Introduction - Uppsala Monitoring Centre

during clinical trials. There are numerous factors, which influence the time to
withdrawal:
1. Incidence rate: type ‘A’ reactions discovered early; type ’B’ discovered late.
2. Strength of evidence: the strongest evidence is from clinical trials, then cohort
studies, case-control studies, case series and finally case reports. The main
source of information for the restriction/withdrawal of drugs are case reports
(Venning III, 1983; Arnaiz, 2001; Clarke, 2006).
3. Failure to follow-up initial signals (Loke et al., 2006).
4. Causality: if we wait for certainty too many people die, if we act on probability
some people will be deprived of help.
5. Alternative treatments: e.g. streptomycin was less ototoxic (cochlea-toxic), but
more vestibule-toxic than di-hydro-streptomycin. The marketing of a new and
safer drug for the same indication may alter the balance of benefit/risk.
6. Efficacy: drugs can be marketed if they are more active than placebo, even if
they are inferior to those already on the market. The inefficacy of old treatments
meant many suffered ADRs unnecessarily, e.g. bleeding.
7. Number of persons who take the drug: this combined with the incidence gives
an approximate proportion of patients who suffered the ADR. Aggressive
marketing of a new drug allows a large number of patients to be treated within
the first few years of marketing and therefore there will be an increased
likelihood that any type ‘B’ ADRs will be discovered early.
8. Availability of databases: none available prior to 1960?
9. Establishment of a clinical entity: erythema multiforme 1866, Stevens-Johnson
syndrome 1922, aplastic anaemia 1888, arterial hypertension 1893,
agranulocytosis 1922, acrodynia 1830, and Reye’s syndrome 1962.
10. Countries in which it is marketed: The more developed countries in which the
drug is marketed the more likely the ADR will be discovered early. If only
marketed in a single country discovery is likely to be delayed. Different
countries are likely to have different ‘toxic thresholds’ (Bakke et al., 1984).
11. Reaction of manufacturer: if a company initiates a prospective safety study, it
will be difficult for a regulatory authority to take decisive action before the study
has reached a conclusion, e.g. amidopyrine and Hoechst in 1980.
12. Cost of treatment: cheap toxic drugs have remained on the market despite the
availability of safer more expensive drugs.
13. Extrapolation from animals to humans:
a. carcinogenicity, e.g. chloral hydrate, phenolphthalein, methapyrilene,
dantron and chloroform
b. other, e.g. chloroform fatalities
14. Class effects allowing potential predictability: pyrazolones/pyrazolidines,
e.g. amidopyrine, dipyrone, butazolidines; MAO inhibitors, e.g. iproniazid