Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Guidance for Industry

Scientific Considerations in

Demonstrating Biosimilarity

to a Reference Product

Guidance for Industry

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

April 2015

Biosimilarity

Scientific Considerations in

Demonstrating Biosimilarity

to a Reference Product

Guidance for Industry

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http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

April 2015

Biosimilarity

Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION............................................................................................................. 1

II. SCOPE ............................................................................................................................... 2

III. BACKGROUND ............................................................................................................... 3

IV. COMPLEXITIES OF PROTEIN PRODUCTS ............................................................. 4

A. Nature of Protein Products and Related Scientific Considerations .......................................... 5

B. Manufacturing Process Considerations ....................................................................................... 5

V. U.S.-LICENSED REFERENCE PRODUCT AND OTHER COMPARATORS ....... 6

VI. APPROACHES TO DEVELOPING AND ASSESSING EVIDENCE TO

DEMONSTRATE BIOSIMILARITY ........................................................................................ 7

A. Using a Stepwise Approach to Demonstrate Biosimilarity ........................................................ 7

B. Using a Totality-of-the-Evidence Approach to Assess a Demonstration of Biosimilarity ........ 8

VII. DEMONSTRATING BIOSIMILARITY ....................................................................... 9

A. Structural Analyses ........................................................................................................................ 9

B. Functional Assays ........................................................................................................................ 10

C. Animal Data .................................................................................................................................. 11

1. Animal Toxicity Studies.................................................................................................................. 11

2. Inclusion of Animal PK and PD Measures .................................................................................... 13

3. Interpreting Animal Immunogenicity Results ................................................................................ 13

D. Clinical Studies – General Considerations ................................................................................ 13

1. Human Pharmacology Data .......................................................................................................... 14

2. Clinical Immunogenicity Assessment ............................................................................................. 16

3. Comparative Clinical Studies ........................................................................................................ 18

4. Extrapolation of Clinical Data Across Indications ........................................................................ 21

VIII. POSTMARKETING SAFETY MONITORING CONSIDERATIONS .................... 22

IX. CONSULTATION WITH FDA..................................................................................... 22

GLOSSARY................................................................................................................................. 24

Contains Nonbinding Recommendations

Scientific Considerations in Demonstrating Biosimilarity to a

Reference Product

Guidance for Industry

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on

this topic. It does not create any rights for any person and is not binding on FDA or the public. You can

use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To

discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title

page.

I. INTRODUCTION

This guidance is intended to assist sponsors in demonstrating that a proposed therapeutic protein

product (hereinafter proposed product

) is biosimilar to a reference product for purposes of the

submission of a marketing application under section 351(k) of the Public Health Service Act

(PHS Act).

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amends

the PHS Act and other statutes to create an abbreviated licensure pathway in section 351(k) of

the PHS Act for biological products shown to be biosimilar to or interchangeable with an FDA-

licensed biological reference product (see sections 7001 through 7003 of the Patient Protection

and Affordable Care Act (Affordable Care Act) (Public Law 111-148). Although the 351(k)

pathway applies generally to biological products, this guidance focuses on therapeutic protein

products and gives an overview of important scientific considerations for demonstrating

biosimilarity. The scientific principles described in this guidance may also apply to other types

of proposed biosimilar biological products.

This guidance is one in a series of guidances that FDA is developing to implement the BPCI Act.

These guidances address a broad range of issues, including:

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein

Product to a Reference Product

This guidance has been prepared by the Office of Medical Policy in the Center for Drug Evaluation and Research

(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug

Administration.

In Section II (Scope) of this document, the term proposed product is also used to describe a product that is the

subject of a new drug application (NDA) submitted through the pathway described by section 505(b)(2) of the

Federal Food, Drug, and Cosmetic Act (FD&C Act).

The statutory definition of biosimilar and definitions of selected other terms used in this guidance are provided in

the glossary at the end of the document.

Contains Nonbinding Recommendations

• Scientific Considerations in Demonstrating Biosimilarity to a Reference 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

• Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a

Reference Product

When applicable, references to information in these guidances are included in this guidance.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities.

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only

as recommendations, unless specific regulatory or statutory requirements are cited. The use of

the word should in Agency guidances means that something is suggested or recommended, but

not required.

II. SCOPE

This guidance gives an overview of FDA’s approach to determining biosimilarity and discusses

important scientific considerations 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, consistent with a longstanding Agency approach to evaluation

of scientific evidence

• General scientific principles in conducting comparative structural analyses,

functional assays, animal testing, human PK and PD studies, clinical

immunogenicity assessments, and comparative clinical studies (including clinical

study design issues)

The guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products

provides insight into the concept of the totality-of-the-evidence approach in a different context (i.e., considerations

of both the quantity and quality of the evidence to support effectiveness for drugs and biological products). Some of

the principles discussed in that guidance may also be relevant in the design of a development program to support a

demonstration of biosimilarity.

We update guidances periodically. For the most recent version of a guidance, check the FDA guidance Web page at

http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

Contains Nonbinding Recommendations

Additional topics discussed include the following:

• Considerations of the complexities of therapeutic protein products when designing a

biosimilar development program, including manufacturing process considerations

• Use of data derived from studies comparing a proposed product with a non-U.S.-

licensed comparator product

• Postmarketing safety monitoring considerations

This guidance applies to applications submitted under section 351(k) of the PHS Act. However,

some scientific principles described in this guidance may be informative for the development of

certain biological products under section 505(b)(2) of the FD&C Act.

Section 505(b)(2) of the

FD&C Act and section 351(k) of the PHS Act are two separate statutory schemes. This guidance

is not intended to describe any relationship between the standards for approval under these

schemes.

III. BACKGROUND

The BPCI Act was enacted as part of the Affordable Care Act on March 23, 2010. The BPCI

Act creates an abbreviated licensure pathway for biological products demonstrated to be

biosimilar to or interchangeable with a reference product. Section 351(k) of the PHS Act (42

U.S.C. 262(k)), added by the BPCI Act, sets forth the requirements for an application for a

proposed biosimilar product and an application or a supplement for a proposed interchangeable

product.

Section 351(i) of the PHS Act defines biosimilarity to mean “that the biological

product is highly similar to the reference product notwithstanding minor differences in clinically

inactive components” and that “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.”

The BPCI Act also amended the definition of biological product to include “protein

(except any chemically synthesized polypeptide).”

Under section 351(k) of the PHS Act, a proposed biological product that is demonstrated to be

biosimilar to a reference product can rely on certain existing scientific knowledge about the

A 505(b)(2) application is an NDA that contains full reports of investigations of safety and effectiveness, where at

least some of the information required for approval comes from studies not conducted by or for the applicant and for

which the applicant has not obtained a right of reference or use (e.g., the Agency’s finding of safety and/or

effectiveness for a listed drug or published literature). A 505(b)(2) application that seeks to rely on a listed drug

(i.e., the reference product) must contain adequate data and information to demonstrate that the proposed product is

sufficiently similar to the listed drug to justify reliance, in part, on FDA’s finding of safety and/or effectiveness for

the listed drug. Any aspects of the proposed product that differ from the listed drug must be supported by adequate

data and information to support the safety and effectiveness of the proposed product.

General scientific issues relating to the demonstration of interchangeability will be addressed separately.

Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.

Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act.

Contains Nonbinding Recommendations

safety, purity, and potency

of the reference product to support licensure. FDA will license a

proposed biological product submitted under section 351(k) of the PHS Act if FDA “determines

that the information submitted in the application . . . is sufficient to show that the biological

product is biosimilar to the reference product . . .” and the 351(k) applicant (or other appropriate

person) consents to an inspection of the facility that is the subject of the application (i.e., a

facility in which the proposed biological product is manufactured, processed, packed, or held).

An application submitted under section 351(k) of the PHS Act must contain, among other things,

information demonstrating that “the biological product is biosimilar to a reference product”

based upon data derived from:

• Analytical studies that demonstrate that the biological product is highly similar to the

reference product notwithstanding minor differences in clinically inactive components;

• Animal studies (including the assessment of toxicity); and

• A clinical study or studies (including the assessment of immunogenicity and

pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety,

purity, and potency in one or more appropriate conditions of use for which the reference

product is licensed and intended to be used and for which licensure is sought for the

biological product.

The Agency has the discretion to determine that an element described above is unnecessary in a

351(k) application.

FDA advises sponsors intending to develop biosimilar products to meet

with FDA to present their product development plans and establish a schedule of milestones that

will serve as landmarks for future discussions with the Agency. FDA anticipates that early

discussions with FDA about product development plans and about approaches to providing

adequate scientific justifications will facilitate biosimilar development.

IV. COMPLEXITIES OF PROTEIN PRODUCTS

A sponsor should consider the complexities of protein products and related scientific issues when

designing a development program to support a demonstration of biosimilarity.

The standard for licensure of a biological product as potent under section 351(a) of the PHS Act has long been

interpreted to include effectiveness (see 21 CFR 600.3(s) and the guidance for industry on Providing Clinical

Evidence of Effectiveness for Human Drug and Biological Products). In this guidance, we use the terms safety and

effectiveness and safety, purity, and potency interchangeably in the discussions pertaining to biosimilar products.

Section 7002(a)(2) of the Affordable Care Act, adding section 351(k)(3) of the PHS Act.

Section 7002(a)(2) of the Affordable Care Act, adding section 351(k)(2)(A)(i)(I) of the PHS Act.

Section 7002(a)(2) of the Affordable Care Act, adding section 351(k)(2)(A)(ii) of the PHS Act.

See the draft guidance for industry Formal Meetings Between the FDA and Biosimilar Biological Product

Sponsors or Applicants for a detailed discussion. When final, this guidance will represent FDA’s current thinking

on this topic.

Contains Nonbinding Recommendations

A. Nature of Protein Products and Related Scientific Considerations

Unlike small molecule drugs, whose structure can usually be completely defined and entirely

reproduced, proteins are typically more complex and are unlikely to be shown to be structurally

identical to a reference product. Many potential differences in protein structure can arise.

Because even minor structural differences (including certain changes in glycosylation patterns)

can significantly affect a protein’s safety and/or effectiveness, it is important to evaluate these

differences.

In general, proteins can differ in at least three ways: (1) primary amino acid sequence;

(2) modification to amino acids, such as sugar moieties (glycosylation) or other side chains; and

(3) higher order structure (protein folding and protein-protein interactions). Modifications to

amino acids may lead to heterogeneity and can be difficult to control. Protein modifications and

higher order structure can be affected by formulation and environmental conditions, including

light, temperature, moisture, packaging materials, container closure systems, and delivery device

materials. Additionally, process- as well as product-related impurities may increase the

likelihood and/or the severity of an immune response to a protein product, and certain excipients

may limit the ability to characterize the protein product.

Advances in analytical sciences enable some protein products to be extensively characterized

with respect to their physicochemical and biological properties, such as higher order structures

and functional characteristics. These analytical methodologies have increasingly improved the

ability to identify and characterize not only the drug substance of a protein product but also

excipients and product- and process-related impurities.

Despite such significant improvements in analytical techniques, however, current analytical

methodology may not be able to detect all relevant structural and functional differences between

two protein products. In addition, there may be incomplete understanding of the relationship

between a product’s structural attributes and its clinical performance. Thus, as set forth in the

PHS Act, data derived from analytical studies, animal studies, and a clinical study or studies are

required to demonstrate biosimilarity unless FDA determines an element unnecessary.

B. Manufacturing Process Considerations

Different manufacturing processes may alter a protein product in a way that could affect the

safety or effectiveness of the product. For example, differences in biological systems used to

manufacture a protein product may cause different posttranslational modifications, which in turn

may affect the safety and/or effectiveness of the product. Thus, when the manufacturing process

for a marketed protein product is changed, the application holder must assess the effects of the

change and demonstrate—through appropriate analytical testing, functional assays, and/or in

some cases animal and/or clinical studies—that the change does not have an adverse effect on

the identity, strength, quality, purity, or potency of the product as they relate to the safety or

Section 7002(a)(2) of the Affordable Care Act, adding section 351(k)(2)(A)(i)(I) of the PHS Act.

Contains Nonbinding Recommendations

effectiveness of the product.

The International Conference on Harmonisation (ICH) guidance

for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes in

Their Manufacturing Process (ICH Q5E) describes scientific principles in the comparability

assessment for manufacturing changes.

Demonstrating that a proposed product is biosimilar to a reference product typically will be more

complex than assessing the comparability of a product before and after manufacturing changes

made by the same manufacturer. This is because a manufacturer that modifies its own

manufacturing process has extensive knowledge and information about the product and the

existing process, including established controls and acceptance parameters. By contrast, the

manufacturer of a proposed product is likely to have a different manufacturing process (e.g.,

different cell line, raw materials, equipment, processes, process controls, and acceptance criteria)

from that of the reference product and no direct knowledge of the manufacturing process for the

reference product. Therefore, even though some of the scientific principles described in ICH

Q5E may also apply in the demonstration of biosimilarity, in general, FDA anticipates that more

data and information will be needed to establish biosimilarity than would be needed to establish

that a manufacturer’s post-manufacturing change product is comparable to the pre-manufacturing

change product.

V. 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.

In general, a sponsor needs to provide information to demonstrate

biosimilarity based on data directly comparing the proposed product with the reference product.

As a scientific matter, analytical studies and at least one clinical PK study and, if appropriate, at

least one PD study, intended to support a demonstration of biosimilarity for purposes of section

351(k) of the PHS Act must include an adequate comparison of the proposed biosimilar product

directly with the U.S.-licensed reference product unless it can be scientifically justified that such

a study is not needed. However, a sponsor may seek to use data derived from animal or clinical

studies comparing a proposed product with a non-U.S.-licensed comparator product to address,

in part, the requirements under section 351(k)(2)(A) of the PHS Act. In such a case, the sponsor

should provide adequate data or information to scientifically justify the relevance of these

comparative data to an assessment of biosimilarity and establish an acceptable bridge to the U.S.-

licensed reference product.

Sponsors are encouraged to discuss with FDA during the

development program their plans to provide an adequate scientific justification and bridge to the

U.S.-licensed reference product. A final decision about the adequacy of such justification and

bridge will be made by FDA during review of the 351(k) application.

See 21 CFR 601.12 and 21 CFR 314.70 for regulatory requirements for changes (including manufacturing

changes) made to a licensed biologics license application (BLA) and an approved NDA, respectively.

Sections 7002(a)(2) and (b)(3) of the Affordable Care Act, adding sections 351(k), 351(i)(2), and 351(i)(4) of the

PHS Act.

For examples of issues that a sponsor may need to address, see the guidance for industry Biosimilars: Questions

and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.

Contains Nonbinding Recommendations

VI. APPROACHES TO DEVELOPING AND ASSESSING EVIDENCE TO

DEMONSTRATE BIOSIMILARITY

FDA recommends that sponsors use a stepwise approach to develop the evidence needed to

demonstrate biosimilarity. FDA intends to consider the totality of the evidence provided by a

sponsor when the Agency evaluates the sponsor’s demonstration of biosimilarity, consistent with

a longstanding Agency approach to evaluating scientific evidence.

A. Using a Stepwise Approach to Demonstrate Biosimilarity

The purpose of a biosimilar development program is to support a demonstration of biosimilarity

between a proposed product and a reference product, including an assessment of the effects of

any observed differences between the products, but not to independently establish the safety and

effectiveness of the proposed product. FDA recommends that sponsors use a stepwise approach

to developing the data and information needed to support a demonstration of biosimilarity. At

each step, the sponsor should evaluate the extent to which there is residual uncertainty about the

biosimilarity of the proposed product and identify next steps to try to address that uncertainty.

Where possible, studies conducted should be designed to maximize their contribution to

demonstrating biosimilarity. For example, a clinical immunogenicity study may also provide

other useful information about the safety profile of the proposed product.

The stepwise approach should start with extensive structural and functional characterization of

both the proposed product and the reference product, which serves as the foundation of a

biosimilar development program (sections VII.A and VII.B). The more comprehensive and

robust the comparative structural and functional characterization—the extent to which these

studies are able to identify (qualitatively or quantitatively) differences in relevant product

attributes between the proposed product and the reference product (including the drug substance,

excipients, and impurities)—the more useful such characterization will be in determining what

additional studies may be needed. For example, rigorous structural and functional comparisons

that show minimal or no difference between the proposed product and the reference product will

strengthen the scientific justification for a selective and targeted approach to animal and/or

clinical testing to support a demonstration of biosimilarity. It may be useful to further quantify

the similarity or differences between the two products using a meaningful fingerprint-like

analyses algorithm that covers a large number of additional product attributes and their

combinations with high sensitivity using orthogonal methods. Such a strategy may further

reduce the possibility of undetected structural differences between the products and lead to a

more selective and targeted approach to animal and/or clinical testing. A sufficient

understanding of the mechanism of action (MOA) of the drug substance and clinical relevance of

any observed structural differences, clinical knowledge of the reference product and its class that

indicates low overall safety risks, and the availability of a relevant PD measure(s) may provide

further scientific justification for a selective and targeted approach to animal and/or clinical

studies.

See footnote 4.

Contains Nonbinding Recommendations

The sponsor should then consider the role of animal data in assessing toxicity and, in some cases,

in providing additional support for demonstrating biosimilarity and in contributing to the

immunogenicity assessment (section VII.C). The sponsor should then conduct comparative

human PK and PD studies (if there is a relevant PD measure(s)) (section VII.D.1) and compare

the clinical immunogenicity of the two products in an appropriate study population (section

VII.D.2). If there is residual uncertainty about biosimilarity after conducting structural analyses,

functional assays, animal testing, human PK and PD studies, and the clinical immunogenicity

assessment, the sponsor should then consider what additional clinical data may be needed to

adequately address that uncertainty (section VII.D.3). FDA encourages sponsors to consult

extensively with the Agency after completion of comparative structural and functional analyses

(before finalizing the clinical program) and throughout development as needed.

FDA recognizes that some of the aforementioned investigations could be performed in parallel;

however, the Agency recommends that sponsors use a stepwise approach to better address

residual uncertainty about biosimilarity that might remain at each step and incorporate FDA’s

advice provided after FDA review of data and information collected at certain milestones.

B. Using a Totality-of-the-Evidence Approach to Assess a Demonstration of

Biosimilarity

In evaluating a sponsor’s demonstration of biosimilarity, FDA will consider the totality of the

data and information submitted in the application, including structural and functional

characterization, nonclinical evaluation, human PK and PD data, clinical immunogenicity data,

and comparative clinical study(ies) data. FDA intends to use a risk-based approach to evaluate

all available data and information submitted in support of the biosimilarity of the proposed

product.

Thus, a sponsor may be able to demonstrate biosimilarity even though there are formulation or

minor structural differences, provided that the sponsor provides sufficient data and information

demonstrating that the differences are not clinically meaningful and the proposed product

otherwise meets the statutory criteria for biosimilarity. For example, differences in certain

posttranslational modifications or differences in certain excipients (e.g., human serum albumin)

might not preclude a finding of biosimilarity if data and information provided by the sponsor

show that the proposed product is highly similar to the reference product notwithstanding minor

differences in clinically inactive components and that there are no clinically meaningful

differences between the products in terms of safety, purity, and potency.

Clinically meaningful

differences could include a difference in the expected range of safety, purity, or potency of the

proposed product and the reference product. By contrast, slight differences in rates of

occurrence of certain adverse events between the two products ordinarily would not be

considered clinically meaningful differences.

In this example, because some excipients may affect the ability to characterize products, a sponsor should provide

evidence that the excipients used in the reference product will not affect the ability to characterize and compare the

products.

Contains Nonbinding Recommendations

VII. DEMONSTRATING BIOSIMILARITY

This section discusses scientific considerations in the stepwise approach to developing data and

information needed to support a demonstration of biosimilarity. To demonstrate biosimilarity, a

sponsor must provide sufficient data and information to show that the proposed product and the

reference product are highly similar notwithstanding minor differences in clinically inactive

components and that there are no clinically meaningful differences between the two products in

terms of safety, purity, and potency.

The type and amount of analyses and testing that will be

sufficient to demonstrate biosimilarity will be determined on a product-specific basis.

A. Structural Analyses

The PHS Act requires that a 351(k) application include information demonstrating biosimilarity

based on data derived from, among other things, analytical studies that demonstrate that the

biological product is highly similar to the reference product notwithstanding minor differences in

clinically inactive components, unless FDA determines that an element is unnecessary in a

351(k) application.

FDA expects that first, a sponsor will extensively characterize the

proposed product and the reference product with state-of-the-art technology, because extensive

characterization of both products serves as the foundation for a demonstration of biosimilarity. It

is expected that the expression construct for a proposed product will encode the same primary

amino acid sequence as its reference product. However, minor modifications such as N- or C-

terminal truncations that are not expected to change the product performance may be justified

and should be explained by the sponsor. Additionally, sponsors should consider all relevant

characteristics of the protein product (e.g., the primary, secondary, tertiary, and quaternary

structure; posttranslational modifications; and biological activities) to demonstrate that the

proposed product is highly similar to the reference product notwithstanding minor differences in

clinically inactive components. The more comprehensive and robust the comparative structural

and functional characterization is, the stronger the scientific justification for a selective and

targeted approach to animal and/or clinical testing.

Sponsors should use appropriate analytical methodologies with adequate sensitivity and

specificity for structural characterization of the proteins. Generally, such tests include the

following comparisons of the proposed product and the reference product:

• Primary structures, such as amino acid sequence

• Higher order structures, including secondary, tertiary, and quaternary structure

(including aggregation)

• Enzymatic posttranslational modifications, such as glycosylation and

phosphorylation

Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.

Section 7002(a)(2) of the Affordable Care Act, adding sections 351(k)(2)(A)(i)(I)(aa) and 351(k)(2)(A)(ii) of the

PHS Act.

Contains Nonbinding Recommendations

• Other potential variations, such as protein deamidation and oxidation

• Intentional chemical modifications, such as PEGylation sites and characteristics

Sponsors should conduct extensive structural characterization of both the proposed product and

the reference product in multiple representative lots to understand the lot-to-lot variability of

both products in the manufacturing processes. Lots used for the analyses should support the

biosimilarity of both the clinical material used in the clinical study(ies) intended to support a

demonstration of biosimilarity, and the to-be-marketed proposed product, to the reference

product. Characterization of lots manufactured during process development for the proposed

product may also be useful. Sponsors should justify the selection of the representative lots,

including the number of lots.

In addition, FDA recommends that sponsors analyze the finished dosage form of multiple lots of

the proposed product and the reference product, assessing excipients and any formulation effect

on purity, product- and process-related impurities, and stability.

Differences in formulation

between the proposed product and the reference product are among the factors that may affect

the extent and nature of subsequent animal or clinical testing.

A sponsor considering

manufacturing changes after completing the initial analytical similarity assessment or after

completing clinical testing intended to support a 351(k) application should perform an additional

analytical similarity assessment with lots manufactured by the new process and the reference

product and establish comparability of the proposed product manufactured by the old and new

manufacturing processes. The nature and extent of the changes may determine the extent of the

analytical similarity and comparability studies and any necessary additional studies.

If the reference product or the proposed product cannot be adequately characterized with state-

of-the-art technology, the application for the proposed product may not be appropriate for

submission under section 351(k) of the PHS Act; and the sponsor should consult FDA for

guidance on the appropriate submission pathway.

B. Functional Assays

The pharmacologic activity of protein products should be evaluated by in vitro and/or in vivo

functional assays. In vitro assays may include, but are not limited to, biological assays, binding

assays, and enzyme kinetics. In vivo assays may include the use of animal models of disease

(e.g., models that exhibit a disease state or symptom) to evaluate functional effects on

pharmacodynamic markers or efficacy measures. A functional evaluation comparing a proposed

product to the reference product using these types of assays is also an important part of the

foundation that supports a demonstration of biosimilarity and may be used to scientifically

justify a selective and targeted approach to animal and/or clinical testing.

See also the guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic

Protein Product to a Reference Product.

See also the guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic

Protein Product to a Reference Product.

Contains Nonbinding Recommendations

Sponsors can use functional assays to provide additional evidence that the biologic activity and

potency of the proposed product are highly similar to those of the reference product and/or to

support a conclusion that there are no clinically meaningful differences between the proposed

product and the reference product. Such assays also may be used to provide additional evidence

that the MOA of the two products is the same to the extent the MOA of the reference product is

known. Functional assays can be used to provide additional data to support results from

structural analyses, investigate the consequences of observed structural differences, and explore

structure-activity relationships.

These assays are expected to be comparative so they can

provide evidence of similarity or reveal differences in the performance of the proposed product

compared to the reference product, especially differences resulting from variations in structure

that cannot be detected using current analytical methods. FDA also recommends that sponsors

discuss limitations of the assays they used when interpreting results in their submissions to FDA.

Such discussions would be useful for the evaluation of analytical data and may guide whether

additional analytical testing would be necessary to support a demonstration of biosimilarity.

Functional assays can also provide information that complements the animal and clinical data in

assessing the potential clinical effects of minor differences in structure between the proposed

product and the reference product. For example, cell-based bioactivity assays may be used to

detect the potential for inducing cytokine release syndrome in vivo. The available information

about these assays, including sensitivity, specificity, and extent of validation, can affect the

amount and type of additional animal or clinical data that may be needed to establish

biosimilarity. As is the case for the structural evaluation, sponsors should justify the selection of

the representative lots, including the number of lots.

C. Animal Data

The PHS Act also requires that a 351(k) application include information demonstrating

biosimilarity based on data derived from animal studies (including the assessment of toxicity),

unless FDA determines that such studies are not necessary in a 351(k) application.

Results

from animal studies may be used to support the safety evaluation of the proposed product and

more generally to support the demonstration of biosimilarity between the proposed product and

the reference product.

1. Animal Toxicity Studies

As a scientific matter, animal toxicity data are considered useful when, based on the

results of extensive structural and functional characterization, uncertainties remain about

the safety of the proposed product that need to be addressed before initiation of clinical

studies in humans (assuming results from animal studies can meaningfully address the

remaining uncertainties).

See also the guidance for industry Quality Considerations in Demonstrating Biosimilarity of a Therapeutic

Protein Product to a Reference Product.

Section 7002(a)(2) of the Affordable Care Act, adding sections 351(k)(2)(A)(i)(I)(bb) and 351(k)(2)(A)(ii) of the

PHS Act.

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The scope and extent of any animal toxicity studies will depend on information about the

reference product, information about the proposed product, and the extent of known

similarities or differences between the two. As described further in section IX, FDA

encourages sponsors to initiate early discussions with the Agency with regard to their

biosimilar development plans, including identifying appropriate scientific justifications

for not conducting an animal toxicity study or for the scope and extent of such a study.

If comparative structural and functional data using the proposed product provide strong

support for analytical similarity to a reference product, then limited animal toxicity data

may be sufficient to support initial clinical use of the proposed product. Such a study

may be non-sacrificial and include endpoints that measure in-life parameters, PD, and PK

(with an assessment of immunogenicity).

If the structural and functional data are limited in scope or there are concerns about the

proposed product quality, a general toxicology study may be needed that includes full

animal pathology, histopathology, PD, PK, and immunogenicity assessments. When

animal toxicology studies are conducted, it will be useful to perform a comparative study

with the proposed product and the reference product (i.e., comparative bridging

toxicology studies). The selection of dose, regimen, duration, and test species for these

studies should provide a meaningful toxicological comparison between the two products.

It is important to understand the limitations of such animal studies (e.g., small sample

size, intra-species variations) when interpreting results comparing the proposed product

and the reference product. For a detailed discussion on the design of animal toxicology

studies relevant to biological products, see the ICH guidance for industry S6(R1)

Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6(R1)).

Safety data derived from animal toxicity studies generally are not expected if clinical data

(e.g., from studies or marketing experience outside the United States) using the proposed

product are available (with the same proposed route of administration and formulation)

that provide sufficient evidence for its safe use, unless animal toxicity studies are

otherwise needed to address a specific product quality concern.

Animal toxicity studies are generally not useful if there is no animal species that can

provide pharmacologically relevant data for the product (i.e., no species in which the

biologic activity of the product mimics the human response). For a detailed discussion

about demonstrating species relevance, see the criteria described in ICH S6(R1).

However, there may be some instances when animal data from a pharmacologically

nonresponsive species (including rodents) may be useful to support clinical studies with a

proposed product that has not been previously tested in human subjects, for example,

comparative PK and systemic tolerability studies. If animal toxicity studies are not

warranted based on an acceptable scientific justification, additional comparative in vitro

testing (using human cells or tissues when appropriate) is encouraged. Data derived

using human cells can provide important comparative information between the proposed

product and the reference product regarding potential clinical effects (section VII.B),

particularly in situations where there are no animal species available for safety testing.

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In general, nonclinical safety pharmacology, reproductive and developmental toxicity,

and carcinogenicity studies are not warranted when the proposed product and the

reference product have been demonstrated to be highly similar through extensive

structural and functional characterization and animal toxicity studies (if such studies were

conducted).

2. Inclusion of Animal PK and PD Measures

Under certain circumstances, a single-dose study in animals comparing the proposed

product and the reference product using PK and PD measures may contribute to the

totality of evidence that supports a demonstration of biosimilarity. Specifically, sponsors

can use results from animal studies to support the degree of similarity based on the PK

and PD profiles of the proposed product and the reference product. PK and PD measures

also can be incorporated into a single animal toxicity study, where appropriate. Animal

PK and PD assessment will not negate the need for human PK and PD studies.

3. Interpreting Animal Immunogenicity Results

Animal immunogenicity assessments are conducted to assist in the interpretation of the

animal study results and generally do not predict potential immune responses to protein

products in humans. However, when differences in manufacturing (e.g., impurities or

excipients) between the proposed product and the reference product may result in

differences in immunogenicity, measurement of anti-therapeutic protein antibody

responses in animals may provide useful information. Additionally, differences observed

in animal immunogenicity assessments may reflect potential structural or functional

differences between the two products not captured by other analytical methods.

D. Clinical Studies – General Considerations

The sponsor of a proposed product must include in its submission to FDA information

demonstrating that “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.”

The nature and scope of the clinical study or studies will depend on the nature and extent of

residual uncertainty about biosimilarity after conducting structural and functional

characterization and, where relevant, animal studies. The frequency and severity of safety risks

Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2)(B) of the PHS Act. To support a

demonstration of biosimilarity, the statute also requires a clinical study or studies (including the assessment of

immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate

conditions of use for which the reference product is licensed and intended to be used and for which licensure is

sought for the biological product, unless FDA determines an element unnecessary (section 7002(a)(2) of the

Affordable Care Act, adding section 351(k)(2)(A)(i)(I)(cc) of the PHS Act). As a general matter, FDA anticipates

that the recommendations described in this guidance designed to demonstrate that the proposed product is highly

similar to its reference product notwithstanding minor differences in clinically inactive components and to

demonstrate that no clinically meaningful differences exist between the two products will provide data sufficient to

demonstrate the safety, purity, and potency of the proposed product. FDA recommends that sponsors identify which

study or studies will provide data regarding no clinically meaningful differences prior to starting clinical studies.

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and other safety and effectiveness considerations (e.g., poor relationship between pharmacologic

effects and effectiveness) for the reference product may also affect the design of the clinical

program. The scope of the clinical program and the type of clinical studies (i.e., comparative

human PK, PD, clinical immunogenicity, or clinical safety and effectiveness) should be

scientifically justified by the sponsor.

As a scientific matter, FDA expects a sponsor to conduct comparative human PK and PD studies

(if there is a relevant PD measure(s))

and a clinical immunogenicity assessment. In certain

cases, the results of these studies may provide adequate clinical data to support a conclusion that

there are no clinically meaningful differences between the proposed biosimilar product and the

reference product. However, if residual uncertainty about biosimilarity remains after conducting

these studies, an additional comparative clinical study or studies would be needed to further

evaluate whether there are clinically meaningful differences between the two products.

1. Human Pharmacology Data

Human PK and PD profiles of a protein product often cannot be adequately predicted

from functional assays and/or animal studies alone. Therefore, human PK and PD studies

comparing a proposed product to the reference product generally are fundamental

components in supporting a demonstration of biosimilarity. Both PK and PD studies

(where there is a relevant PD measure(s)) generally will be expected to establish

biosimilarity, unless a sponsor can scientifically justify that such a study is not needed.

Even if relevant PD measures are not available, sensitive PD endpoints may be assessed

if such assessment may help reduce residual uncertainty about biosimilarity.

Sponsors should provide a scientific justification for the selection of the human PK and

PD study population (e.g., patients versus healthy subjects) and parameters, taking into

consideration the relevance and sensitivity of such population and parameters, the

population and parameters studied for the licensure for the reference product, as well as

the current knowledge of the intra-subject and inter-subject variability of human PK and

PD for the reference product. For example, comparative human PK and PD studies

should use a population, dose(s), and route of administration that are adequately sensitive

to allow for the detection of differences in PK and PD profiles. FDA recommends that,

to the extent possible, the sponsor select PD measures that (1) are relevant to clinical

A PD study may also incorporate PK measures (i.e., a combined PK/PD study).

See the draft guidance for industry Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a

Reference Product for a more detailed discussion on the design and use of clinical pharmacology studies to support

a demonstration of biosimilarity. When final, this guidance will represent FDA’s current thinking on this topic.

PK and PD studies provide quite different types of information. In simple terms, a PK study measures how the

body acts on a drug (how the drug is absorbed, distributed, metabolized, and eliminated), and a PD study measures

how the drug acts on the body (typically assessing a measure(s) related to the drug’s biochemical and physiologic

effects on the body). Therefore, one type of study does not duplicate or substitute for the information provided by

the other. Both PK studies and PD studies provide important information for assessing biosimilarity; and therefore,

as a scientific matter, comparative human PK studies and PD studies (where there is a relevant PD measure(s))

generally will be expected.

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outcomes (e.g., on mechanistic path of MOA or disease process related to effectiveness

or safety); (2) are measurable for a sufficient period of time after dosing to ascertain the

full PD response and with appropriate precision; and (3) have the sensitivity to detect

clinically meaningful differences between the proposed product and the reference

product. Use of multiple PD measures that assess different domains of activities may

also be of value.

When there are established dose-response or systemic exposure-response relationships

(response may be PD measures or clinical endpoints), it is important to select, whenever

possible, a dose(s) for study on the steep part of the dose-response curve for the proposed

product. Studying doses that are on the plateau of the dose-response curve is unlikely to

detect clinically meaningful differences between the two products. Sponsors should

predefine and justify the criteria for PK and PD parameters for studies included in the

application to demonstrate biosimilarity.

A human PK study that demonstrates similar exposure (e.g., serum concentration over

time) for the proposed product and the reference product may provide support for a

demonstration of biosimilarity. A human PK study may be particularly useful when the

exposure correlates with clinical safety and effectiveness. A human PD study that

demonstrates a similar effect on a relevant PD measure(s) related to effectiveness or

specific safety concerns (except for immunogenicity, which is evaluated separately)

represents even stronger support for a biosimilarity determination.

In certain cases, establishing a similar clinical PK, PD, and immunogenicity profile may

provide sufficient clinical data to support a conclusion that there are no clinically

meaningful differences between the two products. PK and PD parameters are generally

more sensitive than clinical efficacy endpoints in assessing the similarity of two products.

For example, an effect on thyroid stimulating hormone (TSH) levels would provide a

more sensitive comparison of two thyroxine products than an effect on clinical symptoms

of euthyroidism.

In cases where there is a meaningful correlation between PK and PD results and clinical

effectiveness, convincing PK and PD results may make a comparative efficacy study

unnecessary. For example, similar dose-response curves of the proposed product and the

reference product on a relevant PD measure, combined with a similar human PK profile

and clinical immunogenicity profile, could provide sufficient evidence to support a

conclusion of no clinically meaningful differences. Even if there is still residual

uncertainty about biosimilarity based on PK and PD results, establishing a similar human

PK and PD profile may provide a scientific basis for a selective and targeted approach to

subsequent clinical testing.

For PD studies using products with a short half-life (e.g., shorter than 5 days), a rapid PD

response, and a low incidence of immunogenicity, a crossover design is appropriate,

when feasible. For products with a longer half-life (e.g., more than 5 days), a parallel

design will usually be needed. Sponsors should provide a scientific justification for the

selection of study dose (e.g., one dose or multiple doses) and route of administration.

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FDA recommends that sponsors consider the duration of time it takes for a PD measure

to change and the possibility of nonlinear PK. FDA also encourages consideration of the

role of modeling and simulation in designing comparative human PK and PD studies.

2. Clinical Immunogenicity Assessment

The goal of the clinical immunogenicity assessment is to evaluate potential differences

between the proposed product and the reference product in the incidence and severity of

human immune responses. Immune responses may affect both the safety and

effectiveness of the product by, for example, altering PK, inducing anaphylaxis, or

promoting development of neutralizing antibodies that neutralize the product as well as

its endogenous protein counterpart. Thus, establishing that there are no clinically

meaningful differences in immune response between a proposed product and the

reference product is a key element in the demonstration of biosimilarity. Structural,

functional, and animal data

are generally not adequate to predict immunogenicity in

humans. Therefore, at least one clinical study that includes a comparison of the

immunogenicity of the proposed product to that of the reference product will be expected.

FDA encourages that, where feasible, sponsors collect immunogenicity data in any

clinical study, including human PK or PD studies.

The extent and timing of the clinical immunogenicity assessment will vary depending on

a range of factors, including the extent of analytical similarity between the proposed

product and the reference product, and the incidence and clinical consequences of

immune responses for the reference product. For example, if the clinical consequence is

severe (e.g., when the reference product is a therapeutic counterpart of an endogenous

protein with a critical, nonredundant biological function or is known to provoke

anaphylaxis), a more extensive immunogenicity assessment will likely be needed to

support a demonstration of biosimilarity. If the immune response to the reference

product is rare, a premarketing evaluation to assess apparent differences in immune

responses between the two products may be adequate to support biosimilarity. In

addition, in some cases certain safety risks may need to be evaluated through

postmarketing surveillance or studies.

The overall immunogenicity assessment should consider the nature of the immune

response (e.g., anaphylaxis, neutralizing antibody), the clinical relevance and severity of

consequences (e.g., loss of efficacy of life-saving therapeutic and other adverse effects),

the incidence of immune responses, and the population being studied. FDA recommends

use of a comparative parallel design (i.e., a head-to-head study) in treatment-naïve

patients as the most sensitive design for a premarketing study to assess potential

differences in the risk of immunogenicity. However, depending on the clinical

experience of the reference and proposed products (taking into consideration the

conditions of use and patient population), a sponsor may need to evaluate a subset of

patients to provide a substantive descriptive assessment of whether a single cross-over

Section VII.C.3 of this guidance contains a discussion concerning the interpretation of animal immunogenicity

results.

Contains Nonbinding Recommendations

from the reference product to the proposed biosimilar would result in a major risk in

terms of hypersensitivity, immunogenicity, or other reactions. The design of any study to

assess immunogenicity and acceptable differences in the incidence and other parameters

of immune response should be discussed with FDA before initiating the study.

Differences in immune responses between a proposed product and the reference product

in the absence of observed clinical sequelae may be of concern and may warrant further

evaluation (e.g., extended period of follow-up evaluation).

The study population used to compare immunogenicity should be justified by the sponsor

and agreed to by the Agency. If a sponsor is seeking to extrapolate immunogenicity

findings for one condition of use to other conditions of use, the sponsor should consider

using a study population and treatment regimen that are adequately sensitive for

predicting a difference in immune responses between the proposed product and the

reference product across the conditions of use. Usually, this will be the population and

regimen for the reference product for which development of immune responses with

adverse outcomes is most likely to occur (e.g., patients on background

immunosuppressants would be less likely to develop immune responses than patients

who are not immunosuppressed).

The selection of clinical immunogenicity endpoints or PD measures associated with

immune responses to therapeutic protein products (e.g., antibody formation and cytokine

levels) should take into consideration the immunogenicity issues that have emerged

during the use of the reference product. Sponsors should prospectively define the clinical

immune response criteria (e.g., definitions of significant clinical events such as

anaphylaxis), using established criteria where available, for each type of potential

immune response and should obtain agreement from FDA on these criteria before

initiating the study.

The duration of follow-up evaluation should be determined 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, for chronically administered agents, the

follow-up period is recommended to be 1 year unless a shorter duration can be

scientifically justified based on the totality of the evidence to support biosimilarity.

As a scientific matter, a sponsor should evaluate the following antibody parameters in the

clinical immunogenicity assessment:

• Titer, specificity, relevant isotype distribution, time course of development,

persistence, disappearance, impact on PK, and association with clinical sequelae

• Neutralization of product activity: neutralizing capacity to all relevant functions

(e.g., uptake and catalytic activity, neutralization for replacement enzyme

therapeutics)

Contains Nonbinding Recommendations

The sponsor should develop assays capable of sensitively detecting immune responses,

even in the presence of the circulating drug product (proposed product and reference

product).

The proposed product and the 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 early in development, and the

validation should consider both the proposed product and the reference product.

Sponsors should consult with FDA on the sufficiency of assays before initiating any

clinical immunogenicity assessment.

3. Comparative Clinical Studies

As a scientific matter, a comparative clinical study will be necessary to support a

demonstration of biosimilarity if there is residual uncertainty about whether there are

clinically meaningful differences between the proposed product and the reference product

based on structural and functional characterization, animal testing, human PK and PD

data, and clinical immunogenicity assessment. A sponsor should provide a scientific

justification if it believes that a comparative clinical study is not necessary.

The following are examples of factors that may influence the type and extent of the

comparative clinical study data needed:

a. The nature and complexity of the reference product, the extensiveness of

structural and functional characterization, and the findings and limitations of

comparative structural, functional, and nonclinical testing, including the extent of

observed differences

b. The extent to which differences in structure, function, and nonclinical

pharmacology and toxicology predict differences in clinical outcomes, in

conjunction with the degree of understanding of the MOA of the reference

product and disease pathology

c. The extent to which human PK or PD is known to predict clinical outcomes (e.g.,

PD measures known to be relevant to effectiveness or safety)

d. The extent of clinical experience with the reference product and its therapeutic

class, including the safety and risk-benefit profile (e.g., whether there is a low

potential for off-target adverse events), and appropriate endpoints and biomarkers

for safety and effectiveness (e.g., availability of established, sensitive clinical

endpoints)

e. The extent of any other clinical experience with the proposed product (e.g., if the

proposed product has been marketed outside the United States)

See the draft guidance for industry Assay Development for Immunogenicity Testing of Therapeutic Proteins for a

detailed discussion. When final, this guidance will represent FDA’s current thinking on this topic.

Contains Nonbinding Recommendations

A sponsor should provide a scientific justification for how it intends to use these factors

to determine what type(s) of clinical study(ies) are needed and the design of any

necessary study(ies). For example, if a comparative clinical study is needed, a sponsor

should explain how these factors were considered in determining the design of such a

study, including the endpoint(s), population, similarity margin, and statistical analyses.

Additionally, specific safety or effectiveness concerns regarding the reference product

and its class (including history of manufacturing- or source-related adverse events) may

warrant more comparative clinical data. Alternatively, if there is information regarding

other biological products that could support a biosimilarity determination (with marketing

histories that demonstrate no apparent differences in clinical safety and effectiveness

profiles), such information may be an additional factor supporting a selective and

targeted approach to the clinical program.

Endpoints

A sponsor should use endpoints that can assess clinically meaningful differences between

the proposed product and the reference product in a comparative clinical study. The

endpoints may be different from those used as primary endpoints in the reference

product’s clinical studies if they are scientifically supported. As discussed in

section VII.D.1, certain endpoints (such as PD measures) are more sensitive than clinical

endpoints and, therefore, may enable more precise comparisons of relevant therapeutic

effects. There may be situations when the assessment of multiple PD measures in a

comparative clinical study will enhance the sensitivity of the study. The adequacy of the

endpoints depends on the extent to which PD measures correlate with clinical outcome,

the extent of structural and functional data support for biosimilarity, the understanding of

MOA, and the nature or seriousness of outcome affected.

Study Population

The choice of study population should allow for an assessment of clinically meaningful

differences between the proposed product and the reference product. Often the study

population will have characteristics consistent with those of the population studied for the

licensure of the reference product for the same indication. However, there are cases

where a study population could be different from that in the clinical studies that

supported the licensure of the reference product. For example, if a genetic predictor of

response was developed following licensure of the reference product, it may be possible

to use patients with the response marker as the study population.

Sample Size and Duration of Study

The sample size for and duration of the comparative clinical study should be adequate to

allow for the detection of clinically meaningful differences between the two products. As

discussed in section VII.D.1, certain endpoints, such as PD measures, may be more

sensitive than clinical endpoints and facilitate the conduct of a smaller study of limited

duration. In such cases where the size and duration of the comparative clinical study may

Contains Nonbinding Recommendations

not be adequate for the detection of relevant safety signals, a separate assessment of

safety and immunogenicity may be needed.

Study Design and Analyses

A comparative clinical study for a biosimilar development program should be designed to

investigate whether there are clinically meaningful differences between the proposed

product and the reference product. The design should take into consideration the nature

and extent of residual uncertainty that remains about biosimilarity based on data

generated from comparative structural and functional characterization, animal testing,

human PK and PD studies, and clinical immunogenicity assessment.

Generally, FDA expects a clinical study or studies designed to establish statistical

evidence that the proposed product is neither inferior to the reference product by more

than a specified margin nor superior to the reference product by more than a (possibly

different) specified margin. Typically, an equivalence design with symmetric inferiority

and superiority margins would be used. Symmetric margins would be reasonable when,

for example, there are dose-related toxicities.

In some cases, it would be appropriate to use an asymmetric interval with a larger upper

bound to rule out superiority than lower bound to rule out inferiority. An asymmetric

interval could be reasonable, for example, if the dose used in the clinical study is near the

plateau of the dose-response curve and there is little likelihood of dose-related effects

(e.g., toxicity). In most cases, use of an asymmetric interval would generally allow for a

smaller sample size than would be needed with symmetric margins. However, if there is

a demonstration of clear superiority, then further consideration should be given as to

whether the proposed product can be considered biosimilar to the reference product.

In some cases, depending on the study population and endpoint(s), ruling out only

inferiority may be adequate to establish that there are no clinically meaningful differences

between the proposed product and the reference product. For example, if it is well

established that doses of a reference product pharmacodynamically saturate the target at

the clinical dose level and it would be unethical to use lower than clinically approved

doses, a non-inferiority (NI) design may be sufficient.

A sponsor should provide adequate scientific justification for the choice of study design,

study population, study endpoint(s), estimated effect size for the reference product, and

margin(s) (how much difference to rule out). Sponsors should discuss their study

proposal(s) and overall clinical development plan with FDA before initiating the

comparative clinical study(ies).

If an NI design is considered appropriate, sponsors are encouraged to refer to the draft guidance for industry Non-

inferiority Clinical Trials. When final, this guidance will represent FDA’s current thinking on this topic.

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4. Extrapolation of Clinical Data Across Indications

If the proposed product meets the statutory requirements for licensure as a biosimilar

product under section 351(k) of the PHS Act based on, among other things, data derived

from a clinical study or studies sufficient to demonstrate safety, purity, and potency in an

appropriate condition of use, the applicant may seek licensure of the proposed product for

one or more additional conditions of use for which the reference product is licensed.

However, the applicant would need to provide sufficient scientific justification for

extrapolating clinical data to support a determination of biosimilarity for each condition

of use for which licensure is sought.

Such scientific justification for extrapolation should address, for example, the following

issues for the tested and extrapolated conditions of use:

• The MOA(s) in each condition of use for which licensure is sought; this may

include:

– The target/receptor(s) for each relevant activity/function of the product

– The binding, dose/concentration response, and pattern of molecular signaling

upon engagement of target/receptor(s)

– The relationships between product structure and target/receptor interactions

– The location and expression of the target/receptor(s)

• The PK and bio-distribution of the product in different patient populations

(Relevant PD measures may also provide important information on the MOA.)

• The immunogenicity of the product in different patient populations

• Differences in expected toxicities in each condition of use and patient population

(including whether expected toxicities are related to the pharmacological activity of

the product or to off-target activities)

• Any other factor that may affect the safety or efficacy of the product in each

condition of use and patient population for which licensure is sought

Differences between conditions of use with respect to the factors described above do not

necessarily preclude extrapolation. A scientific justification should address these

differences in the context of the totality of the evidence supporting a demonstration of

biosimilarity.

In choosing which condition of use to study that would permit subsequent extrapolation

of clinical data to other conditions of use, FDA recommends that a sponsor consider

choosing a condition of use that would be adequately sensitive to detect clinically

meaningful differences between the two products.

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The sponsor of a proposed product may obtain licensure only for a condition of use that

has been previously licensed for the reference product. If a reference product has a

condition of use that was licensed under section 506(c) of the FD&C Act and 21 CFR

part 601, subpart E (accelerated approval), and the reference product’s clinical benefit in

this condition of use has not yet been verified in postmarketing studies, the proposed

product sponsor should consider studying another condition of use for which the

reference product is licensed to avoid potential complications in the event that

postmarketing studies fail to verify the clinical benefit of the reference product for the

condition of use.

VIII. POSTMARKETING SAFETY MONITORING CONSIDERATIONS

Robust postmarketing safety monitoring is an important component in ensuring the safety and

effectiveness of biological products, including biosimilar therapeutic protein products.

Postmarketing safety monitoring should first take into consideration any particular safety or

effectiveness concerns associated with the use of the reference product and its class, the

proposed product in its development and clinical use (if marketed outside the United States), the

specific condition of use and patient population, and patient exposure in the biosimilar

development program. Postmarketing safety monitoring for a proposed product should also have

adequate mechanisms in place to differentiate between the adverse events associated with the

proposed product and those associated with the reference product, including the identification of

adverse events associated with the proposed product that have not been previously associated

with the reference product. Rare, but potentially serious, safety risks (e.g., immunogenicity) may

not be detected during preapproval clinical testing because the size of the population exposed

likely will not be large enough to assess rare events. In particular cases, such risks may need to

be evaluated through postmarketing surveillance or studies. In addition, as with any other

biological product, FDA may take any appropriate action to ensure the safety and effectiveness

of a proposed product, including, for example, requiring a postmarketing study or clinical trial to

evaluate certain safety risks.

Because some aspects of postmarketing safety monitoring are product-specific, FDA encourages

sponsors to consult with appropriate FDA divisions to discuss the sponsor’s proposed approach

to postmarketing safety monitoring.

IX. CONSULTATION WITH FDA

Many product-specific factors can influence the components of a product development program

intended to establish that a proposed product is biosimilar to a reference product. Therefore,

FDA will ordinarily provide feedback on a case-by-case basis on the components of a

development program for a proposed product. In addition, it may not be possible to identify in

advance all the necessary components of a development program; and the assessment of one

element (e.g., structural analyses) at one step can influence decisions about the type and amount

See, for example, sections 505(o)(3) and 505(p)(1)(A)(ii) of the FD&C Act.

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of subsequent data for the next step. For these reasons, FDA recommends that sponsors use a

stepwise approach to establish the totality of the evidence that supports a demonstration of

biosimilarity.

FDA also advises sponsors intending to develop biosimilar products to meet with FDA to present

their product development plans and establish a schedule of milestones that will serve as

landmarks for future discussions with the Agency. FDA anticipates that early discussions with

FDA about product development plans and about the approaches to providing adequate scientific

justifications will facilitate biosimilar development.

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GLOSSARY

As used in this guidance, the following terms are defined below:

• Biological product means “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood

component or derivative, allergenic product, protein (except any chemically synthesized

polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any

other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of

a disease or condition of human beings.”

• Biosimilar or biosimilarity means that “the biological product is highly similar to the

reference product notwithstanding minor differences in clinically inactive components,” and

that “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.”

• Chemically synthesized polypeptide means any alpha amino acid polymer that (a) is made

entirely by chemical synthesis and (b) is less than 100 amino acids in size.

• Product, when used without modifiers in this guidance, is intended to refer to the

intermediates, drug substance, and/or drug product, as appropriate. The use of the term

product is consistent with the use of the term in ICH Q5E.

• Protein means any alpha amino acid polymer with a specific defined sequence that is greater

than 40 amino acids in size.

• Reference product means the single biological product licensed under section 351(a) of the

PHS Act against which a biological product is evaluated in a 351(k) application.

Section 7002(b)(2) of the Affordable Care Act, amending section 351(i)(1) of the PHS Act.

Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(2) of the PHS Act.

Section 7002(b)(3) of the Affordable Care Act, adding section 351(i)(4) of the PHS Act.