Beardsley said she was surprised to hear FDA’s Uhl describe the old OGD as “essentially chaos” in one of her slides. “Maybe that’s not what it meant,” said Beardsley, “because it seems to me that out of that chaos has come an incredibly successful program, and it is so successful, so wildly successful that we have gotten to the point where we need GDUFA because it just couldn’t be managed anymore, because it was so successful.” An interesting perspective for sure, but certainly accompanied by an aura of truth. Beardsley characterized Hatch-Waxman “as being, in some ways … so successful that GDUFA was a result of being a victim of our own success.”
BIOSIMILARS ON THE HORIZON
The Patient Protection and Affordable Care Act (ACA), signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product.
Through this new approval pathway, biological products are approved based on demonstrating they are biosimilar to, or interchangeable with, a biological product that is already approved by the FDA, and called a reference product. The FDA will require licensed biosimilar and interchangeable biological products to meet the Agency’s exacting standards of safety and efficacy.
This differs dramatically from a generic active pharmaceutical ingredient (API) and the innovator API. A generic active ingredient must demonstrate its bioavailability and bioequivalence to the innovator API. In the case of a generic and an innovator API, the chemicals are identical in all respects of their physicochemical structure and pharmacologic activity. However, where the two differ is when they are formulated as a drug product slightly different, mainly due to the fact that the innovator drug product formulation is a private manufacturing process and only known by the innovator and the FDA. This is referred to as a private specification, where the data comes from clinical trials that test the drug product on humans as well as chemistry, manufacturing and controls that are used to create the drug product. Because the innovator drug product formulation is not known by the generic manufacturer, companies can create a drug product using a systematic approach that 1) tests the drug load of the API per each dosage form, 2) the drug content of the API across the entire batch and, 3) most important, the dissolution rate of the drug substance from the formulated product (if it is a solid oral dosage unit). Consequently, the generic drug product does not require clinical trials, and why it must meet the test of bioavailability and bioequivalence.
A biosimilar may be manufactured using the same or different manufacturing process as the FDA-licensed biological product, with variations ranging from starting raw material used to make the culture media (which has high batch variability, versus chemically defined media which has minimal batch variability), starting (cellular or microbial) material, feed stock (consisting of a substance called peptones which are highly variable), feed rate, etc. the list goes on and on. However, similarity to the originator product is demonstrated by comparison of physicochemical and biological characteristics of the biosimilar to the originator product, using process analytical techniques such as mass spectroscopy, X-Ray fluorescence and capillary electrophoresis to name a few. Note that unlike generic drug products that do not go through clinical trials, a biosimilar must go through clinical tests prior to being approved. So what really is the difference and why do biosimilars have to play by a different set of rules?
There are multiple reasons why, but probably the biggest factor that has the biopharmaceutical manufacturers of the reference biologic lined up on one side and the biosimilar manufacturers lined up on the other can best be captured by the statement: “The process is the product.” The biosimilar manufacturer’s process is not the same as the biopharmaceutical manufacturer’s process and therefore, they argue, the biological products are not the same.
First, each biological process is unique because the cell lines from which the product is derived are unique. In their uniqueness, each product that is expressed by the cells that made it comes with what was referred to earlier as “clinically inactive components.” Typically these are polysaccharides and other chemical residues specific to each cell that accompany the product as it makes its way through the biological process. While not clinically significant in the way that the active biological moiety is, these accompanying chemicals are the focus of the intense debate now being played out across the biopharmaceutical landscape.
One of the biggest issues needing resolution is the control of genotoxicity from a biosimilar and its reference product. Yet a bigger ongoing debate is whether or not biologics (biosimilars and perhaps reference product) will need to be subjected to a biological performance test such that a clinically defined end point can be tested in a suitable animal model to verify safety and efficacy on every batch. Some argue that this is not necessary since the analytical profile and the clinical data from the pre-clinical and clinical programs already were shown to have demonstrated interchangeability.