The increasing demand from government agencies, insurers and patients to reduce the steep cost of blockbuster biopharmaceutical products has created considerable opportunities in the global biosimilar market. By the end of this decade, a significant number of blockbuster drugs will go off patent, allowing a large number of biosimilar products to enter the market. Regulatory developments favoring the biosimilar market in countries such as the US are expected to boost the profits and market share of the companies involved. This presentation is compiled from freely available resources like the websites of FDA, EMA, WHO. “Drug Regulations” is a non profit organization which provides free online resource to the Pharmaceutical Professional. Visit http://www.drugregulations.org for latest information from the world of Pharmaceuticals.

1. This presentation is compiled by “ Drug Regulations” a
non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
1/23/2014
1

2. This presentation is compiled from freely
available resources like the websites of FDA,
EMA, WHO.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.

Drug Regulations : Online
Resource for Latest Information
1/23/2014
2

3. 
Significant
demand
to
reduce
steep
cost
of
Biopharmaceuticals
◦ Government agencies,
◦ insurers and patients

Significant
opportunities
in
the
global
biosimilars
market.

Significant number of blockbuster drugs will go off
patent

Regulatory developments favour biosimilars
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4. WHO
FDA
EMA
Japan
Canada
Similar
Biotherapeutic
Product
Follow-on Biologic
Biosimilar
Follow-on Biologic
Subsequent Entry
Biologic
A product highly
similar to the
reference product
without clinically
meaningful
differences in
safety, purity and
potency.
A new biological
medicinal product
claimed to be
“similar” to a
reference
medicinal product,
which has been
granted a
marketing
authorization in
the Community on
the basis of a
complete dossier
in accordance with
the provisions of
Article 8 of
Directive 2001/83.
A biotechnological
product that is
produced by a
subsequent-entry
manufacturer and
claimed to be
comparable to a
biopharmaceutical
product already
approved in Japan.
A biologic drug
that enters the
market
subsequent to a
version previously
authorized in
Canada and with
demonstrated
similarity to a
reference biologic
drug.
A biotherapeutic
product similar to
an already
licensed reference
biotherapeutic
product in terms
of quality, safety
and efficacy.
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5. WHO
FDA
EMA
Japan
Canada
• Case-by-case approach for different classes of products
• Pharmacovigilance is emphasized
• Generic approach is not applicable
• Biosimilar should be similar to the reference in terms of safety,
efficacy and quality
• Step-wise comparability approach: comparison of the similar
biotherapeutic product to reference biotherapeutic product in terms
of quality is a requirement for decrease of non-clinical and clinical
data required for approval
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6. 
Most advanced of any region.

Legislation introduced in 2003

General guidances
◦ First in 2005
◦ Two in 2006 outlining quality, clinical and
nonclinical requirements.
◦ Three additional guidances are in draft.
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7. 
Guideline on Similar Biological Medicinal Products

GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS

GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING
BIOTECHNOLOGY-DERIVED PROTEINS AS ACTIVE SUBSTANCE:
NON-
CLINICAL AND CLINICAL ISSUES

Guideline
on
similar
biological
medicinal
products
containing
biotechnology-derived proteins as active substance: quality issues
(revision 1)

GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING
BIOTECHNOLOGY-DERIVED PROTEINS AS ACTIVE SUBSTANCE: QUALITY
ISSUES
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8. 
Additional guidances apply to six categories of
products
◦ Therapeutic proteins,
◦ Vaccines,
◦ Blood-derived products,
◦ Monoclonal antibodies and
◦ Gene and cell therapies.
◦ Further, in 2011 a concept paper was issued on revision of
the guidance, suggesting the process should focus on
similarity rather than clinical benefit. ( EMA )
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9. 
Generally follows the EU approach of showing similarity based
on quality, safety and efficacy of biosimilar products.

A guideline on the quality, safety and efficacy of biosimilar
products (Guidelines)

Slightly less inclusive scope than the EU guidance.

Guideline covers specific product categories
◦ Recombinant vaccines,
◦ PEGylated recombinant proteins and
◦ Non-recombinant proteins
◦ Excludes others (e.g., polyglycans and synthetic peptides).
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10. 
WHO

Health Canada

Singapore

India

Korea

Malaysia
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11. 
Federal Food Drug and Cosmetic Act („FFDCA‟)
◦ Abbreviated New Drug Application („ANDA‟) process in section
505(j)
◦ was established through the 1984 Hatch-Waxman Amendments to
the FFDCA.
◦ Sets out a regulatory and dispute resolution framework for small
molecule generics.
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12. 
Public Health Services Act („PHSA‟)
◦ Biologics Price Competition and Innovation Act („BPCIA‟)
amends PHSA
◦ Was passed as part of the Affordable Care Act („ACA‟)
◦ President Obama signed into law on 23rd March 2010.
◦ US Supreme Court affirmed the constitutionality of the ACA
and, thus, the BPCIA.
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13. 
Public Health Services Act („PHSA‟)
◦ BPCIA
 For follow-on biologics or Biosimilars
 Sets out a regulatory framework
 Dispute resolution framework
 Inspired by Hatch- Waxman Act
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14. 
Public Health Services Act („PHSA‟)
◦ BPCIA
 For follow-on biologics or Biosimilars
 Sets out a regulatory framework
 Dispute resolution framework
 Inspired by Hatch- Waxman Act
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15. 
Biosimilar development requires significant up-front time and
investment

Average cost estimated to be between US$100m and $200m*

Average cost of bringing small-molecule generic is estimated to
be between US $1m AND $5m

Two categories of follow-on biologics:
◦ Biosimilars
◦ Interchangeable‟ biologic products
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16. 
General application requirements
◦ Biosimilar to reference product
◦ Same mechanism of action as reference product
◦ Share the previously approved condition(s) of use
◦ Employ the same route of administration, strength and dosage from as
reference product
◦ Have facilities that meet standards designed to ensure the biosimilar is
„safe, pure and potent
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17. 
“Highly similar” to reference product
◦ Notwithstanding minor differences in clinically inactive components

How close does the proposed follow-on biologic compare to the
reference product?

Application must demonstrate required biosimilarity through:
◦ Analytical studies
◦ Animal studies
◦ A human clinical study or studies that are sufficient to demonstrate the followon biologic is „safe, pure and potent‟

Scientifically difficult to prove equivalence between a follow-on
biologic and a reference product.
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18. 
Chemical drugs
◦ Small molecules
◦ Easy to demonstrate equivalence of chemical composition

Biopharmaceutical drugs
◦ Larger in size and
◦ Complex in structure
◦ Current technology will not allow complete characterization of biological
products
◦ Additional clinical trials may be necessary before FDA would approve a
follow-on biologic
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19. Structural and Functional Characterisation
Human
Pharmacokinetics & Pharmacodynamics
(PK/PD)
Clinical Knowledge e.g. Post-Market
Experience
Biosimilar
Clinical Immunogenicity
Animal Studies
Highly
Similar
Clinical studies
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20. 
FDA scientists will
◦ Evaluate the applicant‟s integration of various types of
information
◦ Provide advice on scope and extent of development plan
and, ultimately
◦ Provide an overall assessment that a biological product is
(or is not) biosimilar to an approved reference product.
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21. 
Follow-on biologic may be substituted for
the
reference
product
without
the
intervention of the healthcare provider who
prescribed the medication
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22. 
Application must show that
◦ The follow-on biologic can be expected to produce
the same clinical results as the reference product in
any given patient and
◦ If administered more than once, the „risk in terms of
safety
or
diminished
efficacy
of
alternating
or
switching‟ between the products is „not greater than
the risk of using the reference product without such
alternation or switch.
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23. 
The first biosimilar applicant
◦ A period of exclusivity during which no other
product can be deemed interchangeable with the
reference product.
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24. 
Period of exclusivity ends on the earliest of:
◦ One year after first commercial marketing
◦ If no expedited patent litigation suit is brought against that applicant
under the PHSA § 351(l), 18 months after approval;
◦ If an expedited patent litigation suit is brought against that applicant
under PHSA § 351(l), 18 months after final decision on all patents-insuit (or dismissal); or
◦ If an expedited patent litigation is brought against that applicant
under PHSA § 351(l) and still pending, 42 months after approval.
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25. 
No application can be filed until 4 years after the date the
reference product was first licensed.

No application can be approved until 12 years after the date
the reference product was first licensed.

Paediatric exclusivity: can extend 4 and 12 year periods for 6
months each.
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26. Patent Protection : 20 years from filling
Patent filled
Patent issued
Data Exclusivity
Approval of Reference Product
Biosimilar application may be
filled : 4 yrs or 4yrs+ 6m
Patent expires
Biosimilar application may be
effective : 12 yrs or 12 yrs+ 6m
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27. 
BPCIA‟s approach is distinct from Hatch-Waxman Act:
◦ There is no requirement to list in the Orange Book patents the reference
product sponsor believes would be infringed if a generic drug were
marketed before expiration of the patents.
◦ There is no requirement for the FDA to suspend consideration of the
generic drug application in question for 30 months or until the patent in
question is found to be invalid or not infringed.
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28. Biosimilar applicant (BA)submits application to FDA
FDA notifies BA whether application has been accepted for
review
BA provides reference product (RP) sponsor confidential access to
biosimilar application & information describing manufacturing
Within 20 days
after notification
Within 60 days
after receipt
RP sponsor provides BA list of patents for which it believes it or patent
owner that has granted it exclusive license could easily assert a claim of
patent infringement and patents it would license.
Within 60 days
after receipt
BA may provide a RP sponsor a list of patents and shall provide a statement on each
patent on both list, why such patent is invalid , or that BA will not market until such
patent expires, and a response regarding licensing.
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29. RP sponsor provides BA for each patent claimed invalid
a statement why such patent will be infringed &
response to BA‟s statements.
Negotiate for 15
days after receipt
Parties agree to list of patents that will be litigated first . If
no agreement alternative procedure kicks in.
Within 30 days
after agreement
RP sponsor shall bring action for Patent infringement
Within 30 days
of service
BA provides secretary a notice and copy of compliant for publication in
federal register.
BA provides notice of commercial marketing to RP sponsor
If there is no preliminary injunction awarded , BA may market the biosimilar.
(Not latter that 180 days , during which time RP sponsor may seek preliminary
injunction)
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30. No agreement reached with 15 days for regarding
patent list
BA notifies RP sponsor of the number of patents it plans
to list in the alternative procedure‟s list exchange
The parties simultaneously exchange lists of patents they believe should
be litigated (RP sponsor may list at least 1, but otherwise no more patents
than the BA lists)
Within 5 days
after notice
Within 30 days
after exchange
RP Sponsor must bring suit with respect to every
patent on both lists
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31. 
Within 20 days after FDA notifies the biosimilar applicant that
its application has been accepted for review, the biosimilar
applicant must provide the reference product sponsor a copy
of the application and information that describes the
manufacturing process (otherwise, penalty provision applies).
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32. 
Access to the biosimilar application must be
provided to:
◦ Outside counsel for the reference product sponsor (who do
not engage in patent prosecution related to the reference
product)
◦ One in-house lawyer for the reference product sponsor
(who does not engage in patent prosecution related to the
reference product)
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33. 
Access to the biosimilar application
may also be provided to:
◦ A representative of a third-party patent
owner
◦ Any others in the sole discretion of the
biosimilar applicant
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34. 
Conditions
attaching
to
confidential
access:
◦ No disclosure without prior written consent
◦ Information may be used only for purpose of
identifying relevant patents for list exchanges
◦ Confidentiality provisions govern until a court
enters a protective order
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35. 
Within 60 days after receiving the biosimilar
application, the reference product sponsor must
◦ Provide the biosimilar applicant with a list of patents
for which it believes it (or a patent owner that has
granted it an exclusive licence) could reasonably
assert a claim of patent infringement
◦ Identify which of these patent(s) it would be prepared
to license
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36. 
Within 60 days after receiving list, the biosimilar applicant
◦ May provide a list of patents for which it believes the reference
product sponsor (or a patent owner that has granted it an exclusive
licence) could reasonably assert a claim of patent infringement
◦ Must provide a detailed statement as to each patent identified by the
reference sponsor or itself:
 On claim-by-claim basis why such patent is invalid, unenforceable and/or
not infringed, or
 That it intends to wait for patent expiry
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37. 
Reference Product Sponsor must
◦ Respond to any offer to license within 60 after
receiving list and statement.
◦ Provide, for each patent the biosimilar applicant
challenges, a detailed statement, on a claim-by-claim
basis, why such patent will be infringed
◦ Provide a response to the statement concerning
validity and enforceableability
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38. 
For 15 days, the biosimilar applicant and
reference product sponsor engage in good
faith negotiations to agree on list of patent(s)
for immediate litigation

If they agree, the reference sponsor has 30
days to bring an action for patent infringement
on the listed patent(s) (otherwise, penalty
provision applies)
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1/23/2014
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39. 
If they cannot agree on list of patent(s), the parties
exchange lists of patents for immediate litigation:
◦ The biosimilar applicant specifies how many it will list
◦ Within 5 days, the parties exchange lists
◦ The reference product sponsor may list one patent, but
otherwise no more than the number listed by the biosimilar
applicant
◦ The reference sponsor has 30 days to bring an action for
patent infringement on the listed patents (otherwise,
penalty provision applies)
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1/23/2014
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40. 
Once the Complaint is served, the biosimilar
applicant has 30 days to provide FDA with
notice and a copy of the Complaint

FDA publishes the notice in the Federal
Register
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41. 
Biosimilar applicant must provide notice to
the reference product sponsor 180 days
before
the
date
of
first
commercial
marketing of the biosimilar

Reference product sponsor may seek a
preliminary injunction on:

Any patent identified in the lists that were subject of initial exchanges, and

That was not included in the immediate litigation
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42. 
A court must enjoin infringement until
patent expiry if:
◦ The patent was the subject of the immediate
litigation process
◦ There is a final court decision that the patent is
valid and infringed
◦ The 12-year data exclusivity period has not
expired
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1/23/2014
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43. 
The reference product sponsor may recover
only a reasonable royalty (ie, no injunction) if:
◦ It did not initiate patent litigation within 30 days of
the creation of a list for immediate litigation
◦ It initiated litigation within 30 days, but the action was
dismissed without prejudice or was not prosecuted in
good faith
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1/23/2014
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44. 
The reference product sponsor may not
enforce
a
patent
with
respect
to
the
biosimilar product if:
◦ The patent should have been included on the
reference
product
sponsor‟s
initial
or
supplemental list and was not
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1/23/2014
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45. 
If the biosimilar applicant provides a copy of its
application
and
manufacturing
information
to
the
describing
reference
product
sponsor, then:
◦ Neither party may bring a declaratory judgment (DJ)
action
until
the
180-day
notice
of
commercial
marketing with respect to a patent that was on either
party‟s initial list and that was not included in the
immediate litigation
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46. 
Penalty Provision: If the biosimilar applicant
fails to provide a copy of its application and
information
describing
manufacturing,
then:
◦ Only the reference product sponsor can bring a
DJ action with respect to any patent that claims
the reference product or a use of the reference
product
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47. 
Penalty Provision: If the biosimilar applicant fails to:
◦ Provide
a
statement
in
response
to
the
reference
sponsor‟s
initial/supplemental list
◦ Provide a list of patents for immediate litigation after agreement
◦ could not be reached
◦ Provide notice of litigation and a copy of the Complaint to FDA
◦ Provide a detailed statement in response to notification of any newly
issued or licensed patents
◦ Provide notice to the reference product sponsor 180 days before first
commercial marketing of the biosimilar

Then, the reference product sponsor may bring a DJ action on
any patent in its own initial or supplement lists
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1/23/2014
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48. 
If there is a newly issued or licensed patent to the reference
product sponsor after it provides its initial list , then:
◦ Within 30 days, reference product sponsor must supplement its
◦ list and
◦ Within 30 days after receipt of supplemental list, the biosimilar
applicant must:
 On claim-by-claim basis why such patent is invalid, unenforceable and/or
not infringed, or
 That it intends to wait for patent expiry
◦ Otherwise, penalty provision applies
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1/23/2014
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49. 
Scientific Considerations in Demonstrating Biosimilarity to a
Reference Product

Quality Considerations in Demonstrating Biosimilarity to a
Reference Protein Product

Biosimilars:
Questions
and
Answers
Regarding
Implementation of the Biologics Price Competition and
Innovation Act of 2009

Formal Meetings Between the FDA and Biosimilar Biological
Product Sponsors or Applicants
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50. 
FDA has not to issued separate guidances in
different drug product classes.

Sponsors are permitted to use a non-US
licensed comparator in certain studies, with
appropriate associating data.
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Information
1/23/2014
50

51. 
This presentation was compiled from freely
available resources like the websites of FDA,
EMA, WHO.
 “Drug Regulations” is a non profit
organization which provides free online
resource to the Pharmaceutical Professional.
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
Drug Regulations : Online
Resource for Latest Information
1/23/2014
51