literature on the difficulties that are encountered
in getting doctors to observe new contraindica-
tions is very extensive and it is clear that this
procedure is not to be lightly undertaken.3.Consider the formulation:Osmosin was a mod-
ified release preparation of indomethacin. It was
designed to release the active drug under osmo-
tic control. Instead it allowed its potassium con-
tent to be released in a way that caused
perforation of the small bowel distal to the
duodenum. The drug provides an example of
the formulation causing the problem, and the
drug serves as a reminder that consideration
needs to be given to the formulation as a possi-
ble cause of trouble which can be remedied by
reformulation.
4.Get the dose right:Problems readily arise if the
development program gets locked into the
wrong dose range early on. It is important to
titrate dose ranges down to lessen Type A side
effects and to make sure that domiciliary
patients are not treated with a dose that is appro-
priate for seriously ill, hospitalized subjects.
5.Consider the indication:Very little will be tol-
erated, in terms of side effects, for oral contra-
ceptives or other drugs to be used in young, fit
people early in life. The situation is different in
respect of anticancer drugs used late in life in
patients who have a disease with a poor prog-
nosis. Trimming down the indications and
claims made for the drug can materially affect
the benefit-to-risk ratio. In assessing this ratio,
consideration has to be given to the treatability
of any side effects, the drugs available to treat
the indication if the suspect drug is withdrawn
and the fate of those many patients using
the suspect drug with benefit and without
complaint.
6.The availability of additional data:The first
year after launch can be a difficult time as very
few of the important data sources are fully func-
tional apart from the yellow card scheme. Thus,
the Medical Department needs to monitor the
Drug Analysis Print very carefully and review
all Adverse Drug Reaction reports received by
the company with equal diligence. One cannot
set up case control or similar studies until one
knows what cases are relevant. Even then it
needs to be remembered that the GPRD covers
only a minor proportion of the population, so
cases may be few and far between in the first
months of the life of the drug. Prescription-
Event Monitoring (PEM) also tends to start
fairly slowly as there is a delay before the Pre-
scription Pricing Authority sends the first
batches of prescriptions to Southampton; then
there will be a delay of perhaps six months
before the first batches of the green form ques-
tionnaire are sent out. Doctors in Scotland tend
tobecautious aboutprescribing new drugssothe
record-linkage programs of the Medicines Eva-
luation and Monitoring Organization (MEMO)
also tend to get off to a slow start. The point is
that the yellow card data and the Drug Analysis
Printsneed tobewatchedlike ahawk.Ithasbeen
suggested that the DAP data should be reana-
lyzed to make their clinical significance easier to
understand and this exercise may well be worth
the time devoted to it (Mann, 2005). In respect of
matters in the United Kingdom the GPRD is of
special value, and one needs to know, at reason-
ably shortintervals,howmanyreportsofthenew
drug on the database and what those reports
comprise; it is a major feature of the database
that its data were collected before any alert
appeared – the data can be divided into two:
before and after the alert, that is before and after
gross bias distorted the picture.7.Consider the legal position carefully:The tests
are now onerous, because one must consider not
only negligence but also the Product Liability
Directive and the Consumer Protection Act with
its requirement that the product must be as safe
as the consumer might reasonably expect it to be.
Amongst others, the medical people need expert
and objective legal guidance. If one reads noth-
ing else in preparation for dealing with respon-
sibilities in this area it is wise to quietly read
through the approved judgment of Mr Justice
Mackay in the oral contraceptive litigation (Neu-
tral Citation No: (2002) EWHC 1420 (QB)).44.4 ESCAPING FROM THE MAZE 583