It’s true I’ve often been critical of the rules, positions or actions taken by the Food and Drug Administration (FDA). However, the stand the Agency is taking on Biosimilars is something I heartily support. There’s been much press over how the European Medicines Agency (EMA) has brought prices down overseas through simpler rules for Biosimilars as well as reports leveling accusations that the FDA’s stance is “protectionism.” The EMA argues that Biosimilars should be treated as simple generics, while the FDA contends that biologics cannot be considered as simple chemicals, easily tested. (The heparin “incident” a few years back demonstrates that biologics are not either simply or easily characterized.) In this case, the FDA is choosing the side of science (and safety) over politics. In light of the fact that a number of approved drug substances are found to be harmful when used over a long period, the Agency seems less willing to accept biological products as “safe and effective” based on a few short-term clinical studies.
At the moment, a newly introduced generic drug product does not need to be tested in clinical trials to be approved. The new dosage form only need meet “release performance tests” such as dissolution, assay, etc. While synthetic chemical processes are somewhat limited by chemical rules, biologics can vary, beginning with the raw material used to make the culture media (with expected high batch variability versus chemicals with well-defined characteristics), starting cellular or microbial material, feed stock peptones feed rate, batch size, and other variations.
While the major output of these biochemical processes is characterized by both animal testing and physical/chemical tests (e.g., X-ray diffraction), they are also required to undergo clinical testing, unlike small molecule generics. Why is that so? There are many reasons why they may be considered “different,” but the statement, “the process is the product” sums up the Agency’s reasoning.
Each biosimilar manufacturer’s process is likely different from the innovator’s process (they are patent-protected after all) and thus, the FDA suspects that the biological products are not necessarily the same and, therefore, may harbor hidden dangers. The Agency knows that each biological process is unique and (bio) chemically different from the innovator’s process, encompassing specific and largely different routes of biosynthesis. As such, each product expressed by these “different” cell lines comes with potentially widely different trace “clinically inactive components.”
These components could include polysaccharides or other residues specific to the particular cell and may accompany the product through the biological process and clean-up process. These “strangers” are seldom considered as clinically significant as active biological moiety because they are one, a very small component and two, are “likely” cleaned out during purification. But these extra chemicals are the point of the major debate being carried out in the Biopharma industry. The biggest issue (as per the FDA) to be resolved is the control of genotoxicity from a biosimilar and its reference product.
A bigger debate continues on whether or not biologics need to be subjected to biological performance tests, such that a clinically defined end point can be tested via suitable animal model to demonstrate safety and efficacy on every batch, raising the production costs of these “money-saving” medicines. Producers and regulators argue that this is unnecessary since the analytical profile and the clinical data from the pre-clinical and clinical programs already demonstrate interchangeability.
This point could be challenged by the fact that some tests need to be run on established small molecule products from time to time. The movement in the industry (as per PAT, QbD, ICH Q8, 9, 10, and 11, and the Process Validation Guidance) is toward more and more, not less testing, so I feel the Agency is on the side of the “angels” in this issue. We may not need to do all the extra testing, but, if we’re wrong on this issue, the results could be disastrous.