The U.S. Food and Drug Administration (FDA) has published its final guidance on its interpretation of monoclonal antibodies (mAbs) sameness under orphan drug regulations. An Orphan Drug designation is highly sought after by drug sponsors as it awards seven years of marketing exclusivity.
Under Orphan drug regulations, monoclonal antibody drugs are subject to a unique analysis. To guide companies developing mAbs, the agency explains, “A drug containing macromolecules is the same as another, previously approved drug if it ‘contains the same principal molecular structural features (but not necessarily all of the same structural features) and is intended for the same use as a previously approved drug…’”.
In addition, “…if the only differences in structure between them were due to posttranslational events or infidelity of translation or transcription or were minor differences in amino acid sequence,” two protein drugs would be considered the same. However, the FDA says that additional guidance will be necessary in order to demonstrate how two monoclonal antibody drugs would ultimately be considered the same drug. The FDA states, “For monoclonal antibody drugs, these definitions lay the groundwork for the determination of sameness, but, because of the unique considerations applicable to antibody molecules, additional guidance as to how two monoclonal antibody drugs would be considered to be the same drug under the Orphan Drug regulations is needed.”
The FDA said it intends to make determinations on a case-by-case basis. Information that would be used to determine sameness include sequence of heavy and light chain variable regions of the product, any modifications in antibody sequence, and any particular residues established to be crucial for antigen binding.
The agency stated in its industry guidance paper, “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 detected difference in any of the elements could lead to the determination that the molecules are different. The FDA said it would determine two monoclonal antibody conjugates or fusion proteins if both the antibody CDR sequences and functional element of the conjugated molecule were the same.