Principles and Practice of Pharmaceutical Medicine

even aware of these nuances in the IND regula-
tions. Reimbursement systems in the United States
will, however, often refuse to pay for drugs used
‘off label’, and use these regulations as their
justification.
The contrast in philosophy between these
arrangements in the United States and the emer-
gency use of unapproved drugs in Europe was
succinctly put by one German pharmaceutical phy-
sician recently: ‘We don’t need any of that, I can
prescribe cyanide if I want to!’ Although an exag-
geration, this comment is nonetheless telling.
Compared to the United States, there has always
been a tendency for European regulatory authori-
ties to place more discretion and responsibility
on pharmaceutical companies and individual
physicians when using investigational materials.
For example, although recently changed by the
Clinical Trials Directive, the former absence of
the need for a CTX for normal volunteer studies
in the United Kingdom, and indeed the CTX
procedure itself (in comparison to Clinical Trials
Certification), as well as the limited review of
investigational drug dossiers after filing in
Germany, are examples of this difference in
philosophy. In the United States, the regulatory
process, like much else in other areas of govern-
ment, is conceived in terms of full disclosure of
data in their final form, enforcement and affirma-
tive acts of the granting of permission by the
government.

32.3 ‘Compassionate Use’:

the Treatment IND

Although the term is in common usage, ‘Compas-
sionate Use INDs’do not exist. The Treatment IND
aims to make an investigational new drug available
to patients with a defined disease state that is
serious (usually life threatening), and for which
there is no alternative therapy. This application
may be made whether or not an NDA is to be
filed at a later date.
There are several criteria which must be met for
a Treatment IND to be acceptable to FDA, under
21CFR paras 312.34(b)(i)–(iv). Within these

criteria are several terms that further require defini-

tion or justification to the reviewers:

The disease process must be serious or life

threatening.

There must be no feasible alternative therapy.

The drug is already under investigation in an

orthodox IND.

The sponsor of the drug must be actively pursu-

ing marketing approval of the drug with all due

diligence.

Treatment INDs are thus for pharmaceutical

companies, not for individual physicians. All the

usual clinical hold provisions apply.

There must already be information about the

investigational drug supporting the proposed use,

although this needs only to be ‘promising’ and not

as definitive as would be needed for an NDA. The

judgment of what is and what is not ‘promising’ is

by the relevant reviewing division of FDA; in

practice, it is usually the reviewers that have been

responsible for an antecedent, ordinary IND that

make this recommendation.

Frequently, circumstances arise during the inter-

val between NDA submission and approval which

make it desirable for the (still) investigational drug

to be made more widely available. The Treatment

IND or the Emergency Use IND (21CFR para

312.36, see above) generally accommodates this

need (21CFR paras 312.34 and 312.35).

The stated objective of this section of the reg-

ulation, under 21CFR paras 312.34(a) and (b) can,

however, often be achieved using an intelligently

designed ordinary IND. A seriously interested phy-

sician can make this application himself or herself,

and pharmaceutical companies can cooperate by

notifying the FDA that the physician may cross-

refer to the chemistry and toxicology sections of

their own ordinary IND. By quoting these cross-

references, the physician’s IND becomes abbre-

viated. The clinical protocol for the physician’s

IND need only use an open-label design, in

pursuit of tolerability information. Inclusion and

exclusion criteria can be kept broad and to the

32.3 ‘COMPASSIONATE USE’: THE TREATMENT IND 409