applicant. These meetings can also be held by
telephone conference, and FDA is getting quite
good at accepting electronic files of data. An IND
is, however, only allotted a number upon its
submission.
It is fair to say that US companies differ in their
approach to pre-IND meetings. Most companies
probably view pre-IND meetings as desirable.
However, under the law, proprietary information
is only required to be kept confidential by FDA
when it is the subject of an IND. No known major
disclosure has happened, but companies would
have little recourse if FDA leaked information
following a pre-IND meeting. The other problem
is that without an IND in place, FDA has no obliga-
tion to meet with clinical trial sponsors: reviewers
up against a PDUFA deadline on another project
are unlikely to prepare thoroughly for a pre-IND
meeting, and may entirely change their views after
the IND, when they become obligated to adopt a
position. Some companies file the IND first, with a
simultaneous request for a meeting.
Typically, during phase I and II development
there will be sporadic communications between
the IND sponsor and FDA. These might be to
clarify issues over post-IND clinical protocols,
reach agreement on compatibility of toxicology
data with clinical study design, carcinogenicity
testing requirements (typically starting at this
time due to their long duration and the necessity
for their completion before filing the NDA) and the
many technical matters associated with the scale-
up of the chemistry and production processes.
It is typical to hold an end-of-phase II meeting
(EOP2). At this meeting, the FDA will review the
current phase I and phase II clinical data, and the
state of the toxicology program. The objective is to
reach agreement on the design of the phase III
studies that will support NDA approval, as well
as to identify any further problems that may be
ameliorated without delaying the NDA. FDA can
also begin planning for the resources needed when
the NDA arrives.
A pre-NDA meeting is typically held as the
phase III clinical trials are concluding. The princi-
pal objective is to check how the issues identified at
the EOP2 meeting have been resolved. At this
meeting, the entire structure of the forthcoming
NDA can be agreed, and technicalities surrounding
electronic submissions can also be arranged.31.6 The new drug application
(NDA)The best NDAs have a table of contents before the
EOP2 meeting, and are built as the various compo-
nent nonclinical and clinical study reports become
available. Most companies do this both electroni-
cally and as paper hard copy. At present, FDA
requires the submission of both, although
PDUFA requires FDA to be able to accept just an
electronic version by 2002. The structure is well
described in the regulation, which the student is
again urged to read.
Two sections of the NDA are markedly different
from a European submission. These are the Inte-
grated Summaries of Efficacy and Safety. In some
respects, these are the biggest intellectual exercises
that are encountered during the NDA process.
These documents require the pharmaceutical phy-
sician to have thoroughly reviewed and understood
the other sections of the NDA. But further than this,
these summaries require risk–benefit assessment,
crystal clear arguments for choice of dose size and
a full justification of how the NDA data place the
new drug into the current understanding of the
pathology and indication. The new drug must
also be reviewed in comparison with the pharma-
cology and toxicology of kindred drugs. Justifica-
tion for every statement in proposed labeling must
also be provided. These integrated summaries, in
contrast with a European expert report, are often
300–400 pages long.
Assembling an NDA is a long process. Usually
there is a cut-off date for data that by then may be
accruing from all over the world, but which are not
pivotal for NDA approval.
The Integrated Safety Summary is then supple-
mented four months after NDA submission. This
usually provides a significant increase to the safety
database either from ongoing studies that are
rapidly accumulating patients in phase IIIB, or
from marketing data from foreign countries
where the drug may be already approved. The
FDA requires updating on all safety information31.6 THE NEW DRUG APPLICATION (NDA) 403