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Review
. 2024 Oct 1;165(10):2165-2183.
doi: 10.1097/j.pain.0000000000003249. Epub 2024 May 3.

Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement

David Hohenschurz-Schmidt  1   2 , Dan Cherkin  3 , Andrew S C Rice  1 , Robert H Dworkin  4 , Dennis C Turk  5 , Michael P McDermott  6 , Matthew J Bair  7 , Lynn L DeBar  8 , Robert R Edwards  9 , Scott R Evans  10 , John T Farrar  11 , Robert D Kerns  12 , Michael C Rowbotham  13 , Ajay D Wasan  14 , Penney Cowan  15 , McKenzie Ferguson  16 , Roy Freeman  17 , Jennifer S Gewandter  18 , Ian Gilron  19 , Hanna Grol-Prokopczyk  20 , Smriti Iyengar  21 , Cornelia Kamp  22 , Barbara I Karp  23 , Bethea A Kleykamp  24 , John D Loeser  25 , Sean Mackey  26 , Richard Malamut  27 , Ewan McNicol  28 , Kushang V Patel  29 , Kenneth Schmader  30 , Lee Simon  31 , Deborah J Steiner  21 , Christin Veasley  32 , Jan Vollert  33
Affiliations
Review

Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement

David Hohenschurz-Schmidt et al. Pain. .

Abstract

Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

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Conflict of interest statement

The first author Dr Hohenschurz-Schmidt was renumerated by IMMPACT for their work at the consensus meeting and in drafting the manuscript. The project was supported by ACTTION, a public–private partnership. The views expressed in this article are those of the authors and no official endorsement by the Food and Drug Administration (FDA) or the pharmaceutical and device companies that provided unrestricted grants to support the activities of the ACTTION public–private partnership should be inferred. Individual authors' declarations of potential conflicts of interest are as follows: Dr Bair reports grants or contracts from VA Health Services Research and Development, VA Cooperative Studies Program, and National Endowment for the Arts; participation on a Data Safety Monitoring Board or Advisory Board on a 1 NIH project conducted at the University of Utah. This trial is a pragmatic trial of physical therapy intervention; Prof Cherkin reports being paid an honorarium for mentoring the first author with manuscript writing; Prof DeBar reports support for the present manuscript from Kaiser Permanente Washington Health Research Institute (KPWHRI); grants and contracts from National Institutes of Health (NIH), and Patient Centered Outcomes Research Institute (PCORI); an honorarium for a lecture at 2020 IMMPACT Consensus Meeting; support for attending meetings from KPWHRI, and NIH; participation on a Data Safety Monitoring Board or Advisory Board for NCCIH, BACPAC DSMB; Mrs Cowan is the cofounder and secretary of the World Patients Alliance and Board Member Emeritus as well as founder of the American Chronic Pain Association; Prof 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, Beckley, Biogen, Biohaven, Biosplice, Boston Scientific, Braeburn, Cardialen, Celgene, Centrexion, Chiesi, Chromocell, Clexio, Collegium, CoimbiGene, Concert, Confo, Decibel, Editas, Eli Lilly, Endo, Ethismos (equity), Eupraxia, Exicure, GlaxoSmithKline, Glenmark, Gloriana, Grace, Hope, Hospital for Special Surgery, Lotus, Mainstay, Merck, Mind Medicine (also equity), Neumentum, Neurana, NeuroBo, Novaremed, Novartis, OCT, Orion, OliPass, Pfizer, Q-State, Reckitt Benckiser, Regenacy (also equity), Sangamo, Sanifit, Scilex, Semnur, SIMR Biotech, Sinfonia, SK Biopharmaceuticals, Sollis, SPRIM, Teva, Theranexus, Toray, Vertex, Vizuri, and WCG; Prof Edwards reports no conflicts of interest; Prof Evans reports consulting fees from advantagene, AstraZeneca, AtriCure, Degruyter, FHI clinical, Genentech, Horizon Pharma plc, International Drug Development Institute, lung biotech, microbiotix, Neovasc Medical Inc, nobel pharma, roivant, and sab pharma; support for attending meetings or travel from ACTTION, Antimicrobial Resistance and Stewardship Conference, Clinical Trials Transformation Initiative, Council for International Organizations of Medical Sciences, Deming Conference, and the FDA; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, advantagene, Akouos, Alexion Pharmaceuticals, Inc., Apellis, Breast international group, clover, DayOneBio, Duke Clinical Research Institute, FHI clinical, lung biotech, the NIH, nuvelution, Perelman School of Medicine, University of Pennsylvania, Pfizer, Rakuten, Roche, sab pharma, Takeda Oncology, Teva Pharmaceuticals Industries, tracon, and vir; and other royalties from or interests in the Clinical Trials Transformation Initiative, Degruyter, Deming Conference, the FDA, and Taylor & Francis; Prof Farrar reports grants or contracts from the NIH-NCATS – UL1 Grant (Co-I), FDA-BAA Contract, NIH-NIDDK - U01 Grant (CoI), and NIH-NINDS—U24 Grant (PI); consulting fees from Lilly and Vertex Pharma; Participation on a Data Safety Monitoring Board or Advisory Board for NIH-NIA(DSMB); and a role as President Elect US-ASP; Dr Ferguson reports grants or contracts from ACTTION paid to her institution for work on systematic reviews and payment or honoraria for lectures at IMMPACT meetings from ACTTION; Prof Freeman reports consulting fees from AlgoRx, Allergan, Applied Therapeutics, Clexio, Collegium, Cutaneous NeuroDiagnostics, Glenmark, GW Pharma, Glaxo-Smith Kline, Eli Lilly, Lundbeck, Maxona, Novartis, NeuroBo, Regenacy, Vertex, and Worwag; and stock options in Cutaneous Neurodiagnostic Life Sciences, NeuroBo, Maxona, and Regenacy; Dr Gewandter reports grants or contracts from the NIH; consulting fees from AlgoTX, GW Pharma, Magnolia Nuerosciences, Orthogonal, Science Branding Consulting, AKP Pharma, and Eikonizo; and support for attending meetings or travel from SOPATE and INS; Prof Gilron declares a travel stipend to attend ACTTION meeting 2019 and reports consulting fees from Combigene, GW Research, Lilly, and Novaremed; Prof Grol-Prokopczyk reports grants or contracts from the National Institute on Aging of the National Institutes of Health, Award #R01AG065351; and honoraria for an invited lecture for Multidisciplinary Research in Gerontology Colloquium Series, University of Southern California and for an invited lecture at Napa Pain Conference; and travel reimbursement for travel to Napa Pain Conference; Dr Hohenschurz-Schmidt reports support for the present manuscript from a PhD Studentship by the Alan and Sheila Diamond Charitable Trust and a honorarium from IMMPACT; a research grant from The Osteopathic Foundation (paid to institution); consulting fees from Altern Health Ltd.; and the role of executive committee member of the Society for Back Pain Research; Prof Iyengar reports employment and travel support from the NINDS/NIH; stock options in Retiree, and Eli Lilly and Company; other financial or nonfinancial interests through Employee of NINDS/NIH; Adjunct Senior Research Professor, Indiana University School of Medicine, Departments of Anesthesia and Clinical Pharmacology; Prof Kamp reports support for the present manuscript from ACTTION, FDA contract #HHSF223201000078C, with payments made directly to her institution, University of Rochester Medical Center, providing 5% salary support, consulting fees from Clintrex Research Corporation (payments made to her consulting company CLKamp Consulting LLC with none of the consulting in relation to the indication of pain); Dr Karp declares no conflict of interest; Prof Kerns reports Honoraria for presentation at the IMMPACT consensus meeting that informed this manuscript; research grants from NIH, PCORI, and VA paid to his institution; a consulting fee for a NIH-sponsored research grant; a honorarium for planning and participation in an IMMPACT consensus conference on Patient Engagement in Clinical Pain Research; honoraria for participation in NIH and PCORI DSMBs and a honorarium for participation as member of Scientific Advisory Board, Chronic Pain Centre of Excellence for Canadian Veterans; an unpaid role on the Board of Directors, A Place to Nourish your Health; and an honorarium for role as Executive Editor, Pain Medicine; Dr Kleykamp reports income from ACTTION as a full-time employee Oct 2018 - Aug 2021; being the owner and principal of BAK and Associates, LLC a research and science writing consulting firm. Contracts to BAK and Associates, LLC over the last 36 months include: STATinMED, American Society of Addiction Medicine, ECRI, Hayes/Symplr, PinneyAssociates, and Palladian Associates; payments and honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from University of Kentucky, STATinMED, Filter Magazine, and Virginia Commonwealth University; support for attending meetings or travel from University of Kentucky and Virginia Commonwealth University; and a role as Communications Chair for the College on Problems of Drug Dependence; Prof Loeser reports no conflict of interest; Prof Mackey reports support for the present manuscript from the National Institutes of Health, US Food and Drug Administration, Patient-Centered Outcomes Research Institute, Chris Redlich Professorship in Pain Research, and Dodie and John Rosekrans Pain Research Endowment Fund (all through the Stanford University); consulting fees from Oklahoma University – Smith NIH Grant; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events Memorial Sloan, Kettering Cancer Center, National Institutes of Health, Washington University, Oakstone Publishing, Comprehensive, Review of Pain Medicine CME Lecture Series, Walter Reed AFB, Web Based Lecture, Bull Publishing, George Washington University, University of Washington, Veterans Affairs, HSRD Naloxone Distribution IIR Advisory Board, Canadian Pain Society, National Institutes of Health, and New York University; support for attending meetings or travel from American Academy of Pain Medicine, American Society of Regional Anesthesia and Pain Medicine, Washington University, George Washington University, National Institutes of Health, University of Washington, US Federal Drug Administration, New York University, Weill Cornell Medical College, and the International Neuromodulation Society (INS); roles on the Drug Safety and Risk Management Advisory Committee, Anesthetic and Analgesic Drug Products Advisory Committee (DSaRM/AADPAC)/(FDA) (Unpaid role as Advisory Committee Member) and for HSRD Naloxone Distribution IIR Veterans Affairs (VA) (honorarium paid to himself for role as Advisory Board Member); an unpaid role as Vice-Chair - Committee on Temporomandibular Disorders for the National Academies of Sciences, National Institutes of Health, (NAS)/(NIH); and other financial interests through the National Institutes of Health for T32 Postdoctoral Fellows who conduct research in lab; Salary supported by NIH and administered through Stanford University; Dr Malamut reports no conflicts of interest; Prof McDermott declares grants or contracts from the NIH, US Food and Drug Administration, Cure SMA, and PTC Therapeutics; consulting fees from Fulcrum Therapeutics, Inc. and NeuroDerm, Ltd.; Participation on a Data and Safety Monitoring Board or Advisory Board for the NIH, Eli Lilly and Company, Catabasis Pharmaceuticals, Inc., Vaccinex, Inc., Neurocrine Biosciences, Inc., Voyager Therapeutics, Prilenia Therapeutics Development, Ltd., ReveraGen BioPharma, Inc., and NS Pharma, Inc.; Prof McNicol reports grants or contracts from ACTTION paid to his institution for work on systematic reviews and payment or honoraria for lectures and attending IMMPACT meetings from ACTTION; Prof Patel reports grants and contracts from the US Centers for Disease Control and Prevention and the National Institutes of Health and consultancy work for GlaxoSmithKline LLC; Prof Rice reports support for the present manuscript from IMMPACT; grants and studentships from UKRI (Medical Research Council and BBSRC), Versus Arthritis, Royal British Legion, European Commission, UK Ministry of Defence, Dr Jennie Gwynn Bequests, Alan and Sheila Diamond Trust, the British Pain Society, and the Royal Society of Medicine; consultancy and advisory board work for Imperial College Consultants, which, in the last 36 months, has included remunerated work for: Confo, Vertex, Pharmanovo, Lateral, Novartis, Mundipharma, Orion, Shanghai SIMR BiotechAsahi Kasei & Toray; lecture honoraria from MD Anderson Cancer Center, Royal Marsden Hospital, and Ucsf; Prof Rice is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert D.M Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771 & Okuse K. et al. Methods of treating pain by inhibition of vgf activity EP13702262.0/WO2013 110945; a role as Chair of the Trial Steering Committee (TSC) for the OPTION-DM trial, National Institute for Health Research (NIHR); role as councilor for IASP and current position as president-elect; he also was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued upon the acquisition of Spinifex by Novartis in July 2015. The final payment was made in 2019; other interests are in the British National Formulary, Joint Committee on Vaccine and Immunisation-varicella sub-committee, Medicines and Healthcare products Regulatory Agency (MHRA), Commission on Human Medicines - Neurology, Pain & Psychiatry Expert Advisory Group, Non Freezing Cold Injury Independent Senior Advisory Committee (NISAC), and Royal College of Anaesthetists - Heritage and Archives Committee; Prof Rowbotham reports consulting fees from SiteOne Therapeutics, GenEdit and Sustained Therapeutics, payments for expert testimony from Haapala, Thompson & Abern (law firm for clinical payment to himself as medical-legal expert witness), payments from Helixmith Co., LTD for work on a data monitoring or advisory board, and unpaid work as Treasurer of the International Association for the Study of Pain from 2020-2024. He also holds stock options from SiteOne and CODA Biotherapeutics; Dr Schmader reports a grant by GSK for vaccine research, paid to his institution; Dr Steiner reports being full-time employee of Eli Lilly and Company (Pain & Neurodegeneration); Dr Simon reports consulting fees from Astrazeneca, Pfizer, Rigel, Eupraxia, Biosplice, EMDSerono, Horizon, Direct, Lilly, Kaniska, Protalix, Chemomab, TLC, SpineThera, Kyoto, PPD, Galvani, Urica, Transcode, Boehringer Ingelheim, Bristol Myers Squibb, Priovant, Roivant, Ampio, Aura, Aurinia, GSK, Xalud, Neumentum, Neema, Amzell, Applied Bio, Aptinyx, Bexson, Bone Med, Bone Therapeutics, Cancer Prevention, Cerebral Therapeutics, Chemocentryx, Diffusion Bio, Elorac, Enalare, Foundry Therapeutics, Galapagos. Histogen, Gilead, Idera, Intravital, Ingel, Kiel Labs, Mesoblast, Mpathix, Minerva, Regenosine, Samus, Sana, StageBio, Theraly, Unity, and Viridian; Prof Turk reports royalities and licenses from Wolters Kluwer (Editor-n-Chief, Clinical Journal of Pain), and the American Psychological Association (Book Author); consulting fees from GSK/Novartis; and a role as Associate Director of Analgesic, Anesthetic, and Addiction Clinical Trials, Innovations, Opportunities and Networks (ACTTION); Dr Veasley reports no conflicts of interest; Dr Vollert reports consulting fees from Vertex Pharmaceuticals, Embody Orthopaedic, and Casquar. Finally, Prof Wasan reports no conflicts of interest.

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

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