1. Biosimilars Where Are We Now? Where Are We Going? Sheldon Bradshaw January 24, 2008

2. Follow-on Biologics FDA’s Views on Follow-on Biologics  1. An abbreviated pathway already exists for the follow-on versions of protein products approved under Section 505 of the Food, Drug & Cosmetic Act. Section 351 of the Public Health Service Act, however, does not contain a pathway analogous to Section 505(b)(2) of the Act.  2. The idea of sameness, as that term is used in the generic drug approval process under Section 505(j) of the FD&C Act and applied to small molecule drugs, will not usually be appropriate for more structurally complex molecules of the type generally licensed as biological products under the PHS Act. The question should not be whether they are the same, but whether they are sufficiently similar.

3. Follow-on Biologics FDA’s Views on Follow-on Biologics (cont’d) 3. A finding by the FDA that a follow-on protein product is sufficiently similar that it may be approved as safe and effective is distinct from a determination that the follow-on product would be substitutable for the referenced protein product. 4. There are significant scientific challenges involved in determining whether a molecule that is not the same as the approved or licensed product is nevertheless sufficiently similar enough to that product so that the FDA’s conclusions about the safety and effectiveness of the approved or licensed product can be relied on to support approval of the follow-on product.

4. Follow-on Biologics An Abbreviated Pathway Already Exists For Some Follow-On Biologics  A biological product is defined, in relevant part, under the PHS Act as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product.”  The PHS Act definition does not include all living organisms. As a result, some natural source protein products have been regulated as drugs under the FD&C Act.  E.g., insulin, hyaluronidase, human growth hormones  Under the FD&C Act, in addition to the approval pathway involving the submission of a full new drug application, there are two abbreviated pathways for subsequent versions of already approved drug products.  505(j) – product same as the referenced product  505(b)(2) – product similar to the referenced product

5. Follow-on Biologics Under the Two Existing Pathways, Follow-On Protein Products Have Been Approved As Being Similar To, Not The Same As, The Referenced Protein Product  Compared to many small molecule drug products, proteins are usually substantially larger, more complex molecules. Due to the variability and complexity of protein molecules, current limitations of analytical methods, and the difficulties in manufacturing a consistent product, it is unlikely that, for most proteins, a manufacturer of a follow-on product could demonstrate that its product is the same as the referenced product.  As a result, Section 505(j), which is predicated on sameness, is ordinarily not available for protein products. Instead, the FDA has used the Section 505(b)(2) pathway to approve some follow-on protein products, including human growth hormones.

6. Follow-on Biologics Follow-on Biologics are Not Automatically Substitutable  A finding by the FDA that a follow-on protein product is sufficiently similar that it may be approved as safe and effective is distinct from a determination that the follow-on product would be substitutable for the referenced protein product.  To establish substitutability, a manufacturer would need to demonstrate through additional clinical trials that repeated switches from the follow-on product to the referenced product would have no negative effect on the safety of the product as a result of immunogenicity.  Lack of substitutability may mean no significant cost savings.

7. Follow-on Biologics Significant Scientific Limitations In Establishing Similarity  There are significant scientific challenges involved in determining whether one protein molecule is sufficiently similar to another molecule so that the FDA’s conclusions about the safety and effectiveness of the approved or licensed product can be relied on to support approval of the follow-on product.  Current technologies, such as peptide mapping, protein sequencing, and mass spectroscopy, enable manufacturers to determine, with certainty, the amino acid sequence of a recombinant protein. That sequence, however, is the most rudimentary characteristic of a protein.

8. Follow-on Biologics Significant Scientific Limitations In Establishing Similarity (cont’d)  Analysis of the other aspects of a protein’s structure, e.g., the folding of the protein’s amino acid chain, requires much more sophisticated technologies.  While the technology exists to demonstrate structural similarity between relatively simple protein products, the technology is not yet sufficiently advanced to allow the FDA to compare whether more complex protein products are sufficiently similar.  As a result, legislation creating an abbreviated pathway under the PHS Act analogous to the pathway established by Section 505(b)(2) shouldn’t be viewed (without significant advances in technology) as opening the floodgates to Biosimilars.

9. Thank you. Sheldon Bradshaw 202-955-1575 sbradshaw@hunton.com