It is also specified how FDA may withdraw
approval, which is usually threatened when the
sponsor fails to conduct post-marketing research
to which it committed as a condition of approval.
Sub-Part E. 21CFR312.80–88 (‘Sub-Part E’) also
provides for expedited approvals, when reviews can
be accelerated for ‘drugs intended to treat life-
threatening and severely debilitating illnesses’.
This is generally understood to be disease states
where there is noeffective, alternative therapy. Sub-
Part E anticipates flexibility, but continued obser-
vance of the statute, as for all drugs. Such products
are officially termed ‘Fast Track Products’. The
target NDA review time is reduced from the ordin-
ary 10 months to 6 months under these provisions.
Within Sub-Part E, there is no specific anticipa-
tion of a relaxation of the requirement for two
adequate and well-controlled studies. These regu-
lations prescribe meetings and schedules, and sim-
ply suggest that there ought to be more flexibility in
the application of the existing regulations to this
type of drug.
What is‘life threatening’ within the meaning of
these regulations? This definition is not repeated in
the accelerated approvals regulations. Thus, the
presumption is that these definitions are similar
to those provided elsewhere in the IND regulations
(21CFR para 312.32(a), 21CFR para 312.34 and
the previous Chapter on US regulations). One pro-
blem that arises is in the interpretation of regula-
tions couched specifically in terms of adverse
events or justification of a Treatment IND, and
how these apply to NDA approvability or the clin-
ical definitions of a disease process. ‘Life threaten-
ing’ usually is taken to mean that the patient’s life is
actually under threat by the currently observed
disease process (or adverse event), and not that
the sametypeof disease or adverse event, but in
worsedegreethan that actually observed in the
patient, could be life threatening. Clearly, the
burden of proof for demonstration that a disease
is serious or life threatening, and thus an NDA may
be considered for accelerated approval, falls
squarely with the pharmaceutical company, and
FDA will certainly need to be convinced of this
as part of its judgment whether to accept the NDA
application under these regulations.
Post-marketing impact of accelerated approvals.
Safety monitoring, after NDA approval, is required
for almost all drugs in the United States (21CFR
para 314.98). The difference in practice with accel-
erated approvals is that almost always,specificpost-
marketing safety studies (and sometimes efficacy
studies) will be required as a condition of approval.
These post-marketing safety studies range from
agreement on drug surveillance procedures in detail,
through the maintenance of patient registries, to
specific studies with protocols. In February 2007,
FDA announced that a new routine 18 month
post-approval safety review will also be introduced.
Post-marketing safety studies are considered
in their own chapter of this book. However, it should
be noted here that patient registries have been asso-
ciated with grave jeopardyoflitigationin the United
States, and not necessarily on a sound scientific
basis. On more than one occasion, pharmaceutical
companies have been deterred from marketing new
drugs when FDA has required a patient registry as a
condition of NDA approval.
The greater control over promotional practice,
under the accelerated approval process, usually
places less burden on an ethical company than
the post-marketing safety requirements. Promo-
tional materials must be submitted for review
before NDA approval, with the obviously desirable
intention that promotion should not be any broader
than the approved indication, which under these
special circumstances is likely to be narrower than
usual. Furthermore, the package insert should
usually quantitate how narrow or broad the toler-
ability experience with the drug might be; frequent
labeling revisions and NDA supplements should be
planned for.
These special arrangements create two unusual
situations where withdrawal of an NDA approved
on an accelerated basis is more likely than for an
ordinary NDA. First, the approval may be con-
ditional on further clinical studies; FDA can
withdraw NDA approval, if these studies turn
out to be inconsistent with that (those) in the
original NDA. Usually, the interim reporting
frequency for these studies will be agreed as
part of the NDA pre-approval meeting. Second,
as mentioned above, post-marketing research
commitments must be pursued in good faith32.4 ACCELERATED APPROVALS: SERIOUS AND LIFE-THREATENING DISEASES 411