from live, attenuated, or inactivated to
recombinant products
 Addition of adjuvants
 Newer cell culture manufacturing methods
 Increasing serotype number (i.e., broader spectrum
of activity).
 New delivery methods
 E.g., oral, intranasal, transdermal.
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IDENTIFYING OPPORTUNITIES (cont’d)
 Protein hormones
 Insulin is a key target.
 Much focus remains on modes of administration.
 Orally-administered (e.g., Oramed’s ORMD 0801,
Phase II trials).
 Inhaled (e.g., Mannkind’s Afrezza®).
 Transdermal.
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BIOBETTER RESOURCES
 Biobetters require similar resources
necessary for the production of
biosimilars.
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Patent analysis and litigation capabilities
Research and development capabilities
Analytical capabilities
Clinical trial capabilities
Marketing capabilities.
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BIOBETTER PROs
 Benefits
 Greater potential to avoid infringing patents or lower
litigation costs.
 R&D costs to develop a biobetter may be less than
for developing a new biological product.
 “Better” attribute(s) are preferred to the reference
listed product.
 Potentially entitled to 12 years of exclusivity under
the Biosimilars Act (FDA request likely required.).
 Biosimilars Act suggests more stringent requirements
for biosimilars (especially for interchangeable rating)
than biobetters.
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BIOBETTER CONs
 Risks
 Sophisticated patent analyses or litigation costs still
may be required.
 R&D costs are still high relative to drugs and some
biosimilars.
 12-year exclusivity not guaranteed and no exclusivity
vis-à-vis other biobetters filed as original BLA
products.
 Marketing requirements may be high, especially to
convert patients from referenced product to biobetter.
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QUESTIONS?
Brian J. Malkin
Partner, Frommer Lawrence & Haug LLP
Editor, FDA Lawyers Blog
202-292-1530 bmalkin@flhlaw.com
http://www.fdalawyersblog.com
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