They are ‘living’ molecules, and there is variability among lots, even in the reference products. The key issue is whether the variability has any clinical significance. So far, it hasn’t.
January 25, 2019 Thomas Reinke
he acceptance of biosimilars has always been clouded by two words: “highly” and “similar.” The FDA’s approval criteria require a biosimilar to be highly similar to its original biologic and show “no clinically meaningful differences.” But mere similarity is not close enough for many clinicians and some patients; it makes biosimilars seem riskier than the original biologics. Patients and clinicians would be much more comfortable if biosimilars were described as “identical” in the way that the active ingredients of generic small-molecule drugs are identical to their branded counterparts.
Those worries arise from an incomplete understanding of biologics, which are genetically modified living products, generally based upon proteins. Experts say many clinicians have a misconception that biologic compounds never vary. In reality, biosimilars can never be identical to the reference product because variability is inherent in all biologics. The variability is ongoing, as early-stage chain amino acids are folded and transformed into final stage 3-D proteins. Variability also results from frequent changes or minor inconsistencies in biologic manufacturing processes.
“We’ve always had variations in biologics. It was never an issue until biosimilars came along and the question arose as to what is ‘similarity’ for a biosimilar,” says Gillian Woollett, a senior vice president at Avalere and an expert on biologics. It is widely understood that variations occur among individual production lots. And over time, variation occurs as production volume increases, new technologies are implemented, or manufacturing changes are made.
When biosimilar sponsors are applying for approval they must measure and present the variations in different lots of the original biologic. The range of variations in the characteristics of the original biologic then becomes the boundary, or “goalposts,” for acceptable variations of the biosimilar.
In September 2017, the FDA issued draft guidance with more rigorous testing and analysis of the biosimilar to achieve greater similarity with the biologic. The guidance required a biosimilar sponsor to increase its analysis of variability to 10 lots of the original biologic, an onerous and costly step since the original biologic manufacturer does not want to sell its blockbuster to a competitor. But in June 2018 the FDA withdrew that document after biosimilar developers said the new requirements were not necessary and would drive up costs that would limit access to biosimilars.
Woollett says there are four important points about variation. First, all biologics (and their biosimilars) are “living” molecules that naturally vary. Second, the FDA requires extensive, state-of-the-art scientific and clinical analysis and comparison of reference products and biosimilars. Third, variations in the biosimilar must be within the boundaries of the original biologic. And, fourth, when the variations do occur, they haven’t been clinically significant. Remicade is an example. Over its lifetime it has had scores of manufacturing and other changes, yet these changes have not had a negative impact on its efficacy or safety. “From one perspective, Remicade could now be considered to be a biosimilar to its original self,” Woollett says, “and this is just fine.”
Another reason that the “highly similar” standard is adequate for approving a biosimilar is that the analytic tools for examining biologics have improved exponentially since the reference products were first approved. Detection of even slight differences is possible. The new tools are also very capable in analyzing the critical quality attributes (CQAs) of the biosimilar and comparing them to the reference biologic’s CQAs. CQAs are unique to each biologic; they include critically important characteristics that contribute to biologic activities such as pharmacokinetics, pharmacodynamics, and immunogenicity.
The FDA’s steps to minimize the limitations surrounding “highly similar” may work for its approval process but that does not fully address the concerns of clinicians. It also does not address another limitation facing biosimilars in this country. None of the U.S. biosimilars has been approved as interchangeable with the original biologic, which would mean that pharmacists could freely substitute biosimilars for original biologics in the same way they swap generics for brand drugs. Further, the FDA has not issued the final guidance on interchangeability. Achieving that designation is likely to require elaborate, costly phase 3 clinical trials that include switching patients from the original biologic to the biosimilar. However, European and U.S. regulators have agreed that biosimilars are already interchangeable with their reference biologics for the purposes of physician prescribing. Nevertheless, both patients and clinicians must believe that, and interchangeable biosimilars would be a significant step forward for those biologics that are self-administered and could be substituted in a pharmacy.