Retrolective, comparative, epidemiological cohort study with parallel groups design for evaluation of efficacy and safety of drugs with "well-established use".

Unlabelled: The randomized controlled clinical trial (RCT) is accepted as the "golden standard" for the evaluation of efficacy and safety of new drugs. In contrast, to demonstrate efficacy and safety of drugs with "well-established use" that have been on the European Community market for long time, observational comparative epidemiological studies can be used according to the European drug regulation directive. However, because comparative epidemiological cohort studies can share some risk of bias with other nonrandomized observational study designs, there is a need for an approach that could effectively reduce the bias risk in this type of studies.

Study objectives: The purpose of the study was to evaluate the therapeutic efficacy and safety of a long-term complementary therapy of primary, non-metastatic breast carcinoma patients treated with standardized European mistletoe extract Iscador("mistletoe") in addition to the conventional adjuvant oncologic therapy, and compared to the control group treated with the conventional therapy alone.

Methods: The multicenter, comparative, retrolective, pharmaco-epidemiological cohort study with parallel groups design and randomly selected centers that routinely used both treatments was carried out according to Good Epidemiological Practice rules under a standard operating procedure control. The test group patients received the mistletoe extract treatment subcutaneously for at least 3 months, while the control group patients of the same cohort was exclusively treated with the conventional therapy. The patients were followed up for at least 3 years or until death. The primary endpoint of efficacy was the incidence of adverse reactions to the conventional oncologic therapy. Secondary endpoints were change from baseline of the symptoms associated with the disease and treatment as well as overall survival. All endpoints were adjusted to baseline imbalance and confounders. Safety was assessed descriptively by the number of patients with adverse drug reactions (ADRs) attributed to the test treatment.

Results: 1442 patients (710 tests and 732 controls) were eligible for the "per protocol" analysis of efficacy and safety. At baseline, the test group had a more advanced disease and worse prognostic factors profile. After a median follow-up of 66 vs. 60 months, and a median mistletoe therapy duration of 52 months, significantly fewer test group patients (16.2%) than control patients (54.0%) developed ADRs attributed to the conventional therapy [adjusted odds ratio, OR (95% confidence interval, CI), OR = 0.47 (0.32-0.67), p < 0.001]. In the test group, the majority of the symptoms disappeared more frequently, and overall mortality hazard was significantly lower [adjusted hazard ratio, HR (95% CI), HR = 0.46 (0.22-0.96), p = 0.038] than in the control group. Systemic ADRs attributed to the test treatment developed in 0.8%, and local ADRs in 17.3% of the patients. ADR severity was mild to intermediate. Tumor enhancement was not observed.

Conclusions: Complementary therapy of patients with primary, non-metastatic breast carcinoma with the mistletoe extract Iscador was safe and in comparison to the control group within the same study cohort showed considerably fewer ADRs attributed to concurrent conventional therapy, reduced disease symptoms, and suggested a significant improvement of survival. Despite some methodical limitations that require careful study planning and conduction as well as critical interpretation, the applied study design seems suitable to evaluate the efficacy and safety of drugs with "well-established use", particularly in oncology.