Safety case-control studies

Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT A population-based case-control study of the safety of oral anti-tuberculosis drug treatment during pregnancy. Int J Tu-berc Lung Dis 2001 5 564-568. 

There is little doubt, on the one hand, that case-control studies have a valuable place in pharmacoepidemiology, and therefore in the evaluation of drug safety. There is also little doubt that without minute attention to detail and, possibly, a little luck, the method may be unreliable or even completely misleading. A list of... 

Kammersgaard L. P., Rasmussen B. H., Jorgensen H. S., Reith J., Weber U., and Olsen T. S. (2000) Feasibility and safety of inducing modest hypothermia in awake patients with acute stroke through surface cooling a case-control study the Copenhagen Stroke Study. Stroke 31, 2251-2256. 

Other data sets, with a broader coverage of jobs throughout the population, are likely to be needed for estimation of pesticide exposures in case-control studies. For example, Stewart and co-workers (Stewart and Stewart, 1994 Stewart et al, 1998) have used detailed occupational questionnaires with job-specific modules, together with data from the US Occupational Safety and Health Administration (OSHA) Integrated Management Information System to aid in assigning study subjects exposures to multiple chemicals, including pesticides. 

There has been some concern that the shorter-acting calcium channel blockers may adversely affect the risk of myocardial infarction and cardiac death. The evidence is based on case-control studies which cannot escape the possibility that sicker patients, i.e. with worse hypertension or angina, received calcium charmel blockade. The safety and efficacy of the class has been strengthened by the recent findings of two prospective comparisons with other antihypertensives. ... 

The 1994 report of the Institute of Medicine concluded that the evidence was inadequate to accept or reject a causal relation between MMR and encephalopathy, and it is known that the incidence of encephalitis after measles immunization of healthy children tends to be lower than the observed incidence of encephalitis of unknown cause. Two large studies have been negative. In a study analogous to the British Childhood Encephalopathy Study there were no increased risks of either encephalopathy or neurological sequelae after measles immunization (19). A retrospective case-control study through the CDC Vaccine Safety DataUnk assessing the risk for 300 000 doses of MMR found not a single case of encephalitis/ encephalopathy within 30 days of the administration of MMR (20). In contrast, the review mentioned above (18) reported an association between measles vaccine and encephalopathy. However, the conclusion of the report of the Institute of Medicine is still valid, namely that evidence is stiU inadequate to accept or reject a causal relation between measles vaccine and these diseases. 

The renal safety of aspirin used as single ingredient is easier to evaluate. From the seven case-control studies, only 3 showed an increased risk. All 3 suffered from the same ingredient bias as previously mentioned for paracetamol. In contrast however, both observational studies reported a robust, slightly decreased, odds ratio for the use of aspirin (Figure 1). In both studies, calculated odds ratio s were based on hundreds of regular users of aspirin [41, 42]. 

Case-control studies have been used extensively to assess the safety of pharmaceuticals. There are many examples of case-control studies that have identified important associations between drugs and adverse health events vaginal cancer and diethylstilbestrol, Reye s syndrome and aspirin, peptic ulcer disease and nonsteroidal antiinflammatory drugs, and venous thromboembolism and oral contraceptives. Data from case-control studies are used to calculate an odds ratio, which is the ratio of the odds of developing the disease for exposed patients to the odds of developing the disease for unexposed patients. 

Although randomized, controlled trials form the basis for some of the most reliable assessments of drug safety, pregnant women usually are not eligible for participation in clinical trials. Other types of data often are used to estimate the risk associated with medication use during pregnancy, such as animal studies, case reports, case-control studies, prospective cohort studies, historical cohort studies, and voluntary reporting systems. 

On the other hand, certain drugs have gone through the fast-track process and, at the time of authorisation, information on the safety of these medications has been limited, especially for children. In such cases non-interventional observations such as cohort or case-control studies could be a valuable tool to evaluate adverse events. 

Concerns regarding potential HPV vaccine safety in systemic lupus erythematosus (SLE) patients were addressed by a prospective case-control study which evaluated the quadrivalent HPV vaccine. Fifty SLE patients were compared to 50 healthy controls. Importantly, no increase in SLE disease activity was observed in the 12-month follow-up period. However, seroconversion rates of antibodies to HPV serotypes (6,11,16 and 18) for the SLE group were lower than the control group, and the role of immunosuppressive therapy in SLE needs furtiier investigation [11 ]. 

---