Principles of a Science-Based Principles of a Science-Based

Regulatory Pathway for Biosimilar Regulatory Pathway for Biosimilar

ProductsProducts

Kristin Van Goor

Principles of a Science-Based Principles of a Science-Based

Regulatory Pathway for Biosimilar Regulatory Pathway for Biosimilar

ProductsProducts

Kristin Van Goor

Overview

• Biosimilars

• Biologics Price Competition and Innovation Act of 2009 (BPCIA)

• FDA Draft Guidances Relating to Implementation of BPCIA

• PhRMA’s Comments on the FDA’s Draft Guidances

• Summary

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• However, both generics and biosimilars have the same dosage form, strength, and route of administration as their respective parent products for approved conditions of use

Biosimilars Are Not Generics

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= ≠ ≠

Biologics Price Competition and Innovation Act of 2009 (BPCIA)

• Created an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product

• Sponsor must show that the proposed product

• Is highly similar to a single, FDA-licensed biological reference product

• Utilizes the same mechanism(s) of action (to the extent known for the reference product) for the proposed condition(s) of use of the biosimilar that have been previously approved for the reference product

• Has the same route of administration, dosage form, and strength as the reference product

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BPCIA Established a Regulatory Pathway for Two Types of Biosimilar Products

• BPCIA created an approval pathway for biosimilar products and interchangeable biological products

• Both biosimilar and interchangeable biological products must be demonstrated to be highly similar to an innovative biological product

• BPCIA establishes a higher standard for interchangeable products

1. Biosimilar to the reference product

2. Expected to produce the same clinical result as the reference product in any given patient

3. No increased risk associated with alternating or switching between the interchangeable product and the reference product compared with using only the reference product

Must Meet 3 Criteria

Must Meet 3 Criteria

FDA Draft Guidance to Industry Relating to Implementation of BPCIA

• In February 2012, FDA issued three draft guidance documents on biosimilar product development to assist industry in developing these products

• When finalized, these guidances will represent the FDA’s current thinking on these topics

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FDA Draft Guidance: Quality Considerations in Demonstrating Biosimilarity

• Provides FDA’s views on comparative analytical studies that make up one component of the demonstration of biosimilarity to a reference product

• Analytical similarities – amino acid sequence, molecular weight, complexity, degree of heterogeneity, functional properties, impurity profiles, etc

• Extensive, robust comparative physiochemical and functional studies – biological assays, binding assays,enzyme kinetics, etc

• Comparative stability studies – multiple stress conditions,eg, high temperature, freeze/thaw, light exposure, etc

• Describes considerations for additional chemistry, manufacturing, and controls (CMC) information that may be relevant to the assessment of biosimilarity

• In addition to comparative analytical studies, an assessment of biosimilarity will generally include animal studies and clinical trials

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FDA Draft Guidance: Scientific Considerations in Demonstrating Biosimilarity

• Overview of FDA’s current thinking on demonstrating biosimilarity by using atotality-of-the-evidence approach to evaluation of scientific data

• Discusses FDA’s view on important scientific considerations including

• Stepwise approach to demonstrating biosimilarity

• Considerations of the complexities of therapeutic protein products

• General scientific principles in conducting structural and functional analyses and assays

• Animals studies, including toxicity, PK/PD, and immunogenicity studies

• Clinical studies, including pharmacology and immunogenicity studies, and general considerations for clinical safety and efficacy data

• Extrapolation of clinical data across indications

• Postmarketing safety monitoring considerations

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Draft Guidance: Biosimilars: Q&AsRegarding Implementation of the BPCIA

• Provides answers to three categories of common questions from sponsors interested in developing biosimilar products

• Biosimilarity or interchangeability

• Provisions related to a requirement to submit a Biologic License Application (BLA) for a “biological product”

• Reference product exclusivity

• Intended to promote transparency and facilitate development programs for proposed biosimilar products by addressing questions that may arise in the early stages of development

QQ AA

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FDA’s Stepwise Approach to Demonstrate Biosimilarity

• FDA proposes to use risk-based, totality-of-the-evidence approach to evaluate all available data and information

• However, FDA has the discretion to determine that an element above is unnecessary for approval

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PhRMA’s Comments on FDA’s Proposed “Stepwise” Approach

• Evaluation of biosimilars to demonstrate the absence of clinically meaningful differences should include comparative molecular evaluations, preclinical studies and clinical testing

• Seemingly small changes to a product’s structure or means of production may have unintended clinical consequences

• Such consequences may be very difficult to predict, particularly for products for which the sponsor lacks extensive manufacturing experience

• A science-based approach should include at least one comparative clinical trial of adequate size and design to establish that the proposed biosimilar product does not possess clinically meaningful differences in safety and efficacy from its reference product

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• Applicants should minimize controllable process and design differences and provide scientific justification for changes to controllable elements of the proposed biosimilar product

• Intentionally introduced changes may lead to unintended or unanticipated differences between a biosimilar and its reference product, and diminish the feasibility of an abbreviated development program

• Additional analytical, preclinical, and clinical studies may be necessary to demonstrate that a proposed biosimilar product is highly similar to its reference product

PhRMA’s Comments on Minimizing Controllable Differences

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PhRMA’s Comments on Analytical Testing

• Multiple analytical procedures that are sufficiently sensitive should be performed to detect differences between a proposed biosimilar and reference product

• Even state-of-the-art technology may not identify all differences

• Understanding the limitations of the analytical program will be essential to design appropriate preclinical and clinical testing to evaluate remaining uncertainties 13

PhRMA’s Comments on Preclinical Testing

• In vitro functional assays are important to the evaluation of biologic activity and the demonstration of biosimilarity

• In vitro studies alone are insufficient to establish that a proposed biosimilar does not possess clinically meaningful differences compared to a reference product

• Preclinical animal testing, based on sound science and performed according to ICH guidelines, also plays an important role in biosimilarity assessment

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PhRMA’s Comments on Clinical Testing

FDA guidance should recognize that:

•Clinical testing is essential to determine that there are no clinically meaningful differences between a proposed biosimilar product and its reference product

•Patient wellbeing should be ensured with immunogenicity testing and at least one comparative clinical trial to detect safety or efficacy differences

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• Each indication for which a biosimilar applicant is seeking approval will need to be supported with clinical data, unless strong scientific justification for extrapolation is provided

• Should be sufficiently rigorous to ensure that safety and efficacy can be predicted in an unstudied indication

• Applicants seeking to extrapolate data across populations within an indication should study the population(s) most sensitive to differences in safety, efficacy, and immune response

• Important to demonstrate that there are no significant differences in PK and bio-distribution

• Restricting extrapolation to indications that share the same, well-defined mechanism of action will help to ensure that the disease states are similar and well understood

PhRMA’s Comments on Extrapolation of Clinical Data

Approval AApproval A Approval BApproval B

Indication AIndication A Indication BIndication B

Clinical DataClinical Data

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PhRMA’s Comments on Immunogenicity Testing

• Biologics have the potential to evoke an immune response; even seemingly small changes to a reference biologic may significantly alter immunogenicity

• FDA should require that pre- and postmarket testing be performed, including preclinical, clinical, and postmarketing pharmacovigilance

• Increased or decreased immunogenicity relative to a reference product may have potentially severe clinical consequences

• Extrapolation of data to support another indication should include immunogenicity assessments in the patient population most sensitive to immune responses

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PhRMA’s Comments on Product Labeling

• Product labeling should include a clear statement to indicate whether the product is a biosimilar or if it is an interchangeable product

• The labels of biosimilars that are not interchangeable should clearly indicate that the products are not interchangeable with the reference product

• However, PhRMA believes that additional labeling is necessary for health professionals to make informed prescribing decisions, including:

• A description of clinical data (type and quantity) that supports the biosimilar's indications

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PhRMA’s Comments on Pharmacovigilance

• The pharmacovigilance plan for each approved biosimilar should be tailored to the benefit-risk profile of the biosimilar and the reference product

• Postmarket studies and risk evaluation and mitigation strategy (REMS) programs may be required as part of broader postmarket safety monitoring

• Undetected differences may emerge in the postmarket period due to the abbreviated premarket program, data extrapolation, or product drift

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Naming of Biosimilar Products

• Unique non-proprietary names are an essential feature of a robust system for adequately tracking adverse events

• Biosimilars and their reference products should have unique names regardless of possible later approval as an “interchangeable” product

• Necessary to prevent inappropriate substitution of a non-interchangeable product if there are both biosimilar and interchangeable products available for the same reference product

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Summary

• A biosimilar is highly similar to, but not the same as, anFDA-licensed reference biologic product

• A rigorous, science-based process for evaluating proposed biosimilars and their reference products – which includes analytical, preclinical, and clinical testing – is essential to ensure the quality, safety, and efficacy of biosimilars

• Unique non-proprietary names for biosimilar and interchangeable biological products are essential to a robust pharmacovigilance system that adequately protects patient safety

• The decision to take a particular biological medicine should be made with the oversight and guidance of a physician

• Patient well-being is the paramount concern

• Incentive for continued innovation of biologics is critical to ensure patient access to new medicines

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