Biosimilarity refers to the relationship between a proposed protein therapeutic (biologic) product and an approved reference product. Biosimilarity is similar to bioequivalence in proposed generic drugs in the small molecule world. For biologics, a proposed product may gain approval by demonstrating biosimilarity to a reference product using the pathway described in Section 351(k) of the Public Health Service Act (PHS Act).
Scientific Considerations in Demonstrating Biosimilarity
Because protein therapeutics are larger and more complex than small molecules, it can be more difficult to demonstrate structural equivalence between a proposed protein therapeutic and its reference product. Also, because the manufacturing processes for protein therapeutics are biologically based and therefore often variable, it can be difficult to replicate the processes exactly.
Biosimilarity must be demonstrated between the proposed product and a single reference product that has previously been approved by the Food and Drug Administration (FDA). Biosimilarity must be based on a direct comparison of the protein therapeutic and the reference product. No indirect or bridging comparisons are permitted. In some cases, a non-FDA approved reference product can be used if an acceptable bridge to an FDA approved therapeutic is provided.
The FDA guidance suggests that sponsors use a step-wise approach to develop and assess evidence of biosimilarity. Using this approach, sponsors will evaluate evidence of biosimilarity after each step in the process (structural/functional studies, animal studies and human studies). Once the evidence is submitted to the FDA, the agency will consider the totality of the evidence to evaluate the sponsor’s demonstration of biosimilarity.
Generally, the step-wise approach includes three steps:
1) Structural/functional studies that detail extensive structural and functional characterizations of both the proposed product and the reference product. These must include clinical relevance of any observed structural differences.
2) Animal studies that assess and compare toxicity, pharmacokinetic and pharmacodynamic (PK/PD) categories and immunogenicity in animals.
3) Human studies that assess and compare PK/PD and immunogenicity in humans.
Studies should examine multiple lots or batches of the proposed product. The following characteristics could be included in structural studies to determine biosimilarity.
- Primary structure of the protein
- Higher order structure including secondary and tertiary structure
- Post-translational modifications of the protein
- Other possible chemical modifications (e.g., deamidation)
- Intentional modifications (e.g., PEGylation)
Studies should examine multiple lots or batches of the proposed product. The following characteristics could be included in functional studies to determine biosimilarity.
- In vivo/in vitro assays
- Binding assays
- Enzyme kinetics
Animal studies typically fall into three categories:
- Animal toxicity – If there is no species in which the biologic activity of the protein product mimics the human response, animal studies may not be necessary (consult with the FDA to be sure). Animal studies should compare the effects of the proposed product with the reference product, not simply study the effects of the proposed product. If these studies demonstrate a high degree of similarity between the proposed product and the reference product, further animal studies such as safety pharmacology, reproductive toxicity and carcinogenicity may not be required.
- Animal PK, PD and PK/PD – 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. Animal PK and PD assessments will not negate the need for human PK and PD studies.
- Animal immunogenicity – Generally, animal immunogenicity assessments do not predict potential human immunogenic responses to protein products in humans. However, significant differences in the animal immune response profile may indicate that the proposed product and the reference product differ in one or more product attributes not captured by other analytical methods.
Human clinical studies
Human clinical studies are the most critical element of the biosimilar pathway. The sponsor of a proposed product must demonstrate that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity and potency.
Human clinical studies typically fall into three categories:
- Human pharmacology data – This should include a human PK study that demonstrates similar exposure between the proposed and reference products. Also, pharmacology studies will typically include a human PD study to demonstrate similarity between the effects of the proposed and reference products.
- Clinical immunogenicity – The clinical immunogenicity assessment should evaluate potential differences between the proposed product and the reference product in the incidence and severity of human immune responses. At least one clinical study that includes a comparison of the immunogenicity of the proposed product to that of the reference product is typically expected.
- Clinical safety and effectiveness – If the structural/functional, animal, and human clinical studies listed above have been completed and residual uncertainties remain about the biosimilarity of the proposed and reference products, comparative safety and effectiveness data will be necessary to support a demonstration of biosimilarity. A sponsor may provide a scientific justification if it believes that some or all of the comparisons on clinical safety and effectiveness are not necessary.
Clinical studies should be designed to establish that the proposed product has neither decreased nor increased activity compared to the reference product. The FDA also recommends that sponsors consider the use of population pharmacokinetics (PPK) to explain observed differences in safety and effectiveness that may occur due to variability in PK. And the FDA recommends that a sponsor should use endpoints and study populations that will be clinically relevant in discovering differences in safety and effectiveness between the proposed product and the reference product.
Finally, the FDA advises sponsors intending to develop biosimilar products to meet with the FDA early in the process. Sponsors should be prepared to present their product development plans and establish a schedule of milestones that will serve as landmarks for future discussions with the administration.
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- Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
- Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product
- Biosimilars: Additional 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 Guidance for Industry
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Reference Product Exclusivity for Biologic Products Filed Under Section 351(a) of the PHS Act (Aug 2014)