and with all due diligence. Regulators often have
no experience of clinical study management, and
the difficulties of studying the disease in question
may be substantial. Thus, there can be contro-
versy on what does and does not constitute due
diligence under these conditions. Third, failure
to adhere to agreements over promotional mate-
rials can also lead to NDA withdrawal; this is
under the pharmaceutical company’s control,
and is far more predictable than the results of
post-marketing studies. All the usual reviewing
and appeals processes are available to both FDA
and pharmaceutical companies when NDA with-
drawal becomes a possibility.
In practice, good NDA sponsors find that
post-marketing studies lead to package insert
changes much more often than withdrawal of
the entire NDA. There is also no evidence, so
far, that the accelerated approval process has
led to any serious threat to the public health.
This new reviewing practice that appears to be
working well.
32.5 Accelerated approvals:
ANDAs and generic drugsThe Abbreviated New Drug Application (ANDA)
isanother formof accelerated approval, for which
FDA is separately authorized under Section
505(j) of the Food, Drug and Cosmetic Act (as
amended), which is reduced to regulation at
21CFR paras 314.3 and 314.92 through 314.99.
This process applies to generic products that
are bioequivalent to previously approved, inno-
vative drugs. In this case, the submission docu-
ment is not of the same structure as an ordinary
NDA, and this is quite unlike the accelerated
approval for serious and life-threatening diseases
described above. Approval acceleration in this
case is accomplished by a massive reduction in
the documentation needed for FDA review and
approval.
For all practical purposes, the generic equivalent
will challenge a trademark drug, probably by price
competition, in the market place. However, there
are rare situations where a trademark drug may
have been withdrawn from marketing for purely
commercial reasons. Although absent from the
market, such a drug could still be followed by an
ANDA from another company. The commonest
case is where a large company withdraws an inno-
vative, but off-patent drug due to insufficient mar-
ket size. For strategic reasons, the innovator
company may wish neither to license the product
to some other company nor to continue its manu-
facture. The niche thus created can be filled by a
small generic company for whom thatsmall market
size can still comprise a large fraction of their
financial revenues.
The FDA publishes a current list of drugs which
it considers suitable for ANDA applications. This
may be obtained from the Superintendent of Docu-
ments, US Government Printing Office, Washing-
ton, DC, 20402, USA, Tel.:þ1 (202) 783-3238,
and will shortly be available on the World Wide
Web. This includes both antibiotics and orthodox
drugs within the Center for Drugs Evaluation and
Research (CDER).
At the time of writing (January 2006), for rea-
sons relating to manufacturing complexity, FDA
does not believe that it can approve an ANDA for a
‘generic’ (or, more properly ‘follow-on’) biologic.
However, this question is currently being litigated
in the Federal Courts after the submission of the
first abbreviated biologic application.
Supporting information. An unusual aspect of
the ANDA is that there are two ways to apply.
The first is to file a straightforward ANDA, which
describes a copy of an approved drug. The second
way is to file a petition for a drug that is not
identical but may be sufficiently similar for the
ANDA process to apply. The FDA is committed to
reviewing complete ANDAs within six months.
The straightforward ANDA demonstrates that
the generic drug is identical in its route of ad-
ministration, active components, dosage form,
strength and stability. The previously approved
drug must be identified specifically [21CFR para
314.93(d)], or, exceptionally, the applicant can
demonstrate that the new product falls within the
range of previously approved specifications among
several antecedent products. The Freedom of412 CH32 SPECIAL US REGULATORY PROCEDURES