In creating the 351(k) US biosimilar approval pathway, regulators had laid out a methodology in which the totality of evidence is weighted heavily by proof of structural and pharmacologic comparisons of the biosimilar to the originator product (unlike the most critical role of clinical trials in the conventional 351(a) regulatory pathway). Through the initial approvals by the Food and Drug Administration (FDA), the level of scrutiny given to these physical, pharmacodynamics, and pharmacokinetic evaluations has become clearer.
In its latest draft guidance, the FDA has added some more direction, as well as emphasizing one of the key points of the biosimilar and biologic manufacturing process. They spotlight the level of variability of one biologic. Recognizing the potential for variation in one reference biologic, the 351(k) approval criteria include comparisons versus copies of the US-licensed (rather than EU-licensed) originator product. For some approvals, bridging studies, which also test the similarity of the EU- and US-licensed biologics, have been permitted. In the guidance, “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” released earlier in September, the FDA further amplifies this requirement.
In the biosimilar development process, a prospective manufacturer must obtain samples of the biologic from the originator drug maker. However, as has been well documented, lot-to-lot differences in the biologic may well occur, though these are not expected to have implications for clinical safety or effectiveness. Proving structural similarity to this agent goes a long way to progressing down the path to approval. In its draft guidance, the FDA seems to expand its test for analytical similarity. The biosimilar manufacturer must obtain “a minimum of 10 reference product lots” and these lots “should represent the variability of the reference product,” against which the biosimilar drug is evaluated to allow for meaningful comparisons. In other words, the biosimilar manufacturer must consider the likelihood of variation in the local source of the biologic. The FDA is accepting public comments on its draft guidance for 60 days.
This has some basic implications for biosimilar manufacturers. To begin the process of engineering a biosimilar drug, they must obtain samples of the originator product from its manufacturer. This has not always been simple, as the drug maker defending its brand can delay the process or otherwise make it difficult to purchase. Some legislative proposals have been introduced to coerce the originator manufacturer to provide, in a timely manner, the samples required by the prospective biosimilar drug company (e.g. Fair Access for Safe and Timely Generics Act of 2017).