minimum needed to assure patient safety. These
abbreviated INDs are otherwise of orthodox
composition (21CFR para 312.23), and have the
advantage that the complexities of the Treatment
IND, demonstrating ‘promising’ efficacy, can be
avoided. Furthermore, even with a rudimentary
case report form, the pharmaceutical company can
gather tolerability information by this means, even
for products approved for other purposes, because
the exemptions of 21CFR paras 312.2(b)(i)–(iv)
have not been exploited (see above). Pharmaceutical
physicians can use templatewordprocessing files for
these physician’s INDs, can complete the details for
the particular physician over the phone, and mail it to
him or her for signature and forwarding to FDA. The
administrative burden, once this is set up, can be
relatively light, and is often very much quicker and
easier than navigating the complexities of ade novo
Treatment IND.
32.4 Accelerated approvals:
serious and life-threatening
diseasesIn the United States, there are numerous, active,
nonmedical communities that are interested in the
treatment of human immunodeficiency viruses
(HIV), age-associated or Alzheimer syndrome, and,
to a lesser extent, emergency medicine and various
rare genetic diseases. Another community has
formed to support the availability of generic drugs,
because of concern about healthcare costs (with drug
prices as a small but highly visible part of this). These
communities have accomplished a very rare thing:
using various parts of the political process, they have
brought about change in FDA, causing alterations,
and acceleration, in the drug approval process.
The structure and format of NDAs that may be
submitted under these regulations are the same as
that for ordinary NDAs (see the earlier chapter in
this book). But thereviewing practicecan be very
different for these types of accelerated approvals.
Sub-Part H. The accelerated approval of new drugs
for serious or life-threatening illnesses is provided
for in 21CFR314.500–560 (‘Sub-Part H’). This
practice dates from 1992, and applies to all types
of drug, including antibiotics and biologics. Under
Sub-Part H, it is stated thatIf the Secretary determines, based on relevant
science, that data from one adequate and well-
controlled clinical investigation and confirmatory
evidence (obtained prior to or after such investiga-
tion) are sufficient to establish effectiveness, the
Secretary may consider such data and evidence to
constitute substantial evidence...For example, zidovudine (azidothymidine) was
approved under these regulations as a treatment for
AIDS after an NDA that contained only one well-
controlled trial in its support, and variousin vitro
and uncontrolled human data as confirmatory;
moreover, CD4 lymphocyte counts were accepted
as a surrogate end point in the clinical trial.
Surrogate end points are not as radical as it may
first appear. Antihypertensive drugs are approved
using blood pressure as the surrogate end point; and,
until recently, none of the large number of studies
approved that antihypertensive had been demon-
strated to actually reduce strokes or myocardial
infarctions. This concept of surrogate end point
should also be familiar to early-phase clinical trial-
ists. The selection of development candidates at the
IND stage, and assessing their worth during phase I
or II clinical investigation often requires develop-
ment decisions based on surrogate end points, again
because these are usually quicker to obtain than (for
example) mortality data in support of the proposed
indication for the drug.
Thus, the differences in reviewing practice for
accelerated approvals, in comparison to more typi-
cal NDAs, are that the regulations specifically
permit FDA tojudge efficacy on the basis of surrogate end
points,grant marketing permission on condition of
greater degrees of monitoring for safety than
the norm, andto control promotional practices more strin-
gently than usual.410 CH32 SPECIAL US REGULATORY PROCEDURES