Although the FDA has offered a pathway for the interchangeable designation, a recent presentation at the AMCP Nexus meeting shone a new light on some fairly important challenges posed by the interchangeable designation.
Edward Li, PharmD, MPH, Professor of Pharmacy, University of New England, Portland, Maine, raised the well-trod issue of manufacturing drift—that over time, the reference product in particular is often subject to slight changes in structure that may be due to manufacturing changes, or other factors. This is an extremely important concept in biosimilars, as it highlights that these biologics can never be exact copies of the biologic drug. In fact, the originator biologic produced today cannot be expected to be exactly the same as the medication that was first approved 15 years ago. Although the structure may have changed subtly in these complex molecules, the clinical effects and outcomes have not materially changed. With interchangeability, Dr. Li said, “There should be no clinically meaningful differences,” in terms of safety, purity, and potency.
Once the FDA assigns the interchangeability designation to a prospective biosimilar or one that has already been marketed (and subsequent studies have provided FDA with the data to conclude that it is interchangeable with the originator), payers expect to be able to freely substitute this biosimilar for the originator at the point of dispensing—an expected boon to health plans and insurers, as well as the biosimilar maker.
However, what of the interchangeable biosimilar in the future? If manufacturing drift continues to occur over the course of time, the variation in the biosimilar and originator product will have introduced new subtle changes compared with that previously used in the approval process. “Differences may accumulate over time,” said Dr. Li, and hypothetically, these can lead to differences in safety and efficacy.” Does the biosimilar manufacturer need to prove interchangeability all over again, five years later? Is there a possibility that the biosimilar can be reduced back to the ranks of ordinary biosimilars?
These are important questions. Only after we have a biosimilar designated as interchangeable will we be able to broach this question. However, it does perhaps give the reference drug maker a line of defense in sparing loss of marketshare.