FDA has issued a final guidance, Guidance for Industry: Interpreting Sameness of Monoclonal Antibody Products Under the Orphan Drug Regulations, to describe the agency’s current thinking on the criteria by which two monoclonal antibody products would be considered the same under the Orphan Drug Act and its implementing regulations. The guidance applies only to Orphan Drug provisions.
The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) amended the Public Health Service (PHS) Act and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product. "The interpretation of sameness of monoclonal antibody products in this guidance is intended only for the purposes of determining sameness under the Orphan Drug Act, and the agency does not intend to apply the considerations discussed in this guidance to determinations under the BPCI Act," said FDA in the guidance.
For purposes of the guidance, a monoclonal antibody is defined as a clonal product defined as any intact antibody, antibody fragment, conjugate, fusion protein, bispecific, or multi-specific antibody that contains a VH -VL pair, single V domain, or combinations of single V domains where the complementarity-determining regions (CDRs) form the antigen binding site. Antibody fragments or fusion proteins containing only constant region domains are not within the purview of the guidance. Although the mechanisms generating antibody diversity are the same for all antibodies whether they are immortalized as monoclonal antibodies or purified from serum as polyclonal antibodies, the guidance applies only to monoclonal antibody products.
The guidance explains that the sameness of a macromolecule for purposes of the Orphan Drug Act and its implementing regulations is based on its principal molecular structures. For the purpose of determining sameness of unmodified monoclonal antibodies under the Orphan Drug Act and its implementing regulations, FDA said it will consider the complementarity-determining regions of the heavy and light chain variable regions to be the principal molecular structural features of a monoclonal antibody product. The residues comprising the CDRs will be those defined by either the Kabat or International Immunogenetics (IMGT) systems.
Antibodies have two functional regions: the variable region, which is responsible for antigen-specific binding, and the constant region, which carries out effector functions. The variable region is divided into complementarity-determining regions (CDR1, CDR2, and CDR3) and framework regions (FR1, FR2, FR3, and FR4). Using the Kabat system, CDRs 1, 2, and 3 are delineated by amino acid positions 31-35, 50-65, and 95-102, respectively, for heavy chains and amino acid positions 24-34, 50-56, and 89-97, respectively, for light chains. Alternatively, the IMGT information system defines the positions of both heavy and light chain CDRs 1, 2, and 3 as amino acid positions 27 – 38, 56, 65, and 105 – 117, respectively. While these amino acid positions define each CDR’s boundaries, the CDR lengths can vary. CDRs create the antigen-binding pocket of the molecule through the interaction between heavy and light chain variable regions, while the framework regions provide the scaffolding on which the antigen binding pocket sits. The constant region is responsible for antibody effector functions, but has little influence on antibody specificity or affinity.
FDA intends to interpret the applicable regulatory provisions such that two monoclonal antibody drugs would be considered to be the same drug if the CDRs’ amino acid sequences were the same or if there were only minor amino acid differences between them. Other potentially important amino acid differences outside the CDRs, or differences due to glycosylation patterns or posttranslational modifications, would not necessarily cause the products to be considered to be different.
FDA intends to make determinations of this nature on a case-by-case basis. The types of information that would be useful in making such a determination include the sequence of the heavy and light chain variable regions of the product, any modifications in antibody sequence, and whether any particular residues have been established to be important for antigen binding.
Monoclonal antibody products can be conjugated by chemical methods with radionuclides, drugs, macromolecules, or other agents or can be made as fusion proteins. A monoclonal antibody fusion protein contains a VH-VL pair, where one of these chains (usually VH or CHand another protein are synthesized as a single amino-acid chain. These types of products differ from unmodified monoclonal antibodies in that they generally have an important additional functional element: the active moiety of a small molecule or the principal molecular structural feature(s) of the conjugated or fused macromolecule. FDA intends to interpret the applicable regulatory provisions such that the determination of sameness of such monoclonal antibodies will be based on a determination of sameness of the monoclonal antibody element and sameness of the functional element of the conjugated molecule. A difference in any one of these elements can result in a determination that the molecules are different. Conversely, two monoclonal antibody conjugates or fusion proteins would be determined to be the same drug if both the CDR sequences of the antibody and the functional element of the conjugated molecule were the same.