We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

The n-of-1 clinical trial: the ultimate strategy for individualizing medicine?

    Elizabeth O Lillie

    Scripps Health, La Jolla, CA 92037, USA

    The Scripps Translational Science Institute, La Jolla, CA 92037, USA

    ,
    Bradley Patay

    Scripps Health, La Jolla, CA 92037, USA

    The Scripps Translational Science Institute, La Jolla, CA 92037, USA

    ,
    Joel Diamant

    Scripps Health, La Jolla, CA 92037, USA

    The Scripps Translational Science Institute, La Jolla, CA 92037, USA

    ,
    Brian Issell

    Scripps Health, La Jolla, CA 92037, USA

    The Scripps Translational Science Institute, La Jolla, CA 92037, USA

    ,
    Eric J Topol

    Scripps Health, La Jolla, CA 92037, USA

    The Scripps Translational Science Institute, La Jolla, CA 92037, USA

    The Scripps Research Institute, La Jolla, CA 92047, USA

    The West Wireless Health Institute, La Jolla, CA 92037, USA

    &
    Published Online:https://doi.org/10.2217/pme.11.7

    N-of-1 or single subject clinical trials consider an individual patient as the sole unit of observation in a study investigating the efficacy or side-effect profiles of different interventions. The ultimate goal of an n-of-1 trial is to determine the optimal or best intervention for an individual patient using objective data-driven criteria. Such trials can leverage study design and statistical techniques associated with standard population-based clinical trials, including randomization, washout and crossover periods, as well as placebo controls. Despite their obvious appeal and wide use in educational settings, n-of-1 trials have been used sparingly in medical and general clinical settings. We briefly review the history, motivation and design of n-of-1 trials and emphasize the great utility of modern wireless medical monitoring devices in their execution. We ultimately argue that n-of-1 trials demand serious attention among the health research and clinical care communities given the contemporary focus on individualized medicine.

    Papers of special note have been highlighted as: ▪ of interest

    Bibliography

    • Jorgensen JT: Are we approaching the post-blockbuster era? Pharmacodiagnostics and rational drug development. Expert Rev. Mol. Diagn.8(6),689–695 (2008).
    • Jorgensen JT: New era of personalized medicine: a 10-year anniversary. Oncologist14(5),557–558 (2009).
    • Hu SX, Foster T, Kieffaber A: Pharmacogenomics and personalized medicine: mapping of future value creation. Biotechniques39(10 Suppl.),S1–S6 (2005).
    • Langreth R, Waldholz M: New era of personalized medicine: targeting drugs for each unique genetic profile. Oncologist4(5),426–427 (1999).
    • Trusheim MR, Berndt ER, Douglas FL: Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat. Rev. Drug Discov.6(4),287–293 (2007).
    • Guyatt GH, Haynes RB, Jaeschke RZ et al.: Users’ guides to the medical literature: XXV. Evidence-based medicine: principles for applying the users’ guides to patient care. Evidence-Based Medicine Working Group. JAMA284(10),1290–1296 (2000).
    • Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS: Evidence based medicine: what it is and what it isn’t. BMJ312(7023),71–72 (1996).
    • Lauer MS, Collins FS: Using science to improve the nation’s health system: NIH’s commitment to comparative effectiveness research. JAMA303(21),2182–2183 (2010).
    • Collins FS: Research agenda. Opportunities for research and NIH. Science327(5961),36–37 (2010).
    • 10  Ginsburg GS, Willard HF: Genomic and personalized medicine: foundations and applications. Transl. Res.154(6),277–287 (2009).
    • 11  Kraushaar LE, Kramer A: Are we losing the battle against cardiometabolic disease? The case for a paradigm shift in primary prevention. BMC Public Health9,64 (2009).
    • 12  Rich EC: The policy debate over public investment in comparative effectiveness research. J. Gen. Intern. Med.24(6),752–757 (2009).
    • 13  Snyderman R, Yoediono Z: Perspective: prospective health care and the role of academic medicine: lead, follow, or get out of the way. Acad. Med.83(8),707–714 (2008).
    • 14  Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat. Med.10(8),789–799 (2004).
    • 15  Van Cutsem E, Kohne CH, Hitre E et al.: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med.360(14),1408–1417 (2009).
    • 16  Flockhart DA, Skaar T, Berlin DS, Klein TE, Nguyen AT: Clinically available pharmacogenomics tests. Clin. Pharmacol. Ther.86(1),109–113 (2009).
    • 17  Topol EJ: Pharmacy benefit managers, pharmacies, and pharmacogenomic testing: prescription for progress? Sci. Transl. Med.2(44),44cm22 (2010).
    • 18  Hamburg MA, Collins FS: The path to personalized medicine. N. Engl. J. Med.363(4),301–304 (2010).
    • 19  Tsapas A, Matthews DR: Using N-of-1 trials in evidence-based clinical practice. JAMA301(10),1022–1023; 1023 (2009).
    • 20  Guyatt GH, Jaeschke R: N-of-1 randomized trials – where do we stand? West. J. Med.152(1),67–68 (1990).
    • 21  Everitt BS, Pickler A: Statistical Aspects of The Design of Clinical Trials. Imperial College Press, London, UK (2004).
    • 22  Gerss JW, Kopcke W: Clinical trials and rare diseases. Adv. Exp. Med. Biol.686,173–190 (2010).
    • 23  Meinert CL, Tonascia S: Clinical Trials: Design, Conduct, and Analysis. Monographs in Epidemiology and Biostatistics. Oxford University Press, NY, USA, 469 (1986).
    • 24  Barlow DH, Nock M, Hersen M: Single Case Experimental Designs: Strategies for Studying Behavior for Change (3rd Edition). Pearson/Allyn and Bacon, MA, USA, 393 (2009).
    • 25  Guyatt G, Sackett D, Taylor DW, Chong J, Roberts R, Pugsley S: Determining optimal therapy – randomized trials in individual patients. N. Engl. J. Med.314(14),889–892 (1986).▪ Laid the foundation for n-of-1 trials in clinical medicine. Many other papers published by this research group further describe their years of experience in implementing n-of-1 trials.
    • 26  Guyatt GH, Keller JL, Jaeschke R, Rosenbloom D, Adachi JD, Newhouse MT: The n-of-1 randomized controlled trial: clinical usefulness. Our three-year experience. Ann. Intern. Med.112(4),293–299 (1990).
    • 27  Nikles J, Mitchell G, Walters J et al.: Prioritising drugs for single patient (n-of-1) trials in palliative care. Palliat. Med.23(7),623–634 (2009).
    • 28  Kravitz RL, Duan N, Niedzinski EJ, Hay MC, Subramanian SK, Weisner TS: What ever happened to n-of-1 trials? Insiders’ perspectives and a look to the future. Milbank Q.86(4),533–555 (2008).▪ Good review of the history of n-of-1 trials, including interviews with researchers who have been leaders in the field providing valuable direct insight into challenges of n-of-1 trials.
    • 29  Kravitz RL, Paterniti DA, Hay MC et al.: Marketing therapeutic precision: potential facilitators and barriers to adoption of n-of-1 trials. Contemp. Clin. Trials30(5),436–445 (2009).
    • 30  Kraemer HC, Frank E, Kupfer DJ: Moderators of treatment outcomes: clinical, research, and policy importance. JAMA296(10),1286–1289 (2006).
    • 31  Kraemer HC, Wilson GT, Fairburn CG, Agras WS: Mediators and moderators of treatment effects in randomized clinical trials. Arch. Gen. Psychiatry59(10),877–883 (2002).
    • 32  Kent DM, Hayward RA: Limitations of applying summary results of clinical trials to individual patients: the need for risk stratification. JAMA298(10),1209–1212 (2007).
    • 33  Scuffham PA, Nikles J, Mitchell GK et al.: Using n-of-1 trials to improve patient management and save costs. J. Gen. Intern. Med.25(9),906–913 (2010).▪ Analysis using data from the clinical trial service developed in Australia of n-of-1 trials from the cost perspective.
    • 34  Grande GE, Todd CJ: Why are trials in palliative care so difficult? Palliat. Med.14(1),69–74 (2000).
    • 35  Abrahm JL: A Physician’s Guide to Pain and Symptom Management in Cancer Patients (2nd Edition). Johns Hopkins University Press, MD, USA (2005).
    • 36  Zucker DR, Schmid CH, McIntosh MW, D’Agostino RB, Selker HP, Lau J: Combining single patient (n-of-1) trials to estimate population treatment effects and to evaluate individual patient responses to treatment. J. Clin. Epidemiol.50(4),401–410 (1997).▪ This paper and a recently published follow-up paper discuss the statistical methodology involved in combining n-of-1 trials.
    • 37  Huber AM, Tomlinson GA, Koren G, Feldman BM: Amitriptyline to relieve pain in juvenile idiopathic arthritis: a pilot study using Bayesian metaanalysis of multiple n-of-1 clinical trials. J. Rheumatol.34(5),1125–1132 (2007).
    • 38  Senn S: Cross-over Trials in Clinical Research (2nd Edition). Wiley, Chichester, UK (2002).
    • 39  Guyatt GH, Heyting A, Jaeschke R, Keller J, Adachi JD, Roberts RS: N-of-1 randomized trials for investigating new drugs. Control. Clin. Trials11(2),88–100 (1990).
    • 40  Yelland MJ, Nikles CJ, McNairn N, Del Mar CB, Schluter PJ, Brown RM: Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials. Rheumatology46(1),135–140 (2007).
    • 41  Kazdin AE: Single-Case Research Designs: Methods for Clinical and Applied Settings. Oxford University Press, NY, USA, 368 (1982).
    • 42  Barlow DH, Hersen M: Single Case Experimental Designs (2nd Edition). Allyn and Bacon, MA, USA (1984).
    • 43  Spiegelhalter DJ: Statistical issues in studies of individual response. Scand. J. Gastroenterol. Suppl.147,40–45 (1988).
    • 44  Rochon J: A statistical model for the “n-of-1” study. J. Clin. Epidemiol.43(5),499–508 (1990).
    • 45  Topol EJ: Transforming medicine via digital innovation. Sci. Transl. Med.2(16),16cm4 (2010).▪ Recent paper that paints a picture of the future of medicine and the new age of digital medical devices that we are entering.
    • 46  Plasqui G, Westerterp KR: Physical activity assessment with accelerometers: an evaluation against doubly labeled water. Obesity (Silver Spring)15(10),2371–2379 (2007).
    • 47  Reid SC, Kauer SD, Dudgeon P, Sanci LA, Shrier LA, Patton GC: A mobile phone program to track young people’s experiences of mood, stress and coping. Development and testing of the mobiletype program. Soc. Psychiatry Psychiatr. Epidemiol.44(6),501–507 (2009).
    • 48  Sudano I, Flammer AJ, Hermann F et al.: Auricall. A new device for a non-invasive, wireless, continuous monitoring of oxygen saturation and heart rate in patients with heart failure. Int. J. Cardiol.129(1),141–143 (2008).
    • 49  Welch J, Guilak F, Baker S: A wireless ECG smart sensor for broad application in life threatening event detection. Conf. Proc. IEEE Eng. Med. Biol. Soc.5,3447–3449 (2004).
    • 50  Wong LJ, Buckingham BA, Kunselman B, Istoc E, Leach J, Purvis R: Extended use of a new continuous glucose monitoring system with wireless data transmission in children with Type 1 diabetes mellitus. Diabetes Technol. Ther.8(2),139–145 (2006).
    • 51  Vlassov VV, Laktionov PP, Rykova EY: Circulating nucleic acids as a potential source for cancer biomarkers. Curr. Mol. Med.10(2),142–165 (2010).
    • 52  Wu H, Chen H, Hu PC: Circulating endothelial cells and endothelial progenitors as surrogate biomarkers in vascular dysfunction. Clin. Lab.53(5–6),285–295 (2007).
    • 53  Zucker DR, Ruthazer R, Schmid CH: Individual (n-of-1) trials can be combined to give population comparative treatment effect estimates: methodologic considerations. J. Clin. Epidemiol.63(12),1312–1323 (2010).
    • 54  Larson EB, Ellsworth AJ, Oas J: Randomized clinical trials in single patients during a 2-year period. JAMA270(22),2708–2712 (1993).▪ Another research group’s experience of conducting n-of-1 trials is described here. They review the feasibility of n-of-1 trials from a patient, physician and cost perspective.
    • 55  Mahon J, Laupacis A, Donner A, Wood T: Randomised study of n-of-1 trials versus standard practice. BMJ312(7038),1069–1074 (1996).
    • 56  Nikles CJ, Mitchell GK, Del Mar CB, Clavarino A, McNairn N: An n-of-1 trial service in clinical practice: testing the effectiveness of stimulants for attention-deficit/hyperactivity disorder. Pediatrics117(6),2040–2046 (2006).▪ Published by a research group that implemented an n-of-1 service in Australia to treat attention deficit and hyperactivity disorder.
    • 57  Pope JE, Prashker M, Anderson J: The efficacy and cost effectiveness of n-of-1 studies with diclofenac compared with standard treatment with nonsteroidal antiinflammatory drugs in osteoarthritis. J. Rheumatol.31(1),140–149 (2004).
    • 58  Scuffham PA, Yelland MJ, Nikles J, Pietrzak E, Wilkinson D: Are n-of-1 trials an economically viable option to improve access to selected high cost medications? The Australian experience. Value Health11(1),97–109 (2008).
    • 59  Chow SC, Chang M: Adaptive Design Methods in Clinical Trials. Chapman Hall, FL, USA (2007).
    • 60  Rausch TL, Judd TM: The development of an interoperable roadmap for medical devices. Conf. Proc. IEEE Eng. Med. Biol. Soc. Suppl. 6740–6743 (2006).
    • 61  Cepeda MS, Acevedo JC, Alvarez H, Miranda N, Cortes C, Carr DB: An n-of-1 trial as an aid to decision-making prior to implanting a permanent spinal cord stimulator. Pain Med.9(2),235–239 (2008).
    • 62  Nathan PC, Tomlinson G, Dupuis LL et al.: A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial n-of-1 trials design. Support. Care Cancer14(3),268–276 (2006).
    • 63  Woodfield R, Goodyear-Smith F, Arroll B: N-of-1 trials of quinine efficacy in skeletal muscle cramps of the leg. Br. J. Gen. Pract.55(512),181–185 (2005).
    • 64  Nikles CJ, Yelland M, Glasziou PP, Del Mar C: Do individualized medication effectiveness tests (n-of-1 trials) change clinical decisions about which drugs to use for osteoarthritis and chronic pain? Am. J. Ther.12(1),92–97 (2005).
    • 65  Notcutt W, Price M, Miller R et al.: Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘n-of-1’ studies. Anaesthesia59(5),440–452 (2004).
    • 66  Haas DC, Sheehe PR: Dextroamphetamine pilot crossover trials and n-of-1 trials in patients with chronic tension-type and migraine headache. Headache44(10),1029–1037 (2004).
    • 67  Wegman AC, van der Windt DA, de Haan M, Deville WL, Fo CT, de Vries TP: Switching from NSAIDs to paracetamol: a series of n-of-1 trials for individual patients with osteoarthritis. Ann. Rheum. Dis.62(12),1156–1161 (2003).
    • 68  Jansen IH, Olde Rikkert MG, Hulsbos HA, Hoefnagels WH: Toward individualized evidence-based medicine: five ‘n-of-1’ trials of methylphenidate in geriatric patients. J. Am. Geriatr. Soc.49(4),474–476 (2001).
    • 69  Haines DR, Gaines SP: N-of-1 randomised controlled trials of oral ketamine in patients with chronic pain. Pain83(2),283–287 (1999).
    • 70  March L, Irwig L, Schwarz J, Simpson J, Chock C, Brooks P: N-of-1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteoarthritis. BMJ309(6961),1041–1045; discussion 1045–1046 (1994).
    • 71  Nonoyama ML, Brooks D, Guyatt GH, Goldstein RS: Ambulatory gas usage in patients with chronic obstructive pulmonary disease and exertional hypoxemia. J. Cardiopulm. Rehabil. Prev.28(5),323–329 (2008).
    • 72  Hackett A, Gillard J, Wilcken B: N-of-1 trial for an ornithine transcarbamylase deficiency carrier. Mol. Genet. Metab.94(2),157–161 (2008).
    • 73  Martin RT, Whyte J: The effects of methylphenidate on command following and yes/no communication in persons with severe disorders of consciousness: a meta-analysis of n-of-1 studies. Am. J. Phys. Med. Rehabil.86(8),613–620 (2007).
    • 74  Sung L, Tomlinson GA, Greenberg ML et al.: Serial controlled n-of-1 trials of topical vitamin E as prophylaxis for chemotherapy-induced oral mucositis in paediatric patients. Eur. J. Cancer43(8),1269–1275 (2007).
    • 75  Baicus C, Baicus A: Spirulina did not ameliorate idiopathic chronic fatigue in four N-of-1 randomized controlled trials. Phytother. Res.21(6),570–573 (2007).
    • 76  Pereira JA, Holbrook AM, Dolovich L et al.: Are brand-name and generic warfarin interchangeable? Multiple n-of-1 randomized, crossover trials. Ann. Pharmacother.39(7–8),1188–1193 (2005).
    • 77  Coxeter PD, Schluter PJ, Eastwood HL, Nikles CJ, Glasziou PP: Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials. Complement. Ther. Med.11(4),215–222 (2003).
    • 78  Smith BJ, Appleton SL, Veale AJ, McElroy HJ, Veljkovic D, Saccoia L: Eformoterol n-of-1 trials in chronic obstructive pulmonary disease poorly reversible to salbutamol. Chron. Respir. Dis.1(2),63–69 (2004).
    • 79  Suri R, Metcalfe C, Wallis C, Bush A: Predicting response to rhDNase and hypertonic saline in children with cystic fibrosis. Pediatr. Pulmonol.37(4),305–310 (2004).
    • 80  Price JD, Grimley Evans J: An n-of-1 randomized controlled trial (‘n-of-1 trial’) of donepezil in the treatment of non-progressive amnestic syndrome. Age Ageing31(4),307–309 (2002).
    • 81  Wolfe B, Del Rio E, Weiss SL et al.: Validation of a single-patient drug trial methodology for personalized management of gastroesophageal reflux disease. J. Manag. Care Pharm.8(6),459–468 (2002).
    • 82  Bollert FG, Paton JY, Marshall TG, Calvert J, Greening AP, Innes JA: Recombinant DNase in cystic fibrosis: a protocol for targeted introduction through n-of-1 trials. Scottish Cystic Fibrosis Group. Eur. Respir. J.13(1),107–113 (1999).
    • 83  Kent MA, Camfield CS, Camfield PR: Double-blind methylphenidate trials: practical, useful, and highly endorsed by families. Arch. Pediatr. Adolesc. Med.153(12),1292–1296 (1999).
    • 84  Mahon JL, Laupacis A, Hodder RV et al.: Theophylline for irreversible chronic airflow limitation: a randomized study comparing n-of-1 trials to standard practice. Chest115(1),38–48 (1999).