During the past few years, several people and organizations have stated public positions on the feasibility of creating a
legal and regulatory framework for the facilitated approval or licensure of biologics, based on abbreviated applications (1-3).
However, public debate on follow-on biologics is difficult because of the considerable complexity of the interrelated technical,
legal, and regulatory issues. Inappropriate use of biologics terminology and misconceptions of the regulatory grounds for
safe approval of biologics result from an incomplete understanding of the basis for approval of existing biologics within
the same therapeutic category. We seek to clarify some of these issues in this article. We maintain, however, that the regulatory
process for the approval of biologics must be shaped by three cardinal principles:
- The safety of patients is of primary concern. Biologics are associated with clinical issues not shared by chemical drugs.
This necessitates appropriate clinical testing of all follow-on products.
- The approval process for any biologic should recognize the ownership and value of the innovator's intellectual property, including
data submitted for regulatory approval and licensure.
- All aspects of the regulatory framework should be supported by sound science of the same rigor as that used in the original
approval of the innovator's product.
Definitions1. What is a biologic?A biologic is a prophylactic, an in vivo diagnostic, or a therapeutic substance that can be made only by a living system and
that has a large, complex, inherently heterogeneous molecular structure.
Biologics have been defined in disparate terms, depending on the scientific, regulatory, or legal context - no comprehensive
and universally precise definition exists. For the purposes of discussion of follow-on biologics, we use the following operational
definition:
A biologic is a prophylactic, an in vivo diagnostic, or a therapeutic substance that:
- is produced only by a living system, but is not simply a metabolite,
- is stated to contain a single substance that has documented biological activity or activities,
- has a relatively large molecular weight with a high structural complexity compared with biologically active substances that
can be made by chemical synthesis (in practice, this means that biologics will seldom have molecular weights less than 5 kDa),
- is inherently heterogeneous in the molecular species present and has an impurity profile that depends critically upon the
processes used to make and test each batch,
- has activity that is often very sensitive to physical conditions (temperature, shear forces, phase) and enzymatic action,
- usually requires bioassays for batch release and stability assessment, rather than chemical tests for identity and purity.
2. What are "generic biologics"?A "generic" drug is approved by reference to a strict definition of sameness to the innovator's product. Sameness, however,
cannot be determined for biologics from different manufacturers because of the complex nature of the products and their manufacturing
processes. Therefore, "generic biologics" produced by different manufacturers cannot exist.
The phrase "generic biologics" is often used to mean products that would be copies of, and be competitive with, biologics
produced by pioneers (that is, innovative companies that developed and produced the first version of a particular product).
FDA would approve these products by reference to the clinical data generated by the pioneer. This designation is derived from
the regulatory process for approval of generic (chemical) drugs, which was created by the Hatch-Waxman amendments legislation
of 1984 (4) and is codified in §505(j) of the Food, Drug, and Cosmetic Act (FD&C) (5). However, because of major technical
differences between drugs and biologics, FDA stated that the regulatory process under §505(j) would not be appropriate for
the approval of biologics because it would result in the approval of unsafe products (6). More recently, FDA Commissioner
Mark McClellan stated that, "As a scientific matter, it is true that certain biological products, due to their inherent structural
complexity, heterogeneity, and manufacturing process, do not currently lend themselves to being copied generically" (7).
Because the "sameness" standard under §505(j) defines the correct use of the word "generic," and the properties of biologics
do not allow the standard of "sameness" to be met, there can actually be no "generic biologics."
3. What are "follow-on biologics"?"Follow-on biologics" are second and subsequent versions of biologics that are independently developed and approved after
a pioneer has developed an original version. Follow-on biologics may, or may not, be intended to be molecular copies of the
innovator's product. They do, however, depend on the same mechanism of action and are intended to be used for the same indication.
Currently, follow-on biologics are approved or licensed by submitting to FDA a full product license application - either a
New Drug Application (NDA) or a Biologic License Application (BLA). Those products that have been approved or licensed are
not copies of the original, innovative product. They resemble instead the innovative products in much the same way that members
of a class of drugs resemble each other (statins, triptans, and H2 antagonists, for example). It is possible that some follow-on
products could be approved safely on the basis of fewer or smaller efficacy studies than were required for the approval of
the pioneer. Table 1 gives some examples of innovator and follow-on biologics.
The concept of "follow-on biologics" or "generic biologics" does not include the special circumstances in which a manufacturer
may make changes to its production process without conducting new clinical trials (see the answer to Question 10 for further
explanation).
