Unapproved drugs in clinical research are termed
investigational drugsorbiologics.
Normally, a 30-day waiting period applies when
an IND is submitted that describes the initial clin-
ical study with an investigational drug or biologic.
Thereafter, FDA must be notified (by filing an IND
amendment) of further clinical protocols, newly
developed toxicology information and changes to
the chemistry, manufacturing or controls. How-
ever, there is no mandatory review period for
IND amendments, and the changes to the IND
that have been notified can usually be implemented
immediately. Of course, FDA may impose clinical
holds on particular dosing regimes, patient popula-
tions, protocols or entire projects, at any time when
safety issues present themselves. For a detailed
discussion of the typical IND, see the separate
chapter in this book, and Fox (1996).
The Emergency IND(21CFR para 312.36) is
designed to permit a physician to treat a particular
patient with an investigational drug with an
urgency that precludes the writing and filing of an
IND, or even of a clinical protocol. An Emergency
IND does not require the 30-day waiting period.
Part of the philosophy behind the perceived need
for this regulation is that the federal government
does not wish to interfere directly in the relation-
ship between an individual physician and an indi-
vidual patient. The emergency procurement of
materials that are unapproved for human use
would be illegal, without this regulation.
When the need for an investigational drug is too
urgent for the filing of an IND,then the procedure is
for the patient’s physician to identify a source of
the desired compound, and then telephone the FDA
for Emergency IND permission. For biologics, the
telephone number is (301) 443-4864 (the Center
for Biologics Evaluation and Research, HFB-230),
and for all other drugs (301) 443-1240 (the Center
for Drug Evaluation and Research, HFD-53;note
that the telephone number published in the 1995
Edition of 21CFR is out of date). Out of ordinary
office hours (08:00–16:00 Eastern Standard Time),
FDA’s Division of Emergency and Epidemiologi-
cal Operations maintains a 24-h availability on
(202) 857-8400. A confirmation will be provided
to the requesting physician either with a number, or
by a named FDA officer. The physician may then
notify those details to the pharmacy or pharmaceu-
tical company holding the investigational agent,
and the drug may then be legally shipped. This
information is also available by Internet (http://
http://www.fda.gov). It should be noted that this permis-
sion can only be obtained by the treating physician
him/herself; the pharmaceutical company cannot
obtain an Emergency IND on behalf of a treating
physician. It should also be noted that a paper IND
must follow within reasonable time afterwards.
It should be noted that ‘off-label’ use of
approved products (i.e. prescribing lawfully mar-
keted products for indications other than those
stated in their labeling) does not require an Emer-
gency IND, under 21CFR paras 312.2(b)(i)–(v),
provided that the intended use(a) is not designed to support a forthcoming NDA
or Supplemental NDA for a new indication;(b) is not designed to support promotional
materials;(c) does not involve a significantly greater risk
than the usual use of the agent (although not
defined more precisely, large increments in
dose, strange routes of administration or spe-
cial patient populations would all violate this
provision);(d) the ethical provisions of the Declaration of
Helsinki still apply, and informed consent
(which need not necessarily be in writing)
has been obtained, that is, the patient is fully
informed of the unusual drug usage;(e) no representations of safety or efficacy, and
no monetary charges (ordinarily) are made
(21CFR para 312.7); and(f) the usage is not prolonged beyond the time
period needed to reasonably ascertain its
failure.It may be noted that in anesthetics, pediatrics and
intensive care medicine, in particular, drugs are
used ‘off-label’ almost routinely; and in practice,
it is doubtful that physicians in these specialties are408 CH32 SPECIAL US REGULATORY PROCEDURES