Introduction - Uppsala Monitoring Centre

otation.
The lack of databases prior to 1960 meant that were very few retrospective
cohort studies.
4. Randomised controlled clinical trials.
1. The 1944 patulin trial in the common cold of the British Medical Research
Council: the doctor and the patient were blinded to the nature of the contents
of each treatment bottle and to the code letter for the treatment. Special
precautions were taken in addition to using four treatment codes—Q, R, S,
and T. A nurse made the allocations in strict rotation in a separate room, filed
the record counterfoil there, and detached the code label for the appropriate
bottle (which the patient retained throughout the trial) before returning the
patient to the doctor. The statisticians passed this as an effectively random
concurrent allocation of patulin or control solution to the participants, but 95
patients were given patulin and 85 given placebo, which suggests the
allocation system was faulty.
2. The 1948 MRC trial of streptomycin. The investigator allocated the
treatment by means of randomisation numbers and the use of concealed
envelopes.
The collection of adverse events during a clinical trial for both the active group and a
placebo group reveals how false the ‘adverse reactions’ frequency found in a cohort
study without a control group can be. In a low dose Aspirin trial, with 22, 071
patients, comparing 325 mgm Aspirin on alternate days with placebo the figure for
gastrointestinal discomfort was 26.1% on Aspirin and 25.6% on placebo and for
bleeding problems 27.0% for the Aspirin group and 20.4% for the placebo group.
This difference was statistically significant (Physicians’ Health Study Research
Group, 1989; Amery, 1994). How many patients had a bleeding problem because of
Aspirin? If one used the figure obtained from the Aspirin group alone the incidence
would be approximately four times higher than the incidence when the placebo
group was considered in the analysis. A sub-group of clinical trials: large simple
randomised controlled studies are useful for detection excess mortality due to the
drug, e.g. Clofibrate v placebo (Committee of Principal Investigators, 1980),
Salmeterol v Salbutamol (Castle et al., 1993). Randomised controlled clinical trials
played very little part in the period covered in this book. These are useful for
determining common ADRs, but rarely have sufficient numbers to detect very rare,
but important ADRs.
Books on the side-effects and abuse of drugs
The first book dedicated only to side-effects and covering several drugs was
Guérard’s thesis (55 pages) in 1862 followed by a fellow countryman’s thesis,
Berenguier (59 pages) in 1874, covering dermatological effects for 12 and 7 drugs
respectively. This presaged the first major book covering all major drugs and all