The placebo-controlled trial has been the standard method to demonstrate efficacy and safety of antipsychotic drugs. We reviewed the scientific and ethical advantages and disadvantages of the placebo-controlled trial and an alternative method, the active-control trial, focusing more specifically on the active-control noninferiority trial. Recent meta-analyses indicate that a therapeutic dose of second-generation antipsychotic will very likely be statistically superior to placebo in an adequate trial, and that the average improvement of schizophrenia symptoms in a placebo arm will be small. These findings strengthen the scientific and ethical justification for the active-control noninferiority trial. New drugs in the pharmacotherapy for schizophrenia are often claimed to differ from their marketed competitors in their safety profile rather than in antipsychotic efficacy. Thus, in many cases, it appears sufficient to demonstrate mere noninferiority (rather than superiority) of antipsychotic efficacy in comparison with a standard antipsychotic. The active-control noninferiority trial is suitable for such demonstration. Sample size requirements for various equivalence margins in noninferiority trials are provided. Scientific and ethical arguments should lead to a more frequent use of the active-control noninferiority trial design.
Thank you for submitting a comment on this article. It will be reviewed by JAMA Psychiatry editors. You will be notified when your comment has been published. Comments should not exceed 500 words of text and 10 references.
Do not submit personal medical questions or information that could identify a specific patient, questions about a particular case, or general inquiries to an author. Only content that has not been published, posted, or submitted elsewhere should be submitted. By submitting this Comment, you and any coauthors transfer copyright to the journal if your Comment is posted.
* = Required Field
Disclosure of Any Conflicts of Interest*
Indicate all relevant conflicts of interest of each author below, including all relevant financial interests, activities, and relationships within the past 3 years including, but not limited to, employment, affiliation, grants or funding, consultancies, honoraria or payment, speakers’ bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued. If all authors have none, check "No potential conflicts or relevant financial interests" in the box below. Please also indicate any funding received in support of this work. The information will be posted with your response.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Web of Science® Times Cited: 26
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
Enter your username and email address. We'll send you a link to reset your password.
Enter your username and email address. We'll send instructions on how to reset your password to the email address we have on record.
Athens and Shibboleth are access management services that provide single sign-on to protected resources. They replace the multiple user names and passwords necessary to access subscription-based content with a single user name and password that can be entered once per session. It operates independently of a user's location or IP address. If your institution uses Athens or Shibboleth authentication, please contact your site administrator to receive your user name and password.