The 1980s saw emergence of generic drugs in the US that has saved hundreds of billions of dollars to patients and improved accessibility to drugs. The statute that created this abbreviated pathway for approval of generic drugs stated that therapeutic equivalence means same concentration of active drug at the site of action, an evaluation that was neither possible nor practical. So, the FDA recommended using blood level studies as a surrogate test demonstrating bioequivalence. Later, FDA agreed to remove this requirement, the biowaiver, for drugs that are highly soluble. I am now introducing a new concept--thermodynamic equivalence, in lieu of bioequivalence testing.
Thermodynamic equivalence (TE) is by another name, the “basis” for biowaivers, in place for years. For a highly soluble drug, the barrier Delta G is small, overcoming any differences between two products. I am expanding this concept to drugs subject to blood level studies. Why would a drug product fail in BE, when it has the same chemical entity? It is inevitably the release profile at the site of delivery, since this point forward, all factors apply equally. Dissolution rate testing is the best example of measuring chemical potential and while it works well for products with small DG, it fails for drugs that are not released instantly. Creating a matrix of dissolution profiles, independent of any physiologic conditions, such as a 3x3 matrix, may be able to discern the differences not picked up by current dissolution testing. This is not a theoretical suggestion, it is already in practice, such as in the comparison of biologics, where a different approach to matching CQAs allows FDA to approve them without requiring phase 3 studies. The industry should attempt now to use this concept to request biowaivers, particularly for highly complex product designs to reduce cost and time to market.
It was after years of similar discussion that the FDA agreed to look into the concept of TE that can be continually used to assure life-cycle therapeutic equivalence. The FDA has now opened up this discussion agreeing that the concept needs to be explored further.
From writing the suggestions for the first guidance for bioequivalence to biosimilarity testing, I have been engaged with FDA and I am now confident that we are entering a phase of scientific reality that can bring another phase of reduced burden on development of drugs.