Pharmaceutical Manufacturing Handbook: Production and

LEGAL ARGUMENTS RELATED TO FOLLOW-ON PROTEINS 45
• Two products are bioequivalent in “ the absence of a signifi cant difference in the
rate and extent to which the active ingredient or active moiety in pharmaceutical
equivalents or pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar conditions in an
appropriately designed study ” [21 CFR 320.1(e)]. An appropriately designed
comparison could include (1) pharmacokinetic (PK) studies, (2) pharmacodynamic
(PD) studies, (3) comparative clinical trials, and/or (4) in vitro studies.
• Pharmaceutical equivalents are those drug products which are formulated to
contain the same amount of active ingredient in the same dosage form to meet
the same (compendial or other applicable) standards of quality.
• Pharmaceutical alternatives are drug products that contain the same therapeutic
moiety, or its precursor, but not necessarily in the same amount or dosage form.
Drug products are considered to be therapeutic equivalents only if they are
pharmaceutical equivalents and if they can be expected to have the same clinical
effect and safety profi le when administered to patients under the conditions
specifi ed in the labeling. Although pharmaceutical alternatives may ultimately
be proven bioequivalent, given their differences they are not automatically
presumed to be.
Given these defi nitions, FOPs would likely be considered pharmaceutical alternatives
if one presumes that pioneer and follow - on proteins are identical at a precursor
stage, prior to potential post - translational modifi cation. This presumption may also
be consistent with the similarity standard the agency applies to ascertain orphan
drug status (see discussion in Section 1.2.6 ). Follow - on proteins cannot be considered
to be therapeutic equivalents since they are not pharmaceutical equivalents
and cannot be expected to have the same clinical effect and safety profi le in the
absence of testing. This assertion is supported by the following:
• The potential impact of how posttranslational modifi cations, such as glycosylation,
can directly impact protein conformation and subsequently affect biological
activity, including the overall safety and effi cacy of the drug product.
• An underlying premise of bioequivalence assessments is a clearly defi ned pharmacokinetic/pharmacodynamic
relationship; however, the relation between
blood levels and effect is less clearly established for proteins [20] .
Consequently, within the current regulatory framework, FOPs are unique products
that may be “ similar ” but are not the same as innovator proteins, consistent with
their approval via a 505(b)(2) pathway. This interpretation is supported by the
FDA ’ s designation of Omnitrope as having a BX rating in the Orange Book. The
code BX in the Orange Book refers to drug products for which the data are insuffi
cient to determine therapeutic equivalence as compared to a therapeutic rating of
A indicative of interchangeability. This concept of similarity is also consistent with
the defi nitions proposed by the European Agency for the Evaluation of Medicinal
Products (EMEA) for generic versions of proteins [21] :
Bio - similar products: second and subsequent versions of biologics that are independently
developed and approved after a pioneer has developed an original version.
Bio - similar products may or may not be intended to be molecular copies of the innovator
’ s product; however, they rely on the same mechanism of action and therapeutic
indication.