S-58-01

Placebo controlled studies to establish efficacy and safety of antidepressants: Regulatory requirements for the development of antidepressive drugs

K. Broich, A. Koch. Bundesinstitut für Arzneimittel. Bonn, Germany

Objective: Controlled, randomized, double-blind parallelgroup clinical trials are needed to establish efficacy and safety of new antidepressants. Usually this is done by clinical trials including placebo control. These placebo controlled trials have been critizized as being unethical in clinical situations where effective and acceptable treatment options are available. It has been argued that studies with potential new antidepressants should employ only a comparator-controlled design, whereby new drugs have to be non-inferior or superior to existing treatment. However, sole acceptance of ,,superior" compounds will hinder the development of more efficacious and better tolerated drugs. Moreover, acceptance of non-inferiority designs in psychopharmacology will be associated with the risk to approve ineffective compounds. In general both active-controlled designs require the inclusion of larger patient populations. Therefore from a regulatory point of view placebo-controlled studies of new antidepressants are still justified and necessary, both ethically and scientifically. However, it has to be secured that patients are not harmed by the act of forgoing established treatment options and did provide fully informed consent. The methodological and ethical rationales for the requirement of placebo-controlled trials with antidepressants are reviewed.

S-58-02

Placebo-controlled studies in depression: Necessary, ethical and feasible

D. Baldwin. Royal South Hampshire Hospital, Southhampton, United Kingdom

Objective: Placebo-controlled trials are used widely in the development of new pharmacological treatments. They have sometimes been challenged as being unethical, in clinical situations where patients can receive an existing effective and acceptable treatment.

Methods: It has been argued that studies of potential antidepressants should employ only a comparator-controlled design, whereby new compounds have to be found at least as efficacious as existing treatments. By contrast, others have argued that sole use of comparator-controlled trials is itself unethical, as more patients will be exposed to potentially unhelpful treatments.

Results: This presentation reviews the rationale for conducting placebo-controlled treatment studies in depressed patients, examines the underlying ethical issues, and describes the provisions that should be applied when investigating the efficacy and tolerability of potentially valuable new antidepressant treatments.

Conclusion: A European Expert Forum on Placebo-Controlled Studies in Depression (Baldwin et al., 2003) has concluded that placebo-Controlled studies of new antidepressants are justified, both scientifically and ethically. Restrictions on placebo-controlled investigations will hinder the arrival of more efficacious and better tolerated antidepressants. Reference Baldwin DS, Broich K, Fritze J, Kasper S. Westenberg H, M~ller H-J, on behalf of the European Expert Forum on Placebo-Controlled Studies in Depression. Placebo-controlled studies in depression: necessary, ethical and feasible. European Archives of Psychiatry and Clinical Neuroscience 2003; 253: 22-28.

S-58-03

Placebo-controlled studies in depression from the patient's point of view: Efficacy and safety

S. Kasper, R. Frey. Medizinische Universitdt Allgem. Psychiatrie, Wien, Austria

Objective: Placebo response can be attributed to non-specific measurements as well as in connection to spontaneuos outcome. In large pools of placebo-controlled trials, it has been demonstrated that there is a negative correlation between mean baseline Hamilton Score and change scores in depression ratings which indicate that higher severity of depression is associated with a lower placebo rate. Epidemiological data indicated that the placebo response cannot be attributed to factors such as gender, age, smoking or personality variables (obsessive vs. histrionic). The placebo effect appears to be a contextual-situational phenomenon which is more likely than an enduring personality trait and the specific physicianpatient relationship can be discussed within the most important factors of placebo-nocebo response. Therefore, it seems to be necessary to standardize the patient-doctor relationship and there is also the necessity to measure expectations prior to the start of treatment. Placebo can also be viewed as a symbolic value since placebo-treated patients receive all the ,,healer's" commitment, enthusiasm and positive reward. There are several myths associated with placebo treatment, e.g. there should be a reduced recovery from placebo treatment which has not been demonstrated, at least in the last ten years and furthermore, there seems a myth of attempted of completed suicide rates which also cannot be demonstrated in randomized controlled trials. For placebocontrolled studies, from a patient's perspective, it's necessary for researchers to include safeguards, standardized exit criteria, informed consent etc. to avoid a detrimental outcome.

S-58-04

The feasibility of placebo-controlled studies in depression in Europe: A survey by GlaxoSmithKline

D. Angersbach. GlaxoSmithKline GmbH & Co. KG Medizinische Abteilung, München, Germany

Despite the availability of rous effective antidepressants, psychiatrists agree that in everyday clinical practice there is a large need of still more potent substances. From a scientific point of view, placebo-controlled, double-blind studies are inevitable in having new drugs approved for marketing and they are actually a regulatory requirement. In a "Note of Clarification" on the Declaration of Helsinki, the World Medical Association (WMA) clarified that on certain conditions, which also apply to antidepressants, placebo-controlled studies are admissible from an ethical point of view, even if effective drugs are available. In order to explore the feasibility of such studies in Europe, a survey was conducted in more than 900 psychiatric centers (psychiatrists established in private practices, smaller hospitals and university hospitals) in 21 European countries to examine their interest and potential for participating in such studies with predefined study designs. Just over half of the 331 centers answering the survey were interested in participating, but no more than every other of these centers expected the respective ethics committee to provide an approval for such a study. However, even among this diminished number of centers it is believed that about 800 depressive patients could be screened for a two-armed, phase II study and about 1200 for a three-armed phase III study within one year. The rous centers which were unsure about the ethics committee's opinion to be expected might involve a large potential for contributing additional patients.