Determinants of decision-making and patient participation in paediatric clinical trials: A literature review


Background: Studies have shown that many drugs used in children may not have been authorised for use in this age group. This poses significant risks on children. A new EU regulation came into effect in 2007 to ensure that medicinal products that are researched, developed and authorised will also meet the therapeutic needs of children. This will mean an increased demand for children to participate in clinical trials. Objectives: To identify the needs and motivations of children and their families who have participated, might participate or declined to participate in clinical trials. Methods: We did a literature search and reviewed empirical studies which examined eligible outcomes. The findings of these studies were analyzed in a broad qualitative and descriptive bottom-up process. Results: We found that the understanding of advanced concepts of research such as randomisation is often insufficient. The needs of families affected by a serious disease are not addressed explicitly. Personal benefit and altruistic motives were two important reasons for participation. Conclusions: The comprehension of information given in the consent process should be secured by improving the information material. The communication process should be more mutual. Children and their families should be empowered to address their needs in the process of considering participation in a clinical trial.

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Wulf, F. , Krasuska, M. and Bullinger, M. (2012) Determinants of decision-making and patient participation in paediatric clinical trials: A literature review. Open Journal of Pediatrics, 2, 1-17. doi: 10.4236/ojped.2012.21001.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Caldwell, P., Murphy, S., Butow, P. and Craig, J. (2004) Clinical trials in children. The Lancet, 364, 803-811. doi:10.1016/S0140-6736(04)16942-0
[2] Smyth, R. (2001) Research with children. British Medical Journal, 322, 1377-1378. doi:10.1136/bmj.322.7299.1377
[3] Smyth, R. and Weindling, A. (1999) Research in children: Ethical and scientific aspects. The Lancet, 354, SII21-SII24. doi:10.1016/S0140-6736(99)90253-2
[4] Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004.
[5] European Medicines Agency (2002) ICH Topic E 6 (R1) guideline for good clinical practice.
[6] Directive 2001/20/EC of the European Parliament and of the Council (2001) Approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal L, 121, 34-44.
[7] The ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. (2008) Ethical considerations for clinical trials on medicinal products conducted with the paediatric population.
[8] Pinxten, W., Nys, H. and Dierickx, K. (2010) Frontline ethical issues in pediatric clinical research: Ethical and regulatory aspects of seven current bottlenecks in pediatric clinical research. European Journal of Pediatrics, 169, 1541-1548. doi:10.1007/s00431-010-1268-6
[9] Altavilla, A., Giaquinto, C. and Ceci, A. (2008) European survey on ethical and legal framework of clinical trials in paediatrics: Results and perspectives. Journal International de Bioéthique, 19, 17-48.
[10] Frosch, D.L. and Kaplan, R.M. (1999) Shared decision making in clinical medicine: Past research and future directions. American Journal of Preventive Medicine, 17, 285-294. doi:10.1016/S0749-3797(99)00097-5
[11] Allmark, P. and Mason, S. (2006) Improving the quality of consent to randomised controlled trials by using continuous consent and clinician training in the consent process. Journal of Medical Ethics, 32, 439-443. doi:10.1136/jme.2005.013722
[12] Drotar, D., Miller, V., Willard, V., Anthony, K. and Kodish, E. (2004) Correlates of parental participation during informed consent for randomized clinical trials in the treatment of childhood leukemia. Ethics & Behavior, 14, 1-15. doi:10.1207/s15327019eb1401_1
[13] Hazen, R., Drotar, D. and Kodish, E. (2007) The role of the consent document in informed consent for pediatric leukemia trials. Contemporary Clinical Trials, 28, 401-408. doi:10.1016/j.cct.2006.10.011
[14] Kodish, E., Eder, M., Noll, R., Ruccione, K., Lange, B., Angiolillo, A., Pentz, R., Zyzanski, S., Siminoff, L. and Drotar, D. (2004) Communication of randomization in childhood leukemia trials. Journal of the American Medical Association, 291, 470-475. doi:10.1001/jama.291.4.470
[15] Morris, M., Besner, D., Vazquez, H., Nelson, R. and Fischbach, R. (2007) Parental opinions about clinical research. The Journal of Pediatrics, 151, 532-537.
[16] Eder, M., Yamokoski, A., Wittmann, P. and Kodish, E. (2007) Improving informed consent: Suggestions from parents of children with leukemia. Pediatrics, 119, 849-859. doi:10.1542/peds.2006-2208
[17] Tait, A., Voepel-Lewis, T. and Malviya, S. (2003) Do they understand? (part II): Assent of children participating in clinical anesthesia and surgery research. Anesthesiology, 98, 609-614. doi:10.1097/00000542-200303000-00006
[18] Broome, M., Richards, D. and Hall, J. (2001) Children in research: The experience of ill children and adolescents. Journal of Family Nursing, 7, 32-49. doi:10.1097/00000542-200303000-00006
[19] John, T., Hope, T., Savulescu, J., Stein, A. and Pollard, A.J. (2008) Children’s consent and paediatric research: Is it appropriate for healthy children to be the decisionmakers in clinical research? Archives of Disease in Childhood, 93, 379-383. doi:10.1136/adc.2007.118299
[20] Ondrusek, N., Abramovitch, R., Pencharz, P. and Koren, G. (1998) Empirical examination of the ability of children to consent to clinical research. Journal of Medical Ethics, 24, 158-165. doi:10.1136/jme.24.3.158
[21] Tait, A., Voepel-Lewis, T. and Malviya, S. (2007) Presenting research information to children: A tale of two methods. Anesthesia & Analgesia, 105, 358-364. doi:10.1213/01.ane.0000270326.44507.11
[22] Ford, K., Sankey, J. and Crisp, J. (2007) Development of children’s assent documents using a child-centred approach. Journal of Child Health Care, 11, 19-28. doi:10.1177/1367493507073058
[23] Chappuy, H., Doz, F., Blanche, S., Gentet, J. and Treluyer, J. (2007) Children’s views on their involvement in clinical research. Pediatric Blood & Cancer, 50, 1043-1046. doi:10.1002/pbc.21359
[24] Unguru, Y., Sill, A. and Kamani, N. (2010) The experiences of children enrolled in pediatric oncology research: Implications for assent. Pediatrics, 125, e876-e883. doi:10.1542/peds.2008-3429
[25] Blake, D., Lemay, C., Kearney, M. and Mazor, K. (2010) Adolescent perspectives on informed assent for an HIV vaccine trial. Journal of Adolescent Health, 46, S28. doi:10.1016/j.jadohealth.2009.11.066
[26] Simon, C., Zyzanski, S., Eder, M., Raiz, P., Kodish, E. and Siminoff, L. (2003) Groups potentially at risk for making poorly informed decisions about entry into clinical trials for childhood cancer. Journal of Clinical Oncology, 21, 2173-2178. doi:10.1200/JCO.2003.03.003
[27] Campbell, F. (2004) The effect of format modifications and reading comprehension on recall of informed consent information by low-income parents: A comparison of print, video, and computer-based presentations. Patient Education and Counseling, 53, 205-216. doi:10.1016/S0738-3991(03)00162-9
[28] Tait, A., Voepel-Lewis, T., Malviya, S. and Philipson, S. (2005) Improving the readability and processability of a pediatric informed consent document: Effects on parents’ understanding. Archives of Pediatrics & Adolescent Medicine, 159, 347-352. doi:10.1001/archpedi.159.4.347
[29] Hazen, R., Eder, M., Drotar, D., Zyzanski, S., Reynolds, A., Reynolds, C., Kodish, E. and Noll, R. (2010) A feasibility trial of a video intervention to improve informed consent for parents of children with leukemia. Pediatric Blood & Cancer, 55, 113-118.
[30] Angiolillo, A.L., Simon, C., Kodish, E., Lange, B., Noll, R.B., Ruccione, K. and Matloub, Y. (2004) Staged informed consent for a randomized clinical trial in childhood leukemia: Impact on the consent process. Pediatric Blood & Cancer, 42, 433-437. doi:10.1002/pbc.20010
[31] Freer, Y., McIntosh, N., Teunisse, S., Anand, K. and Boyle, E. (2009) More information, less understanding: A randomized study on consent issues in neonatal research. Pediatrics, 123, 1301-1305. doi:10.1542/peds.2007-3860
[32] Massimo, L. and Wiley, T.J. (2005) Randomization, informed consent and physicians’ communication skills in pediatric oncology: A delicate balance. Bulletin du Cancer, 92, E67-E69.
[33] Chantler, T., Lees, A., Moxon, E., Mant, D., Pollard, A. and Fiztpatrick, R. (2007) The role familiarity with science and medicine plays in parents’ decision making about enrolling a child in vaccine research. Qualitative Health Research, 17, 311-322. doi:10.1177/1049732306298561
[34] Singhal, N., Oberle, K., Burgess, E. and Huber-Okrainec, J. (2002) Parents’ perceptions of research with newborns. Journal of Perinatology, 22, 57-63. doi:10.1038/
[35] Simon, C., Siminoff, L., Kodish, E. and Burant, C. (2004) Comparison of the informed consent process for randomized clinical trials in pediatric and adult oncology. Journal of Clinical Oncology, 22, 2708-2717. doi:10.1200/JCO.2004.10.034
[36] Kodish, E., Pentz, R., Noll, R., Ruccione, K., Buckley, J. and Lange, B. (1998) Informed consent in the children’s cancer group. Cancer, 82, 2467-2481. doi:10.1002/(SICI)1097-0142(19980615)82:12%3C2467::AID-CNCR22%3E3.0.CO;2-M
[37] Levi, R., Marsick, R., Drotar, D. and Kodish, E. (2000) Diagnosis, disclosure, and informed consent: Learning from parents of children with cancer. Journal of Pediatric Hematology/Oncology, 22, 3-12. doi:10.1097/00043426-200001000-00002
[38] Stevens, P. and Pletsch, P. (2002) Ethical issues of informed consent: Mothers’ experiences enrolling their children in bone marrow transplantation research. Cancer Nursing, 25, 81-87. doi:10.1097/00002820-200204000-00001
[39] Chappuy, H., Baruchel, A., Leverger, G., Oudot, C., Brethon, B., Haouy, S., Auvrignon, A., Davous, D., Doz, F. and Tréluyer, J.M. (2010) Parental comprehension and satisfaction in informed consent in paediatric clinical trials: a prospective study on childhood leukaemia. Archives of Disease in Childhood, 95, 800-804. doi:10.1136/adc.2009.180695
[40] Tait, A., Voepel-Lewis, T. and Malviya, S. (2004) Factors that influence parents’ assessments of the risks and benefits of research involving their children. Pediatrics, 113, 727-732. doi:10.1542/peds.113.4.727
[41] Snowdon, C., Elbourne, D. and Garcia, J. (2006) “It was a snap decision”: Parental and professional perspectives on the speed of decisions about participation in perinatal randomised controlled trials. Social Science & Medicine, 62, 2279-2290. doi:10.1016/j.socscimed.2005.10.008
[42] Caldwell, P., Butow, P. and Craig, J. (2003) Parents’ attitudes to children’s participation in randomized controlled trials. The Journal of Pediatrics, 142, 554-559. doi:10.1067/mpd.2003.192
[43] Eiser, C., Davies, H., Jenney, M. and Glaser, A. (2005) Mothers’ attitudes to the randomized controlled trial (RCT): The case of acute lymphoblastic leukaemia (ALL) in children. Child: Care, Health and Development, 31, 517-523. doi:10.1111/j.1365-2214.2005.00538.x
[44] Kupst, M., Patenaude, A., Walco, G. and Sterling, C. (2003) Clinical trials in pediatric cancer: Parental perspectives on informed consent. Journal of Pediatric Hematology/Oncology, 25, 787-790. doi:10.1097/00043426-200310000-00009
[45] Greenley, R., Drotar, D., Zyzanski, S. and Kodish, E. (2006) Stability of parental understanding of random assignment in childhood leukemia trials: An empirical examination of informed consent. Journal of Clinical Oncology, 24, 891-897. doi:10.1200/JCO.2005.02.8100
[46] Wiley, F.M., Ruccione, K., Moore, I., McGuire-Cullen, P., Fergusson, J., Waskerwitz, M., Perin, G., Ge, J. and Sather, H. (1999) Parents’ perceptions of randomization in pediatric clinical trials. Cancer Practice, 7, 248-256. doi:10.1046/j.1523-5394.1999.75010.x
[47] Miller, V., Drotar, D., Burant, C. and Kodish, E. (2005) Clinician-parent communication during informed consent for pediatric leukemia trials. Journal of Pediatric Psychology, 30, 219-229. doi:10.1093/jpepsy/jsi032
[48] Burgess, E., Singhal, N., Amin, H., McMillan, D., Devrome, H. and Fenton, A. (2003) Consent for clinical research in the neonatal intensive care unit: A retrospective survey and a prospective study. Archives of Disease in Childhood Fetal and Neonatal Edition, 88, F280-F286. doi:10.1136/fn.88.4.F280
[49] Mason, S. and Allmark, P. (2000) Obtaining informed consent to neonatal randomised controlled trials: Interviews with parents and clinicians in the Euricon study. The Lancet, 356, 2045-2051. doi:10.1016/S0140-6736(00)03401-2
[50] Stenson, B.J., Becher, J.C. and McIntosh, N. (2004) Neonatal research: The parental perspective. Archives of Disease in Childhood Fetal and Neonatal Edition, 89, F321-F324. doi:10.1136/adc.2002.021931
[51] Varma, S., Jenkins, T. and Wendler, D. (2008) How do children and parents make decisions about pediatric clinical research? Journal of Pediatric Hematology, 30, 823-828. doi:10.1097/MPH.0b013e318180bc0d
[52] Geller, G., Tambor, E., Bernhardt, B., Fraser, G. and Wissow, L. (2003) Informed consent for enrolling minors in genetic susceptibility research: A qualitative study of at-risk children’s and parents’ views about children’s role in decision-making. Journal of Adolescent Health, 32, 260-271. doi:10.1016/S1054-139X(02)00459-7
[53] Olechnowicz, J., Eder, M., Simon, C., Zyzanski, S. and Kodish, E. (2002) Assent observed: Children’s involvement in leukemia treatment and research discussions. Pediatrics, 109, 806-814. doi:10.1542/peds.109.5.806
[54] Brody, J., Scherer, D., Annett, R., Turner, C. and Dalen, J. (2006) Family and physician influence on asthma research-participation decisions for adolescents: The effects of adolescent gender and research risk. Pediatrics, 118, e356-e362. doi:10.1542/peds.2005-2589
[55] Hayman, R., Taylor, B., Peart, N., Galland, B. and Sayers, R. (2001) Participation in research: Informed consent, motivation and influence. Journal of Paediatrics and Child Health, 37, 51-54. doi:10.1046/j.1440-1754.2001.00612.x
[56] Dolan, L., Sabesan, V., Weinstein, S. and Spratt, K. (2008) Preference assessment of recruitment into a randomized trial for adolescent idiopathic scoliosis. The Journal of Bone and Joint Surgery (American), 90, 2594-2605. doi:10.2106/JBJS.G.01460
[57] Morris, M., Nadkarni, V., Ward, F. and Nelson, R. (2004) Exception from informed consent for pediatric resuscitation research: Community consultation for a trial of brain cooling after in-hospital cardiac arrest. Pediatrics, 114, 776-781. doi:10.1542/peds.2004-0482
[58] McGrath, P. (2002) Beginning treatment for childhood acute lymphoblastic leukemia: Insights from the parents’ perspective. Oncology Nursing Forum, 29, 988-996. doi:10.1188/02.ONF.988-996
[59] Sammons, H., Atkinson, M., Choonara, I. and Stephenson, T. (2007) What motivates British parents to consent for research? A questionnaire study. BMC Pediatrics, 7, 12. doi:10.1186/1471-2431-7-12
[60] Wagner, K., Martinez, M. and Joiner, T. (2006) Youths’ and their parents’ attitudes and experiences about participation in psychopharmacology treatment research. Journal of Child and Adolescent Psychopharmacology, 16, 298-307. doi:10.1089/cap.2006.16.298
[61] Stuijvenberg, M., Suur, M., Vos, S., Tjiang, G., Steyerberg, E., Derksen-Lubsen, G. and Moll, H. (1998) Informed consent, parental awareness, and reasons for participating in a randomised controlled study. Archives of Disease in Childhood, 79, 120-125. doi:10.1136/adc.79.2.120
[62] Brody, J., Annett, R., Scherer, D., Perryman, M. and Cofrin, K. (2005) Comparisons of adolescent and parent willingness to participate in minimal and above minimal risk pediatric asthma research protocols. The Journal of adolescent health, 37, 229-235. doi:10.1016/j.jadohealth.2004.09.026
[63] Scherer, D., Brody, J., Annett, R., Hetter, J., Roberts, L. and Cofrin, K. (2005) Financial compensation to adolescents for participation in biomedical research: Adolescent and parent perspectives in seven studies. The Journal of Pediatrics, 146, 552-558. doi:10.1016/j.jpeds.2004.12.024
[64] Hoehn, K., Wernovsky, G., Rychik, J., Gaynor, J., Spray, T., Feudtner, C. and Nelson, R. (2005) What factors are important to parents making decisions about neonatal research? Archives of Disease in Childhood Fetal and Neonatal Edition, 90, F267-F269. doi:10.1136/adc.2004.065078
[65] Rothmier, J.D., Lasley, M.V. and Shapiro, G.G. (2003) Factors influencing parental consent in pediatric clinical research. Pediatrics, 111, 1037-1041. doi:10.1542/peds.111.5.1037
[66] Pletsch, P.K. and Stevens, P.E. (2001) Inclusion of children in clinical research: Lessons learned from mothers of diabetic children. Clinical Nursing Research, 10, 140-162. doi:10.1177/10547730122158842
[67] Zupancic, J., Gillie, P., Streiner, D., Watts, J. and Schmidt, B. (1997) Determinants of parental authorization for involvement of newborn infants in clinical trials. Pediatrics, 99, E6. doi:10.1542/peds.99.1.e6
[68] Simon, C., Eder, M., Kodish, E. and Siminoff, L. (2006) Altruistic discourse in the informed consent process for childhood cancer clinical trials. The American Journal of Bioethics, 6, 40-47. doi:10.1080/15265160600862395
[69] Fernandez, C., Gao, J., Strahlendorf, C., Moghrabi, A., Pentz, R., Barfield, R., Baker, J., Santor, D., Weijer, C. and Kodish, E. (2009) Providing research results to participants: Attitudes and needs of adolescents and parents of children with cancer. Journal of Clinical Oncology, 27, 878-883. doi:10.1200/JCO.2008.18.5223
[70] Fernandez, C., Santor, D., Weijer, C., Strahlendorf, C., Moghrabi, A., Pentz, R., Gao, J. and Kodish, E. (2007) The return of research results to participants: Pilot questionnaire of adolescents and parents of children with cancer. Pediatric Blood & Cancer, 48, 441-446. doi:10.1002/pbc.20766
[71] Snowdon, C., Garcia, J. and Elbourne, D. (1998) Reactions of participants to the results of a randomised controlled trial: Exploratory study. British Medical Journal, 317, 21-26.
[72] Gómez-Marín, O., Prineas, R. and Sinaiko, A. (1991) The sodium-potassium blood pressure trial in children: Design, recruitment, and randomization: The children and adolescent blood pressure program. Controlled Clinical Trials, 12, 408-423. doi:10.1016/0197-2456(91)90020-M
[73] Tercyak, K., Johnson, S., Kirkpatrick, K. and Silverstein, J. (1998) Offering a randomized trial of intensive therapy for IDDM to adolescents. Reasons for refusal, patient characteristics, and recruiter effects. Diabetes Care, 21, 213-215. doi:10.2337/diacare.21.2.213
[74] Crom, D., Tyc, V., Rai, S., Deng, X., Hudson, M., Booth, A., Rodrigues, L., Zhang, L., Mccammon, E. and Kaste, S. (2006) Retention of survivors of acute lymphoblastic leukemia in a longitudinal study of bone mineral density. Journal of Child Health Care, 10, 337-350. doi:10.1177/1367493506067886
[75] Sederberg-Olsen, J., Sederberg-Olsen, N., Thomsen, J. and Balle, V. (1998) Problems in recruiting patients to controlled trials on children with secretory otitis media: A demographic comparison of excluded versus included patients. International Journal of Pediatric Otorhinolaryngology, 43, 229-233. doi:10.1016/S0165-5876(98)00004-4
[76] Reitamo, S., Rustin, M., Harper, J., Kalimo, K., Rubins, A., Cambazard, F., Brenninkmeijer, E., Smith, C., Berth- Jones, J., Ruzicka, T., Sharpe, G. and Taieb, A. (2008) A 4-year follow-up study of atopic dermatitis therapy with 0.1% tacrolimus ointment in children and adult patients. British Journal of Dermatology, 159, 942-951. doi:10.1111/j.1365-2133.2008.08747.x
[77] Ruperto, N., Lovell, D., Cuttica, R., et al. (2010) Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: Findings from an open-label treatment extension. Annals of the Rheumatic Diseases, 69, 718-722. doi:10.1136/ard.2009.100354

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