more frequently in the early part of the product
life cycle than later on. The least restrictive
ordinary situation is when clinical hazard is seen
as being so slight that prescription is judged
unnecessary. Products can then be licensed for
over-the-counter use, with or without pharmacist
oversight. In the opposite direction, ‘black box’
labeling might recommend restriction of the
distribution of the product to practitioners with
specific training (e.g. in the United States, neuro-
muscular junction blocking drugs to anesthesiolo-
gists, and cytotoxic agents to oncologists and
rheumatologists). ‘Black box’ warnings might
also draw attention to particularly serious adverse
event types, and restrictions on advertising and
marketing can therebyalso attach.
These common situations are discussed in the
previous chapters on regulatory affairs. They can
be viewed as the default set of risk management
programs to be implemented in the absence of any
special clinical hazard.
Special regulatory provisions: United States.
Subchapter D of theCode of Federal Regulations
(CFR) authorizes the Food and Drug Adminis-
tration (FDA) to approve new drug products on
an accelerated basis, provided that the indication
is for a serious or life-threatening condition (see:
21 CFR314.500–560, also known colloquially as
‘Sub-part H’ because of where it resides in the
Subchapter). This regulatory innovation took
place in 1992, with a minor amendment in 1999.
The candidate new drug productmust alsooffer
‘meaningful clinical benefit’ to be approved under
these provisions; FDA must be able to anticipate
that there are patients for whom alternative treat-
ments are clearly inferior, either through lacking
efficacy or risking substantial intolerability.
Accelerated, Sub-part H, approvals rely less on
clinical data than an ordinary approval. On the
efficacy side, this might include, for example, the
use of a surrogate end point instead of a disease
outcome (for example, an antihypertensive drug
can be approved without ap-value for reduction of
stroke). On issues of tolerability, an accelerated
approval almost always means a database with
fewer patients than would be otherwise desirable.
It is in this latter case that FDA will mandate a
special risk management program. The Agency
will review and approve a specific program
design, to which the Sponsor must agree, before
issuing the product approval.
The design of these special risk management
programs may involve one or more components.
In general, these components fall into thefollowing
categories:(a) Restriction in product distribution (location,
medical procedure or quantity of dispensing).(b) Need for special training of prescriber or phar-
macist before authority to prescribe or dispense.(c) Need for special education of patient prior to
dispensing.(d) Specific clinical tests prior to patient eligibility.(e) Documentation of patient’s informed consent
prior to dispensing.(f) Mandated patient registries.(g) Targeted post-marketing clinical studies.The term ‘access program’ is often used when
publicizing these special measures. The Sponsor’s
performance according to the agreed plan becomes
a condition for the approval to remain active; how-
ever, if the FDA does wish subsequently to with-
draw approval for failure to follow a post-
marketing risk management plan, then the Sponsor
is entitled first to a hearing.
Special regulatory provisions:European Eco-
nomic Area(EEA). The components of risk man-
agement programs in Europe have been similar to
those listed above. However, it is probably fair to
say that, overall, there has been less experience
with these programs in Europe than in the United
States.
Pan-Community, both the European Commis-
sion and the EMEA have interests in risk manage-
ment programs for pharmaceutical products. Both
organizations are interested in the safety of the
general public and also in ensuring equal access
to pharmaceutical products across the Community.
The Commission tends to take a more economic558 CH41 RISK MANAGEMENT IN PRODUCT APPROVAL AND MARKETING