provided by orphan drug status. This might be a
rare situation where the toxicology of an orphan
drug product is well known due to its severity,
relatively high incidence and prior exposure to a
larger patient population for a previous, failed
indication. But, thus far, there have been no
reported disasters.
European views about STEPS-type programs
are very different. First, there is conflict between
patient (and probably clinician) registration and
privacy laws in many countries. Second, the patient
registers and documentation of informed consent is
seen as interfering with the doctor–patient rela-
tionship. Thirdly, there is the potential for iniquity
of drug distribution; some of Europe, including
areas where leprosy is to be found, is only sparsely
provided with physicians and pharmacists, and
those that are unregistered for this special purpose
effectively block access for a proportion of the EU
population. Fourthly, for the cultural reasons
described above, the patient registries would prob-
ably have to be at the national level; the cost–
benefit ratio of these schemes might be less attrac-
tive to smaller countries than large ones, again
creating iniquity. Fifthly, there is skepticism that
the required documentation can automatically cor-
respond with the quality of education imparted to
clinicians and patients alike (this concern applies
more widely to many matters of continuing medi-
cal education and revalidation in Europe). Lastly,
the STEPS Program can be seen as one where the
Marketing Authorization Holder actually decides
whether a patient is eligible to receive the treat-
ment, and whether a doctor is qualified to prescribe
it, thus pre-empting those who would otherwise be
duly empowered to do so, either by reason of ethics
or by law. In Europe, no risk management program
has been implemented, and there is no marketing
authorization for thalidomide.
Major clinical hazard:mifepristone. This pros-
taglandin analog is capable of inducing abortion of
a uterine pregnancy of less than 49 days duration
when administered orally. In 2000, it was approved
in the United States amidst controversy associated
with the cultural aspects of pregnancy and its
termination.
The risk management program that has been
deployed for mifepristone is less restrictive than
that for thalidomide. The use of the product is
restricted to those physicians who are capable of
determining the duration of pregnancy, and who
can identify ectopic implantation. Availability and
training in the use of ultrasound is therefore
required. Doctors who prescribe the drug must
also be able to provide surgical intervention in
cases of incomplete abortion or severe bleeding,
although it is unclear whether this includes (for
example) the situation of an endocrinologist pre-
scriber who works with a gynecologist in a closely
coordinated environment, or whether the prescri-
ber and the surgeon-in-reserve has to be the same
person.
At the time of writing, about four years have
elapsed since product launch. The most widely
reported serious adverse events during those four
years have been four cases of fatal sepsis, a clinical
hazard that is much smaller than the general risks
associated with pregnancy to full term.
This is an example of a risk management pro-
gram that currently appears to have been scaled
appropriately for the minimization of direct clin-
ical hazard. Cultural aspects of this form of therapy
continue to provoke protest at product availability,
and reported adverse events are also used to keep
these protests in the public eye.
Examples of International disharmony. The
examples of diacetylmorphine and thalidomide
(see above) are examples of pharmaceutical pro-
ducts that are available either only in Europe or
only in the United States, respectively. Within
Europe, the existence of National Competent
Authorities provides further scope for nonuniform
risk management plans.
A good example is cisapride, a propulsive gas-
trointestinal drug, which was found (especially in
the context of drug interactions) to cause prolon-
gation of the QT interval and predispose to
torsade de pointesventricular tachyarrythmia.
This information caused some of the National
Competent Authorities in Europe to suspend mar-
keting authorization for this drug. The CHMP
within the EMEA subsequently reviewed the
pan-European pharmacovigilance data on this
product. Cisapride has now been returned to the
marketplace with various restrictions having been
placed on national authorizations, including a41.3 PRACTICAL EXAMPLES 561