This FD&C Act definition of drug, particularly at sections B and C above, is obviously quite broad and applicable to virtually
any conceivable pharmaceutical product. Biogeneric mimics of target protein products approved as NDAs have a number of clear,
well-established regulatory paths to follow, including potentially, the 505(b)(1) or full NDA pathway, the 505(b)(2) or limited
NDA pathway, or the 505(j) or ANDA (Abbreviated New Drug Application) pathway.4,5,6 Of these three potential pathways, the most often suggested for biogenerics is the 505(b)(2) pathway, which involves reliance,
in part, upon data for which the applicant has no right of reference. What is meant by the regulatory term "no right of reference"
is simply that the applicant does not own the data or have written authorization from the data's owner to use the data. The
505(b)(2) pathway thus allows an applicant to rely on data from another party that may not be connected in any way with the
applicant or that may not want to cooperate with the applicant (e.g., the target product manufacturer). The former situation
can arise when an applicant relies on a published scientific article for which the author of the article has no connection
with the applicant. The latter situation can arise when an applicant relies on the fact that the target product was approved
as safe and effective. This last point is the underlying principle by which generic drugs are approved — showing that the
generic drug is equivalent to an approved brand drug and so possesses all of the safety and efficacy properties proved in
the original studies that were submitted by the brand manufacturer.
The Public Health Services Act (PHSA),7 (later amended by the Food and Drug Administration Modernization Act of 1997 [FDAMA]) provides an alternative regulatory
pathway for pharmaceuticals classified as biological products.8 Such products are licensed, but not approved. The PHSA defines "biological product" as follows:
"In this section, the term 'biological product' means a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood
component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other
trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings."9
This definition is clearly much narrower than the definition of drug in the FD&C Act. Therefore, biological products are also
drugs, but not all drugs are biological products. In other words, the universe of all biological products is a subset of the
universe of all drugs.
Looking naively at these definitions and not knowing anything about the manner in which the products are actually registered
in the US, most people would instinctively classify recombinant protein products that are not vaccines, toxins, or antitoxins,
as drugs, rather than biological products. However, the FDA actually classified some recombinant protein products as drugs
and others as biological products. It did this by using administrative rulemaking to create a broad interpretation of the
definition of biological product in the PHS Act.
"600.3(h). Biological product means any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the
prevention, treatment or cure of diseases or injuries of man:
1. A virus is interpreted to be a product containing the minute living cause of an infectious disease and includes but
is not limited to filterable viruses, bacteria, rickettsia, fungi, and protozoa.
2. A therapeutic serum is a product obtained from blood by removing the clot or clot components and the blood cells.
3. A toxin is a product containing a soluble substance poisonous to laboratory animals or to man in doses of 1 milliliter
or less (or equivalent in weight) of the product, and having the property, following the injection of non-fatal doses into
an animal, of causing to be produced therein another soluble substance which specifically neutralizes the poisonous substance
and which is demonstrable in the serum of the animal thus immunized.
4. An antitoxin is a product containing the soluble substance in serum or other body fluid of an immunized animal, which
specifically neutralizes the toxin against which the animal is immune.
5. A product is analogous:
(i) To a virus if prepared from or with a virus or agent actually or potentially infectious, without regard to the degree
of virulence or toxicogenicity of the specific strain used.
(ii) To a therapeutic serum, if composed of whole blood or plasma or containing some organic constituent or product other
than a hormone or an amino acid, derived from whole blood, plasma, or serum.
(iii) To a toxin or antitoxin, if intended, irrespective of its source of origin, to be applicable to the prevention, treatment,
or cure of disease or injuries of man through a specific immune process."10
The broad interpretation of the term "virus" provides clear evidence of the latitude FDA took in interpreting the statute
through the rulemaking process. Applying a similarly broad interpretation of the PHSA definition of "biological product,"
FDA classified many protein products that are now targets for biogeneric mimics as "biological products."
Nevertheless, many other biogeneric targets were classified as drugs and approved as NDAs under the FD&C Act. The implications
for manufacturers seeking to register a biogeneric mimic of a given target protein product is significant; the regulatory
pathway is clear if the target product was approved as an NDA, but it is not nearly as clear if the target product was licensed
as a biological product. Although some ideas about how a manufacturer potentially could seek registration for a biogeneric
mimic of a licensed biological product have been proposed, these pathways have not been tested.
The well-characterized biotechnology products that were licensed as BLAs and are typically included in the public discussion
of biogenerics were originally under the jurisdiction of FDA's Center for Biological Evaluation and Research (CBER). On June
30, 2003, these products were transferred to the jurisdiction of the Center for Drug Evaluation and Research (CDER). This
move reflects the drug-like qualities of biotech products. The more "classical" biological products, such as gene therapy
products and blood products, i.e., those that fit the literal definition in the PHSA, have remained under CBER's jurisdiction. (The only exceptions are two botulinum toxin preparations.)
Medical Device Pathway
The third pathway to market for innovative drugs, which is often overlooked because of the limited number of products to which
it applies, involves filing the product as a medical device, under the FD&C Act. Examples of such products include gelatin
hemostatic wound-care products (e.g., Surgifoam, Gelfoam). These products are excluded from the discussion of biogeneric targets
because the protein in these products acts in a nonspecific manner.
The fourth pathway available is to market a product containing an old, pre-1938 drug without an approval or license. Some
selected active ingredients in use before 1938 are still under Drug Efficacy Study Implementation (DESI) review. This program
was initiated to review the efficacy data of old drug products that had been marketed before FDA registration was required
and thereby ensure that such older products did indeed work as claimed. Drug products containing active ingredients under
DESI review may still be marketed legally as long as the manufacturers follow GMP regulations.
This pathway is also often overlooked because of the limited number of products involved. We believe this pathway was used
to market such topical wound debridement products as Xenaderm (containing the protease trypsin) and Accuzyme (containing the
protease papain), although this is difficult to confirm given the virtual absence of publicly available regulatory information
on these products. Any DESI target products that met the financial criteria were excluded from the final list because the
protein component was only a small fraction of the total amount of active ingredients present, and because such products have
not been part of the mainstream discussion of biogenerics.