‘Fast Track’designations for accelerating review
and approval
However, in the United States, illogicalities still
persist. For example, the Waxman-Hatch legisla-
tion gave authority for generics and provided
patent term exclusivity for drugs, but not for bio-
logical products licensed prior to 1972. Similarly,
the pediatric ‘exclusivity’that the Act initiated also
only pertained to the drugs with unexpired patent
or Orphan Drug exclusivity. Lastly, the Centers for
Disease Control remains involved with compensa-
tion issues for pediatric vaccines, a unique admin-
istrative arrangement.
22.4 Biotechnology versus
conventional drug productsThere is a widespread, but largely unreasonable,
perception that biotechnology products differ in
their properties to conventional small molecule
drugs. For example, it is widely believed that sim-
ple pharmacokinetic models cannot adequately
describe the behavior of biological agentsin vivo.
Although quantitative data relating to the intracel-
lular distribution of these agents may not be known
or easy to measure, the underlying principals of
absorption, distribution, metabolism and excretion
(ADME) are the same, even though new paradigms
and different quantitative models may be required
to describe the properties of biological compounds.
However, Table 22.1 lists the factors that need
to be considered when modeling pharmacokinetic
(PK)–pharmacodynamic (PD) relationships for
the extreme case of gene therapy products, most
having correlates with features of orthodox drugs.
While biotechnology products have compli-
cated PK–PD relationships, this can also be the
case for orthodox drugs (e.g. antidepressant thera-
pies, where three weeks or more is usually needed
before any therapeutic response may be seen, or
angiotensin converting enzyme (ACE) inhibitors
that remain antihypertensive after several months
of therapy, even after serum ACE activity has been
restored). Likewise, both corticosteroid therapy
and gene therapies require access to the cell
nucleus; the intercompartmental transfer coeffi-
cients (serum/cytosol/nucleus) are complex and
immeasurable in human beings in both cases. In
contrast, complexity among biotechnology pro-
ducts include antibody complement fixation, cel-
lular attack may be an all-or-none phenomenon,
DNA lysis in sputum may not require drug absorp-
tion at all and clot lysis may depend on awide range
of endogenous plasma proteins, each with its own
concentration–response relationships. The pro-
blems and analysis of tachyphylaxis are common
to both orthodox and biotechnology products.22.5 Manufacturing issues
Manufacturing changes are more likely to affect
the clinical profile of biological compounds than
small chemical entities. Small changes in the three-
dimensional folding, posttranslational modifica-
tion or glycosylation of proteins can significantlyTable 22.1 Pharmacokinetic considerations for gene therapy agents [Adapted from Ledley TS, Ledley FD. 1994.
Multicompartment numerical model of cellular events in the pharmacokinetics of gene therapies.Hum.Gene
Ther. 5 : 679–691]
Absorption DNA vector distribution
Distribution Vector fraction target cell uptake
Distribution Genetic material traffic in organelles
Metabolism DNA degradation
Metabolism mRNA production
Metabolism Protein production – quantity
Excretion Protein production – stability
Metabolism, excretion Protein production – compartmentalization
Excretion Protein production – secretory fate
22.5 MANUFACTURING ISSUES 281