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How should we design future mechanistic and/or efficacy clinical trials?

Neuropsychopharmacology volume 49, pages 197–204 (2024)Cite this article

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Abstract

The emergence of new molecular targets, together with the development of new approaches to neuropsychiatric diseases, involving psychedelics as well as gene and cell therapies, are creating the need to improve the efficiency of mechanistic and/or efficacy clinical trials. This review article will discuss a number of issues that have hampered our ability to detect therapeutic signals, from excessive placebo/sham response rates to the imprecision of diagnostic and outcome assessments. In addition to reviewing the limitations of current efficacy and mechanistic neuropsychiatric clinical trials, this review presents some of the methodological approaches that may improve the overall performance of our neuropsychiatric trials, including the adoption of novel study designs such as the sequential parallel comparison design and independent confirmation of the appropriateness of subjects’ enrollment. In addition, this review will discuss several designs that make mechanistic clinical trials more precise.

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Fig. 1: Sequential Parallel Comparison Design (SPCD).

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Authors and Affiliations

  1. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Maurizio Fava

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MF’s 3-year disclosures of competing interests—Research Support: AbbVie; Acadia Pharmaceuticals; Aditum Bio Management Company, LLC; Allergan, Alkermes, Inc.; Altimate Health Corporation; Alto Neuroscience, Inc.; Ancora Bio, Inc.; Angelini S.p.A; Aptinyx; Arbor Pharmaceuticals LLC; Avanir Pharmaceuticals Inc.; Axsome; Benckiser Pharmaceuticals, Inc.; BioClinica, Inc.; Biogen; BioHaven; BioShin Limited; Cambridge Science Corporation; Centrexion Therapeutics Corporation; Cerecor; Cybin IRL Limited; Damona Pharmaceuticals; EmbarkNeuro; Eliem Therapeutics LTD; Gate Neurosciences, Inc.; GenOmind, LLC; Gentelon, LLC; Gerbera Therapeutics, Inc.; Happify; Johnson & Johnson; Lundbeck Inc.; Marinus Pharmaceuticals; Medpace, Inc.; Methylation Sciences, Inc.; Millennium Pharmaceutics, Inc.; Minerva Neurosciences; Neuralstem; Neurocrine Biosciences, Inc.; NeuroRX Inc.; Novaremed; Novartis; Otsuka; Pfizer; Premiere Research International; Praxis Precision Medicines; Protagenic Therapeutics, Inc.; Relmada Therapeutics Inc.; Reckitt; Shenox Pharmaceuticals; Stanley Medical Research Institute (SMRI); Taisho; Takeda; University of Michigan; Vistagen; WinSanTor, Inc.; Xenon Pharmaceuticals, Inc.; National Institute of Drug Abuse (NIDA); National Institutes of Health (NIH); National Institute of Mental Health (NIMH); and PCORI. MF has not done any personal consulting. Any consulting he has done has been on behalf of Massachusetts General Hospital, except for Revival Therapeutics and Sensorium Therapeutics. Speaking/Publishing: lecture given at Global Medical Education, Inc. Mood Disorders Summit, November 2020. Stock/Other Financial Options: Equity Holdings: Compellis; Neuromity; Psy Therapeutics; Revival Therapeutics; Sensorium Therapeutics Royalty/patent, other income: patents for Sequential Parallel Comparison Design (SPCD) (US_7840419, US_7647235, US_7983936, US_8145504, US_8145505), all expired; patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to BioHaven. Patents for pharmacogenomics of Depression Treatment with Folate (US_9546401, US_9540691), licensed by MGH to Nestle. Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Belvior; Lippincott, Williams & Wilkins; Wolters Kluwer; World Scientific Publishing Co. Pte. Ltd. All lifetime disclosures can be viewed online by navigating to: https://mghcme.org/maurizio-fava-bio-disclosure/.

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Fava, M. How should we design future mechanistic and/or efficacy clinical trials?. Neuropsychopharmacol. 49, 197–204 (2024). https://doi.org/10.1038/s41386-023-01600-9

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