"In a randomized withdrawal study, patients who have an apparent response to treatment in an open-label period or in the treatment arm of a randomized trial are randomized to continued drug treatment or to placebo treatment. Because such trials generally involve only patients who appear to have responded, this is a study enriched with apparent responders, an empiric strategy. The study evaluation can be based on signs or symptoms during a specified interval (e.g., BP, angina rate), on recurrence of a condition that had been controlled by the drug (e.g., depression), or on the fraction of patients developing a rate or severity of symptoms that exceeds some specified limit (i.e., a failure criterion). "
Even though the FDA encourages the use of the randomized withdrawal design in clinical trials, the use of RWD is still very limited, especially in pivotal, confirmatory studies. The reluctance in using the RWD is usually due to the safety concern - it will be perceived as unethical to discontinue the experimental treatment in the Placebo group when the experimental treatment has just been shown to be effective. Another concern is the size of the safety database - there is usually a sufficient number of patients exposed to the experimental drug so that the safety can be adequately assessed (see a previous post "The Size of Safety Database In Drug Development Program")
In the recent issue of the New England Journal of Medicine, the results of the HARMONY study (sponsored by Acadia Pharmaceuticals) were published: Tariot et al "Trial of Pimavanserin in Dementia-Related Psychosis". While the term 'randomized withdrawal' was not explicitly used in the study, the HARMONY study was a randomized withdrawal study and was described as the following:"a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms–Hallucinations and Delusions (SAPS–H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression–Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. "As we can see from the study design diagram below, all patients received pimavanserin during the open-label period. Those subjects who had responses to the pimavanserin (i.e., reduction in SAPS-H+D) were randomized to continue the treatment of pimavanserin or withdraw the treatment of pimavanserin (i.e., receiving the placebo).
Study Protocol [PDF] July 16, 2010Statistical Analysis Plan [PDF] August 5, 2014
With the HARMONY study using a randomized withdrawal design, the sponsor was able to demonstrate the efficacy of pimavanserin in treating patients with dementia-related psychosis. The reduced sample size due to the use of the randomized withdrawal design was further reduced after the sponsor stopped the study early for positive efficacy. The sponsor subsequently submitted the sNDA for pimavanserin in treating patients with dementia-related psychosis. Unfortunately, they received a complete response letter from FDA citing the reasons not related to the study design but related to the insufficient sample size for certain sub-groups.
- ACADIA Pharmaceuticals Announces Pivotal Phase 3 HARMONY Trial Stopped Early for Positive Efficacy as Pimavanserin Meets the Primary Endpoint in Patients with Dementia-Related Psychosis
- ACADIA Pharmaceuticals Announces U.S. FDA Accepted for Filing the Supplemental New Drug Application for NUPLAZID® (pimavanserin) for the Treatment of Hallucinations and Delusions Associated with Dementia-Related Psychosis
- Acadia Pharmaceuticals Receives Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Pimavanserin for the Treatment of Hallucinations and Delusions Associated with Dementia-Related Psychosis
- Furious Acadia takes shot at FDA, alleging sudden about-face in costly Nuplazid rejection
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The FDA guidance "Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness of Human Drugs and Biological Products" mentions the Randomized Withdrawal Design (RWD) as one of the enrichment strategies that "allow us to reduce the sample size of the study while demonstrating the efficacy of the experimental drug." Knowledgeable article.
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