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. 2021 Jul 1;162(7):1935-1956.
doi: 10.1097/j.pain.0000000000002204.

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations

Nathaniel Katz, Robert H Dworkin, Richard North, Simon Thomson, Sam Eldabe, Salim M Hayek, Brian H Kopell, John Markman, Ali Rezai, Rod S Taylor, Dennis C Turk, Eric Buchser, Howard Fields, Gregory Fiore, McKenzie Ferguson, Jennifer Gewandter, Chris Hilker, Roshini Jain, Angela Leitner, John Loeser, Ewan McNicol, Turo Nurmikko, Jane Shipley, Rahul Singh, Andrea Trescot, Robert van Dongen, Lalit Venkatesan

Research design considerations for randomized controlled trials of spinal cord stimulation for pain: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials/Institute of Neuromodulation/International Neuromodulation Society recommendations

Nathaniel Katz et al. Pain. .

Abstract

Spinal cord stimulation (SCS) is an interventional nonpharmacologic treatment used for chronic pain and other indications. Methods for evaluating the safety and efficacy of SCS have evolved from uncontrolled and retrospective studies to prospective randomized controlled trials (RCTs). Although randomization overcomes certain types of bias, additional challenges to the validity of RCTs of SCS include blinding, choice of control groups, nonspecific effects of treatment variables (eg, paresthesia, device programming and recharging, psychological support, and rehabilitative techniques), and safety considerations. To address these challenges, 3 professional societies (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, Institute of Neuromodulation, and International Neuromodulation Society) convened a meeting to develop consensus recommendations on the design, conduct, analysis, and interpretation of RCTs of SCS for chronic pain. This article summarizes the results of this meeting. Highlights of our recommendations include disclosing all funding source and potential conflicts; incorporating mechanistic objectives when possible; avoiding noninferiority designs without internal demonstration of assay sensitivity; achieving and documenting double-blinding whenever possible; documenting investigator and site experience; keeping all information provided to patients balanced with respect to expectation of benefit; disclosing all information provided to patients, including verbal scripts; using placebo/sham controls when possible; capturing a complete set of outcome assessments; accounting for ancillary pharmacologic and nonpharmacologic treatments in a clear manner; providing a complete description of intended and actual programming interactions; making a prospective ascertainment of SCS-specific safety outcomes; training patients and researchers on appropriate expectations, outcome assessments, and other key aspects of study performance; and providing transparent and complete reporting of results according to applicable reporting guidelines.

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Conflict of interest statement

The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by medical device companies and others had received consulting fees or honoraria from 1 or more pharmaceutical or device companies. The authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by funds from the Analgesic, Anesthetic, and ACTTION public–private partnership with the US FDA, the Institute of Neuromodulation (IoN), and the INS, which have received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, philanthropy, and other sources. Preparation of background literature reviews and draft manuscripts was also supported by ACTTION. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION, IoN, and INS should be inferred. E. Buchser has received consulting fees from Medtronic, and his department has received research funding from Medtronic. R.H. Dworkin has received in the past 5 years' research grants and contracts from the US Food and Drug Administration and the US National Institutes of Health, and compensation for serving on advisory boards or consulting on clinical trial methods from Abide, Acadia, Adynxx, Analgesic Solutions, Aptinyx, Aquinox, Asahi Kasei, Astellas, AstraZeneca, Biogen, Biohaven, Boston Scientific, Braeburn, Celgene, Centrexion, Chromocell, Clexio, Concert, Coronado, Daiichi Sankyo, Decibel, Dong-A, Editas, Eli Lilly, Eupraxia, Glenmark, Grace, Hope, Hydra, Immune, Johnson & Johnson, Lotus Clinical Research, Mainstay, Medavante, Merck, Neumentum, Neurana, NeuroBo, Novaremed, Novartis, NSGene, Olatec, Periphagen, Pfizer, Phosphagenics, Quark, Reckitt Benckiser, Regenacy (also equity), Relmada, Sanifit, Scilex, Semnur, Sollis, Spinifex, Syntrix, Teva, Thar, Theranexus, Trevena, Vertex, and Vizuri. S. Eldabe has received consulting fees from Medtronic, Saluda Medical, and Mainstay Medical. His department has received research funding from Medtronic and Nevro. G. Fiore is an employee of Fiore Healthcare Advisors which provides services to sponsors of clinical trials and manufacturers of commercial products. Fiore Healthcare Advisors receives consulting fees from Sollis Therapeutics. J. Gewandter has received consulting income in the past 36 months from MundiPharma, Disarm Therapeutics, Asahi Kasei Pharma, SK Life Science, Orthogonal, and Science Branding. S.M. Hayek has received in the past 36 months' honoraria for consulting from Biotronik and Boston Scientific. N. Katz is an employee of WCG Analgesic Solutions, which provides services to sponsors of clinical trials. WCG Analgesic Solutions has received consulting fees from Mainstay Medical and Boston Scientific. A. Leitner is an employee of Saluda Medical. E. McNicol has nothing to declare. R.B. North serves as an unpaid officer of (1) the charitable nonprofit Institute of Neuromodulation, which in turn receives support from the nonprofit North American Neuromodulation Society, and (2) the charitable nonprofit Neuromodulation Foundation, Inc, to which (like his former employer Johns Hopkins University) grants and support have been provided by Abbott, Boston Scientific Corp, Medtronic, Inc, Nevro Corp, Nuvectra, and Stimwave, Inc. He receives royalties from Abbott, royalties and consulting fees from Nuvectra, and consulting fees from Stimwave, Inc, in which his wife holds shares. T. Nurmikko has nothing to declare. A.R. Rezai: Board of Directors and potential equity position in Autonomic Technologies (ATI), Neurotechnology Innovation Management (NIM), and Sollis Therapeutics. R. Taylor is a paid consultant for Medtronic, Nevro, and Saluda. S. Thomson has received honoraria for work as a consultant for British Standards of Industry, Boston Scientific Neuromodulation, and Mainstay Medical. D. Turk has received research grants and contracts from the US Food and Drug Administration and US National Institutes of Health and compensation for consulting on clinical trial and patient preferences from AcelRx, Eli Lilly, Flexion, GlaxoSmithKline, Pfizer, and Swing Therapeutics. J. Shipley's employer, The Neuromodulation Foundation, a charitable, nonprofit corporation, has received grants and/or consulting income from Abbott (formerly St. Jude), Boston Scientific, Greatbatch, Medtronic, Nevro, Nuvectra, and Stimwave.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
(A) Types of generators. All spinal cord stimulation systems include an external, portable (and therefore battery powered) transmitter which emits (and in some cases receives) a wireless or radiofrequency signal providing telemetry and/or power. The implanted generator may contain a battery (which may be rechargeable), allowing autonomous operation, or it may operate on external power alone. (B) Types of electrodes.
Figure 2.
Figure 2.
Interpretation of noninferiority studiesa. The letters indicate the point estimate of efficacy, and the error bars the 95% confidence intervals in these hypothetical trials. The vertical line labeled “0” indicates the point of zero difference between “new treatment” and comparator treatment. Δ indicates the prespecified noninferiority margin. Adapted from Ref. 61, with permission.
See this image and copyright information in PMC

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