Open Access Open Access  Restricted Access Subscription or Fee Access

Towards Patient-Centered Clinical Trial Designs

Souraya Sidani, Mary Fox, Laura Collins


Rationale, aims and objectives: Evidence shows a trend towards low enrollment in randomized clinical trials (RCTs), which negatively affect validity of conclusions. Low enrollment is associated with different factors, but has recently been attributed to an increasing proportion of patients expressing concerns about randomization. In this paper, we summarize the evidence on reasons for non-enrollment, and we propose preference-based and shared decision-making as alternative methods for allocating patients to treatments in effectiveness and comparative effectiveness trials.

Methods: This paper is a narrative review of available literature.

Results: Converging findings of quantitative and qualitative studies revealed three interrelated and frequently mentioned reasons for declining enrollment in RCTs: 1) concerns about randomization related to the lack of understanding of equipoise, lack of appreciation of the scientific merits of randomization, and unfavorable perceptions of randomization as not reflecting methods of treatment selection used in practice; 2) preferences for treatments under evaluation, which contribute to unwillingness to be randomized; and 3) desires for involvement in treatment decision-making, which are not respected with randomization.

Conclusions: Alternative methods for treatment allocation are needed to make effectiveness and comparative effectiveness trials attractive to patients. Preference-based and shared decision-making are viable methods that respectively represent the informed choice and the collaborative choice styles of treatment selection commonly used in practice. The extent to which these two methods of treatment allocation enhance enrollment should be further investigated. 

Full Text:



Millard, W.B. (2012). The gold standard’s flexible allay - Adaptive designs on the advance. Annals of Emergency Medicine 60, 22A-27A.

Luce, B.R., Kramer, J.M., Goodman, S.N., Connor, J.T., Tunis, S., Whicher, D. & Schwartz, S. (2009). Rethinking randomized clinical trials for comparative effectiveness research: The need for transformational change. Annals of Internal Medicine 151, 206-209.

Winter, A.C. & Colditz, G.A. (2014). Clinical trial design in the era of comparative effectiveness research. Open Access Journal of Clinical Trials 6, 101-110.

Pirolla, E.H., Ribeiro, F.P.G., Pirola, F.J.C., Cosmo, C. & DiBiasi, M. (2016). Methods of randomization: Overview and application in small clinical trials. International Journal of Multidisciplinary & Current Research 4, 700-705.

Sidani, S., Epstein, D.R., Bootzin, R.R., Miranda, J. & Cousins, J. (2015). The contribution of treatment allocation method to outcomes in intervention research. Canadian Journal of Nursing Research 47, 62-80.

Horwood, J., Johnson, E. & Goodberman-Hill, R. (2016). Understanding involvement in surgical orthopedic randomized trials: A qualitative study of patient and health professional views and experiences. International Journal of Orthopedic & Trauma Nursing 20, 3-12.

Butler, J., Tahhan, A.S., Georgiopoulou, Kelkar, A., Lee, M., Khan, B., Peterson, E., Fonarow, G.C., Kalogeropoulos, A.P. & Gheorghiade, M. (2015). Trends in characteristics of cardiovascular clinical trials 2001-2012. American Heart Journal 170, 263-272.

Hughes Morley, A., Young, B., Waheed, W., Small, N. & Bower, P. (2015). Factors affecting recruitment into depression trials: Systematic review, meta-synthesis and conceptual framework. Journal of Affective Disorders 172, 274-290.

Mills, E.J., Seely, D., Rochlis, B., Griffith, L., Wu, F., Wilson, K., Ellis, P. & Wright, J.R. (2006). Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncology 7, 141-148.

McCambridge, J., Kypri, K. & Elbourne, D. (2014). In randomization we trust? There are overlooked problems in experimenting with people in behavioral intervention trials. Journal of Clinical Epidemiology 67, 247-253.

Sidani, S. (2015). Health intervention research: Advances in research design and methods. London, UK: Sage.

Stacey, D. & Légaré, F. (2015). Engaging patients using an interprofessional approach to shared decision making. Canadian Oncology Nursing Journal 24, 455-461.

Sidani, S. & Fox, M. (2014). Patient-centered care: A clarification of its active ingredients. Journal of Interprofessional Care 28, 134-141.

McDonald, A.M., Knight, R.M., Campbell, M.K., Entwistle, V.A., Grant, A.M., Cook, J.A., Elbourne, D.R., Francis, D., Garcia, J., Roberts, I. & Snowdon, C. (2006). What influences recruitment to randomized controlled trials? A review of trials funded by two UK funding agencies. Trials 7, 0. DOI: 10.1186/1745-6215-7-9

Califf, R.M., Zarin, D.A., Kramer, J.M., Sherman, R.E., Aberle, L.H. & Tasneem, A. (2012). Characteristics of clinical trials registered in, 2007-2010. Journal of the American Medical Association 307, 1838-1847.

Treweek, S., Lockhart, P., Pitkethly, Cook, J.A., Kjeldstrøm, M., Johansen, M., Taskila, T.K., Sullivn, F.M., Wilson, S., Jackson, C., Jones, R. & Mitchell, E.D. (2013). Methods to improve recruitment to randomised controlled trials: Cochrane systematic review and meta-analysis. BMJ Open 3, e002360.

McCann, S., Campbell, M. & Entwistle, V. (2013). Recruitment to clinical trials: A meta-ethnographic synthesis of studies of reasons for participation. Journal of Health Services Research & Policy 18, 233-241.

Murphy, V., Awatagiri, K.R., Tike, P.K., Ghosh-Laskar, S., Gupta, T., Budrukkar, A., Deshpande, M.S., Chaukar, D.A., Pantavaidya, G.H. & Aqarwal, J.P. (2012). Prospective analysis of reasons for non-enrollment in a phase III randomized controlled trial. Journal of Cancer Research & Therapeutics 8, S94-S99.

Brusby Grant, J., Mackinnon, A.J., Christensen, H. & Walker, J. (2009). Participants’ perceptions of motivation, randomisation and withdrawal in a randomized controlled trial of interventions for prevention of depression. Journal of Medical Ethics 35, 768-773.

Costenbader, K.H., Brome, D., Blanch, D., Gall, V., Karlson, E. & Liang, M.H. (2007). Factors determining participation in prevention trials among systematic lupus erythematosus patients: A qualitative study. Arthritis Care & Research 57, 49-55.

Fayler, D., McDaid, C. & Eastwood, A. (2007). A systematic review highlights threats to validity in studies of barriers to cancer trial participation. Journal of Clinical Epidemiology 60, 990-1001.

Madsen, S.M., Holm, S. & Riis, P. (2007). Attitudes towards clinical research among cancer trial participants and non-participants: An interview study using a Grounded Theory approach. Journal of Medical Ethics 33, 234-240.

Meinich Peterson, S., Zoffmann, V., Kjaergaard, J., Steensballs, L.G. & Greisen, G. (2013). Disappointment and adherence among parents of newborns allocated to the control group: A qualitative study of a randomized clinical trial. Trials 15, 126-136.

Relton, C., Torgerson, D., O’Cathain, A. & Nicholl, J. (2010). Rethinking pragmatic randomized controlled trials: Introducing the “cohort multiple randomized controlled trial” design. British Medical Journal 340, 963-967.

Fleming, K., Adamson, J. & Atkin, K. (2008). Improving the effectiveness of interventions in palliative care: The potential role of qualitative research in enhancing evidence from randomized controlled trials. Palliative Medicine 22, 123-131.

Khalil, S.S., Silverman, H.J., Raafat, M., El-Kamary, S. & El-Setouhy, M. (2007). Attitudes, understanding, and concerns regarding medical research among Egyptians: A qualitative pilot study. BMC Medical Ethics 8, 9-20.

Paramasivan, S., Huddart, R., Hall, E., Lewis, R., Birtie, A. & Donovan, J.L. (2011). Key issues in recruitment to randomised controlled trials with very different interventions: A qualitative investigation of recruitment to the SPARE trial (CRUK/07/011). Trials 12, 78-92.

Rengerink, K.O., Logtenberg, S., Hooft, L., Bossuyt, P.M. & Mol, B.W. (2015). Pregnant women’s concerns when invited to a randomized trial: A qualitative case control study. BMC Pregnancy & Childbirth 15, 207-217.

Harrison, G.W., Lau, M.I. & Rustrӧm, E.E. (2009). Risk attitudes, randomization to treatment, and self-selection into experiments. Journal of Economic Behavior & Organization 70, 498-507.

Krieger, J.L., Parrott, R.L. & Nussbaum, J.F. (2010). Metaphor use and health literacy: A pilot strategies to explain randomization in cancer clinical trials. Journal of Health Communication 16, 3-16.

Nishimura, A., Jantey, C. & Erwin, P.J. (2013). Improving understanding in the research informed consent process: A systematic review of 54 interventions tested in randomized control trials. BMC Medical Ethics 14, 28-42.

Appelbaum, P.S., Grisso, T., Frank, E., O’Donnell, R.N. & Kupfer, D.J. (1999). Competence of depressed patients for consent to research. American Journal of Psychiatry 156, 1380-1384.

Eiser, C., Davies, H., Jenney, M. & Glaser, A. (2005). Mothers’ attitudes to the randomized controlled trial (RCT): The case of acute lymphoblastic leukemia (ALL) in children. Child: Care, Health & Development, 31, 517-523.

Ellis, P.M. (2000). Attitudes toward and participation in randomised clinical trials in oncology, A review of the literature. Annals of Oncology 11, 939-945.

Featherstone, K. & Donovan, J.L. (2002). Why don’t they just tell me straight, why allocate it? The struggle to make sense of participating in a randomised controlled trial. Social Science & Medicine 55, 709-719.

Lidz, C.W., Applebaum, P.S., Grisso, T. & Renaud, M. (2004.) Therapeutic misconceptions and the application of risks in clinical trials. Social Science & Medicine 58, 1689-1697.

Snowdon, C., Garcia, J. & Elbourne, D. (1997). Making sense of randomisation: Responses of parents of critically ill babies to random allocation of treatment in a clinical trial. Social Science & Medicine 45, 1385-1387.

Wade, J., Donovan, J.L., Lane, J.A., Neal, D.E. & Hamdy, F.C. (2009). It’s not just what you say, it’s also how you say it: Opening the black box of informed consent appointments in randomised controlled trials. Social Science & Medicine 68, 2018-2028.

Wendler, D. (2009). Must research participants understand randomization? The American Journal of Bioethics 9, 3-8.

Yap, T.Y., Kassimatis, K.A. & Kodish, E. (2010). Both sides of the coin: Randomization from the perspectives of physician-investigators and patient-subjects. Ethics Behavior 20, 380-386.

Glasgow, R.E., Magid, D.J., Beck, A., Ritzwoller, D. & Estabrooks, P.A. (2005). Practical clinical trials for translating research to practice: Design and measurement recommendations. Medical Care 43, 551-559.

Robinson, E.J., Kerr, C., Stevens, A., Lilford, R., Braunholtz, D. & Edwards, S. (2004). Lay conceptions of the ethical and scientific justifications for random allocation in clinical trials. Social Science & Medicine 58, 811-824.

Robinson, E.J., Biggerstaff, D., Jennings, S. & Maylor, E.A. (2012). Do the public share practitioners’ views about the best evidence? Patient Education & Counseling 88, 325-329.

Kerr, C., Robinson, E., Stevens, A., Braunholtz, D., Edwards. S. & Liford, R. (2014). Randomisation in trials: Do potential trial participants understand it and find it acceptable? Journal of Medical Ethics 30, 80-84.

Sidani, S., Fox, M. & Epstein, D.R. (2017). Contribution of treatment acceptability to acceptance of randomization: An exploration. Journal of Evaluation in Clinical Practice. 23 (1) 14-20.

Buck, D., Hogan, V., Powell, C.J., Slopper, J.J., Speed, C., Taylor R.H., Tiffin, P., Clarke, M.P. & SmaExo (Surgery versus active monitoring in intermittent exotropia) trial. (2015). Surrendering control, or nothing to lose: Parents’ preferences about participation in a randomised trial of childhood strabismus surgery. Clinical Trials 12, 384-393.

O’Reilly, P., Martin, L. & Collins, G. (1999). Few patients with prostate cancer are willing to be randomized to treatment. British Medical Journal 318, 1556.

Coward, D. (2002). Partial randomized design in a support group intervention study. Western Journal of Nursing Research 24, 406-421.

North-West Uro-Oncology Group. (2002). A preliminary report on patient-preference study to compare treatment options in early prostate cancer. British Journal of Urology International 90, 253-256.

Rothwell, P.M. (2005). External validity of randomized controlled trials: “To whom do the results of this trial apply?” Lancet 365, 82-93.

King, M., Nazareth, I., Lampe, F., Bower, P., Chandler, M., Morou, M., Sibbald, B. & Lai, R. (2005). Impact of participant and physician intervention preferences on randomized trials. A systematic review. Journal of the American Medical Association 293, 1089-1099.

Gross, C.P., Krumholz, H.M., Van Wye, G., Emanuel, E.J. & Wendler, D. (2006). Does random treatment assignment cause harm to research participants? PLoS Med 3, e188.

Lilienfeld, S.O, Ritschel, L.A., Lynn, S.J., Cautin. R. & Latzman, R.D. (2013). Why many psychologists are resistant to evidence-based practice: Root causes and constructive remedies. Clinical Psychology Review 33, 883-900.

Preference Collaborative Review Group. (2009). Patients’ preferences within randomized trials: Systematic review and patient level meta-analysis. British Medical Journal 337: a1864.

Jenkins, V. & Fallowfield, L. (2000). Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy. British Journal of Cancer 82, 1783-1788

Stone, D.A., Kerr, C.E., Jacobson, E., Conboy, L. & Kaptchuk, D.J. (2005). Patient expectations in placebo-controlled randomized clinical trials. Journal of Evaluation in Clinical Practice 11, 77-84.

Raue, W., Langelotz, C., Paolucci, V., Pross, M., Ludwig, K., Asperger, W. & Schwenk, W. (2011). Problems of randomization to open or laparoscopic sigmoidectomy for diverticular disease. International Journal of Colorectal Disease 26, 369-375.

Caligor, E., Hilsenroth, M.J., Derlin, M., Rutherford, B.R., Terry, M. & Roose, S.P. (2012). Will patients accept randomization to psychoanalysis? A feasibility study. Journal of the American Psychoanalysis Association 60, 337-360.

Arega, A., Birkmeyer, N.J., Lurie, J.D., Tosteson, T., Gibson, J., Taylor, B.A., Morgan, T.S. & Weinstein, J.N. (2006). Racial variation in treatment preferences and willingness to randomize in the Spine Patient Outcomes Research Trial (SPORT). Spine 31, 2263-2269.

Matthias, M.S., Salyers, M.P. & Frankel, R.M. (2013). Re-thinking shared decision-making: Context matters. Patient Education & Counseling 91, 176-179.

Muscat, D.M., Morony, S., Shepherd, H.L., Smith, S.K., Dhillon, H.M., Trevena, L., Hayen, A., Luxford, K., Nutbeam, D. & McCaffery, K. (2015). Development and field testing of a consumer shared decision-making program for adults with low literacy. Patient Education & Counseling 98, 1180-1188.

Stigglebout, A.M., Pieterse, A.H. & De Haes, J.C.J.M. (2015). Shared decision making: Concepts, evidence, and practice. Patient Education & Counseling 98, 1172-1179.

Légaré, F. & Thompson-Leduc, P. (2014). Twelve myths about shared decision making. Patient Education & Counseling 96, 281-286.

Olsen, R.B., Bell, S.H. & Nichols, A. (2016). Using preferred applicant random assignment (PARA) to reduce randomization bias in randomized trials of Discretionary Program.

Gemmel, I. & Dunn, G. (2011). The statistical pitfalls of the partially randomized preference design in non-blinded trials of psychological interventions. International Journal of Methods in Psychiatric Research 20, 1-9.

McKay, J.R., Alterman, A.I., McLellan, T., Boardman, C.R., Mulvaney, F.D. & O’Brien, C.P. (1998). Random versus nonrandom assignment in the evaluation of treatment for cocaine abusers. Journal of Consulting and Clinical Psychology 66, 697-701.

Westerberg, V.S., Miller, W.R. & Tonigan, J.S. (2000). Comparison of outcomes for clients in randomized versus open trials of treatment for alcohol use disorders. Journal of Studies on Alcohol 61, 720-732.

Woods, M.N., Harris, K.J., Mayo, M.S., Catley, D., Scheibmeir, M. & Ahluwalia, J.S. (2002). Participation of African Americans in a smoking cessation trial: A quantitative and qualitative study. Journal of the National Medical Association 94, 609-618.

Makoul, G. & Clayman, M.L. (2006). An integrative model of shared decision making in medical encounters. Patient Education & Counseling 60, 301-312.

Umar, N., Schaarschmidt, M., Schmeider, A., Peitsch, W.K., Schöllgen, I. & Terris, D.D. (2013). Matching physicians’ treatment recommendations to patients’ treatment preferences is associated with improvement in treatment satisfaction. Journal of the European Academy of Dermatology & Venereology 27, 763-770.

Bowling, A., Reeves, B. & Rowe, G. (2008). Patient preferences for treatment for angina: An overview of findings from three studies. Journal of Health Services Research & Policy 13, 104-108.

Hauber, A.B., Mohamed, A.F., Johnson, F.R. & Falvey, H. (2009). Treatment preferences and medication adherence of people with Type 2 diabetes using oral glucose-lowering agents. Diabetic Medicine 26, 416-424.

Witteman, H.O., Dansokho, S.C., Colghoun, H. et al. (2015). User-centered design and the development of patient decision aids: Protocol for a systematic review. Systematic Reviews 4, 11-18.

Bridges, J.F.F., Mohamed, A.F., Finnern, H.W., Woehl, A. & Hauber, A.B. (2012). Patients’ preferences for treatment outcomes for advanced small cell lung cancer: A conjoint analysis. Lung Cancer 77, 224-231.

Harrison, M., Rigby, D., Vass, C., Flynn, T., Louviere, J. & Payne, K. (2014). Risk as an attribute in discrete choice experiments: A systematic review of the literature. Patient 7, 151-170.

Lawton, T., Rankin, D., Elliott, J. & United Kingdom National Institute for Health Research Dose Adjustment for Normal Eating (DAFNE) Study Group (2013). Is consulting patients about their health services preferences a useful exercise? Qualitative Health Research 23, 876-886.

Sidani, S., Epstein, D.R., Miranda, J. & Fox, M. (2016). Psychometric properties of the Treatment Perception and Preferences scale. Clinical Nursing Research, 1-19.

Coutu, M-F., Légaré, F., Stacey, D., Durand, M-J., Corbiere, M., Brainbridge, L. & Labrecque, M-E. (2015). Occupational therapists’ shared decision-making behaviors with patients having persistent pain in a work rehabilitation context: A cross-sectional study. Patient Education & Counseling 98, 864-970.

Shay, L.A. & Lafata, J.E. (2014). Understanding patient perceptions of shared decision making. Patient Education & Counseling 96, 295-301.

Cooper, K.G., Grant, A.M. & Garratt, A.M. (1997). The impact of using a partially randomised patient preference design when evaluating alternative managements for heavy menstrual bleeding. British Journal of Obstetrics & Gynecology 104, 1367-1373.

Hubacher, D., Spector, H., Monteith, C., Chen, P-L. & Hart, C. (2015). Rationale and enrollment results for a partially randomized patient preference trial to compare continuation rates of short-acting and long-acting reversible contraception. Contraception 91, 185-192.

Kwan, B.M., Dimidjian, S. & Rizvi, S.L. (2010). Treatment preferences, engagement, and clinical improvement in pharmacotherapy versus psychotherapy for depression. Behavior Research & Therapy 48, 799-804.

Lindheim, O., Bennett, C.B., Trentacosta, C.J. & McLear, C. (2014). Client preferences affect treatment satisfaction, completion, and clinical outcome: A meta-analysis. Clinical Psychology Review 34, 506-517.

Raue, P.J., Schulberg, H.C., Heo, M., Klimstra, S. & Bruce, M.L. (2009). Patients’ depression treatment preferences and initiation, adherence, and outcome: A randomized primary care study. Psychiatric Services 60, 337-343.

Swift, J.K., Callahan, J.L. & Vollmer, B.M. (2011). Preferences. Journal of Clinical Psychology: In Session 67, 155-165.

Katz, S.J., Belkora, J. & Elywn, G. (2014). Shared decision making for treatment of cancer: Challenges and opportunities. Journal of Oncology Practice 10, 206-208.



  • There are currently no refbacks.