Innovation in the Pharmaceutical Industry: The Process of Drug Discovery and Development - Innovation and Marketing in the Pharmaceutical Industry - page 37

decision to focus on its most loyal segment and harvest the market by maintaining
premium pricing (Grabowski and Vernon 1992 ). However, the average market price
for the molecule with the lost patent will decrease over time as the lower-priced
generic alternatives achieve signifi cant gains in market share.
Generic drugs are required to have the same active ingredients, strength, safety,
quality, route of administration, and dosage form (e.g., capsule, tablet, liquid) as the
brand name product, but may or may not contain the same inactive ingredients as
the original brand (e.g., binders, coating, fi llers), and must differ in appearance
(most often, by shape or color). As the company that makes the original drug has
already proved during extensive clinical trials that the drug formula is both safe and
effective, the FDA approval process may not require the same rounds of clinical
trials from the generic candidates, but will nevertheless demand evidence of suffi -
cient bioequivalence .
The complex biomolecular and chemical processes involved with the action of a
drug suggest that often, demonstrating identical active ingredients and concentra-
tions may not be suffi cient for a generic alternative to be approved by the FDA. With
the more common small-molecule drugs, an exactly identical generic drug can be
reliably produced and marketed, and minor differences in inactive ingredients may
be largely inconsequential. But this is not the case with biopharmaceuticals (macro-
molecule drugs produced with the complex tools of biotechnology). Even a slightly
different manufacturing process may result in large variations in the effects of
biopharmaceuticals. The generic drug manufacturer may not have the same cell
bank or compound library as the brand name manufacturer. Nearly undetectable
differences in impurities and/or breakdown products have been known to incur seri-
ous health complications. This is why the generics must show that they are, within
acceptable limits, bioequivalent to the original brand.
A bioequivalence test is a study to determine whether the administration of the
same dosage of the generic brand will result in the same release pattern, i.e., whether,
over time, it will produce the same levels of concentration in the bloodstream as the
original brand. Although acceptable deviations are not disclosed by the FDA, many
experts seem to believe that the generic drug must fall within an 80-125 % range of
bioequivalence to the original brand. 11 Besides, all manufacturing, packaging, and
testing sites for the generic drugs are held to the same quality standards as those of
the original drug.
Often, generic drug manufacturers can reverse-engineer the original brand, or
reproduce it by getting access to its patent documentation that discloses the active
ingredients. If generic drug manufacturers choose to press on with fi ling for approval
11 Although such a range of variation seems perfectly acceptable for many treatments and condi-
tions, there are situations where severe adverse effects can occur if the drug concentrations exceed
or fall below those ruled as safe and effi cacious—for instance, when a precise calibration of a
process is necessary (e.g., in the treatment of seizures, for regulating blood pressure, blood clotting
and blood thinning, heart rhythm, thyroid activity). FDA will fi nd it necessary to apply much
stricter standards in these cases, which can explain its reluctance to publicly acknowledge the
often-cited 80-125 % bioequivalence range.