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The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development

Nature Reviews Drug Discovery volume 18, pages 82–84 (2019)Cite this article

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The low probability of success has resulted in such high costs for developing much-needed novel drugs for central nervous system (CNS) disorders that several major pharmaceutical companies have stopped investment in this area1. A key contributor is early-phase trial methods, which are slow and frequently mislead companies into pursuing extremely costly unsuccessful phase III studies1. The NIMH FAST-FAIL initiative sought to address this problem by supporting early-phase drug development methodologies designed to lower the risk of failure in large clinical trials. Under the auspices of the NIMH Fast Mood and Anxiety Disorders Program (Fast-MAS), we were the first to successfully implement this approach, applying it to assess the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia cross-diagnostically. In this article, we share the methodology we developed and the lessons we learned in the hopes that this will facilitate future applications of the 'fast-fail' approach, thus accelerating much-needed drug development.

The fast-fail approach is based on the premise that most candidate drugs will ultimately fail to be approved for their intended clinical application, so the goal should be to eliminate them earlier and at lower cost than is currently possible. It requires early-phase methodology to be modified so that it provides a more reliable basis for 'go/no-go' decision-making rooted in objective measures (Table 1).

Table 1 Summary of the 'fast-fail' approach to early-phase psychiatric drug development
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Acknowledgements

Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Contract HHS N271 2012 000006 I. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. D.A.P. was partially supported by R37MH068376 and R01MH101521.

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Authors and Affiliations

  1. University of California San Francisco, San Francisco, CA, USA

    Andrew D. Krystal

  2. Duke University School of Medicine, Durham, NC, USA

    Andrew D. Krystal, Richard Keefe, Allen Song, Sarah H. Lisanby, Moria Smoski, Richard Weiner & Steven Szabo

  3. McLean Hospital, Harvard Medical School, Belmont, MA, USA

    Diego A. Pizzagalli

  4. Baylor School of Medicine, Houston, TX, USA

    Sanjay J. Mathew & Wayne Goodman

  5. Yale University School of Medicine, New Haven, CT, USA

    Gerard Sanacora

  6. Case Western Reserve School of Medicine, Cleveland, OH, USA

    Joseph Calabrese

  7. National Institute of Mental Health, Bethesda, MD, USA

    Andrew Goddard, Sarah H. Lisanby & William Potter

  8. New York University School of Medicine, New York, NY, USA

    Dan Iosifescu

  9. Indiana University School of Medicine, Indianapolis, IN, USA

    John Nurnberger Jr & Anantha Shekhar

  10. Mount Sinai School of Medicine, New York, NY, USA

    James Murrough

Authors
  1. Andrew D. Krystal
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  2. Diego A. Pizzagalli
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  3. Sanjay J. Mathew
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  10. Sarah H. Lisanby
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  13. Dan Iosifescu
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  18. William Potter
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Corresponding author

Correspondence to Andrew D. Krystal.

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Competing interests

A. Krystal: Consultant: Adare, Eisai, Ferring, Galderma, Idorsia, Jazz, Janssen, Takeda, Merck, Neurocrine, Pernix, Physician's Seal; Research Support: NIH, Janssen, Jazz. Axsome, Reveal Biosensors.

D. Pizzagalli: Consulting: Akili Interactive Labs, BlackThorn Therapeutics, Boehreinger Ingelheim, Posit Science and Takeda Pharmaceuticals

S. Matthew: Consultant: Allergan, Alkermes, Sage Therapeutics; Research Support: Janssen, NIH, NeuroRx, VistaGen Therapeutics; Drug from Biohaven for NIMH funded study

G. Sanacora: Consulting: Allergan, Alkermes, AstraZeneca, Avanier Pharmaceuticals, Axsome Therapeutics Biohaven Pharmaceuticals, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Hoffman La-Roche, Intra-Cellular Therapies, Janssen, Merck, Naurex, Navitor Pharmaceuticals, Novartis, Noven Pharmaceuticals, Otsuka, Praxis Therapeutics, Sage Pharmaceuticals, Servier Pharmaceuticals, Taisho Pharmaceuticals, Teva, Valeant, and Vistagen Therapeutics; Research Funding: AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Johnson & Johnson, Hoffman La-Roche, Merck, Naurex, and Servier; Equity Interest: Biohaven Pharmaceuticals; Patent Royalties: Biohaven.

J. Murrough: Consultation: Boehreinger Ingelheim, Sage Therapeutics, Novartis, Allergan, Fortress Biotech, Janssen Research and Development, Medavante-Prophase, and Global Medical Education (GME); Research Support: Avanir Pharmaceuticals.

R. Keefe: Consultant, Speaker, or Advisory Board Member: Abbvie, Acadia, Aeglea, Akebia, Akili, Alkermes, Allergan, ArmaGen, Astellas, Avanir, AviNeuro/ChemRar, Axovant, Biogen, Boehringer-Ingelheim, Cerecor, CoMentis, Critical Path Institute, FORUM, Gammon Howard & Zeszotarski, Global Medical Education (GME), GW Pharmaceuticals, Intracellular Therapeutics, Janssen, Kempharm, Lundbeck, Lysogene, MedScape, Mentis Cura, Merck, Merrakris Therapetics, Minerva Neurosciences Inc., Mitsubishi, Montana State University, Monteris, Moscow Research Institute of Psychiatry, Neuralstem, Neuronix, Novartis, NY State Office of Mental Health, Orygen, Otsuka, Paradigm Testing, Percept Solutions, Pfizer, Pharm-Olam, Regenix Bio, Reviva, Roche, Sangamo, Sanofi, SOBI, Six Degrees Medical, Sunovion, Takeda, Targacept, Teague Rotenstreich Stanaland Fox & Holt, Thrombosis Research Institute, University of Moscow, University of Southern California, University of Texas Southwest Medical Center, WebMD, and Wilson Therapeutics; Research Funding: The National Institute of Mental Health and Boehringer-Ingelheim; Royalties: Versions of the BAC testing battery, the MATRICS Battery (BACS Symbol Coding), and the Virtual Reality Functional Capacity Assessment Tool (VRFCAT); Shareholder: NeuroCog Trials and Sengenix.

S.H. Lisanby: contributed to this article while at Duke University, prior to joining NIMH. The views expressed are her own and do not necessarily represent the views of the National Institutes of Health or the United States Government. Dr Lisanby is a co-inventor on a patent for TMS technology, unrelated to this manuscript.

J. Nurnberger: Research Funding: Janssen and Assurex

A. Song: Research Support: NIH, GE Healthcare

W. Goodman: Consulting: Biohaven Pharmaceuticals; Research funding: NIH, Simons Foundation and Biohaven Pharmaceuticals; Device Donation: Medtronic.

A. Goddard: Consultant: UpToDate, Biohaven Pharmaceuticals, Almatica Pharma; Research Funding: National Network of Depression Centers.

M. Smoski: None

R. Weiner: None.

S. Szabo: Consultant: Otsuka Pharmaceuticals, Neurocrine Biosciences, Jazz Pharmaceuticals, Teva Pharmaceuticals, Centers of Psychiatric Excellence, Continuous Precision Medicine; Research Support: Otsuka Pharmaceuticals

W. Potter: Advisory Board/Consultant: Takeda, Lilly, Praxis, Astellas, Otsuka and Noven: DSMB: Agene-Bio; Stock Ownership: Merck.

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Krystal, A., Pizzagalli, D., Mathew, S. et al. The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development. Nat Rev Drug Discov 18, 82–84 (2019). https://doi.org/10.1038/nrd.2018.222

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