Medical Rehabilitation: Guidelines to Advance the Field With High-Impact Clinical Trials

Published:August 24, 2018DOI:


      The purpose of this Special Communication is to summarize guidelines and recommendations stemming from an expert panel convened by the National Institutes of Health, National Center for Medical Rehabilitation Research (NCMRR) for a workshop entitled The Future of Medical Rehabilitation Clinical Trials, held September 29-30, 2016, at the NCMRR offices in Bethesda, Maryland. The ultimate goal of both the workshop and this summary is to offer guidance on clinical trials design and operations to the medical rehabilitation research community, with the intent of maximizing the effect of future trials.


      List of abbreviations:

      AE (adverse event), DSMB (data and safety monitoring board), CRC (clinical research coordinator), CRF (case report form), GCP (good clinical practice), ICH (International Council on Harmonization), IRB (institutional review board), MOP (manual of procedures), NCMRR (National Center for Medical Rehabilitation Research), PCT (pragmatic clinical trial), PI (principal investigator), PRECIS (Pragmatic-Explanatory Continuum Indicator Summary), REACT (Rehabilitation Research Resource to Enhance Clinical Trials), RCT (randomized controlled trial), SCI (spinal cord injury), SCT (social cognitive theory), SMART (sequential, multiple assignment, randomized trial)
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        • Simon R.
        • Maitournam A.
        Evaluating the efficiency of targeted designs for randomized clinical trials.
        Clin Cancer Res. 2004; 10: 6759-6763
        • Cutter G.
        • Kappos L.
        Clinical trials in multiple sclerosis.
        Handb Clin Neurol. 2014; 122: 445-453
        • Zhang X.
        • Cutter G.
        Bayesian interim analysis in clinical trials.
        Contemp Clin Trials. 2008; 29: 751-755
        • Bhatt D.L.
        • Mehta C.
        Adaptive designs for clinical trials.
        N Engl J Med. 2016; 375: 65-74
        • Gomes-Osman J.
        • Cortes M.
        • Guest J.
        • Pascual-Leone A.
        A systematic review of experimental strategies aimed at improving motor function after acute and chronic spinal cord injury.
        J Neurotrauma. 2016; 33: 425-438
        • Constantini S.
        • Young W.
        The effects of methylprednisolone and the ganglioside GM1 on acute spinal cord injury in rats.
        J Neurosurg. 1994; 80: 97-111
        • Geisler F.H.
        • Dorsey F.C.
        • Coleman W.P.
        Recovery of motor function after spinal-cord injury--a randomized, placebo-controlled trial with GM-1 ganglioside.
        N Engl J Med. 1991; 324: 1829-1838
        • Backman C.L.
        • Harris S.R.
        Case studies, single-subject research, and N of 1 randomized trials: comparisons and contrasts.
        Am J Phys Med Rehabil. 1999; 78: 170-176
        • Senn S.
        Are placebo run ins justified?.
        BMJ. 1997; 314: 1191
        • Senn S.
        • Lee S.
        The analysis of the AB/BA cross-over trial in the medical literature.
        Pharm Stat. 2004; 3: 123-131
        • Sackett D.L.
        • HR
        • Guyatt G.H.
        • Tugwell P.
        Clinical epidemiology: a basic science for clinical medicine.
        2nd ed. Little, Brown & Co, Boston1991
        • Onghena P.
        Single case designs.
        in: Everitt B.S. Howell D. Encyclopedia of statistics in behavioral science. John Wiley & Sons Ltd, Chichester2005
        • Hawkins N.G.
        • Sanson-Fisher R.W.
        • Shakeshaft A.
        • D'Este C.
        • Green L.W.
        The multiple baseline design for evaluating population-based research.
        Am J Prev Med. 2007; 33: 162-168
        • DiMasi J.A.
        • Grabowski H.G.
        • Hansen R.W.
        Innovation in the pharmaceutical industry: new estimates of R&D costs.
        J Health Econ. 2016; 47: 20-33
        • Institute of M
        Envisioning a transformed clinical trials enterprise in the United States: establishing an agenda for 2020: workshop summary.
        National Academies Press, Washington, DC2012
        • Sherman R.E.
        • Anderson S.A.
        • Dal Pan G.J.
        • et al.
        Real-world evidence—what is it and what can it tell us?.
        N Engl J Med. 2016; 375: 2293-2297
        • Schwartz D.
        • Lellouch J.
        Explanatory and pragmatic attitudes in therapeutical trials.
        J Chronic Dis. 1967; 20: 637-648
        • Fletcher R.H.
        • Fletcher S.W.
        • Wagner E.H.
        Clinical epidemiology - the essentials.
        2nd ed. Williams & Wilkins, Baltimore1988
        • Pincus T.
        • Sokka T.
        Clinical trials in rheumatic diseases: designs and limitations.
        Rheum Dis Clin North Am. 2004; 30 (v-vi): 701-724
        • Eapen Z.J.
        • Lauer M.S.
        • Temple R.J.
        The imperative of overcoming barriers to the conduct of large, simple trials.
        JAMA. 2014; 311: 1397-1398
        • US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research
        Determining the extent of safety data collection needed in late-stage premarket and postapproval clinical investigations: guidance for industry.
        (Available at:) (Accessed February 8, 2017)
        • Thorpe K.E.
        • Zwarenstein M.
        • Oxman A.D.
        • et al.
        A pragmatic-explanatory continuum indicator summary (PRECIS): a tool to help trial designers.
        J Clin Epidemiol. 2009; 62: 464-475
        • Loudon K.
        • Treweek S.
        • Sullivan F.
        • Donnan P.
        • Thorpe K.E.
        • Zwarenstein M.
        The PRECIS-2 tool: designing trials that are fit for purpose.
        BMJ. 2015; 350: h2147
        • Saag K.G.
        • Mohr P.E.
        • Esmail L.
        • et al.
        Improving the efficiency and effectiveness of pragmatic clinical trials in older adults in the United States.
        Contemp Clin Trials. 2012; 33: 1211-1216
        • World Health Organization
        International Classification of Functioning, Disability and Health.
        (Accessed June 15, 2018)
        • Hart T.
        • Ehde D.M.
        Defining the treatment targets and active ingredients of rehabilitation: Implications for rehabilitation psychology.
        Rehabil Psychol. 2015; 60: 126-135
        • VanHiel L.R.
        Treatment and enablement in rehabilitation research.
        Arch Phys Med Rehabil. 2014; 95: S88-S90
        • Whyte J.
        Contributions of treatment theory and enablement theory to rehabilitation research and practice.
        Arch Phys Med Rehabil. 2014; 95: S17-S23.e12
        • Whyte J.
        • Dijkers M.P.
        • Hart T.
        • et al.
        Development of a theory-driven rehabilitation treatment taxonomy: conceptual issues.
        Arch Phys Med Rehabil. 2014; 95: S24-S32.e22
        • Bamman M.M.
        • Petrella J.K.
        • Kim J.S.
        • Mayhew D.L.
        • Cross J.M.
        Cluster analysis tests the importance of myogenic gene expression during myofiber hypertrophy in humans.
        J Appl Physiol (1985). 2007; 102: 2232-2239
        • Mayhew D.L.
        • Hornberger T.A.
        • Lincoln H.C.
        • Bamman M.M.
        Eukaryotic initiation factor 2B epsilon induces cap-dependent translation and skeletal muscle hypertrophy.
        J Physiol. 2011; 589: 3023-3037
        • Petrella J.K.
        • Kim J.S.
        • Mayhew D.L.
        • Cross J.M.
        • Bamman M.M.
        Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis.
        J Appl Physiol. 2008; 104: 1736-1742
        • Stec M.J.
        • Kelly N.A.
        • Many G.M.
        • Windham S.T.
        • Tuggle S.C.
        • Bamman M.M.
        Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro.
        Am J Physiol Endocrinol Metab. 2016; 310: E652-E661
        • Thalacker-Mercer A.
        • Stec M.
        • Cui X.
        • Cross J.
        • Windham S.
        • Bamman M.
        Cluster analysis reveals differential transcript profiles associated with resistance training-induced human skeletal muscle hypertrophy.
        Physiol Genomics. 2013; 45: 499-507
        • Stec M.J.
        • Thalacker-Mercer A.
        • Mayhew D.L.
        • et al.
        Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy.
        Exp Gerontol. 2017; 99: 98-109
        • Long D.E.
        • Peck B.D.
        • Martz J.L.
        • et al.
        Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial.
        Trials. 2017; 18: 192
        • Knutson J.S.
        • Gunzler D.D.
        • Wilson R.D.
        • Chae J.
        Contralaterally controlled functional electrical stimulation improves hand dexterity in chronic hemiparesis: a randomized trial.
        Stroke. 2016; 47: 2596-2602
        • Kelly N.A.
        • Ford M.P.
        • Standaert D.G.
        • et al.
        Novel, high-intensity exercise prescription improves muscle mass, mitochondrial function, and physical capacity in individuals with Parkinson’s disease.
        J Appl Physiol. 2014; 116: 582-592
        • Corcos D.M.
        • Robichaud J.A.
        • David F.J.
        • et al.
        A two-year randomized controlled trial of progressive resistance exercise for Parkinson’s disease.
        Mov Disord. 2013; 28: 1230-1240
        • McDonald A.M.
        • Knight R.C.
        • Campbell M.K.
        • et al.
        What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies.
        Trials. 2006; 7: 9
        • Kadam R.A.
        • Borde S.U.
        • Madas S.A.
        • Salvi S.S.
        • Limaye S.S.
        Challenges in recruitment and retention of clinical trial subjects.
        Perspect Clin Res. 2016; 7: 137-143
        • Frank G.
        Current challenges in clinical trial patient recruitment and enrollment.
        SOCRA Source. 2004; 2: 9
        • Shalowitz D.I.
        • Miller F.G.
        Communicating the results of clinical research to participants: attitudes, practices, and future directions.
        PLoS Med. 2008; 5: e91
        • Caldwell P.H.
        • Hamilton S.
        • Tan A.
        • Craig J.C.
        Strategies for increasing recruitment to randomised controlled trials: systematic review.
        PLoS Med. 2010; 7e1000368
        • Fouad M.N.
        • Acemgil A.
        • Bae S.
        • et al.
        Patient navigation as a model to increase participation of African Americans in cancer clinical trials.
        J Oncol Pract. 2016; 12: 556-563
        • Lai B.
        • Young H.J.
        • Bickel C.S.
        • Motl R.W.
        • Rimmer J.H.
        Current trends in exercise intervention research, technology, and behavioral change strategies for people with disabilities: a scoping review.
        Am J Phys Med Rehabil. 2017; 96: 748-761
        • Larkin L.
        • Kennedy N.
        • Gallagher S.
        Promoting physical activity in rheumatoid arthritis: a narrative review of behaviour change theories.
        Disabil Rehabil. 2015; 37: 2359-2366
        • Ellis T.
        • Motl R.W.
        Physical activity behavior change in persons with neurologic disorders: overview and examples from Parkinson disease and multiple sclerosis.
        J Neurol Phys Ther. 2013; 37: 85-90
        • Adamson B.C.
        • Learmonth Y.C.
        • Kinnett-Hopkins D.
        • Bohri M.
        • Motl R.W.
        Feasibility study design and methods for Project GEMS: guidelines for exercise in multiple sclerosis.
        Contemp Clin Trials. 2016; 47: 32-39
        • Learmonth Y.C.
        • Adamson B.C.
        • Kinnett-Hopkins D.
        • Bohri M.
        • Motl R.W.
        Results of a feasibility randomized controlled study of the guidelines for exercise in multiple sclerosis project.
        Contemporary Clin Trials. 2017; 54: 84-97
        • Beidas R.S.
        • Paciotti B.
        • Barg F.
        • et al.
        A hybrid effectiveness-implementation trial of an evidence-based exercise intervention for breast cancer survivors.
        J Natl Cancer Inst Monogr. 2014; 2014: 338-345
        • Schmitz K.H.
        • Ahmed R.L.
        • Troxel A.
        • et al.
        Weight lifting in women with breast-cancer-related lymphedema.
        N Engl J Med. 2009; 361: 664-673
        • Schmitz K.H.
        • Ahmed R.L.
        • Troxel A.B.
        • et al.
        Weight lifting for women at risk for breast cancer-related lymphedema: a randomized trial.
        JAMA. 2010; 304: 2699-2705
      1. International Counceil for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). Available at Accessed January 10, 2017.

        • Treweek S.
        • Zwarenstein M.
        Making trials matter: pragmatic and explanatory trials and the problem of applicability.
        Trials. 2009; 10: 37
        • Ehde D.M.
        • Wegener S.T.
        • Williams R.M.
        • et al.
        Developing, testing, and sustaining rehabilitation interventions via participatory action research.
        Arch Phys Med Rehabil. 2013; 94: S30-S42
        • Williams G.C.
        • Grow V.M.
        • Freedman Z.R.
        • Ryan R.M.
        • Deci E.L.
        Motivational predictors of weight loss and weight-loss maintenance.
        J Pers Soc Psychol. 1996; 70: 115-126
        • Chan D.K.
        • Lonsdale C.
        • Ho P.Y.
        • Yung P.S.
        • Chan K.M.
        Patient motivation and adherence to postsurgery rehabilitation exercise recommendations: the influence of physiotherapists' autonomy-supportive behaviors.
        Arch Phys Med Rehabil. 2009; 90: 1977-1982
        • Collins F.S.
        • Tabak L.A.
        Policy: NIH plans to enhance reproducibility.
        Nature. 2014; 505: 612-613
        • Department of Health and Human Services
        Notice of proposed rulemaking.
        Fed Regist. 2015; 80: 53933-54061
        • National Center for Advancing Translational Sciences
        NCATS SMART IRB reliance platform.
        (Available at:) (Accessed February 8, 2017)