Factors to be Considered in Bio-Similar Product Development – Overview of FDA Draft Guidance

  • By: Staff Editor
  • Date: March 16, 2012
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On February 9, 2012, the U.S FDA released draft guidelines about scientific and quality considerations in bio-similar product development. These guidelines provide insight into the procedures which are required to show high similarity with an FDA-licensed biological product and provide an overview of FDA’s approach in determining bio-similarity of a biologic product.
Sponsor Responsibilities
The draft guidelines recommend that a Sponsor of a biological product should
  • Conduct extensive data collection prior to filing of a 351(k) application as data collection is the foundation in establishing the bio-similarity of the biological product
  • Follow a step-by-step approach to data collection in developing the biologic.
  • Closely follow the guidelines during the data collection process.
  • The draft guidelines are useful for the Sponsor to position their biological product for approval and for demonstrating that a proposed therapeutic protein product is bio-similar to a reference product.
Scientific Considerations in Demonstrating Bio-similarity to a Reference Product
Manufacturing process considerations:
When the manufacturing process for a marketed protein product is changed, the Sponsor should assess the effects of the change by demonstrating through various studies and prove that the change does not have an adverse effect on various aspects of the product such as:
  • Identity
  • Strength
  • Quality
  • Purity
  • Potency
Licensed reference product and other comparators
  • Sponsors should demonstrate that the proposed product is bio-similar to a single reference product by providing relevant data and scientific justification, in order to obtain licensure of a proposed product.
  • Sponsors should consider the complexities of protein products and other relevant scientific issues when a development program is designed to support a demonstration of bio- similarity.
  • Sponsors should discuss with FDA, the development program used for providing adequate scientific justification
  •  FDA has the discretion to determine that an element described in a 351(k) application is unnecessary.
Approaches in developing and assessing evidence to demonstrate bio-similarity
  • Sponsors should consider the role of animal data in assessing toxicity and immunogenicity in the process of demonstrating bio-similarity.
  • Sponsors should compare the clinical immunogenicity of the proposed and the reference product and if uncertainties are noticed, even after conducting all studies, the Sponsor should then consider comparative clinical safety and effectiveness data.
  • FDA will consider the totality of the data and information provided in the application in the process of evaluating a Sponsor’s demonstration of bio-similarity of the proposed product with the reference product.
Structural Analysis
  • The 351(k) application should include analytical studies data to demonstrate the bio-similarity of the proposed product with the reference product.
  • The FDA expects Sponsors to use advanced technology for characterization of both the products and a scientific justification may be provided for minor modifications in the process (which do not affect the safety and effectiveness of the product).
  • Sponsor should consider all relevant characteristics of the proposed product and should use appropriate methodology with sufficient sensitivity for characterization of proteins.
  • Sponsors should conduct a comprehensive structural characterization in multiple lots of the proposed product and the reference product in order to examine lot-to-lot variability.
  • If the reference product cannot be properly characterized with advanced technology, then the Sponsor should consult the FDA for guidance on whether an application for such comparator is suitable for 351(k) submission
Functional assays
  • Sponsors can make use of functional assays to provide adequate evidence that the biologic activity and potency of the proposed product is similar to that of the reference product.
  • Any limitations of the assays, if detected, while interpreting the results should be discussed with the FDA.
Animal Data
An application for bio-similar and inter-changeable biologic product should include data derived from animal studies unless specified by the FDA. This data can be used by Sponsors to demonstrate bio-similarity.
Clinical Studies – General Considerations
The Sponsor should include substantial evidence that there are no clinically relevant differences in safety, purity, and potency of the proposed product when compared with the comparator.
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Clinical Study Design:
  • An appropriate equivalence margin should be set for the biologic product through use of clinical knowledge of the reference product.
  • Sponsors should provide a scientific proof about:
    1. the proposed size product and the reference product,
    2. detection of safety signals,
    3. methods to detect clinically relevant differences in efficacy and safety between the biologic and the reference product
    4. selection of study population and endpoints
  • Sponsors should consult the Population Pharmacokinetics (PK) guidance to ensure the validity of the results.
  • Sponsors should ensure that the study population (for a study on comparative safety and effectiveness,) has characteristics (use of concomitant medications, presence of co-morbidities, disease state, intra-subject and inter-subject variability of human PK and PD etc) similar to the population studied for the licensure of the reference product.
  • FDA suggests use of a crossover design for products with a short half-life and a parallel study for products with a long half-life, in case of human PK and PD studies.
  • Sponsors should predefine and justify the criteria for PK and PD parameters for studies carried out to demonstrate bio-similarity.
  • Sponsors should provide a scientific justification about the factors which they have considered while determining the type and design of clinical trials.
Clinical immunogenicity assessment
  • At least one clinical study should include a comparison of the immunogenicity of the proposed product with the reference product.
  • Differences in incidence and immune response (those which are acceptable and do not affect safety and efficacy) should be discussed with the FDA, prior to the study.
  • Sponsors should consider using the study population and treatment regimen which is most appropriate, in the process of extrapolating immunogenicity findings of one indication to other.
  • Sponsors should predefine the immune response criteria and obtain an approval from the FDA on these criteria prior to the study.
  • The follow-up period should be appropriately determined and only those assays should be developed and validated (with respect to both the products) which are capable of sensitively detecting immune responses.
  • The proposed product and reference product should be assessed using the same assays with the same patient sera.
  • Sponsors should consult the Agency on the adequacy of assays prior to any clinical immunogenicity study.
Post-marketing safety monitoring for a proposed product should also have required mechanism to differentiate between the adverse events associated with the proposed product and those specific with the reference product.

 Additional Resources

Read the FDA guidance in full.

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