We note with interest FDA’s recently released Guidance for Industry: Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations (April 2014). The guidance summarizes the Agency’s approach to considering sameness for two monoclonal antibody formulations for the same clinical indication, a key feature for determining orphan drug exclusivity protection. The 7-year period of exclusivity is a significant economic driver for developing products that would not, based on the definition of an orphan indication, be marketed to more than a small patient population. Once a drug is given orphan status, a follow-on monoclonal antibody product that precisely targets the antigen of the innovator can only be approved if it is deemed clinically superior.
The guidance is relatively technical, given the high degree of complexity of monoclonal antibodies. As would be expected, the Agency identified the hypervariable domain complementarity-determining regions (CDRs) responsible for antigen binding as the principal structural component of the antibody for determination of sameness. This approach is scientifically reasonable when considering the potency and specificity of antigen binding by an antibody molecule, i.e., assessing critical efficacy features for a therapeutic antibody. Enough detail is provided in the guidance with regard to antibody CDR structural features, including the precise definition of key amino acid regions of the antibody heavy and light chains, to generally summarize FDA’s thinking despite the explicit caveat that “FDA intends to make determinations of this nature on a case-by-case basis”.
Whereas the definition of CDR structural features as critical for determinations of sameness is a helpful key message, what we find equally of interest is the definition of structural features of antibodies that appear not to be particularly critical in FDA’s thinking for determination of sameness. In particular, the antibody constant region is identified as a component of the macromolecule which is less important for determination of sameness. Near the end of the guidance is discussion which acknowledges the possibility that sponsors could engineer some changes in constant region or humanization framework amino acids which would not necessarily cause the follow-on molecule to be considered different from the innovator antibody. We consider this a second key message from the guidance. However, while it is implied that sequence differences in these regions might, or might not, impact the determination of sameness, the guidance does not discuss how any such differences should be evaluated.
We find this second message of interest because the constant region contains the Fc region of the antibody, an area known to have great biological function independent of binding of the antibody to antigen. These functions prominently include activation of the complement system and activation of effector blood cells of the immune system. In some situations these functions contribute to efficacy, e.g., in the case of antibodies that function as cytotoxic or anti-inflammatory agents. A pertinent example is from the EMA’s approval of a biosimilar version of infliximab (biosimilar to Remicade for rheumatoid arthritis and other inflammatory disorders), in which secondary clinical endpoints which were evaluated in comparative clinical trials included binding affinities for complement proteins and leukocyte Fc receptors as well as leukocyte cytotoxicity assays.
However, the Fc functions also can be important features of an antibody’s toxicity, and many monoclonal antibodies have been specifically engineered in this area to minimize effector functions in an effort to improve the product’s safety profile. Therefore, we find it interesting that two antibody products might differ in Fc structures and the accompanying effector functions, yet be considered the same with regard to orphan drug sameness determination. A follow-on antibody preparation may in fact be improved compared to another with respect to effector functions yet not be deemed clinically superior, and therefore bypass orphan exclusivity. On the other hand, the opposite situation would also be possible. A sponsor might improve a follow-on antibody preparation with respect to the effector functions when compared to the innovator antibody and still be able to bypass orphan exclusivity under this guidance, without being required to exhibit clinical superiority.
We expect that the evaluation of engineered changes in the Fc region of monoclonal antibodies will prove to be an important facet for FDA’s consideration of follow-on monoclonal antibodies developed under the Orphan Drug regulations. We expect that sponsors will need to carefully consider the impact of changes in the Fc region of the molecule, and be able to provide convincing arguments, with supporting data, that any such differences from the innovator antibody have no functional consequences. Athough not discussed in the guidance, we believe that to avoid clinical investigations related to effector function safety endpoints sponsors will need to generate comparative in vitro data using models that are sufficiently sensitive.
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