Differences between Biosimilars (generic biologics) and Generic Drugs

Generic drugs are chemically derived products that are pharmaceutically equivalent to Reference listed drugs (innovative drugs), whereas generic biologics are products of a biologic nature that are similar to innovative biologics. It is not currently possible to demonstrate that two biologic drugs are pharmaceutically equivalent, and the regulatory approval process for generics and Biosimilars is different: Biosimilars are approved using the new drug submission pathway, while generic drugs are approved using the abbreviated new drug submission pathway.

The 1984 Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) amended the FD&C Act and created the section 505(j) generic drug approval pathway. However, this pathway does not apply to the well-characterized proteins regulated by Center for Drug Evaluation and Research (CDER). This is primarily because of the difficulty in demonstrating that two biologic drugs are identical, which arises from the variability and complexity of protein molecules, the current limitations of analytical methods and the difficulties in manufacturing a consistent product. Thus, protein products that are considered similar to an approved product are not being called "generic biologics" or "biogenerics;" rather, FDA has adopted the term "follow-on protein products" to refer to proteins and peptides intended to be sufficiently similar to an approved product to permit the applicant to rely upon certain existing scientific knowledge about the approved protein product's safety and effectiveness. There are a number of challenges for gaining approval of such follow-on protein products.

First, the ability to predict the clinical comparability of two products depends upon understanding the relationship between the protein's structural characteristics and its function, as well as the ability to demonstrate structural similarity between the follow-on protein and the reference product. Although this currently may be possible for some relatively simple protein products, technology is not yet sufficiently advanced to allow this type of comparison for more-complex protein products, and clinical testing therefore may be required. Similarly, the ability to predict the immunogenicity of a protein product, particularly more-complex proteins, is extremely limited. Therefore, some degree of clinical assessment of a new product's immunogenic potential ordinarily will be required. The extent of independent testing needed will depend upon a variety of scientific factors such as:

The indication

Whether the product is to be administered chronically

The overall assessment of the product's immunogenic potential

Whether there is the possibility of generating a cross-reaction with an important endogenous molecule

Moreover, to establish that two protein products would be substitutable, a follow-on product's sponsor would need to demonstrate through additional clinical data that repeated switches from the follow-on product to the reference product and vice versa would have no negative effect on the product/s safety and/or effectiveness as a result of immunogenicity.

Thus, sponsors may contact FDA to request advice on a case-by-case basis regarding the development of a follow-on protein product for submission in an application under section 505 of the FD&C Act. There are already several examples of proteins approved under 505(b)(1), and now under 505(b)(2), including growth hormone, calcitonin and hyaluronidase. However, formal guidance for establishing an abbreviated approval pathway for follow-on protein products is still anticipated.

The guidance document states that Biosimilars are new drugs that are not declared to be pharmaceutically or therapeutically equivalent with their reference products, and this should inform decisions regarding interchangeability and substitutability. The authority to declare two biologic products automatically substitutable by a pharmacist does not rest with the federal government.

A Biosimilar will not always have the same indications for use as its reference biologic drug. It can also be granted indications different from those of the reference biologic product if a full clinical data is submitted for those indications.