FDA Issues Biosimilars Guidance. Now Tell Us Something We Don't Already Know.

On the same day last week that Paul Howard was discussing the Biosimilars User Fee Act, the FDA issued the first two in a series of long awaited guidance documents that will lay the groundwork for implementing the Biologics Price Competition and Innovation Act. Folks in the biotech and generic drugs industries have been anticipating the documents since at least last summer, when CDER head Janet Woodcock announced that the documents had been completed. But FDA kept putting off their release in order to fine tune its approach intended to navigate a course between the very strict process advocated by innovator biotech companies on the one hand and the comparatively less strict process advocated by generic manufacturers on the other.

The result, however, is a little underwhelming, as the draft guidance docs still leave many details of the process undefined. As this article on the Nature blog explains:

"Ultimately, the FDA provided few concrete details about what would be required, preferring to judge on a case-by-case basis. That offers flexibility, but companies may be deterred by the lack of specificity, cautions D'vorah Graeser, a patent agent at Graeser Associates International, a law firm based in Chicago and Israel. 'I don't think [the FDA] gave much guidance,' she says, noting that the first few companies to jump in are still taking on a big risk. 'They may be rejected and have to go back to the drawing board several times,' she says."

Or, as Jim Czaban at the law firm Wiley Rein explains, "the Guidances are very small baby steps that leave many important questions unanswered."

Essentially, the guidance on Scientific Considerations in Demonstrating Biosimilarity to a Reference Product tells us that "FDA intends to consider the totality of the evidence provided by a sponsor to support a demonstration of biosimilarity, and recommends that sponsors use a stepwise approach in their development of biosimilar products." This stepwise approach "can include a comparison of the proposed product and the reference product with respect to structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness." And, at each step, manufacturers should examine "the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to try to address that uncertainty."

Un-huh! We had to wait nearly two years for this?

On the one hand, the supreme amount of flexibility the FDA approach allows is a plus. We know, for example, that even the simplest biologics are orders of magnitude more complicated than small molecule drugs, and that there will be a huge amount of variation in manufacturers' ability to replicate approved biological products with anything approaching perfect fidelity. So, tying the process down to a simple, detailed flowchart in which all the possible variations are accounted for would be difficult, if not impossible.

Still, the European Medicines Agency (which, admittedly had a few years' head start on the FDA) has issued a larger and more comprehensive set of rather more detailed guidance that makes it easier for manufacturers to know what they need to do to secure approval. FDA may well be able to follow in EMEA's footsteps and eventually issue its own more detailed proposals. But why did it take so long to get a set of documents from FDA that tell us essentially nothing we did not already know?

After all, FDA has been slowly but surely approving a very small number of biosimilar products since 1998. [No, that's not a typo. The correct date is 1998.] Through a quirk of FDA history that I described in this paper, a small number of follow-on biological products (primarily hormones) have been eligible for approval through an abbreviated regulatory pathway created in 1984 along with the "true generic" pathway. Examples of products approved this way include GlucaGen in 1998, Follistim in 2002, Hylenex and Fortical in 2005, and Omnitrope in 2006.

The abbreviated 505(b)(2) process (named for the section of the Food, Drug, and Cosmetic Act in which it is described) involves a great deal of analytical data from laboratory and animal testing, supported by somewhat less clinical testing than is required for innovator products. Section 505(b)(2) wasn't designed with follow-on biological products in mind, but its approach is essentially the process envisioned under the Biologics Price Competition and Innovation Act. The problem with these new guidance documents is that they convey practically no useful information about the process that could not have been learned merely from observing how the approval of those other biosimilar products had been managed.

Don't get me wrong, it IS nice to see these documents finally in print. But if the agency is serious about creating a reasonable, transparent, and predictable pathway for approving biosimilar products, it's going to have to do better than this.

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