demonstration of biosimilarity
Regulatory Considerations for the Assessment of Analytical Similarity Maria Teresa Gutierrez Lugo, Ph.D. Office of Biotechnology Products CDER/FDA Open Forum: Characterization and Comparability of Biotherapeutics and BiosimilarsCurrent State of the Art in Analytical, Biophysical and Mass Spectrometric Methods AAPS National Biotechnology Conference June 8-10, 2015 San Francisco, CA
Outline • General concepts on biosimilarity • Development program for a biosimilar product vs a new biological entity product • Analytical similarity
• Role and expectations for state-of-the-art analytical technologies • Concluding remarks
2
Definition of Biosimilarity Biosimilar or Biosimilarity means: 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.
Reference Product means the single biological product licensed under 351(a) of the PHS Act Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act.
3
FDA Approach to Assess the Demonstration of Biosimilarity FDA intends to consider the totality of the evidence provided by a sponsor and recommends a stepwise approach to demonstrating biosimilarity, which can include a comparison of the proposed biosimilar 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. FDA Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, page 2, Section II
4
Product Development Apply a step-wise approach to data generation and the evaluation of residual uncertainty* Analytical Studies Animal Studies Clinical PK/PD Studies
Clinical Immunogenicity Assessment Additional Clinical Studies * The list is not intended to imply that all types of data described here are necessary for any given biosimilar development program. FDA may determine, in its discretion, that certain studies are unnecessary in a 351(k) application. From: “Biosimilars in the US: Learning from the first application and future outlook” by Leah Christl, PhD. EBG meeting. April, 2015
5
Biosimilar Development − Goal “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”
Guidance for Industry “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”. April 2015 6
Data Collection During New Biological Entity Product Development Preclinical Toxicology Studies Short term Long term IND Enabling
Phase I
Clinical Studies Dose ranging Safety
Product Quality
351(a) package
Phase II
Dose ranging Safety Efficacy
Phase III
Efficacy Safety
7 Adapted from a slide by Tony Mire-Sluis. From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
Product Quality Progression During New Biological Entity Product Development Development Decision
Research Early purification studies Immuno-assay based lot release
Developmental Research Protein selection
Bioassay Development
IND Enabling Limited Structural characterization Preliminary biological characterization Limited viral clearance Limited stability
BLA
IND
Phase I II III In depth structural and biological characterization Assay development Validated Lot release assay development
IV Post Marketing Lot release
Post-marketing surveillance Stability Manufacturing changes
Specification setting Manufacturing scale up Stability Viral Clearance
Adapted from a slide by Tony Mire-Sluis. From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
8
Data Collection During Biosimilar Product Development Preclinical Toxicology Studies Short term
351(k) package
Initial Clinical Studies
IND Enabling
Additional Clinical Studies
Clinical Studies PK/PD
Product Quality
Immunogenicity Additional Clinical Studies
Depends on extent of analytical similarity and PK/PD similarity prior to this point
From: “Quality Considerations for Biosimilars” by Marjorie Shapiro, PhD. DIA/FDA Biosimilars Conference. Sep 12, 2012
9
Preferred Biosimilar Product Quality Development Process Development Decision Biosimilar Initial Advisory Meeting
Developmental Research Purchase reference product lots
Analyze reference product lots
In depth characterization assay development
Preliminary analytical/ Develop biosimilar construct and cell line functional similarity studies Manufacturing process development Formulation studies
BLA
IND BPD Type 1/2/3
IND Enabling Analytical and functional similarity studies
Initial Clinical Studies Continuous characterizatio n
Specification Qualified/ setting validated release and stability assays Final Mf scale
BPD Type 4
Additional Clinical Studies Final analytical and functional similarity studies Specification setting
Stability
Stability Viral Clearance
From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
10
What Can and Cannot be Different? • Must be the same – Strength – Dosage form – Route of administration
• Can be different – Formulation – Container closure system and delivery device • Design differences may be accepted if the proposed biosimilar product meets the statutory standard for biosimilarity and performance data supports its used (e.g. performance testing, human factor studies)
– Can be approved for fewer than all presentations, ROA and indications that the reference product – Expression system 11
Analytical Similarity Structural
Impurity profiles
• •
•
• •
Primary structure Higher order structure including aggregates Molecular weight Degree of heterogeneity (derived from enzymatic, unintended and intentional modifications)
Functional • • • • • •
Biological activity (i.e. potency) Functional domain Enzyme kinetics Receptor binding Protein-target binding Fc effector function
•
Product-related impurities – Inactive protein variants generated during manufacture or storage Process-related impurities – Host cell proteins & DNA – Media components – Column leachates (e.g., protein A)
Stability •
Degradation profiles under accelerated, stress (high temperature, freeze-thaw, light exposure, agitation), forced conditions
Collectively, these quality attributes can be used to define identity, purity, potency, and stability of the products, and if critical, they correlate with safety and efficacy 12
Role of State-of-the-Art Analytical Technologies • Improved the ability to identify and characterize biotech products. • Enhance the likelihood that a propose product can be demonstrated to be highly similar to a reference product by better targeting the reference product’s physicochemical and functional properties and the ability to identify product differences. • However, despite improvements, current analytical technologies may not be able to detect and characterize all relevant structural and functional differences – A through understanding of each analytical method’s limitations is critical to successful identification of residual uncertainties, and in turn, to the design of subsequent testing Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
13
Analytical Similarity Methods • Use appropriate analytical technologies that has adequate sensitivity and specificity to detect and characterize differences between the products. Use of state-of-the-art analytical technologies are encouraged. • Capability of the methods used in the analytical assessment, as well as their limitations should be described by the sponsor. – Information regarding the ability of the method should be provided along with the analytical similarity data.
• Use of orthogonal high resolution, quantitative methods to definitively distinguish any differences in product attributes. – Orthogonal methods provide independent data to support a quality attribute
– Differences should be addressed. Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
14
Analytical Similarity Methods • Test used to characterize the products do not necessarily need to be validated for routine quality control purposes but should be: – Scientifically sound – Fit for the intended purpose – Produce results that are reproducible and reliable • Capable of identifying product differences – Qualitative – Quantitative • Sensitive – Analysis of spiked samples Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
15
Functional Assays • If clinically relevant mechanisms of action (MOA) are known for the reference product, the functional assays should reflect these MOAs • If multiple MOAs and multiple indications, understand MOA for specific indications and CQAs for that MOA • Understand potential impact of protein modifications – Oxidation of methionine and deamidation of asparagine may impact function or immunogenicity of some proteins but not others.
• Understand how combinations of quality attributes interact to impact clinical performance • Functional assays are often highly variable, less variable assays should be developed: – High assay variability might preclude detection of small but significant differences between the products.
Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
16
Concluding Remarks • Analytical similarity is the foundation of the biosimilar program • Analytical studies are generally more sensitive than clinical studies • Differences between proposed biosimilar product and reference product should be evaluated in terms of potential impact on activity, PK/PD, safety and immunogencity • Methods used in the analytical similarity assessment should be demonstrated to be fit for intended use
17
Concluding Remarks • The more comprehensive and robust the comparative structural and functional characterization, the stronger the scientific justification for a selective and targeted approach to animal and/or clinical testing to support a demonstration of biosimilarity
18
Guidances • Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Protein Product. April 2015 • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April 2015 • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. April 2015 • Draft Guidance: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. March 2013 • Draft Guidance: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. May 2014 19
Thank you for your attention
20
Outline • General concepts on biosimilarity • Development program for a biosimilar product vs a new biological entity product • Analytical similarity
• Role and expectations for state-of-the-art analytical technologies • Concluding remarks
2
Definition of Biosimilarity Biosimilar or Biosimilarity means: 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.
Reference Product means the single biological product licensed under 351(a) of the PHS Act Section 7002(b)(2) of the Affordable Care Act, amending section 351(i) of the PHS Act.
3
FDA Approach to Assess the Demonstration of Biosimilarity FDA intends to consider the totality of the evidence provided by a sponsor and recommends a stepwise approach to demonstrating biosimilarity, which can include a comparison of the proposed biosimilar 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. FDA Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, page 2, Section II
4
Product Development Apply a step-wise approach to data generation and the evaluation of residual uncertainty* Analytical Studies Animal Studies Clinical PK/PD Studies
Clinical Immunogenicity Assessment Additional Clinical Studies * The list is not intended to imply that all types of data described here are necessary for any given biosimilar development program. FDA may determine, in its discretion, that certain studies are unnecessary in a 351(k) application. From: “Biosimilars in the US: Learning from the first application and future outlook” by Leah Christl, PhD. EBG meeting. April, 2015
5
Biosimilar Development − Goal “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”
Guidance for Industry “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”. April 2015 6
Data Collection During New Biological Entity Product Development Preclinical Toxicology Studies Short term Long term IND Enabling
Phase I
Clinical Studies Dose ranging Safety
Product Quality
351(a) package
Phase II
Dose ranging Safety Efficacy
Phase III
Efficacy Safety
7 Adapted from a slide by Tony Mire-Sluis. From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
Product Quality Progression During New Biological Entity Product Development Development Decision
Research Early purification studies Immuno-assay based lot release
Developmental Research Protein selection
Bioassay Development
IND Enabling Limited Structural characterization Preliminary biological characterization Limited viral clearance Limited stability
BLA
IND
Phase I II III In depth structural and biological characterization Assay development Validated Lot release assay development
IV Post Marketing Lot release
Post-marketing surveillance Stability Manufacturing changes
Specification setting Manufacturing scale up Stability Viral Clearance
Adapted from a slide by Tony Mire-Sluis. From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
8
Data Collection During Biosimilar Product Development Preclinical Toxicology Studies Short term
351(k) package
Initial Clinical Studies
IND Enabling
Additional Clinical Studies
Clinical Studies PK/PD
Product Quality
Immunogenicity Additional Clinical Studies
Depends on extent of analytical similarity and PK/PD similarity prior to this point
From: “Quality Considerations for Biosimilars” by Marjorie Shapiro, PhD. DIA/FDA Biosimilars Conference. Sep 12, 2012
9
Preferred Biosimilar Product Quality Development Process Development Decision Biosimilar Initial Advisory Meeting
Developmental Research Purchase reference product lots
Analyze reference product lots
In depth characterization assay development
Preliminary analytical/ Develop biosimilar construct and cell line functional similarity studies Manufacturing process development Formulation studies
BLA
IND BPD Type 1/2/3
IND Enabling Analytical and functional similarity studies
Initial Clinical Studies Continuous characterizatio n
Specification Qualified/ setting validated release and stability assays Final Mf scale
BPD Type 4
Additional Clinical Studies Final analytical and functional similarity studies Specification setting
Stability
Stability Viral Clearance
From: “Quality Considerations for Biosimilars” by Marjorie Shapiro. DIA/FDA Biosimilars Conference. Sep, 2012
10
What Can and Cannot be Different? • Must be the same – Strength – Dosage form – Route of administration
• Can be different – Formulation – Container closure system and delivery device • Design differences may be accepted if the proposed biosimilar product meets the statutory standard for biosimilarity and performance data supports its used (e.g. performance testing, human factor studies)
– Can be approved for fewer than all presentations, ROA and indications that the reference product – Expression system 11
Analytical Similarity Structural
Impurity profiles
• •
•
• •
Primary structure Higher order structure including aggregates Molecular weight Degree of heterogeneity (derived from enzymatic, unintended and intentional modifications)
Functional • • • • • •
Biological activity (i.e. potency) Functional domain Enzyme kinetics Receptor binding Protein-target binding Fc effector function
•
Product-related impurities – Inactive protein variants generated during manufacture or storage Process-related impurities – Host cell proteins & DNA – Media components – Column leachates (e.g., protein A)
Stability •
Degradation profiles under accelerated, stress (high temperature, freeze-thaw, light exposure, agitation), forced conditions
Collectively, these quality attributes can be used to define identity, purity, potency, and stability of the products, and if critical, they correlate with safety and efficacy 12
Role of State-of-the-Art Analytical Technologies • Improved the ability to identify and characterize biotech products. • Enhance the likelihood that a propose product can be demonstrated to be highly similar to a reference product by better targeting the reference product’s physicochemical and functional properties and the ability to identify product differences. • However, despite improvements, current analytical technologies may not be able to detect and characterize all relevant structural and functional differences – A through understanding of each analytical method’s limitations is critical to successful identification of residual uncertainties, and in turn, to the design of subsequent testing Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
13
Analytical Similarity Methods • Use appropriate analytical technologies that has adequate sensitivity and specificity to detect and characterize differences between the products. Use of state-of-the-art analytical technologies are encouraged. • Capability of the methods used in the analytical assessment, as well as their limitations should be described by the sponsor. – Information regarding the ability of the method should be provided along with the analytical similarity data.
• Use of orthogonal high resolution, quantitative methods to definitively distinguish any differences in product attributes. – Orthogonal methods provide independent data to support a quality attribute
– Differences should be addressed. Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
14
Analytical Similarity Methods • Test used to characterize the products do not necessarily need to be validated for routine quality control purposes but should be: – Scientifically sound – Fit for the intended purpose – Produce results that are reproducible and reliable • Capable of identifying product differences – Qualitative – Quantitative • Sensitive – Analysis of spiked samples Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
15
Functional Assays • If clinically relevant mechanisms of action (MOA) are known for the reference product, the functional assays should reflect these MOAs • If multiple MOAs and multiple indications, understand MOA for specific indications and CQAs for that MOA • Understand potential impact of protein modifications – Oxidation of methionine and deamidation of asparagine may impact function or immunogenicity of some proteins but not others.
• Understand how combinations of quality attributes interact to impact clinical performance • Functional assays are often highly variable, less variable assays should be developed: – High assay variability might preclude detection of small but significant differences between the products.
Guidance for industry: Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein
16
Concluding Remarks • Analytical similarity is the foundation of the biosimilar program • Analytical studies are generally more sensitive than clinical studies • Differences between proposed biosimilar product and reference product should be evaluated in terms of potential impact on activity, PK/PD, safety and immunogencity • Methods used in the analytical similarity assessment should be demonstrated to be fit for intended use
17
Concluding Remarks • The more comprehensive and robust the comparative structural and functional characterization, the stronger the scientific justification for a selective and targeted approach to animal and/or clinical testing to support a demonstration of biosimilarity
18
Guidances • Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Protein Product. April 2015 • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. April 2015 • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009. April 2015 • Draft Guidance: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants. March 2013 • Draft Guidance: Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product. May 2014 19
Thank you for your attention
20
