On February 9, 2012, after significant time had elapsed since the passage of the Biologics Price Competition and Innovation Act (BPCIA) of 2009, the FDA finally issued three draft guidances, which provide the agency’s current positions on important scientific and regulatory factors to be considered in the development and submission of applications to the FDA for biosimilar products. The BPCIA amended the Public Health Service Act (PHS Act) to create an approval pathway for biosimilar and interchangeable versions of reference products, establish a 12-year exclusivity period for reference products licensed under PHS Act, Section 351(a), and created a very complex, interactive mechanism wherein the innovator and biosimilar companies exchange information to identify and attempt to reach agreement on the relevant patents that are subject to challenge by the biosimilar company. The FDA’s three draft guidances provide general principles and interpretations to help guide companies in developing information to establish biosimilarity, the foundation for biosmilar applications, and then approaches to developing nonclinical and clinical data to ultimately support approvals. These guidances are general in nature — they do not discuss any specific product — and provide flexibility in the approach to develop the necessary data to support biosimilarity.
The FDA news release provides a succinct summary of the Biologics Price Competition and Innovation Act section of the Patient Protection and Affordable Care Act that was signed into law by President Obama on March 23, 2010:
[The law] created an abbreviated approval pathway ... for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with a FDA-licensed biological product.
Biological products are therapies used to treat diseases and health conditions. They include a wide variety of products such as vaccines, blood and blood components, gene therapies, tissues, and proteins. Unlike most prescription drugs made through chemical processes, biological products generally are made from human and/or animal materials.
A biosimilar is a biological product that is highly similar to an already approved biological product, notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biosimilar and the approved biological product in terms of the safety, purity, and potency.
Through this new approval pathway, biological products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biological product that is already approved by the FDA, which is called a reference product.
The Draft Guidance Documents
The draft guidance documents focus on therapeutic protein products. Interestingly, the FDA interprets “protein” as “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.” This suggests that shorter peptides will not fall under the biologics paradigm, unless they qualify as a “biological product” on some other basis, such as by being a vaccine. The FDA interprets “chemically synthesized polypeptides” (which are excluded from the definition of a “biological product”) as “any alpha amino acid polymer that 1) is made entirely by chemical synthesis and 2) is less than 100 amino acids in size.”
Draft Guidance Number One — Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
Draft guidance number one is an attempt by the FDA to provide answers to common questions companies interested in developing biosimilar products. The guidance is in a question-and-answer format to address concerns that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics. The questions and answers are grouped below in the following categories:
- Biosimilarity or interchangeability
- Provisions related to requirement to submit a BLA for a “biological product”
The questions and proposed responses address many issues that, to date, have been the subject of much speculation, but no definitive answers. These questions include:
- Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?
- Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product is licensed?
- Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closure systems) for which a reference product is licensed?
- Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?
- Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar to the reference product?
- Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposed biosimilar product in one or more additional conditions of use for which the reference product is licensed?
This draft guidance provides the FDA’s interpretation and definition of the category of “protein” (except any chemically synthesized polypeptide) in the amended definition of “biological product” in PHS Act § 351(i)(1). The FDA defines the term “protein” to mean any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size, and the term “chemically synthesized polypeptide” to mean any alpha amino acid polymer that 1) is made entirely by chemical synthesis; and 2) is less than 100 amino acids in size.” FDA further states that the agency considers “any polymer composed of 40 or fewer amino acids to be a peptide and not a protein.” Therefore, the FDA maintains that “unless a peptide otherwise meets the statutory definition of a biological product,” it will be regulated as a drug under the FDC Act.
Draft Guidance Number Two — Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
According to the FDA, this draft guidance document “is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product. … This draft guidance describes a risk-based ‘totality-of-the-evidence’ approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. As outlined in the draft guidance, FDA recommends a stepwise approach in the development of biosimilar products.” Some of the steps include:
- Extensive structural and functional characterization of the proposed product and reference product, including primary and higher order structural analysis, as well as in vitro and/or in vivo functional assays.
- If little or no differences are identified from such a comprehensive and robust comparison, “the stronger the scientific justification for a selective and targeted approach to animal and/or clinical testing to support a demonstration of biosimilarity.”
- Animal data should be considered for assessing toxicity and in some cases, immunogenicity, as well as human pharmacokinetics studies and pharmacodynamics studies. But when “residual uncertainties” about biosimilarity exist, additional clinical studies regarding safety and efficacy also may be required.
The FDA encourages extensive consultation with the agency after completion of the structural and functional analyses, and throughout development.
Draft Guidance Number Three — Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
As summarized in the FDA news release, this draft guidance document “provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product” and highlights “the importance of extensive analytical, physico-chemical and biological characterization in demonstrating that the proposed biosimilar product is highly similar to the reference product notwithstanding minor differences in clinically inactive components.” Relevant factors include:
- Expression system
- Manufacturing process
- Physicochemical properties
- Functional activities
- Receptor binding and immunochemical properties
- Characterization of the reference product and reference standards
- Characterization of the finished drug product
The guidance indicates that “information demonstrating biosimilarity based upon data derived from animal studies (including the assessment of toxicity) and a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) will be required unless the FDA determines that such data is not necessary in a specific case.”
Foley attorneys will continue to study the draft guidance and other aspects of the Biologics Price Competition and Innovation Act implementation process and will share updates and insight in future client alerts and on our PharmaPatentsBlog.
The complete draft guidance documents are available online.