Summary of FDA Draft Guidance on BPCIA

On February 9, 2012, the U.S. Food and Drug Administration (“FDA”) released three draft guidance documents related to implementation of the Biologics Price Control and Innovation Act of 2009 (“BPCIA”):

1. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (“Q & A”);
2. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (“Scientific Considerations”); and
3. Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product (“Quality Considerations”).

Comments regarding the draft guidance should be submitted to the FDA by April 16, 2012, before the Agency begins finalizing the guidance. 77 Fed. Reg. 8883-86. This article outlines the first draft guidance documents that the FDA has issued regarding the implementation of the BPCIA.

I. Practice Points

These are the first draft guidance documents that the FDA has issued regarding the implementation of the BPCIA. While they are limited in scope in terms of the product class (proteins) and type of follow-on biologic (biosimilar rather than interchangeable) they address, these guidance documents illuminate some useful practice points.

1. The release of these guidance documents indicates that the FDA is working toward implementing the BPCIA and highlights the fact that biosimilar filings and approvals are on the horizon.
2. In view of the approaching advent of biosimilar applications, branded biologics companies need to review the patent protection for their current biological products, as well as biological products currently in development. The FDA’s focus on protein products suggests that priority attention should be given to these products.
3. In reviewing their patent coverage, branded biologics companies should identify potential “design arounds” to avoid infringement. Biosimiliar applicants will likely target “minor differences in clinically inactive components” and minor structural differences as strategies to maintain biosimilarity while avoiding infringement.
4. The fact that some degree of variability may be compatible with biosimilarity highlights the importance of the use of functional claim language.
5. Given the FDA’s focus on detailed structural and functional characterization in assessing biosimilarity, branded companies should consider additional patent protection beyond primary amino acid sequence, including higher order structures, post-translational modifications, as well as other potential variants and intentional chemical modifications.
6. The FDA’s recognition of the potential for the production process to introduce unacceptable variability in proposed protein products highlights the value of claims directed to methods for preparing, purifying, or manufacturing the biological product.

II. Scope of Draft Guidance

A. Biosimilarity (Not Interchangeability)

• Guidance documents address scientific and quality considerations in demonstrating biosimilarity.
• “At this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application. . . FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Q & A at 11-12 (emphasis added).

B. Therapeutic Protein Products

• “[G]uidance applies specifically to therapeutic protein products, [but] the general scientific principles may be informative for the development of other proteins, such as in vivo protein diagnostic products.” Quality Considerations at 4.

C. Applications Under § 351(k) of the PHS Act

• “This guidance applies to applications submitted under section 351(k) of the PHS [(Public Health Service)] 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 [(Food, Drug, and Cosmetic)] 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.” Scientific Considerations at 3 (footnote omitted).

III. Relevant Definitions

A. Protein

• “[A]ny alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.” Q & A at 13 (emphasis added).
• “Compounds greater than 40 amino acids in size will be scrutinized to determine whether they are related to a natural peptide of shorter length and, if so, whether the additional amino acids raise any concerns about the risk/benefit profile of the product.” Q & A at 13.

B. Chemically Synthesized Polypeptide

• “[A]ny alpha amino acid polymer that (1) is made entirely by chemical synthesis; and (2) is less than 100 amino acids in size.” Q & A at 13.
  • “A chemically synthesized polypeptide, as defined, is not a ‘biological product’ and will be regulated as a drug under the FD&C Act unless the polypeptide otherwise meets the statutory definition of a ‘biological product.’” Q & A at 13 (emphasis added).
  • “Chemically synthesized compounds greater than 99 amino acids in size will be scrutinized to determine whether they are related to a natural peptide of shorter length and, if so, whether the additional amino acids raise any concerns about the risk/benefit profile of the product.” Q & A at 13.

C. Peptide

• “FDA considers any polymer composed of 40 or fewer amino acids to be a peptide and not a protein.” Q & A at 13.
• “[U]nless a peptide otherwise meets the statutory definition of a ‘biological product’ (e.g., a peptide vaccine), it will be regulated as a drug under the FD&C Act.” Q & A at 13-14 (emphasis added).

IV. Communication with FDA Is Essential 

• “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 appropriate scientific justifications will facilitate biosimilar development.” Scientific Considerations at 21.
• “FDA encourages sponsors to consult extensively with the Agency after completion of comparative structural and functional analysis (before finalizing the clinical program), and throughout development as needed.” Scientific Considerations at 7-8.

V. General Approaches to Demonstrating and Assessing Evidence to Demonstrate Biosimilarity

A. Stepwise Approach to Demonstrate 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.” Scientific Considerations at 7.

    1.   Structural and Functional Characterization

• “The stepwise approach should start with extensive structural and functional characterization of both the proposed product and the reference product . . .” Scientific Considerations at 7 (emphasis added).
  • “Generally, such tests include the following comparisons of the drug substances of the proposed product and reference product:
    • Primary structures, such as amino acid sequence
    • Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation)
    • Enzymatic post-translational modifications, such as glycosylation and phosphorylation
    • Other potential variants, such as protein deamidation and oxidation
    • Intentional chemical modifications, such as PEGylation sites and characteristics.” Scientific Considerations at 9.

    2.   Animal Data

• “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 . . .” Scientific Considerations at 7.

                      a. 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. Animal toxicity studies are generally not useful if there is no animal species that can provide pharmacologically relevant data for the protein product . . .” Scientific Considerations at 11.

                       b. Animal Pharmacokinetic (PK) and Pharmacodynamic (PD) 
                           Measures

• “Under certain circumstances, a single-dose study in animals comparing the proposed product and reference product using PK and PD measures may contribute to the totality of evidence that supports a demonstration of biosimilarity.” Scientific Considerations at 12.

                      c. Animal Immunogenicity Studies

• “Animal immunogenicity assessments generally do not predict potential immunogenic 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-protein antibody responses in animals may provide useful information relevant to patient safety.” Scientific Considerations at 12.

    3.    Human Studies

• “In general, the clinical program for a 351(k) application must include a clinical study or studies (including an 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, as set forth in the PHS Act. The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies.” Scientific Considerations at 12 (emphasis added) (footnote omitted).

                      a. PK/PD Studies

• “The sponsor should then conduct comparative human PK studies, and PD studies if there is a clinically relevant PD measure, in an appropriate study population . . .” Scientific Considerations at 7.
  • “We have determined that both PK and PD studies . . . generally will be expected to establish biosimilarity, unless a sponsor can scientifically justify that an element is unnecessary.” Scientific Considerations at 13 (emphasis added).

                      b. Clinical Immunogenicity Studies

• “Sponsors should then compare the clinical immunogenicity of the two products . . .” Scientific Considerations at 7.
  • “[A]t least one clinical study that includes a comparison of the immunogenicity of the proposed product to that of the reference product will generally be expected.” Scientific Considerations at 14 (emphasis added).
• “As a scientific matter, it is expected that the following will be assessed in clinical immunogenicity studies:
  • Binding antibody: titer, specificity, relevant isotype distribution, time course of development, persistence, disappearance, and association with clinical sequelae
  • Neutralizing antibody: all of the above, plus neutralizing capacity to all relevant functions (e.g., uptake and catalytic activity, neutralization for replacement enzyme therapeutics).” Scientific Considerations at 15.

                      c. Comparative Clinical Safety and Effectiveness Data

• “If there are residual uncertainties about the biosimilarity of the two products after conducting structural and functional studies, animal toxicity studies, human PK and PD studies, and clinical immunogenicity assessment, the sponsor should then consider what comparative clinical safety and effectiveness data may be adequate . . . .” Scientific Considerations at 7.
• “Clinical studies should be designed such that they can demonstrate that the proposed product has neither decreased nor increased activity compared to the reference product. Decreased activity ordinarily would preclude licensure of a proposed product. Increased activity might be associated with more adverse effects, or might suggest that the proposed product should be treated as an entirely different product with superior efficacy, in which case the appropriate licensure pathway would be section 351(a) of the PHS Act.” Scientific Considerations at 17 (emphasis added).
• “The following are examples of factors that may influence the type and extent of the comparative clinical safety and effectiveness data needed.

1. 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
2. The extent to which differences in structure, function and nonclinical pharmacology and toxicology predict differences in clinical outcomes, as well as the degree of understanding of the MOA of the reference product and disease pathology
3. The extent to which human PK or PD predicts clinical outcomes (e.g., PD measures known to be clinically relevant to effectiveness)
4. 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)
5. The extent of any clinical experience with the proposed product.” Scientific Considerations at 16 (emphasis added).

B. Risk-based Totality of the Evidence in Assessing Biosimilarity

• “FDA intends to use a risk-based, totality-of-the evidence approach to evaluate all available data and information submitted in support of the biosimilarity of the proposed product.” Scientific Considerations at 8.

               1.    Some Minor Structural/Formulation Differences May Be 
                      Compatible with a Finding of Biosimilarity

• “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.” Scientific Considerations at 8 (emphasis added).
  • “[D]ifferences in certain post-translational modifications, or differences in certain excipients (e.g., human serum albumin)” may be compatible with a finding of biosimilarity. Scientific Considerations at 8 (emphasis added).
  • “FDA expects that the expression construct for a proposed product will encode the same primary amino acid sequence as the reference product. However, minor modifications such as N- or C-terminal truncations that will not affect safety and effectiveness may be justified and should be explained by the sponsor.” Scientific Considerations at 9 (emphasis added).
• “Clinically meaningful differences could include a difference in the expected range of safety, purity, and potency of the proposed and reference products.” Scientific Considerations at 8 (emphasis added).
• Non-clinically meaningful differences could include “slight differences in rates of occurrence of adverse events between the two products.” Scientific Considerations at 8.

               2.    Delivery Device/Container Closure Differences May Be 
                      Compatible with a Finding of Biosimilarity

• “[S]ome design differences in the delivery device or container closure system used with the proposed biosimilar product may be acceptable. It may be possible, for example, for an applicant to obtain licensure of a proposed biosimilar product in a pre-filled syringe or in an auto-injector device (which are considered the same ‘injectable’ dosage form), even if the reference product is licensed in a vial presentation . . .” Q & A at 5.
• “However, a prospective biosimilar applicant will not be able to obtain licensure under section 351(k) for its product when a design difference in the delivery device or container closure system results in:
  • a clinically meaningful difference between the proposed product and the reference product in terms of safety, purity, and potency;
  • a different route of administration or dosage form; or
  • a condition of use for which the reference product has not been previously approved;
  • or otherwise does not meet the standard for biosimilarity.” Q & A at 5.

C. Product-by-Product Assessment

• “The type and amount of analyses and testing that will be sufficient to demonstrate biosimilarity will be determined on a product-specific basis.” Scientific Considerations at 8 (emphasis added).
• “[M]any 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.” Scientific Considerations at 21 (emphasis added).

VI. Factors for Manufacturers to Consider in Assessing Whether Products Are Highly Similar

A. Expression System

• “Differences between the chosen expression system of the proposed biosimilar product and that of the reference product should be carefully considered because the type of expression system and host cell will significantly affect the types of process- and product-related substances and impurities (including potential adventitious agents) that may be present in the protein product.” Quality Considerations at 9.

B. Manufacturing Process

• “A type II Drug Master File (DMF) would not be acceptable for a 351(k) application because, as with 351(a) BLAs, the license holder needs to have knowledge of and control over the manufacturing process for the biological product. Other types of contract manufacturing arrangements can be considered if the applicant does not intend to manufacture the product for licensure.” Quality Considerations at 10 (footnote omitted).

C. Assessment of Physiochemical Properties

• “[I]t will be important to understand the heterogeneity of the proposed biosimilar product and the reference product (e.g., the nature, location, and levels of glycosylation) and the ranges of variability of different isoforms, including those that result from post-translational modifications.” Quality Considerations at 10.

D. Functional Activities

• “Depending on the structural complexity of the protein and available analytical technology, the physicochemical analysis may be unable to confirm the integrity of the higher order structures. Instead, the integrity of such structures can be inferred from the product’s biological activity.” Quality Considerations at 11.

E. Receptor Binding and Immunochemical Properties

• “When binding or immunochemical properties are part of the activity attributed to the protein product, analytical tests should be performed to characterize the product in terms of these specific properties . . . .” Quality Considerations at 12.

F. Impurities

• “The applicant should characterize, identify, and quantify impurities (product- and process-related as defined in ICH Q6B) in the proposed biosimilar product and the reference product.” Quality Considerations at 12.

G. Reference Product and Reference Standards

• “A thorough physicochemical and biological assessment of the reference product should provide a base of information from which to develop the proposed biosimilar product and justify reliance on certain existing scientific knowledge about the reference product.” Quality Considerations at 13.

H. Finished Drug Product

• “Product characterization studies should be performed on the most downstream intermediate best suited for the analytical procedures used.” Quality Considerations at 14.

I. Stability

• “An appropriate physicochemical and functional comparison of the stability of the proposed biosimilar product with that of the reference product should be initiated.” Quality Considerations at 15.

VII. Other Issues

A. Reliance on Non-U.S. Licensed Product Comparisons

• “In general, a sponsor needs to provide information to demonstrate biosimilarity based on data directly comparing the proposed protein product with the reference product. Analytical studies intended to support a demonstration of biosimilarity for purposes of section 351(k) of the PHS Act must as a scientific matter include an adequate comparison to the reference product licensed under section 351(a). However, under certain circumstances, a sponsor may seek to use data derived from animal or clinical studies comparing a proposed protein product with a non U.S. licensed 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 this comparative data to an assessment of biosimilarity and to establish an acceptable bridge to the U.S. licensed reference product.” Quality Considerations at 9.

B. Extrapolating to Other 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 sufficient to demonstrate safety, purity, and potency in an appropriate condition of use, the potential exists for the proposed product to be licensed for one or more additional conditions of use for which the reference product is licensed. However, the sponsor will 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.” Scientific Considerations at 19; Q & A at 9.

C. Publicly Available Information

• “‘Publicly-available information’ in this context generally includes the types of information found in the ‘action package’ for a BLA (see section 505(1)(2)(C) of the FD&C Act). However, FDA notes that submission of publicly available information composed of less than the action package for the reference product BLA will generally not be considered a bar to submission or approval of an acceptable 351(k) application.” Q & A at 11.
• “FDA intends to post on the Agency’s Web site publicly available information regarding FDA’s previous determination that certain biological products are safe, pure, and potent in order to facilitate biosimilar development programs and submission of 351(k) applications. We note, however, that the publicly available information posted by FDA in this context does not necessarily include all of the information that would otherwise be disclosable in response to a Freedom of Information Act request.” Q & A at 11.