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Off-Label Promotion of Transcranial Magnetic Stimulation on Provider Websites

  • Anna Wexler
    Correspondence
    Corresponding author. Blockley Hall, 423 Guardian Drive, University of Pennsylvania, Philadelphia, PA, 19104, USA.
    Affiliations
    Department of Medical Ethics & Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Ashwini Nagappan
    Affiliations
    Department of Medical Ethics & Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
    Department of Health Policy and Management, UCLA Fielding School of Public Health, Los Angeles, CA, USA
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  • Deena Kopyto
    Affiliations
    Department of Medical Ethics & Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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  • Emiliano Santarnecchi
    Affiliations
    Berenson-Allen Center for Non-Invasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
    Department of Neurology, Harvard Medical School, Boston, MA, USA
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  • Alvaro Pascual-Leone
    Affiliations
    Department of Neurology, Harvard Medical School, Boston, MA, USA
    Hinda and Arthur Marcus Institute for Aging Research and Deanna and Sidney Wolk Center for Memory Health, Hebrew SeniorLife, Boston, MA, USA
    Guttmann Brain Health Institute, Institut Guttmann, Institut Universitari de Neurorehabilitació adscrit a la UAB, Badalona, Barcelona, Spain
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Open AccessPublished:April 22, 2021DOI:https://doi.org/10.1016/j.brs.2021.04.013
      Since 2008, several transcranial magnetic stimulation (TMS) devices and protocols have been cleared by the Food and Drug Administration (FDA) for treatment-resistant depression, severe migraines, obsessive-compulsive disorder (OCD), and smoking cessation. A variety of TMS stimulation protocols targeting different brain regions are being studied for their potential to treat other psychiatric and neurological conditions. While device manufacturers cannot legally promote TMS for off-label indications, providers face no analogous restrictions [
      • Dresser R.
      • Frader J.
      Off-label prescribing: a call for heightened professional and government oversight.
      ]. Promotion by providers of off-label uses of TMS raises ethical concerns [
      • Horvath J.C.
      • Perez J.M.
      • Forrow L.
      • Fregni F.
      • Pascual-Leone A.
      Transcranial magnetic stimulation: a historical evaluation and future prognosis of therapeutically relevant ethical concerns.
      ], but there are no published empirical data about this phenomenon. We aimed to address this knowledge gap by analyzing the websites of clinics offering TMS in the United States (U.S.).
      We identified eight online directories of TMS clinics by conducting Google searches for relevant keywords (e.g., directory, TMS, clinic) and examining results. Two directories were excluded: one required entry of a zip code prior to retrieving clinic details and another did not provide websites. Of the six directories included, three were from TMS device manufacturers: Brainsway (https://www.brainsway.com/find-a-provider), CloudTMS (mycloudtms.com/providers), and MagVenture (https://www.magventure.com/us/find-provider); one was hosted by a professional clinical society (https://www.clinicaltmssociety.org/providers); another was a pay-for-listing directory (https://tmstherapynearme.com/), and one was owned by a marketing firm (http://tmsyou.com/directory/).
      All individual clinic listings from these directories (N = 2,222; not excluding duplicates) were reviewed by a single coder between February and June 2020, and included in our sample if the clinic was based in the U.S. and had a website that mentioned the provision of any kind of TMS for an off-label indication. Websites stating that research was ongoing for a condition (e.g., “TMS is being studied for Alzheimer’s”) without touting benefits were excluded. Two coders coded all unique resultant websites for off-label indications (N = 104), as well as the provision of other therapies commonly defined as complementary and alternative medicine (CAM) [
      • Wieland L.S.
      • Manheimer E.
      • Berman B.M.
      Development and classification of an operational definition of complementary and alternative medicine for the Cochrane collaboration.
      ]. A subset of websites (n = 28) were double-coded to assess interrater reliability (IRR; 87.8%).
      Table 1 depicts the most common off-label indications offered by the identified clinics (N = 104). The language used when mentioning off-label indications varied considerably. Some clinics made misleading claims with regard to regulatory status, such as incorrectly stating that TMS is FDA approved for certain indications. Others misrepresented the nature of the evidence base, falsely claiming that TMS has “proven to be effective” for certain indications. Still others cited their clinic’s success in treating off-label indications, such as claiming that their “personalized treatment options” for a wide variety of indications are “proving successful.” The most conservative clinics noted that certain indications were off-label or experimental, but did so in a visual manner—such as listing the off-label indications in a large font size, centered in the middle of the page—wherein the overwhelming impression (as judged by three authors—AN, DK, and AW) was that the clinic was promoting the use of TMS for these off-label indications.
      Table 1Top off-label clinical indications referenced by TMS clinic websites in our sample (N = 104).
      Clinical indications referenced by <5.0% of websites include epilepsy, Tourette’s syndrome, traumatic brain injury, and sleep disorders.
      Off-label indicationNo. (%)
      Anxiety/panic attacks70 (67.3)
      Post-traumatic stress disorder (PTSD)/trauma62 (59.6)
      Bipolar disorder52 (50.0)
      Addiction/substance use disorder46 (44.2)
      Pain/fibromyalgia43 (41.3)
      Schizophrenia/hallucinations31 (29.8)
      Autism30 (28.8)
      Parkinson’s disease26 (25.0)
      Attention-deficit disorder (ADD)/attention-deficit hyperactivity disorder (ADHD)24 (23.1)
      Tinnitus22 (21.2)
      Stroke20 (19.2)
      Multiple sclerosis18 (17.3)
      Eating disorders17 (16.3)
      Alzheimer’s disease16 (15.4)
      Dementia9 (8.7)
      Mild cognitive impairment/cognitive decline6 (5.8)
      a Clinical indications referenced by <5.0% of websites include epilepsy, Tourette’s syndrome, traumatic brain injury, and sleep disorders.
      In addition, nine clinics (8.7%) offered TMS for non-therapeutic cognitive or performance enhancement and 44 (42.3%) offered other CAM therapies, such as acupuncture, biofeedback, and intravenous nutrient therapy.
      Although physicians may legally provide off-label therapeutics, the public promotion of off-label uses is an ethical gray area. Some of the off-label TMS indications promoted by providers—including autism, post-traumatic stress disorder, and tinnitus—have a weaker body of scientific evidence supporting efficacy than others, like bipolar disorder and anxiety [
      • Lefaucheur J.-P.
      • Aleman A.
      • Baeken C.
      • Benninger D.H.
      • Brunelin J.
      • Lazzaro V.D.
      • et al.
      Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014–2018).
      ]. We suggest that ethical concerns exist on a continuum, with the weaker the evidence base for an off-label indication, the greater the responsibility of providers to be transparent about efficacy and to exercise restraint when promoting its use [
      • Largent E.A.
      • Miller F.G.
      • Pearson S.D.
      Going off-label without venturing off-course: evidence and ethical off-label prescribing.
      ]. This is a particularly great imperative given providers’ conflict of interest related to the income associated with offering TMS, and the financial burden passed to the patient due to lack of insurance coverage for off-label indications.
      Study limitations include the fact that our sample was biased towards providers who maintain websites and those listed in one of the six directories analyzed. Furthermore, our data did not capture off-label use across devices and protocols, such as those who use TMS devices and protocols that have been cleared for one indication (e.g., the Brainsway Deep TMS device with a specific H-coil for medication-resistant depression) for another indication (e.g., OCD for which a different H-coil is FDA-cleared); or those who use a component that has not been cleared (e.g., a given stimulation coil model) instead of the cleared equipment. For these reasons our findings are likely to be an underestimate of the phenomenon of off-label use and promotion of TMS in the United States. At minimum, however, our results show that there are at least a hundred clinics promoting TMS for a broad range of off-label indications.
      While TMS may be an appealing non-pharmaceutical therapy, it is still experimental for the many psychiatric and neurological indications for which it is promoted. Providers should therefore employ caution when advertising its use and not promote the technique as a panacea.

      Declaration of competing interest

      Dr. Pascual-Leone is a co-founder of Linus Health and TI Solutions AG; serves on the scientific advisory boards for Starlab Neuroscience, Magstim Inc., Nexstim, and MedRhythms; and is listed as an inventor on several issued and pending patents on the real-time integration of noninvasive brain stimulation with electroencephalography and magnetic resonance imaging. Dr. Santarnecchi serves on the scientific advisory boards for Neurocare and EBNeuro; and is listed as an inventor on several issued and pending patents on noninvasive brain stimulation applications in the field of neurology. Dr. Wexler, Ms. Nagappan, and Ms. Kopyto confirm that they have no known conflicts of interest associated with this publication and that there has been no significant financial support for this work that could have influenced its outcome.

      Acknowledgements

      Dr. Wexler, Ms. Nagappan, and Ms. Kopyto acknowledge support from the Office of the Director of the National Institutes of Health ( DP5OD026420 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of funding bodies.

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