The finding of a new, nonobvious use for an old
drug can also be patented. This type of patent is
known as a ‘Method of Use’ patent, and its eventual
enforcement is probably easier in the United States
than in other jurisdictions. Nonetheless, theview of
the corporate patent attorney on any proposed
phase IV exploration for a new indication should
always be sought.
Stimulation of the process of finding new uses
for old drugs is often done when companies offer
investigator research grants. It is fairly common
that individual prescribers will have bright ideas
about the use of medical products, and indeed some
specialties use most drugs ‘off-label’ (e.g. inten-
sive care physicians, anesthesiologists and pedia-
tricians). Small grants to such individuals, in order
toobservesuch niche usesunder organized circum-
stances can lead to new indications. At the very
least, such programs encourage disclosure of new
ideas to the company and allow for some review of
the safety aspects of what these inventive indivi-
duals are getting up to!
New dosage forms
Initial dosage forms are usually those that are most
easily developed, most stable and at least reason-
ably acceptable to adult patients. Such formula-
tions can often be improved upon, whether for
matters of convenience (e.g. a bioequivalent
melt-in-the-mouth wafer that, unlike a tablet,
does not require access to water for its administra-
tion) or to enlarge the patient population that
might use the product (e.g. a linctus instead of a
tablet for use in children or to permit smaller
increments in dose adjustment). Again, when
there are serious physicochemical constraints on
formulations, the discovery of a new one can itself
be patentable.
A variety of regulatory approaches are needed
when adding to the range of formulations, and
each, in turn, dictates a different phase IV clinical
trial design. When the route of administration does
not change (e.g. the wafer vs. tablet example
above), then orthodox bioequivalence and
absence of formulation-dependent intolerability
might be all that is needed. A pseudo-phase I
approach during phase IV might then be all that
is required.
On the contrary, the new formulation might be
deliberately designed not to be bioequivalent.
Slow-release formulations are, by definition, not
bioequivalent but often associated with therapeutic
superiority due to reduced probability ofCmax-
related adverse events and better compliance
because of reduced dosage frequency. In this
case, efficacy data will normally be required of
the scale and rigor of the earlier phase III program.
It should be noted that the company might be
wise to consider, when developing new formula-
tions, that the minimum database acceptable to
regulators might be insufficient for their own pur-
poses. The decision to launch a new formulation
has to be based not only on its technical success but
also according to a financial analysis of the type
referred to above for new indications. Crucial
information on that question can usually only be
obtained by studying the new formulation using
one of the other authentic phase IV approaches
described in this chapter.Special populationsSpecial populations have their own chapters in this
book, to which the reader is referred. In the United
States, many product approvals now come with the
condition that future studies in children are man-
datory. This is probably the commonest special
population that phase IV development units now
routinely deal with.
Other, newly identified special populations result
from pharmacovigilance signals, unexpected use of
the product in an unanticipated population, require-
ments for regulatory filings in non-ICH nations, or
even the spread of disease into new geographical
areas. Traditional pharmacokinetic approaches are
usually the first step in assessing whether these
events will alter product efficacy or safety.Drug interactionsThese are essentially another form of special popu-
lation, and almost all drugs can exhibit at least10.1 OBJECTIVES OF THE PHASE IV CLINICAL DEVELOPMENT PROGRAM 123