Pharmaceutical Manufacturing Handbook: Production and

44 REGULATORY CONSIDERATIONS IN APPROVAL
and process information contained in an innovator ’ s application. Further, this use
and disclosure would violate Trade Secret and Constitutional Law (Fifth Amendment
“ taking clause ” ) [17, 18] .
The concept of “ the product is the process ” may have been applicable to early
biologics, but current capabilities allow the chemical, biologic, and functional comparison
of well - characterized protein drugs. The follow - on manufacturer need not
necessarily utilize the identical method of manufacture or proprietary technology
to reproduce a follow - on biologic with similar clinical safety and effi cacy. Additionally,
it is important to distinguish between the regulatory requirements for approval
of an actual generic protein (duplicate of innovator; see discussion below) and those
associated with a 505(b)(2), which requires a showing of similarity between two
products. Any differences between the two would need to be adequately supported
by bridging studies and appropriate clinical and/or nonclinical data.
The FDA has confi rmed this interpretation in its response to petitions fi led
regarding FOPs (both in general and targeted to specifi c applications). The FDA
has clearly said, “ the use of the 505(b)(2) pathway does not entail disclosure of trade
secret or confi dential commercial information, nor does it involve unauthorized
reliance on such data ” [18] .
1.2.5.3 Applicability of 505(j)(1) or ANDA Process to Biogenerics
Biogenerics per se, that is, protein drug products approved via 505(j)(1), would need
to demonstrate their bioequivalence to the innovator protein. However, due to their
complexity and heterogeneity, the classical biopharmaceutical principles upon which
the current ratings of therapeutic equivalence are based do not apply in their current
language to complex macromolecules. For example, due to the nature and complexity
of an immunogenic response, one concern would be if traditional bioequivalence
appropriately addresses the complex safety issues associated with biologics.
1.2.5.4 Current Rules Relating to Bioequivalence of Generic Drugs
The list of approved drug products with therapeutic equivalence (Orange Book)
was originally intended as an information source to states seeking formulary guidance
[19] . The list provides the FDA ’ s recommendations as to which generic prescription
drug products are acceptable substitutes for innovator drugs. The term
innovator is used to describe the reference listed drug, or RLD [21 CFR 314.94(a)(3)],
upon which an applicant (generic) relies in seeking approval of its ANDA. In layman
’ s terms the RLD describes the original NDA - approved drug and is often
referred to as the “ pioneer ” drug.
Under the Drug Price Competition and Patent Term Restoration Act of 1984,
manufacturers seeking approval to market a generic drug need to submit data to
the FDA demonstrating that their proposed drug product is bioequivalent to the
pioneer (innovator) drug product. A major premise underlying the 1984 law is that
bioequivalent drug products are therapeutically equivalent, will produce the same
clinical effect and safety profi le as the innovator product, and are therefore, interchangeable
[19] .
So how would FOPs be classifi ed using conventional defi nitions of bioequivalence?
To answer this question, it is necessary to review current legal defi nitions of
bioequivalence terms [19] :