management programs. Most countries recognize
the need for four or five degrees of scheduling with
graded increases in product restrictions, thus form-
ing a usefully flexible system. This is also now
harmonized internationally by the signatories to
the United Nations Psychotropic Drugs Conven-
tion, which covers opioids, thebaine derivatives,
barbitals (barbiturates), amphetamines, the natural
and semi-synthetic products ofErythoxylon coca
andEphedraspp., as well as other drugs with both
medical purposes and abuse liability.
Even in the most extreme case of risk manage-
ment program, where the risk-benefit assessment is
deemed to be so hopeless that a drug is absolutely
banned, there can be a lack of international harmo-
nization. The easy illustration within this class of
drugs is diacetylmorphine (diamorphine, ‘heroin’).
In the United States, this is a Schedule 1 controlled
substance, defined as being without any medical
value; prescribing and dispensing is absolutely pro-
hibited. In contrast, several European countries
valuethisdrugforthetreatmentofpaininterminally
ill patients, and for its greater solubility than mor-
phine (making large doses of opioid easier to swal-
low).IntheEEA,thisisachievedbyalowergradeof
‘Scheduling’ than in the United States, although
prescription, storage and dispensing nonetheless
require greater storage security and accountability
than for ordinary prescription-only medicines.
Note, too, that this well-established type of risk
management program has indirectly led to compe-
titive advantage in at least one case. One manufac-
turer of a modern product for insomnia advertises
in the United States that this drug ‘is not a narcotic’.
Simplicity in prescribing and dispensing, and a
perception of the relative safety of an unscheduled
product, is attractive to physicians, pharmacists
and patients with insomnia, alike.
Major issues of toxicity:thalidomide. The story
of thalidomide in the 1960s is too well known to
need any repetition here. The full spectrum of its
pharmacology and toxicology is still not fully
understood, but in addition to its supposed anti-
emetic effects during pregnancy, this drug is also
immunomodulatory. In the 1990s, interest in this
latter property grew, and thalidomide (often in
combination with dapsone) was found to be effec-
tive for erythema nodosum in patients with
Hansen’s Disease (leprosy) and without peripheral
neuritis. What has been the response, in terms of
risk management programs, to allow patients to
have access to this teratogenic drug?
In the United States, thalidomide was approved
in 1998 under the ‘Sub-part H’ provisions. The
product label carries no fewer than seven different
‘Black Box Warnings’, some of which appear
twice. These describe precisely the teratogenicity
and risk management plan associated with this
drug. More or less every component from the list
above is deployed, in what is known as the System
for Thalidomide Education & Prescribing Safety
(the ‘STEPS Program’), including the following:Product supply chain to a small number of regis-
tered pharmacies (fewer than an average of one
per State).Dispensing permitted-against prescriptions writ-
ten by only a small number of named, specially-
registered physicians.Requirements for special training of these regis-
tered physicians and pharmacists.Documented informed consent by patients,
emphasizing contraception, pregnancy testing
and the risks of teratogenicity.For minors, documented informed consent from
parents or guardians.Mandatory regular pregnancy testing for women
of child-bearing potential.Maximum one-month supply per prescription,
with no refills permitted.Mandatory patient registration by name and
location prior to dispensing.Close pharmacovigilance of all registered
patients with frequent FDA reporting.Erythema nodosum associated with Hansen’s Dis-
ease is a rare disorder in the United States, and the
manufacturer of thalidomide enjoys the exclusivity560 CH41 RISK MANAGEMENT IN PRODUCT APPROVAL AND MARKETING