The placebo arm in clinical studies for treatment of psychiatric disorders: a regulatory dilemma.
BACKGROUND
The use of placebo in clinical trials, and, related to this, ethical and feasibility aspects, are often debated. However, regulatory authorities must ensure that only new drugs with a positive benefit/risk would be granted a marketing authorization. It is therefore not surprising that they often put forward the need for placebo control in clinical trials in an area where many trials fail, and assay sensitivity is not self-evident. To illustrate the complexity that regulatory authorities encounter when faced with the registration dossier of products in the main psychiatric therapeutic areas, Major Depressive Disorder (MDD) and schizophrenia, the trial outcome for products receiving an opinion in the EU during the past 15 years were reviewed.


METHODS
European Public Assessment Reports and registration files.


RESULTS
A total of 45 studies qualified for analysis. For the indication MDD 38% of the studies (10/26) were recorded as failed, and another 15% (4/26) as negative. For schizophrenia, these figures were 16% (3/19) and 11% (2/19). Further exploration of the trials in MDD revealed an inconsistent pattern in terms of magnitude of placebo- and drug-mediated response (i.e. similar studies with consistent placebo response provided different treatment outcomes).


CONCLUSIONS
From a regulatory perspective the dilemma of a priori exclusion of the placebo arm in clinical trials in the domains of depression or schizophrenia cannot be solved at this time as long as factors influencing trial variability are not better identified or understood. This counts in particular for MDD where the added drug effect is not consistent across trials with almost identical inclusion criteria. Unfortunately, this trend has not changed over the past 15 years. However, all efforts should be taken to optimize the clinical development of drugs in the psychiatric domain, and improve the intrinsic quality of the clinical trials in order to allow for a different viewpoint.
Medicines Evaluation Board, Utrecht, The Netherlands. cc.gispen@cbg-meb.nl
Christine
C
Gispen-de Wied
Violeta
V
Stoyanova
Yang
Y
Yu
Maria
M
Isaac
Luca
L
Pani
Fernando
F
de Andres-Trelles
D000928:Antidepressive Agents / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D018849:Controlled Clinical Trials as Topic / Q000941:ethics / Q000331:legislation & jurisprudence / Q000592:standards*; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000523:psychology*; D004351:Drug Resistance; D015507:Drugs, Investigational / Q000627:therapeutic use*; D005062:European Union; D006801:Humans; D015990:Placebo Effect; D011600:Psychopharmacology / Q000941:ethics / Q000331:legislation & jurisprudence / Q000379:methods; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000188:drug therapy; D012565:Schizophrenic Psychology
D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D015507:Drugs, Investigational