Essentials of US FDA Biosimilar Guidance 2012- Impact and Opportunities for Chinese

BioPharma Companies 

美国 FDA2012 年生物彷制药指南的要点- 影响和中国生物制药业的机遇

魏晓雄 (Jim Wei), MD, PhD

June 30, 2012

Taizhou, China

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

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.

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.

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.

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

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)

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”

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

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

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

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.

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.

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

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.

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.

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)

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.

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.

Clinical

Animal Studies

Clinical Immunogenicit

yClinical Knowledge e.g. post-market

ExperienceHuman Pharmacokinetics and Pharmacodynamics

(PK/PD)

Structural and Functional Characterization

FDA “Totality of the Evidence” Approach- No “one size fits all” assessment

Highly Similar

Biosimilar

FDA will evaluate an overall assessment that a biological product is (or is not) biosimilar to an approved reference product

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.

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.

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.

Regulatory Pathways for Biosimilars

351(a) or 505(b)(2)• User Fee paid at

BLA/NDA filing in lump sum

• Labeling contains results of clinical studies

• No exclusivity• No demonstration of

“highly similar” or “sameness in any given patient”

• Substitution not prohibited

351(k)• User Fee paid earlier

and in increments• Labeled as “biosimilar”

or “interchangeable”• Exclusivity for first

interchangeable product

• FDA unsure of requirements for interchangeability

• Allows for substitution

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.

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

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

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

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

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

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

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

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

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/UCM291128.pdf

FDA Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Product , February 2012.

• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.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.htm

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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