1. Essentials of US FDA Biosimilar Guidance 2012
- Impact and Opportunities for Chinese
BioPharma Companies
FDA2012
-
(Jim Wei), MD, PhD
June 30, 2012
Taizhou, China

2. Background
 Public Health Service Act
• The Biologics Price Competition and Innovation Act (BPCI
Act) was passed as part of the Affordable Care Act that
President Obama signed into law on March 23, 2010.
• BPCI Act creates an abbreviated licensure pathway for
biological products shown to be biosimilar to or
interchangeable with an FDA-licensed reference product
[section 351(k) of the Public Health Service Act].
 Federal Food Drug and Cosmetic Act (FFDCA)
• The Abbreviated New Drug Application process in section
505(j) was established through the 1984 Hatch-Waxman
Amendments to the FFDCA thus creating the generic drug
program for “small molecule” drugs

3. Background cont’d
 “Biological Product” in the Public Health Service Act (PHS Act)
now includes “protein”:
• . . . a virus, therapeutic serum, toxin, antitoxin, vaccine,
blood, blood component or derivative, allergenic product,
protein (except any chemically synthesized polypeptide),
or analogous product …applicable to the prevention,
treatment, or cure of a disease or condition of human
beings…
 Historically, some proteins have been approved as drugs
under section 505 of the FD&C Act and other proteins have
been licensed as biologics under section 351 of the PHS Act.
• Growth hormone
 Under the BPCI Act, a protein, except any chemically
synthesized polypeptide, will be regulated as a biological
product.

4. Biologics Price Competition and
Innovation Act (BPCI Act)
 The Biologics Price Competition and Innovation Act (BPCI Act) was passed as
part of the Affordable Care Act that President Obama signed into law on
March 23, 2010. BPCI Act creates an abbreviated licensure pathway for
biological products shown to be biosimilar to or interchangeable with an FDA-
licensed reference product [section 351(k) of the Public Health Service Act].
 “Biological Product” in the Public Health Service Act (PHS Act) now includes
“protein”:. . . a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, protein (except any chemically
synthesized polypeptide), or analogous product …applicable to the
prevention, treatment, or cure of a disease or condition of human beings…
 Historically, some proteins have been approved as drugs under section 505 of
the FD&C Act and other proteins have been licensed as biologics under
section 351 of the PHS Act. Under the BPCI Act, a protein, except any
chemically synthesized polypeptide, will be regulated as a biological product.

5. Biologics Price Competition and
Innovation Act (BPCI Act) cont’d
 A 351(k) application must include information demonstrating that the
biological product:
• Is biosimilar to a reference product;
• Utilizes the same mechanism(s) of action for the proposed
condition(s) of use -- only to the extent known for the reference
product;
• Condition(s) of use proposed in labeling have been previously
approved for the reference product; and
• Has the same route of administration, dosage form, and strength
as the reference product.
• That the biological product is highly similar to the reference
product notwithstanding minor differences in clinically inactive
components; and
• There are no clinically meaningful differences between the
biological product and the reference product in terms of the
safety, purity, and potency of the product.

6. FDA Biosimilar Guidance
-February 2012
 Scientific Considerations in Demonstrating
Biosimilarity to a Reference product
 Quality Considerations in Demonstrating Biosimilarity
to a Reference Product
 Biosimilars: Questions and Answers Regarding
Implementation of Biologics Price Competition and
Innovation Act of 2009

7. FDA Biosimilar Guidance
-February 2012 cont’d
 The guidance reflects public input and questions received by
FDA.
 The initial draft guidance is targeted to the highest priority
issues and directed to clarifying expectations and providing
predictability to sponsors initiating biosimilar development
programs.
 The initial scope of the guidance includes
• Characterization of the proposed biosimilar product and
the reference product (Scientific Considerations; Quality
Considerations)
• Data needed, such as PK/PD, preclinical, clinical (Scientific
Considerations; Q&A)
• Common questions regarding FDA’s initial interpretation of
certain statutory terms and requirements (Q&A)

8. FDA Biosimilar Guidance
-February 2012 cont’d
 Definition
• Protein means any alpha amino acid polymer with a
specific defined sequence that is greater than 40 amino
acids in size.
• Chemically synthesized polypeptide means any alpha
amino acid polymer that is (a) made entirely by chemical
synthesis, and (b) is less than 100 amino acids in size.
 FDA Biosimilar guidance only applied to “protein products”

9. FDA Biosimilar Guidance
-Quality Considerations Draft Guidance
 This guidance focuses on analytical studies that may be
relevant to assessing the similarity between a proposed
biosimilar protein product and a reference product.
 General principles include:
• Importance of extensive analytical, physico- chemical and
biological characterization
• Advances in manufacturing science and Quality by Design
approaches may facilitate “fingerprint”-like analysis
• Identification of lots used in the various analyses for
biosimilarity determination

10. FDA Biosimilar Guidance
-Quality Considerations Draft Guidance cont’d
 Factors for consideration in assessing whether
products are highly similar:
• Expression system
• Manufacturing process
• Assessment of physicochemical properties
• Functional activities
• Receptor binding and immunochemical properties
• Impurities
• Reference product and reference standards
• Finished drug product
• Stability

11. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance
 FDA intends to consider the totality of the evidence to support a
demonstration of biosimilarity,
 FDA recommends to use a stepwise approach in their development
of biosimilar products.
 Scope of this guidance in demonstrating biosimilarity, including:
• A stepwise approach to demonstrating biosimilarity, which can
include a comparison of the proposed product and the
reference product with respect to structure, function, animal
toxicity, human pharmacokinetics (PK) and pharmacodynamics
(PD), clinical immunogenicity, and clinical safety and
effectiveness
• The totality-of-the-evidence approach that FDA will use to review
applications for biosimilar products
• General scientific principles in conducting comparative studies

12. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Complexities of protein products
• Nature of Protein Products and Related Scientific
Considerations
- Proteins are typically more complex and are unlikely to
be shown to be structurally identical to a reference
product.
• Manufacturing Process Considerations
- Different manufacturing processes may alter a protein
product in a way that could affect the safety or
effectiveness of the product.

13. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 U.S.-licensed reference product and other comparators
• To obtain licensure of a proposed product under section 351(k) of
the PHS Act, a sponsor must demonstrate that the proposed
product is biosimilar to a single reference product that previously
has been licensed by FDA.
• Under certain circumstances, a sponsor may seek to use data
derived from animal or clinical studies comparing a proposed
product with a non-U.S.-licensed product to address, in part, the
requirements under section 351(k)(2)(A) of the PHS Act.
- to scientifically justify the relevance of this comparative data
to an assessment of biosimilarity and to establish an acceptable
bridge to the U.S.-licensed reference product.

14. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Demonstrating biosimilarity
• Structural Analysis
• Functional Assays
• Animal Data
- Animal Toxicity Studies
- Inclusion of Animal PK and PD Measures
- Animal Immunogenicity Studies
• Clinical Studies
- Human Pharmacology Data
• Pharmacokinetics
• pharmacodynamics
- Clinical Immunogenicity Assessment
- Clinical Safety and Effectiveness Data

15. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Clinical studies – general considerations
• Clinical Immunogenicity Assessment
- Extent and timing:
• If the immune response to the reference product is rare, two
separate studies may be sufficient to evaluate immunogenicity:
(1) a premarket study powered to detect major differences in
immune responses between the two products and (2) a post-
market study designed to detect more subtle differences in
immunogenicity.
- Study design:
• FDA recommends use of a comparative parallel design (i.e., a
head-to-head study)
- Study population:
• If a sponsor is seeking to extrapolate immunogenicity findings for
one indication to other indications, the sponsor should consider
using the study population and treatment regimen that are the
most sensitive for detecting a difference in immune responses.

16. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Clinical Immunogenicity Assessment (cont’d)
• Selection endpoints: prospectively define the clinical immune response
criteria (e.g., definitions of significant clinical events), using established
criteria where available, for each type of potential immune response and
obtain agreement from FDA on these criteria before initiating the study.
• Follow-up period: based on
- (1) the time course for the generation of immune responses (such as
the development of neutralizing antibodies, cell-mediated immune
responses), and expected clinical sequelae (informed by experience
with the reference product),
- (2) the time course of disappearance of the immune responses and
clinical sequelae following cessation of therapy, and
- (3) the length of administration of the product.
For example, the minimal follow-up period for chronically administered
agents should be one year, unless a shorter duration can be justified by
the sponsor.

17. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Clinical Immunogenicity Assessment (cont’d):
As a scientific matter, it is expected that the following will be
assessed in clinical immunogenicity studies:
• Binding antibody: titer, specificity, relevant isotype
distribution, time course of development, persistence,
disappearance, and association with clinical sequelae
• Neutralizing antibody: all of the above, plus neutralizing
capacity to all relevant functions (e.g., uptake and
catalytic activity, neutralization for replacement enzyme
therapeutics)

18. FDA Biosimilar Guidance:
-Scientific Considerations Draft Guidance cont’d
 Clinical Immunogenicity Assessment (cont’d):
• To develop assays capable of sensitively detecting
immune responses, even in the presence of circulating
drug product (proposed product and reference product)
- The proposed product and reference product should be
assessed in the same assay with the same patient sera
whenever possible.
- FDA recommends that immunogenicity assays be
developed and validated with respect to both the
proposed product and reference product early in
development.
- Sponsors should consult with FDA on the sufficiency of
assays before initiating any clinical immunogenicity study.

19. FDA Review Process of Biosimilar Applications
 FDA traditionally relies on integrating various kinds of evidence
in making regulatory decisions; a “totality of the evidence”
approach can be applied to assessing biosimilars.
• It is possible to exceed a current state-of-the-art analysis by
evaluating more attributes and combination of attributes
at greater sensitivities with multiple complementary
methods;
• such fingerprint-like characterization may reduce further
the scope and extent of additional animal and clinical
studies.
 To provide the best advice on the scope of any required
animal and human studies, FDA should already have
completed a thorough review of data from structural and
functional analyses.

20. FDA “Totality of the Evidence” Approach
- No “one size fits all” assessment
FDA will evaluate an overall assessment
Clinical that a biological product is (or is not)
biosimilar to an approved reference product
Animal
Studies
Clinical
Immunogenicity Biosimilar
Clinical Knowledge e.g.
post-market Experience
Human Pharmacokinetics and
Pharmacodynamics (PK/PD)
Highly Similar
Structural and Functional
Characterization

21. Pediatric Study Requirements
 Under the Pediatric Research Equity Act (PREA), all
applications for new active ingredients, new indications, new
dosage forms, new dosing regimens, or new routes of
administration are required to contain a pediatric assessment
to support dosing, safety, and effectiveness of the product for
the claimed indication unless this requirement is waived,
deferred, or inapplicable (see section 505B of FD&C Act).
 For purposes of PREA, a biological product determined to be:
biosimilar is considered to have a “new active ingredient”;
interchangeable is not considered to have a “new active
ingredient.” FDA however, encourages applicants to submit
plans for pediatric studies during the IND stage of product
development.

22. Interchangeable or Interchangeability
 Definition: The interchangeable product may be substituted for the
reference product without the authorization of the health care
provider.
 How to meet:
• The biological product is biosimilar to the reference product.
• It can be expected to produce the same clinical result as the
reference product in any given patient;
• and for a product administered more than once, the safety and
reduced efficacy risks of alternating or switching are not greater
than with repeated use of the reference product without
alternating or switching.

23. Exclusivity
 First Interchangeable Biosimilar Product
• The first biosimilar product to be licensed as
interchangeable is granted a period of exclusivity.
• During the exclusivity period, a subsequent biosimilar
product relying on the same reference product cannot be
licensed as interchangeable.
• Exclusivity calculus is based on date of approval, date of
first commercial marketing, and patent litigation
milestones.
 Reference Product
• A 351(k) application may not be submitted until 4 years
after the date of first licensure of the reference product.
• A 351(k) application may not be approved until 12 years
after the date of first licensure of reference product.

24. Regulatory Pathways for Biosimilars
 351(a) or 505(b)(2)  351(k)
• User Fee paid at • User Fee paid earlier and
BLA/NDA filing in lump in increments
sum • Labeled as “biosimilar”
• Labeling contains results or “interchangeable”
of clinical studies • Exclusivity for first
• No exclusivity interchangeable
• No demonstration of product
“highly similar” or • FDA unsure of
“sameness in any given requirements for
patient” interchangeability
• Substitution not • Allows for substitution
prohibited

25. Transition Provisions
 An application for a “biological product” must be submitted
under section 351 of the PHS Act.
• Exception: An application for a biological product may be
submitted under the FD&C Act through March 23, 2020, if
the product is in a product class for which there is already
an approved application under the FD&C Act,
» unless there is another biological product licensed
under section 351(a) of the PHS Act that could serve as
its reference product.
 As of March 23, 2020, an application for a biological product
approved under section 505 of the FD&C Act will be deemed
a biologics license application (“BLA”) licensed under section
351 of the PHS Act.

26. Biosimilar User Fees
 Starting October 1, 2012:
• User Fee for Biosimilars is the same as for an 505(b)(1) or
(b)(2) product
 Initial Biosimilar Biological Product Development Fee
• It will trigger at the time:
- A request for a biosimilar biological product
development meeting or
- An IND that contains a clinical protocol
• Within 5 days of granting the request for the meeting or
upon submission of the IND
• 10% of the fee established for a BLA that year

27. Biosimilar User Fees cont’d
 Annual fee
• 10% of the fee established for a BLA that year
 Remainder due when file the 351(k) BLA
 Discontinuation of fee
• No intention of further developing the product
 If don’t pay - will not be granted meeting or will not consider
IND or BLA as received
 No refunds, waivers, exemptions, or reductions
• Waiver for first biosimilar BLA for a small business

28. User Fees Performance Goals
 Biosimilar Initial Advisory Meeting
• General discussion on whether licensure under 351(k) is
feasible and general advice on the development program
 Biological Product Development (BPD) Meetings
• Type 1 – otherwise stalled development program
• Type 2 – discuss a specific issue or questions
• Type 3 - in depth data review and advice
• Type 4 – format and content of BLA or sBLA
 Meeting minutes available within 30 days of meeting date

29. User Fees Performance Goals cont’d
 Response to meeting request and date of meeting
based on receipt of meeting request:
Type Response (days) Date (days)
Advisory 21 90
BPD Type 1 14 30
BPD Type 2 21 75
BPD Type 3 21 120
BPD Type 4 21 60

30. Status of Biosimilar Applications at FDA
 As of February 2012 at US FDA:
• 35 Pre-IND meeting requests for proposed biosimilar
products to 11 reference products
• 21 Pre-IND sponsor meetings held to date
- Development programs include:
-Prospective development programs
-“Global” programs
– “Retrospective” development programs
- Programs seeking licensure in US for
similar biological products licensed outside the US
• 9 INDs received

31. EU versus US Biosimilar Products
 EU has approved 14 biosimilar products, with
reference products being:
• Filgrastim
• Epoetin
• Somatropin
 FDA approved 1 biosimilar product in 2006 under
505(b)(2) pathway:
• Omnitrope by Sandoz

32. Opportunities for China Pharma Industry
 The development of a biosimilar is cheaper, faster
and less risk than an innovative product
 Huge market and profit
 Can have a different formulation or delivery system
as long as there are no clinically meaningful
differences
 Select the right talent
 Regulatory pathways are well defined with FDA

33. Challenges
 When to meet with FDA
 User Fees
 Product differentiation
• 351(a) versus 351(k)
 How much difference is still treated as “highly
biosimilar”
 How to meet requirements for interchangeability
 Bridging studies for U.S. licensed versus non-U.S.
licensed reference product
 cGMP requirements on facilities/manufacturing
• More costly than small molecules

34. References
 Biologics Price Competition and Innovation Act
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.
pdf
 FDA Guidance for Industry: Scientific Considerations in Demonstrating
Biosimilarity to a Reference Product, February 2012.
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM291128.pdf
 FDA Guidance for Industry: Quality Considerations in Demonstrating
Biosimilarity to a Reference Product , February 2012.
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM291134.pdf
 FDA Guidance for Industry: Biosimilars: Questions and Answers Regarding
Implementation of the Biologics Price Competition and Innovation Act of
2009, February 2012.
• http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259797.h
tm
 Proposed PDUFA V Reauthorization Performance Goals and Procedures; Fiscal
Years 2013 through 2017 http://pharma.about.com/od/FDA/a/2012-Renewal-Of-The-
Prescription-Drug-User-Fee-Act-Pdufa.htm

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谢谢!
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Sheng Shi Long Yuan
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Sheng Shi Long Yuan
No 1005, Gao Bei Dian Xiang Xi Dian
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Fax: +86 10 87706411
E-mail: info@medpacelab.com