emergent safety issue, or ‘routine’. Pivotal clinical
trials in a submitted NDA or BLA will usually
garner an inspection of the clinical trial sites and
statutory documentation.
This inspection process has recently been aug-
mented with the establishment of an Office of the
Inspector General (OIG) which reports at the level
of the Secretary, not the FDA Commissioner. One
of the first announced targets of the OIG, selected
from the entire realm of foods and drugs that FDA
regulates, is clinical trials. In particular, the OIG is
actively investigating informed consent docu-
ments, and also has notified institutional review
boards (the US equivalent of the ethics committee)
that they are in for close scrutiny.
Make no mistake. One big difference between
the EMEA and FDA is that the FDA is also the
police (and often the judge and jury, as well). Do
not take lightly the appearance of your name on
Form 1571.
31.4 Investigational new drugs
(IND)The student is urged to read the Code of Federal
Regulations with this title, beginning at
21CFR310.
The legal basis for an IND was set up in the 1962
amendments. It is unlawful to transport an unap-
proved drug across state lines unless FDA has
issued an exemption. The IND is technically an
exemption from the requirements of an NDA.
Drugs labeled ‘Not for human use’ are also exempt
from the NDA requirements, before being trans-
ported, but carry regulatory restrictions. Note that
technically and legally these regulations apply just
as much to noncommercial research physicians,
for example in universities, as to pharmaceutical
companies.
The structure of an IND application is contained
in the regulation and is quite easily followed.
Almost all pharmaceutical companies, contract
research organizations and universities have tem-
plates for the writing of these documents. All the
animal data, the proposed clinical study protocol, a
clinical investigators’ brochure and the chemistry
and manufacturing controls must be described.
Once an IND is active, then it can be amended
with further clinical protocols, additional toxicol-
ogy data and so on, as the development program
proceeds.
The IND differs in a number of ways from its
European counterparts. First, it is much longer; a
typical IND is of at least 1000 pages, and for drugs
with foreign human experience, often many multi-
ples of this number. The UK Clinical Trials Certi-
ficate, used very rarely for this reason, and not the
Clinical Trials Exemption (‘CTX’), would be the
nearer comparison. Second, an IND is required for
all human exposure to INDs, and this includes
normal volunteer studies. Third, all being well,
there is only a 30-day wait between filing and
commencement of the clinical study; no news
from FDA after this time period has elapsed is
presumptive evidence that the study may proceed
(most FDA divisions will, in fact, issue affirmative
letters that this is the case, within 30 days). Fourth,
once an IND has become active, there is no sub-
sequent 30-day wait when further clinical proto-
cols are submitted.
FDA is at liberty to impose partial or total clin-
ical holds on any protocols that it receives. Partial
holds might limit, for example, the maximum dose
that can be employed, prevent commencement
until additional safety monitoring measures have
been instituted or restrict dose frequency.
It is no longer the case that an IND is needed
merely for the export of an investigational agent to
another jurisdiction, provided that the regulations
that obtain in that jurisdiction are adhered to. This
was one former peculiarity of the restriction on
transportation of unapproved drugs across state
lines.
There are variants of the IND process. These are
described in the chapter entitled Special INDs.31.5 Meetings with FDA
Many Europeans are surprised at the access that
pharmaceutical companies have to the reviewing
divisions of FDA. The typical investigational drug
will be the subject of a pre-IND meeting, which
FDA will provide at its discretion and for
which the agenda may be set by the prospective402 CH31 UNITED STATES REGULATIONS