Randomized and Double-Blind Studies – Demands and Reality as Demonstrated by Two Examples of Mistletoe Research

Abstract

Background: Two examples of clinical research with mistletoe extracts were used to demonstrate essential difficulties in carrying out randomized and placebo-controlled trials. Study 1: In a randomized, placebo-controlled, double-blind study investigating the immunological effects of mistletoe extract, healthy subjects were asked to state whether, in their estimation, they had been treated with verum or a placebo. Due to the intrinsic effects of the mistletoe therapy – local inflammatory reactions at the injection site – 100% of the subjects treated with verum and 77% of those treated with a placebo made a correct assessment of their therapy. Although double-blind trials are preferable from the methodological point of view – above all in QoL research – this study shows that double blinding is barely achievable when the investigated therapy has obvious (side) effects. Study 2: A prospective, randomized, multicenter study of a mistletoe therapy complementary to chemotherapy treatment of breast cancer had to be stopped after a period of 28 months, because it proved impossible to recruit more than 16 patients in six large study centers. With regard to this example and to other failed, GCP-compliant clinical trials on mistletoe therapy we describe which factors interfere with successful clinical trials. One important point, especially in the investigation of complementary cancer treatments, is that cancer patients are unwilling to have their treatment determined by randomization. Many cancer patients in Germany have their own point of view, as to whether a complementary treatment could be of benefit to them or not. Faced with a life-threatening disease they wish to determine this part of their treatment themselves. Conclusion: This background elucidates the need for improving the methodology of non-randomized trials to obtain objective and reliable results even in these fields of clinical research.

Efficacy and Safety of Mistletoe Preparations (Viscum album) for Patients with Cancer Diseases

“…observational) as well, and so it would not have been a general quality score. The decision to include observational studies was based on the fact that problems with recruiting patients for randomised trials on mistletoe have repeatedly been reported [60][61][62]. Hence, observational trials which have been performed in the last years, give at least some additional information close to daily medical practice.…”

“…Additionally, one could question the possible blinding of trials on mistletoe because patients might know from various sources that injecting mistletoe extracts can cause local reactions. As a matter of fact, it has been published that the majority of study participants were able to correctly identify whether Supportive Mistletoe Therapy for Patients with Cancer Disease 221 they had received mistletoe or placebo [61] and local side-effects are common [75]. Moreover, awareness of randomisation can controvert greatly a patient's intention for a specific therapy.…”

“…Explicitly choosing a therapy that contradicts a patient's own subjective vision [63] can be a significant factor regarding efficacy, which seems specifically associated with the use of mistletoe and cannot be casually transferred to comparable therapies or placebo treatments. Therefore, requirement for randomisation can deter a considerable percentage of patients intending to use mistletoe treatment from participating in a study [60,61]. This relativises the principle of randomisation as a criterion of quality in the context of mistletoe treatment.…”

Prospective Controlled Cohort Studies on Long-Term Therapy of Breast Cancer Patients with a Mistletoe Preparation (Iscador®)

“…The first feature is an important add-on to the existing literature; most of the 14 studies mentioned above were based on rather short terms of therapy (≤12 months) compared with the established long-time use. The second feature might present a solution to a problem well known among investigators of mistletoe therapies, in particular Iscador therapy [6,7]: At least in German-speaking countries, female patients are well informed about different options of complementary therapy and have often made up their mind concerning these before they are even asked to participate in a study. Furthermore, many patients who use mistletoe therapy are highly motivated and of a different socioeconomic, educational and medical background than patients who use only conventional treatment [8].…”

Klinische Forschung zur Anthroposophischen Medizin – Update eines «Health Technology Assessment»-Berichts und Status Quo

“…Dennoch können wir eine Vollständigkeit der Studienerfassung nicht garantieren und halten sie auch nicht für wahrscheinlich: Viele Studien zur AM sind nicht als solche klassifiziert und deshalb nur schwer zu finden; auch werden Studien zur AM bisweilen nicht oder nur als Zusammenfassung publiziert und sind oft nicht in öffentlichen Datenbanken gelistet und identifiziert. Darüber hinaus ist es möglich, dass Studien mit negativem Ergebnis, insbesondere wenn sie Herstellerinteressen betreffen, eventuell nicht publiziert werden [72] [70,71]. Eine mögliche Alternative zur Verblindung ist die Behandlung der Kontrollgruppe mit einer anderen wirksamen Therapie, wie sie in manchen der Studien realisiert wurde, was dann allerdings nur eine ungefähre und relative Einschätzung der Wirkgröße ermöglicht.…”