To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI).
With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified.
Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.
Subscribe to Journal
Get full journal access for 1 year
only $24.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Tuszynski MH, Steeves JD, Fawcett JW, Lammertse D, Kalichman M, Eask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial inclusion/exclusion and ethics. Spinal Cord. 2007;45:222–31.
Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Dittuno JF, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord. 2007;45:206–21.
Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH, Lammertse D, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord. 2007;45:190–205.
Lammertse D, Tuszynski MH, Steeves JD, Curt A, Fawcett JW, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial design. Spinal Cord. 2007;45:232–42.
Kwon BK, Bloom O, Wanner I, Curt A, Schwab JM, Fawcett J, et al. Neurochemical biomarkers in spinal cord injury. Spinal Cord. 2019;57:819–31.
Seif M, Wheeler-Kingshott CAM, Cohen-Adad J, Flanders AE, Freund P. Guidelines for the conduct of clinical trials in spinal cord injury: neuroimaging biomarkers. Spinal Cord. 2019;57:717–28.
Hubli M, Kramer JLK, Jutzeler CR, Rosner J, Furlan JC, Tansey KE, et al. Application of electrophysiological measures in spinal cord injury clinical trials: a narrative review. Spinal Cord. 2019;57:909–23.
Blight AR, Hsieh J, Curt A, Fawcett JW, Guest JD, Leitman N, et al. The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury. Spinal Cord. 2019;57:348–59.
Geisler FH, Coleman WP, Grieco G, Poonian D. Sygen Study. Recruitment and early treatment in a multicenter study of acute spinal cord injury. Spine. 2001;26(Suppl 24):S58–67.
Fehlings MG, Kim KD, Aarabi B, Rizzo M, Bond LM, McKerracher L, et al. Rho inhibitor VX-210 in acute traumatic subaxial cervical spinal cord injury: design of the SPinal Cord Injury Rho INhibition Investigation (SPRING) clinical trial. J Neurotrauma. 2018;35:1049–56.
Fehlings MG, Nakashima H, Nagoshi N, Chow D, Grossman RG, Kopjar B. Acute spinal cord injury study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multicenter. Spinal Cord. 2016;54:1–8.
Food and Drug Administration. Innovation or stagnation: challenge and opportunity on the critical path to new medical products. Washington, DC: Food and Drug Administration; 2004. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html.
Matte WB, Walker EG, Abadie E, Sistare FD, Vonderscher J, Woodcock J, et al. Research at the interface of industry, academia and regulatory science. Nat Biotechnol. 2010;28:432–3.
Reier PJ, Lane MA, Hall ED, Teng YD, Howland DR. Translational spinal cord injury research: preclinical guidelines and challenges. Handb Clin Neurol. 2012;109:411–33.
Amiri-Kordestani L, Fojo T. Why do phase III clinical trials in oncology fail so often? J Natl Cancer Inst. 2012;104:568–9.
Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–57.
Stein DG. Embracing failure: what the phase III progesterone studies can teach about TBI clinical trials. Brain Inj. 2015;29:1259–72.
Kim YH, Ha KY, Kim SI. Spinal cord injury and related clinical trials clinics. Clin Orthop Surg. 2017;9:1–9.
Lammertse D. Clinical trials in spinal cord injury: lessons learned on the path to translation. The 2011 International Spinal Cord Society Sir Ludwig Guttmann Lecture. Spinal Cord. 2013;51:2–9.
Scott CT, Magnus D. Wrongful termination: lessons learned from the Geron clinical trial. Stem Cells Transl Med. 2014;3:1398–401.
Badhiwala JH, Wilson JR, Kwon BK, Casha S, Fehlings MG. A review of clinical trials in spinal cord injury including biomarkers. J Neurotrauma. 2018;35:1906–17.
Nichol AD, Bailey M, Cooper DJ, POLAR, EPo Investigators. Challenging issues in randomised controlled trials. Injury. 2010;41(Suppl 1):S20–3.
Dvorak MF, Noonan VK, Fallah N, Fisher CG, Rivers CS, Ahn H, et al. Minimizing errors in acute traumatic spinal cord injury trials by acknowledging the heterogeneity of spinal cord anatomy and injury severity: an observational Canadian cohort analysis. J Neurotrauma. 2014;31:1540–7.
Berry DA. Bayesian statistics and the efficiency and ethics of clinical trials. Stat Sci. 2004;19:175–87. https://doi.org/10.1214/088342304000000044.
Food and Drug Administration. Innovation or stagnation: critical path opportunities list. Washington, DC: Food and Drug Administration; 2006. http://wayback.archive-it.org/7993/20180125075636/https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/default.htm.
Bracken MB, Shepard MJ, Collins WF, Holford TR, Young W, Baskin DS, et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury: results of the Second National Acute Spinal Cord Injury Study. N Engl J Med. 1990;322:1405–11.
Geisler FH, Coleman WP, Grieco G, Poonian D, Sygen Study Group. The Sygen Multicenter Acute Spinal Cord Injury Study. Spine. 2001;26(Suppl 24):S87–98.
Cardenas DD, Ditunno JF, Graziani V, McLain AB, Lammertse DP, Potte PJ, et al. Two phase 3, multicenter, randomized, placebo-controlled clinical trials of fampridine-SR for treatment of spasticity in chronic spinal cord injury. Spinal Cord. 2014;52:70–6.
Lammertse DP, Jones LA, Charlifue SB, Kirshblum SC, Apple DF, Ragnarsson KT, et al. Autologous incubated macrophage therapy in acute, complete spinal cord injury: results of the phase 2 randomized controlled multicenter trial. Spinal Cord. 2012;50:661–71.
Levinson B, Lee J, Chou H, Maiman D. SUN13837 in treatment of acute spinal cord injury, the ASCENT-ASCI Study. Clin Neurol Neurosci. 2017;2:1–8.
Levi AD, Anderson KD, Okonkwo DO, Park P, Bryce TN, Kurpad SN, et al. Clinical outcomes from a multi-center study of human neural stem cell transplantation in chronic cervical spinal cord injury. J Neurotrauma. 2019;36:891–902.
Thall PF, Cook JD. Dose-finding based on efficacy-toxicity trade-offs. Biometrics. 2004;60:684–93. https://doi.org/10.1111/j.0006-341X.2004.00218.x.
Haley EC, Thomapson JLP, Grotta JC, Lyden PD, Hemmen TG, Brown DL. Phase IIB/II trial of tenecteplase in acute ischemic stroke results of a prematurely terminated randomized clincal trial. Stroke. 2010;41:707–11.
Food and Drug Administration. Adaptive design clinical trials for drug and biologics draft guidance. Washington, DC: Food and Drug Administration; 2010. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf.
Chow SC, Chang M. Adaptive design methods in clinical trials—a review. Orphanet J Rare Dis. 2008. https://doi.org/10.1186/1750-1172-3-11.
Berry DA. Emerging innovations in clinical trial design. Clin Pharm Ther. 2016;99:82–91.
Chang M, Balser J. Adaptive design—recent advancement in clinical trials. J Bioanal Biostat. 2016;1:1–14.
Food and Drug Administration. Adaptive designs for clinical trials of drugs and biologics guidance for industry. Washington, DC: Food and Drug Administration; 2019. https://www.fda.gov/media/78495/download.
Dragalin V. Adaptive designs: terminology and classification. Drug Inf J. 2006;40:425–35.
Bauer P, Bretz F, Dragalin V, Koniga F, Wassmere G. Twenty-five years of confirmatory adaptive designs: opportunities and pitfalls. Stat Med. 2016;35:325–47.
Meurer WJ, Lewis RJ, Tagle D, Fetters MD, Legocki L, Berry S, et al. An overview of the adaptive designs accelerating promising trials into treatment (ADAPT-IT) project. Ann Emerg Med. 2012;60:451–7.
Meurer WJ, Barsan WG. Spinal cord injury neuroprotection and promise of flexible adaptive clinical trials. World Neurosurg. 2014;82:e541–6. https://doi.org/10.1016/j.wneu.2013.06.017.
Jaja BNR, Jiang F, Badhiwala JH, Schar R, Kurpad S, Grossman RG, et al. Association of pneumonia, wound infection, and sepsis with clinical outcomes after acute traumatic spinal cord injury. J Neurotrauma. 2019;36:3044–50.
Kelly PJ, Sooriyarachchi MR, Stallard N, Todd S. A practical comparison of group-sequential and adaptive designs. J Biopharm Stat. 2005;15:719–38.
Posch M, Maurer W, Bretz F. Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim. Pharm Stat. 2011;10:96–104. https://doi.org/10.1002/pst.413.
Le Tourneau C, Lee J, Siu LL. Dose escalation methods in phase I cancer clinical trials. J Natl Cancer Inst. 2009;101:708–20.
Quigley J, Pepe M, Fisher L. Continual reassessment method—a practical design for phase-1 clinical trials in cancer. Biometrics. 1990;46:33–48.
Kairalla JA, Coffey CS, Thomann MA, Muller KE. Adaptive trial designs: a review of barriers and opportunities. Trials. 2012;13:1–45.
Garrett-Mayer E. The continual reassessment method for dose-finding studies: a tutorial. Clin Trials. 2006;3:57–71.
Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA, Esserman LJ. I-SPY 2: an adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharm Ther. 2009;86:97–100.
Miyanji F, Furlan JC, Aarabi B, Arnold P, Fehlings MG. Acute cervical traumatic spinal cord injury: MR imaging findings correlated with neurologic outcome—prospective study with 100 consecutive patients. Radiology . 2007;243:820–7.
Flanders AE, Schaefer DM, Doan HT, Mishkin MM, Gonzalez CF, Northrup BE. Acute cervical spine trauma: correlation of MR imaging findings with degree of neurologic deficit. Radiology. 1990;177:25–33.
Flanders AE, Spettell CM, Tartaglino LM, Friedman DP, Herbison GJ. Forecasting motor recovery after cervical spinal cord injury: value of MR imaging. Radiology. 1996;201:649–65.
Talbott JF, Whetstone WD, Readdy WJ, Ferguson AR, Bresnahan JC, Saigal R, et al. The Brain and Spinal Injury Center score: a novel, simple, and reproducible method for assessing the severity of acute cervical spinal cord injury with axial T2-weighted MRI findings. J Neurosurg Spine. 2015;23:495–504.
Kwon BK, Streijger F, Fallah N, Noonan VK, Bẻlanger LM, Ritchie L, et al. Cerebrospinal fluid biomarkers to stratify injury severity and predict outcome in human traumatic spinal cord injury. J Neurotrauma. 2017;34:567–80. https://doi.org/10.1089/neu.2016.4435.
Streijger F, Skinnider MA, Rogalski JC, Balshaw R, Shannon CP, Prudova, et al. A targeted proteomics analysis of cerebrospinal fluid after acute human spinal cord injury. J Neurotrauma. 2017;34:2054–68. https://doi.org/10.1089/neu.2016.4879.
Dalkilic T, Fallah N, Noonan VK, Elizei SS, Belanger L, Ritchie L, et al. Predicting injury severity and neurological recovery after acute cervical spinal cord injury: a comparison of cerebrospinal fluid and magnetic resonance imaging biomarkers. J Neurotrauma. 2018;35:435–45. https://doi.org/10.1089/neu.2017.5357.
Pirouzmand F. Epidemiological trends of spine and spinal cord injuries in the largest Canadian adult trauma center from 1986 to 2006 Clinical article. J Neurosurg-Spine. 2010;12:131–40.
Anderson KD, Guest JD, Dietrich WD, Bartlett Bunge M, Curiel R, Dididze M, et al. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma. 2017;34:2950–63.
Layer RT, Ulich TR, Coric D, Arnold PM, Guest JD, Heary RH, et al. New clinical-pathological classification of intraspinal injury following traumatic acute complete thoracic spinal cord injury: postdurotomy/myelotomy observations from the INSPIRE trial. Neurosurgery. 2017;64(CN_suppl_1):105–9.
Zariffa J, Kramer JL, Fawcett JW, Lammertse DP, Blight AR, Guest JD, et al. Characterization of neurological recovery following traumatic sensorimotor complete thoracic spinal cord injury. Spinal Cord. 2011;49:463–71.
Levi AD, Okonkwo DO, Park P, Jenkins AL, Kurpad SN, Parr AM, et al. Emerging safety of intramedullary transplantation of human neural stem cells in chronic cervical and thoracic spinal cord injury. Neurosurgery . 2018;82:562–75. https://doi.org/10.1093/neuros/nyx250.
Anderson KD, Guest JD, Dietrich WD, Bunge MB, Curiel R, Dididze M, et al. Safety of autologous human Schwann cell transplantation in subacute thoracic spinal cord injury. J Neurotrauma. 2017;34:2950–63. https://doi.org/10.1089/neu.2016.4895.
Lin Y, Zhu M, Zheng S. The pursuit of balance:an overview of covariate adaptive randomization techniques in clinical trials. Contemp Clin Trials. 2015;45:21–5.
Gould AL, Shih WJ. Sample size re-estimation without unblinding for normally distributed outcomes with unknown variance. Commun Stat Theory Methods. 1992;21:2833–53.
Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, Bracken MB, et al. Clinical trials in head injury. J Neurotrauma. 2002;19:503–57.
Aarabi B, Sansur CA, Ibrahimi DM, Simard JM, Hersh DS, Le E, et al. Intramedullary lesion length on postoperative magnetic resonance imaging is a strong predictor of ASIA impairment scale grade conversion following decompressive surgery in cervical spinal cord injury. Neurosurgery. 2017;80:610–20.
Gupta SK. Use of Bayesian statistics in drug development: advantages and challenges. Int J Appl Basic Med Res. 2012;2:3–6.
Thorlund K, Haggstrom J, Parks JH, Mills EJ. Key design considerations for adaptive clinical trials: a primer for clinicians. BMJ. 2018;360:k698.
Curt A, Schwab ME, Dietz V. Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury. Spinal Cord. 2004;42:1–6.
Becker BE, DeLisa JA. Model spinal cord injury system trends, and implications for the future. Arch Phys Med Rehabil. 1999;80:1514–21.
Grossman RG, Toups EJ, Frankowski RF, Burau KD, Howley S. North American clinical trials network for the treatment of spinal cord injury: goals and progress. J Neurosurg Spine. 2012;17(Suppl 1):6–10.
Fehlings MG, Wilson JR, Frankowski RF, Toups EG, Aarabi B, Harrop JS, et al. Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine. 2012;17(Suppl 1):151–6.
Grossman RG, Fehlings MG, Frankowski RF, Burau KD, Chow DS, Tator C, et al. A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma. 2014;31:239–55.
Food and Drug Administration. Master protocols: efficient clinical trial design strategies to expedite development of oncology drugs and biologics. Guidance for Industry. Washington, DC: Food and Drug Administration; 2018. https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/default.htm.
Saville BR, Berry SM. Efficiencies of platform clinical trials: a vision of the future. Clin Trials. 2016;13:358–66.
Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–20.
Redig AT, Jänne PA. Basket trials and the evolution of clinical trial design in the era of genomic medicine. J Clin Oncol. 2015;33:975–7.
Simon R, Geyer S, Subramanian J, Roychowdhury S. The Bayesian basket design for genomic variant-driven phase II trials. Semin Oncol. 2016;43:13–8.
Vallejo R, Tiley DM, Cedeño DL, Kelley CA, Demaegd M, Benyamin R. Genomics of the effect of spinal cord stimulation on an animal model of neuropathic pain. Neuromodulation. 2016;19:576–86.
Smith J, Morgan JR, Zottoli SJ, Smith PJ, Buxbaum JD, Bloom OE. Regeneration in the era of functional genomics and gene network analysis. Biol Bull. 2011;221:18–34.
Renfrot LA, Sargent DJ. Statistical controversies in clinical research: basket trials, umbrella trials and other master protocols: a review and examples. Ann Oncol. 2017;28:34–43.
Saxman SB. Ethical considerations for outcome-adaptive trial designs: a clinical researcher’s perspective. Bioethics. 2015;29:59–65.
Bothwell LE, Kesselheim AS. The real-world ethics of adaptive-design clinical trials. Hastings Cent Rep. 2017;47:27–37.
This paper is the fifth of a series facilitated by STUDI. Donald Berry, Ph.D., Daniel Graves, Ph.D., and Megan Moynahan, MS, contributed to initial discussions about the scope of this review paper. Megan Moynahan, Jane Hsieh, MSc, Armin Curt, MD, and James Fawcett, MD, Ph.D., provided constructive reviews of the manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Mulcahey, M.J., Jones, L.A.T., Rockhold, F. et al. Adaptive trial designs for spinal cord injury clinical trials directed to the central nervous system. Spinal Cord (2020). https://doi.org/10.1038/s41393-020-00547-8