Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the "evidence puzzle".

Department of Paediatric Oncology University Hospital Brno and School of Medicine Masaryk University Cernopolni 9 613 00 Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

International Clinical Research Centre St Anne's University Hospital Brno Pekarska 53 656 91 Brno Czech Republic

Zobrazit více v PubMed

Sackett D.L. Randomized Trials in Individual Patients. Complement. Med. Res. 1996;3:140–147. doi: 10.1159/000210215. DOI

European Medicines Agency. Committee for Human Medicinal Products. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice E6 (R2) Step 5, EMA/CHMP/ICH/135/1995. [(accessed on 28 October 2021)];2016 December 1; Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-R2-guideline-good-clinical-practice-step-5_en.pdf.

Murad M.H., Asi N., Alsawas M., Alahdab F. New Evidence Pyramid. Evid. Based Med. 2016;21:125–127. doi: 10.1136/ebmed-2016-110401. PubMed DOI PMC

Aguayo-Albasini J.L., Flores-Pastor B., Soria-Aledo V. GRADE System: Classification of Quality of Evidence and Strength of Recommendation. Cir. Esp. Engl. Ed. 2014;92:82–88. doi: 10.1016/j.ciresp.2013.08.002. PubMed DOI

National Health and Medical Research Council NHMRC Additional Levels of Evidence and Grades for Recommendations for Developers of Guidelines. Canberra. [(accessed on 28 October 2021)];2009 Available online: https://www.mja.com.au/sites/default/files/NHMRC.levels.of.evidence.2008-09.pdf.

Bothwell L.E., Greene J.A., Podolsky S.H., Jones D.S. Assessing the Gold Standard—Lessons from the History of RCTs. N. Engl. J. Med. 2016;374:2175–2181. doi: 10.1056/NEJMms1604593. PubMed DOI

Gatta G., Botta L., Rossi S., Aareleid T., Bielska-Lasota M., Clavel J., Dimitrova N., Jakab Z., Kaatsch P., Lacour B., et al. Childhood Cancer Survival in Europe 1999–2007: Results of EUROCARE-5—A Population-Based Study. Lancet Oncol. 2014;15:35–47. doi: 10.1016/S1470-2045(13)70548-5. PubMed DOI

Hilgers R. Design and Analysis of Clinical Trials for Small Rare Disease Populations. J. Rare Dis. Res. Treat. 2016;1:53–60. doi: 10.29245/2572-9411/2016/3.1054. DOI

Korn E.L., McShane L.M., Freidlin B. Statistical Challenges in the Evaluation of Treatments for Small Patient Populations. Sci. Transl. Med. 2013;5:sr3–sr178. doi: 10.1126/scitranslmed.3004018. PubMed DOI

Friede T., Posch M., Zohar S., Alberti C., Benda N., Comets E., Day S., Dmitrienko A., Graf A., Günhan B.K., et al. Recent Advances in Methodology for Clinical Trials in Small Populations: The InSPiRe Project. Orphanet J. Rare Dis. 2018;13:186. doi: 10.1186/s13023-018-0919-y. PubMed DOI PMC

Day S., Jonker A.H., Lau L.P.L., Hilgers R.-D., Irony I., Larsson K., Roes K.C., Stallard N. Recommendations for the Design of Small Population Clinical Trials. Orphanet J. Rare Dis. 2018;13:195. doi: 10.1186/s13023-018-0931-2. PubMed DOI PMC

Howard A.F., Goddard K., Rassekh S.R., Samargandi O.A., Hasan H. Clinical Significance in Pediatric Oncology Randomized Controlled Treatment Trials: A Systematic Review. Trials. 2018;19:539. doi: 10.1186/s13063-018-2925-8. PubMed DOI PMC

Joseph P.D., Craig J.C., Caldwell P.H.Y. Clinical Trials in Children: Clinical Trials in Children. Br. J. Clin. Pharmacol. 2015;79:357–369. doi: 10.1111/bcp.12305. PubMed DOI PMC

Hee S.W., Willis A., Tudur Smith C., Day S., Miller F., Madan J., Posch M., Zohar S., Stallard N. Does the Low Prevalence Affect the Sample Size of Interventional Clinical Trials of Rare Diseases? An Analysis of Data from the Aggregate Analysis of Clinicaltrials.Gov. Orphanet J. Rare Dis. 2017;12:44. doi: 10.1186/s13023-017-0597-1. PubMed DOI PMC

Vassal G., Rousseau R., Blanc P., Moreno L., Bode G., Schwoch S., Schrappe M., Skolnik J., Bergman L., Bradley-Garelik M.B., et al. Creating a Unique, Multi-Stakeholder Paediatric Oncology Platform to Improve Drug Development for Children and Adolescents with Cancer. Eur. J. Cancer. 2015;51:218–224. doi: 10.1016/j.ejca.2014.10.029. PubMed DOI

Moher D., Hopewell S., Schulz K.F., Montori V., Gøtzsche P.C., Devereaux P.J., Elbourne D., Egger M., Altman D.G. CONSORT 2010 Explanation and Elaboration: Updated Guidelines for Reporting Parallel Group Randomised Trials. Int. J. Surg. 2012;10:28–55. doi: 10.1016/j.ijsu.2011.10.001. PubMed DOI

Siepmann T., Spieth P.M., Kubasch A.S., Penzlin A.I., Illigens B.M.-W., Barlinn K. Randomized Controlled Trials—A Matter of Design. Neuropsychiatr. Dis. Treat. 2016;12:1341. doi: 10.2147/NDT.S101938. PubMed DOI PMC

Cragg J.J., Kramer J.L.K., Borisoff J.F., Patrick D.M., Ramer M.S. Ecological Fallacy as a Novel Risk Factor for Poor Translation in Neuroscience Research: A Systematic Review and Simulation Study. Eur. J. Clin. Investig. 2019;49:e13045. doi: 10.1111/eci.13045. PubMed DOI

Wang B., Wu P., Kwan B., Tu X.M., Feng C. Simpson’s Paradox: Examples. Shanghai Arch. Psychiatry. 2018;30:139–143. doi: 10.11919/j.issn.1002-0829.218026. PubMed DOI PMC

Longford N.T. Selection Bias and Treatment Heterogeneity in Clinical Trials. Stat. Med. 1999;18:1467–1474. doi: 10.1002/(SICI)1097-0258(19990630)18:12<1467::AID-SIM149>3.0.CO;2-H. PubMed DOI

Kravitz R.L., Duan N., Braslow J. Evidence-Based Medicine, Heterogeneity of Treatment Effects, and the Trouble with Averages. Milbank Q. 2004;82:661–687. doi: 10.1111/j.0887-378X.2004.00327.x. PubMed DOI PMC

Greenfield S., Kravitz R., Duan N., Kaplan S.H. Heterogeneity of Treatment Effects: Implications for Guidelines, Payment, and Quality Assessment. Am. J. Med. 2007;120:S3–S9. doi: 10.1016/j.amjmed.2007.02.002. PubMed DOI

Ashley E.A. The Precision Medicine Initiative: A New National Effort. JAMA. 2015;313:2119. doi: 10.1001/jama.2015.3595. PubMed DOI

Lindsey J.K., Lambert P. On the Appropriateness of Marginal Models for Repeated Measurements in Clinical Trials. Stat. Med. 1998;17:447–469. doi: 10.1002/(SICI)1097-0258(19980228)17:4<447::AID-SIM752>3.0.CO;2-G. PubMed DOI

Caldwell P.H., Murphy S.B., Butow P.N., Craig J.C. Clinical Trials in Children. Lancet. 2004;364:803–811. doi: 10.1016/S0140-6736(04)16942-0. PubMed DOI

Evans C.H., Ildstad S.T., Institute of Medicine (U.S.), editors. Small Clinical Trials: Issues and Challenges. National Academy Press; Washington, DC, USA: 2001. (Compass Series). PubMed

Meacham C.E., Morrison S.J. Tumour Heterogeneity and Cancer Cell Plasticity. Nature. 2013;501:328–337. doi: 10.1038/nature12624. PubMed DOI PMC

Averitt A.J., Weng C., Ryan P., Perotte A. Translating Evidence into Practice: Eligibility Criteria Fail to Eliminate Clinically Significant Differences between Real-World and Study Populations. NPJ Digit. Med. 2020;3:67. doi: 10.1038/s41746-020-0277-8. PubMed DOI PMC

Hajdu S.I. A Note from History: Landmarks in History of Cancer, Part 1. Cancer. 2011;117:1097–1102. doi: 10.1002/cncr.25553. PubMed DOI

Janiszewska M. The Microcosmos of Intratumor Heterogeneity: The Space-Time of Cancer Evolution. Oncogene. 2020;39:2031–2039. doi: 10.1038/s41388-019-1127-5. PubMed DOI PMC

Butler E., Ludwig K., Pacenta H.L., Klesse L.J., Watt T.C., Laetsch T.W. Recent Progress in the Treatment of Cancer in Children. CA. Cancer J. Clin. 2021;71:315–332. doi: 10.3322/caac.21665. PubMed DOI

Renfro L.A., Ji L., Piao J., Onar-Thomas A., Kairalla J.A., Alonzo T.A. Trial Design Challenges and Approaches for Precision Oncology in Rare Tumors: Experiences of the Children’s Oncology Group. JCO Precis. Oncol. 2019;3:1–13. doi: 10.1200/PO.19.00060. PubMed DOI PMC

Kennes L.N., Rosenberger W.F., Hilgers R.-D. Inference for Blocked Randomization under a Selection Bias Model: Inference under Selection Bias. Biometrics. 2015;71:979–984. doi: 10.1111/biom.12334. PubMed DOI

Lachin J.M. Properties of Simple Randomization in Clinical Trials. Control. Clin. Trials. 1988;9:312–326. doi: 10.1016/0197-2456(88)90046-3. PubMed DOI

Bell J.A.H., Forcina V., Mitchell L., Tam S., Wang K., Gupta A.A., Lewin J. Perceptions of and Decision Making about Clinical Trials in Adolescent and Young Adults with Cancer: A Qualitative Analysis. BMC Cancer. 2018;18:629. doi: 10.1186/s12885-018-4515-2. PubMed DOI PMC

Nikles J., Mitchell G.K., Schluter P., Good P., Hardy J., Rowett D., Shelby-James T., Vohra S., Currow D. Aggregating Single Patient (n-of-1) Trials in Populations Where Recruitment and Retention Was Difficult: The Case of Palliative Care. J. Clin. Epidemiol. 2011;64:471–480. doi: 10.1016/j.jclinepi.2010.05.009. PubMed DOI

Stallard N., Miller F., Day S., Hee S.W., Madan J., Zohar S., Posch M. Determination of the Optimal Sample Size for a Clinical Trial Accounting for the Population Size: Optimal Clinical Trial Sample Size Accounting for Population Size. Biom. J. 2017;59:609–625. doi: 10.1002/bimj.201500228. PubMed DOI PMC

Kýr M., Klement G.L., Zdrazilova-Dubska L., Demlova R., Valik D., Slaby O., Slavc I., Sterba J. Editorial: Precision/Personalized Pediatric Oncology and Immune Therapies: Rather Customize Than Randomize. Front. Oncol. 2020;10:377. doi: 10.3389/fonc.2020.00377. PubMed DOI PMC

Zhang J., Pilar M.R., Wang X., Liu J., Pang H., Brownson R.C., Colditz G.A., Liang W., He J. Endpoint Surrogacy in Oncology Phase 3 Randomised Controlled Trials. Br. J. Cancer. 2020;123:333–334. doi: 10.1038/s41416-020-0896-5. PubMed DOI PMC

Ellenberg S.S., Hamilton J.M. Surrogate Endpoints in Clinical Trials: Cancer. Stat. Med. 1989;8:405–413. doi: 10.1002/sim.4780080404. PubMed DOI

O’Leary M., Krailo M., Anderson J.R., Reaman G.H. Progress in Childhood Cancer: 50 Years of Research Collaboration, a Report from the Children’s Oncology Group. Semin. Oncol. 2008;35:484–493. doi: 10.1053/j.seminoncol.2008.07.008. PubMed DOI PMC

The SIOP Story: An Informal History of the International Society of Pediatric Oncology. Pediatr. Blood Cancer. 2016;63:S5–S42. doi: 10.1002/pbc.26170. PubMed DOI

Cornu C., Kassai B., Fisch R., Chiron C., Alberti C., Guerrini R., Rosati A., Pons G., Tiddens H., Chabaud S., et al. Experimental Designs for Small Randomised Clinical Trials: An Algorithm for Choice. Orphanet J. Rare Dis. 2013;8:48. doi: 10.1186/1750-1172-8-48. PubMed DOI PMC

Gagne J.J., Thompson L., O’Keefe K., Kesselheim A.S. Innovative Research Methods for Studying Treatments for Rare Diseases: Methodological Review. BMJ. 2014;349:g6802. doi: 10.1136/bmj.g6802. PubMed DOI PMC

Griggs R.C., Batshaw M., Dunkle M., Gopal-Srivastava R., Kaye E., Krischer J., Nguyen T., Paulus K., Merkel P.A. Clinical Research for Rare Disease: Opportunities, Challenges, and Solutions. Mol. Genet. Metab. 2009;96:20–26. doi: 10.1016/j.ymgme.2008.10.003. PubMed DOI PMC

Pediatric Rare Diseases—A Collaborative Approach for Drug Development Using Gaucher Disease as a Model Guidance for Industry, FDA-2017-N-6476. [(accessed on 28 October 2021)];2017 December; Available online: https://www.fda.gov/media/109465/download.

Mitroiu M., Oude Rengerink K., Pontes C., Sancho A., Vives R., Pesiou S., Fontanet J.M., Torres F., Nikolakopoulos S., Pateras K., et al. Applicability and Added Value of Novel Methods to Improve Drug Development in Rare Diseases. Orphanet J. Rare Dis. 2018;13:200. doi: 10.1186/s13023-018-0925-0. PubMed DOI PMC

Isakov L., Lo A.W., Montazerhodjat V. Is the FDA Too Conservative or Too Aggressive? A Bayesian Decision Analysis of Clinical Trial Design. J. Econom. 2019;211:117–136. doi: 10.1016/j.jeconom.2018.12.009. DOI

Jones B., Lewis J.A. The case for cross-over trials in phase III. Stat. Med. 1995;14:1025–1038. doi: 10.1002/sim.4780140921. PubMed DOI

Haslam A., Prasad V. When Is Crossover Desirable in Cancer Drug Trials and When Is It Problematic? Ann. Oncol. 2018;29:1079–1081. doi: 10.1093/annonc/mdy116. PubMed DOI PMC

Chow S.-C., Chang M. Adaptive Design Methods in Clinical Trials—A Review. Orphanet J. Rare Dis. 2008;3:11. doi: 10.1186/1750-1172-3-11. PubMed DOI PMC

Chow S.-C., Chang M., Pong A. Statistical Consideration of Adaptive Methods in Clinical Development. J. Biopharm. Stat. 2005;15:575–591. doi: 10.1081/BIP-200062277. PubMed DOI

Chang M., Chow S.-C., Pong A. Adaptive Design in Clinical Research: Issues, Opportunities, and Recommendations. J. Biopharm. Stat. 2006;16:299–309. doi: 10.1080/10543400600609718. PubMed DOI

Kelly L.E., Dyson M.P., Butcher N.J., Balshaw R., London A.J., Neilson C.J., Junker A., Mahmud S.M., Driedger S.M., Wang X. Considerations for Adaptive Design in Pediatric Clinical Trials: Study Protocol for a Systematic Review, Mixed-Methods Study, and Integrated Knowledge Translation Plan. Trials. 2018;19:572. doi: 10.1186/s13063-018-2934-7. PubMed DOI PMC

Lin J., Lin L.A. A General Overview of Adaptive Randomization Design for Clinical Trials. J. Biom. Biostat. 2016;7:294. doi: 10.4172/2155-6180.1000294. DOI

Curran P.J., Hussong A.M. Integrative Data Analysis: The Simultaneous Analysis of Multiple Data Sets. Psychol. Methods. 2009;14:81–100. doi: 10.1037/a0015914. PubMed DOI PMC

Matowe L.K., Leister C.A., Crivera C., Korth-Bradley J.M. Interrupted Time Series Analysis in Clinical Research. Ann. Pharmacother. 2003;37:1110–1116. doi: 10.1345/aph.1A109. PubMed DOI

Kyr M., Polaskova K., Kuttnerova Z., Merta T., Neradil J., Berkovcova J., Horky O., Jezova M., Veselska R., Klement G.L., et al. Individualization of Treatment Improves the Survival of Children with High-Risk Solid Tumors: Comparative Patient Series Analysis in a Real-Life Scenario. Front. Oncol. 2019;9:644. doi: 10.3389/fonc.2019.00644. PubMed DOI PMC

Magirr D., Jaki T., Koenig F., Posch M. Sample Size Reassessment and Hypothesis Testing in Adaptive Survival Trials. PLoS ONE. 2016;11:e0146465. doi: 10.1371/journal.pone.0146465. PubMed DOI PMC

Urach S., Posch M. Multi-arm Group Sequential Designs with a Simultaneous Stopping Rule. Stat. Med. 2016;35:5536–5550. doi: 10.1002/sim.7077. PubMed DOI PMC

Nikolakopoulos S., van der Tweel I., Roes K.C.B. Dynamic Borrowing through Empirical Power Priors That Control Type I Error: Dynamic Borrowing with Type I Error Control. Biometrics. 2018;74:874–880. doi: 10.1111/biom.12835. PubMed DOI

Sun H., Temeck J.W., Chambers W., Perkins G., Bonnel R., Murphy D. Extrapolation of Efficacy in Pediatric Drug Development and Evidence-Based Medicine: Progress and Lessons Learned. Ther. Innov. Regul. Sci. 2018;52:199–205. doi: 10.1177/2168479017725558. PubMed DOI PMC

Gamalo-Siebers M., Savic J., Basu C., Zhao X., Gopalakrishnan M., Gao A., Song G., Baygani S., Thompson L., Xia H.A., et al. Statistical Modeling for Bayesian Extrapolation of Adult Clinical Trial Information in Pediatric Drug Evaluation: Extrapolation in Pediatric Drug Evaluation through Bayesian Methods. Pharm. Stat. 2017;16:232–249. doi: 10.1002/pst.1807. PubMed DOI

Reflection Paper on Extrapolation of Efficacy and Safety in Paediatric Medicine Devel-Opment, EMA/199678/2016. Apr 1, 2016. [(accessed on 28 October 2021)]. Available online: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/draft-reflection-paper-extrapolation-efficacy-safety-paediatric-medicine-development-first-version_en.pdf.

Von Hoff D.D., Stephenson J.J., Rosen P., Loesch D.M., Borad M.J., Anthony S., Jameson G., Brown S., Cantafio N., Richards D.A., et al. Pilot Study Using Molecular Profiling of Patients’ Tumors to Find Potential Targets and Select Treatments for Their Refractory Cancers. J. Clin. Oncol. 2010;28:4877–4883. doi: 10.1200/JCO.2009.26.5983. PubMed DOI

Mick R., Crowley J.J., Carroll R.J. Phase II Clinical Trial Design for Noncytotoxic Anticancer Agents for which Time to Disease Progression Is the Primary Endpoint. Control. Clin. Trials. 2000;21:343–359. doi: 10.1016/S0197-2456(00)00058-1. PubMed DOI

Gajjar A., Robinson G.W., Smith K.S., Lin T., Merchant T.E., Chintagumpala M., Mahajan A., Su J., Bouffet E., Bartels U., et al. Outcomes by Clinical and Molecular Features in Children With Medulloblastoma Treated With Risk-Adapted Therapy: Results of an International Phase III Trial (SJMB03) J. Clin. Oncol. 2021;39:822–835. doi: 10.1200/JCO.20.01372. PubMed DOI PMC

Zucker D.R., Ruthazer R., Schmid C.H. Individual (N-of-1) Trials Can Be Combined to Give Population Comparative Treatment Effect Estimates: Methodologic Considerations. J. Clin. Epidemiol. 2010;63:1312–1323. doi: 10.1016/j.jclinepi.2010.04.020. PubMed DOI PMC

Mirza R., Punja S., Vohra S., Guyatt G. The History and Development of N-of-1 Trials. J. R. Soc. Med. 2017;110:330–340. doi: 10.1177/0141076817721131. PubMed DOI PMC

Guyatt G., Sackett D., Taylor D.W., Ghong J., Roberts R., Pugsley S. Determining Optimal Therapy—Randomized Trials in Individual Patients. N. Engl. J. Med. 1986;314:889–892. doi: 10.1056/NEJM198604033141406. PubMed DOI

Tate R.L., Perdices M., Rosenkoetter U., Wakim D., Godbee K., Togher L., McDonald S. Revision of a Method Quality Rating Scale for Single-Case Experimental Designs and n -of-1 Trials: The 15-Item Risk of Bias in N -of-1 Trials (RoBiNT) Scale. Neuropsychol. Rehabil. 2013;23:619–638. doi: 10.1080/09602011.2013.824383. PubMed DOI

Kravitz R.L., Paterniti D.A., Hay M.C., Subramanian S., Dean D.E., Weisner T., Vohra S., Duan N. Marketing Therapeutic Precision: Potential Facilitators and Barriers to Adoption of n-of-1 Trials. Contemp. Clin. Trials. 2009;30:436–445. doi: 10.1016/j.cct.2009.04.001. PubMed DOI

Li J., Gao W., Punja S., Ma B., Vohra S., Duan N., Gabler N., Yang K., Kravitz R.L. Reporting Quality of N-of-1 Trials Published between 1985 and 2013: A Systematic Review. J. Clin. Epidemiol. 2016;76:57–64. doi: 10.1016/j.jclinepi.2015.11.016. PubMed DOI

Gabler N.B., Duan N., Vohra S., Kravitz R.L. N-of-1 Trials in the Medical Literature: A Systematic Review. Med. Care. 2011;49:761–768. doi: 10.1097/MLR.0b013e318215d90d. PubMed DOI

Punja S., Bukutu C., Shamseer L., Sampson M., Hartling L., Urichuk L., Vohra S. N-of-1 Trials Are a Tapestry of Heterogeneity. J. Clin. Epidemiol. 2016;76:47–56. doi: 10.1016/j.jclinepi.2016.03.023. PubMed DOI

Guyatt G., Sackett D., Adachi J., Roberts R., Chong J., Rosenbloom D., Keller J. A Clinician’s Guide for Conducting Randomized Trials in Individual Patients. CMAJ Can. Med. Assoc. J. 1988;139:497–503. PubMed PMC

Kent D.M., Steyerberg E., van Klaveren D. Personalized Evidence Based Medicine: Predictive Approaches to Heterogeneous Treatment Effects. BMJ. 2018;363:k4245. doi: 10.1136/bmj.k4245. PubMed DOI PMC

Kravitz R.L. N-of-1 Trials in Hypertension Are Feasible, but Are They Worthwhile? J. Gen. Intern. Med. 2019;34:781–782. doi: 10.1007/s11606-019-04938-3. PubMed DOI PMC

Fortin M. Randomized Controlled Trials: Do They Have External Validity for Patients With Multiple Comorbidities? Ann. Fam. Med. 2006;4:104–108. doi: 10.1370/afm.516. PubMed DOI PMC

Zucker D.R., Ruthazer R., Schmid C.H., Feuer J.M., Fischer P.A., Kieval R.I., Mogavero N., Rapoport R.J., Selker H.P., Stotsky S.A., et al. Lessons Learned Combining N-of-1 Trials to Assess Fibromyalgia Therapies. J. Rheumatol. 2006;33:2069–2077. PubMed

Lillie E.O., Patay B., Diamant J., Issell B., Topol E.J., Schork N.J. The N-of-1 Clinical Trial: The Ultimate Strategy for Individualizing Medicine? Pers. Med. 2011;8:161–173. doi: 10.2217/pme.11.7. PubMed DOI PMC

Sidman M. Normal Sources of Pathological Behavior. Science. 1960;132:61–68. doi: 10.1126/science.132.3419.61. PubMed DOI

Duan N., Kravitz R.L., Schmid C.H. Single-Patient (n-of-1) Trials: A Pragmatic Clinical Decision Methodology for Patient-Centered Comparative Effectiveness Research. J. Clin. Epidemiol. 2013;66:S21–S28. doi: 10.1016/j.jclinepi.2013.04.006. PubMed DOI PMC

Kronish I.M., Cheung Y.K., Shimbo D., Julian J., Gallagher B., Parsons F., Davidson K.W. Increasing the Precision of Hypertension Treatment Through Personalized Trials: A Pilot Study. J. Gen. Intern. Med. 2019;34:839–845. doi: 10.1007/s11606-019-04831-z. PubMed DOI PMC

Kravitz R.L., Duan N., The DEcIDE Methods Center N-of-1 Guidance, Panel . In: Design and Implementation of N-of-1 Trials: A User’s Guide. Duan N., Eslick I., Gabler N.B., Kaplan H.C., Kravitz R.L., Larson E.B., Pace W.D., Schmid C.H., Sim I., Vohra S., editors. Agency for Healthcare Research and Quality; Rockville, MD, USA: Feb, 2014. [(accessed on 28 October 2021)]. AHRQ Publication No. 13(14)-EHC122-EF. Available online: https://effectivehealthcare.ahrq.gov/sites/default/files/pdf/n-1-trials_research-2014-5.pdf.

Nathan P.C., Tomlinson G., Dupuis L.L., Greenberg M.L., Ota S., Bartels U., Feldman B.M. 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 Cancer. 2006;14:268–276. doi: 10.1007/s00520-005-0875-7. PubMed DOI

Tate R.L., Mcdonald S., Perdices M., Togher L., Schultz R., Savage S. Rating the Methodological Quality of Single-Subject Designs and n -of-1 Trials: Introducing the Single-Case Experimental Design (SCED) Scale. Neuropsychol. Rehabil. 2008;18:385–401. doi: 10.1080/09602010802009201. PubMed DOI

Vohra S., Shamseer L., Sampson M., Bukutu C., Schmid C.H., Tate R., Nikles J., Zucker D.R., Kravitz R., Guyatt G., et al. CONSORT Extension for Reporting N-of-1 Trials (CENT) 2015 Statement. BMJ. 2015;350:h1738. doi: 10.1136/bmj.h1738. PubMed DOI

Shamseer L., Sampson M., Bukutu C., Schmid C.H., Nikles J., Tate R., Johnston B.C., Zucker D., Shadish W.R., Kravitz R., et al. CONSORT Extension for Reporting N-of-1 Trials (CENT) 2015: Explanation and Elaboration. J. Clin. Epidemiol. 2016;76:18–46. doi: 10.1016/j.jclinepi.2015.05.018. PubMed DOI

Guyatt G.H., Heyting A., Jaeschke R., Keller J., Adachi J.D., Roberts R.S. N of 1 Randomized Trials for Investigating New Drugs. Control. Clin. Trials. 1990;11:88–100. doi: 10.1016/0197-2456(90)90003-K. PubMed DOI

European Medicines Agency. Committee for Human Medicinal Products Guideline on Clinical Trials in Small Populations, EMA/CHMP/EWP/83561/2005. [(accessed on 28 October 2021)];2006 July 27; Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-trials-small-populations_en.pdf.

Scuffham P.A., Yelland M.J., 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 Health. 2008;11:97–109. doi: 10.1111/j.1524-4733.2007.00218.x. PubMed DOI

Scuffham P.A., Nikles J., Mitchell G.K., Yelland M.J., Vine N., Poulos C.J., Pillans P.I., Bashford G., del Mar C., Schluter P.J., et al. Using N-of-1 Trials to Improve Patient Management and Save Costs. J. Gen. Intern. Med. 2010;25:906–913. doi: 10.1007/s11606-010-1352-7. PubMed DOI PMC

Henry D., Taylor C. Pharmacoeconomics of Cancer Therapies: Considerations with the Introduction of Biosimilars. Semin. Oncol. 2014;41:S13–S20. doi: 10.1053/j.seminoncol.2014.03.009. PubMed DOI