Table 5 shows the products classified by expression system and by filing pathway. Although mammalian cell culture production
methods were the most common (about 45 percent of the total), microbial systems (yeast, and especially bacterial) were nearly
as prevalent (39 percent of the total). Only one natural extract (aprotinin, derived from bovine lung) was found among the
final data set. With the exception of the target products produced synthetically, which were filed only through the NDA pathway,
there was substantial overlap between the expression systems used for NDA and BLA products.
Table 5. Breakdown of products by pathway and expression system
From this analysis, it is clear that potential biogeneric target products span a wide range of characteristics ranging from
very small homogeneous peptides to large heterogeneous glycoproteins. Presented with this information, there is little point
in trying to create an artificial boundary between products that are small enough to call peptides and larger compounds that
might be called proteins. As protein size increases, complexity tends to follow, though not in any direct way, and certainly
not in any discontinuous way that would warrant a peptide–protein boundary of sorts. Therefore, the regulatory requirements
should be graded similarly to reflect product complexity, without any sharp lines of demarcation. Likewise, while some may
argue that the smallest entries in Table 2a should not be called proteins, they are, nevertheless, included for completeness,
as well as to illustrate the broad continuum of target products available.
Although more of the target products were approved as BLAs, a substantial number (45 percent) were approved as NDAs. Thus,
even if the regulatory pathway for the registration of biogeneric mimics of BLA target products is not entirely clear at this
time, there are still numerous protein products approved as NDAs. Biogeneric firms can target those knowing that a clear regulatory
There is substantial overlap between the characteristics of target products approved as NDAs and the characteristics of those
approved as BLAs. The notion that the products that were licensed as BLAs somehow fit the statutory definition of "biological
product" any better than many of the target products approved as NDAs is puzzling. All of the products in this analysis clearly
fit the broader FD&C Act definition of "drug." This overlap between target products registered through the two pathways also
argues in favor of a graded scientific approach to the development of biogeneric mimics of both types of target products rather
than two distinct, dissimilar scientific approaches.
There are two groups of products that could conceivably be targeted by biogeneric companies, but which have not been part
of the mainstream discussion of biogenerics. These two groups are, first, what could be termed "classical" biological products
(i.e., those less well characterized products that clearly fit the literal PHSA definition and remain under CBER's jurisdiction,
such as vaccines, toxins, antitoxins, blood products, etc.), and second, some highly specialized protein products not registered
via the NDA or BLA pathways (such as wound care products). Because these two groups of products have not undergone substantial
public discussion, guidances may take some time to develop. Therefore, the most urgent need is to issue guidances that address
the development of biogeneric mimics of well-characterized protein and peptide products such as those listed in Table 2.
Although only a few of these products have as yet received Orange Book A ratings, (and are thus, deemed to be fully interchangeable
with other products), the technology exists to establish therapeutic equivalence and/or comparability between biogenerics
and the corresponding target protein products listed in Table 2.