Human research is important. It is necessary if we as a society are to overcome illness and disease. Illness and disease are understood through its study, as are interventions which may impact upon it such as medications, devices and gene transfers. Early research ideas involving these new ‘agents’ are typically tested in laboratories, often on cells, and then in animals (usually flies, mice, primates, and dogs). Invariably however there comes a time in clinical research when the progression of a study aiming to understand the effects of the novel ‘agent’ on a particular human condition, must be tested in human beings [1, 2].

These studies are known as ‘early phase’ or ‘first-in-human’ studies (EPR) and they constitute the vast majority, some 61%, of all human studies [3].

The primary objective of these early experimental studies is to test agents for their safety in human beings. They are not designed to be of any direct benefit to participants. Furthermore, published data of results of toxicity in EPR show that significant potential for harm should be expected. In general because of the grave level of uncertainty, often EPR is undertaken with participants with lifelimiting or lifethreatening disease or conditions. Often these participants have advanced, refractory illness, that is, all conventional treatment options have been exhausted [3-5]. As noted by Kimmelman, this preference for participants with refractory, advanced illness is sometimes referred to as the ‘oncology model’ of subject selection because ‘oncology phase I trials almost universally enroll such patients’ [3, p. 32]. The preference for limiting exposure to risk to those volunteers already facing certain death illustrates the great uncertainty of predicting risks in early phase research. Ultimately however, the uncertainty is immeasurable.

Due to the rarity of disease in children, and the lack of generalisability of results from adult studies, there is a strong research culture among pediatric clinicians [6]. This extends to include EPR [3, 6, 7]. This strong research culture has contributed to an increased likelihood that children will survive serious disease, and within the oncology setting has led to an improved five year survival rate from 20% thirty years ago, to 75% (in part also due to improvements in supportive care) [6, 8, 9]. Although researchers and paediatric clinicians employ a number of strategies to reduce harm, published data of results of toxicity in research show 17-50% of children in phase I studies experience doselimiting toxicities, 21% of children are hospitalised due to research induced toxicities, 5% of phase I studies are discontinued due to toxicity, and approximately 0.4-2.7% of children may die a toxic death [10, 11]. The recognition of potential for harm is also demonstrated in studies of attitudes of paediatric clinicians involved in research on children [10-13]. Estlin et al. found the greater majority of paediatric clinicians (71%) involved in early phase research expected a child to have a least a 50% chance of experiencing toxicity by participating, with the perceived risk of a lifethreatening toxicity estimated at 40%, and the estimated risk of a child dying from toxicity at 16% [12, 13]. In comparison to the potential for risk, few studies adequately capture participant benefit with suggested potential for benefit remaining as low as 2% [14, 15]. In part, this may be due to the lack of a consistent, generalisable standard as what counts as a ‘benefit’ [15].

The nature of EPR—including the limited potential for benefit and significant potential for harm—raises significant implications for the consent process. Parents of child participants must understand and fully comprehend the uncertainty of EPR involvement. However, as noted by de Vries and colleagues, the strong culture of research among paediatric clinicians raises ethical concerns as the boundaries between clinical research and clinical care become more blurred [6]. This is particularly the case for parents who are tasked with making decisions about the care of their dying child in a very emotionally charged environment [16, 17]. Decision-making under these circumstances is fraught with difficulty for three main reasons: (a) there may be a lack of a clear, knowable distinction between the roles of researcher and treating clinician; (b) parents may be unaware or fail to understand that the primary nature of research and the primary nature of clinical care are different, and (c) parents may simply be unable to accept that the demise of their child is inevitable. These key issues may cause parents to overestimate the likelihood of benefit for their child, underestimate the likelihood of harm, and falsely attribute therapeutic values and expectations, a phenomenon known as a ‘therapeutic misconception’ [17-19]. This discrepancy in understanding or awareness of the true nature and prospects of EPR enables the construction of an altered reality of clinical research participation from that which the parent is actually consenting. Indeed, some parents enrol their child in early phase research under the mistaken belief it is another form of conventional treatment [20-22] .

A doctoral research project is currently being undertaken by the Center for Health and Society, and the Melbourne Medical School (University of Melbourne) which considers the ethical implications for the consent process when parents who hold therapeutic misconceptions agree for their child to take part in EPR. The study will also consider whether the existence of therapeutic misconceptions invalidates consent under current Australian laws.

Primarily the justification for the study is a concern that any therapeutic misconceptions about research participation, as perceived by the parents of child participants, may impact on their ability to deliberate and make a meaningful, valid decisions about their child’s involvement in EPR [23, 24]. This is particularly the case for parents deliberating about enrolling children with refractory disease in experimental clinical studies that may involve limited potential for benefit but great potential for uncertain risks and harms.

####References####

  1. Nossal, G., Medical Science and Human Goals. 1975, Port Melbourne: Edward Arnold Australia.
  2. Cheng, J., et al., Impact of quality of life on patients expectations regarding phase I clinical trials. Journal Of Clinical Oncology, 2000. 18(2): p. 421-428.
  3. Kimmelman, J., Gene Transfer and the Ethics of First-in-Human Research: Lost in Translation, ed. C. Medicine. 2012, Cambridge: Cambridge University Press.
  4. Travis, K., For Phase 1 Studies, Ethical and Practical Concerns Abound. Journal of the National Cancer Institute, 2004: p. 1354-1355.
  5. Miller, V., et al., Clinician-parent communication during informed consent for pediatric leukemia trials. Journal Of Pediatric Psychology, 2005. 30 (3): p. 219-229.
  6. de Vries, M., et al., Ethical issues at the interface of clinical care and research practice in pediatric oncology: a narrative review of parents’ and physicians’ experiences. BMC Medical Ethics, 2011. 12(18).
  7. Keech, A., V. Gebski, and R. Pike, Interpreting and Reporting Clinical Trials. A guide to the consort statement and the principles of randomised controlled trials. 2007, Sydney: Australian Medical Publishing.
  8. Cancer Statistics Review, 1975-2004 National Cancer Institute (based on November 2006 data submission), L. Ries, et al., Editors. 2007 National Cancer Institute: Bethesda, MD.
  9. Jemal, A., et al., Cancer statistics. Journal of Clinical Cancer. 2002. 52: p. 23-47.
  10. Kim, A., et al., Characteristics and Outcomes of pediatric patietns Enrolled in Phase I Oncology Trials. The Oncologist, 2011. 17: p. 5982-5990.
  11. Furman, W., C. Pratt, and G. Rivera, Mortality in pediatric phase I clinical trials. Journal of National Cancer Institute, 1989. 81(15): p. 1193-1194.
  12. Estlin, E., S. Ablett, and D.e.a. Newell, Phase I trials in pediatric oncology: The European perspective- the New Agents group of the United Kingdom Children’s Cancer Study Group. Invest New Drugs, 1996. 14: p. 23-32.
  13. Estlin, E., et al., Phase I Trials in Pediatric Oncology: Perceptions of Pediatricians From the United Kingdom Children’s Cancer Study Group and the Pediatric Oncology Group. Journal Of Clinical Oncology, 2000. 18(9): p. 1900-1905.
  14. Gupter, K., J. Gupter, and S. Singh, Surrogate Endpoints: How Reliable Are They? Journal of Clinical Research Best Practice, 2012. 6(5).
  15. Stepanov, N., In the Absence of Benefit: Questioning the Legitimacy of Parents’ Rights to Enrol their Child in Early-Phase and First-in-human Research, in Australasian Association of Bioethics and Health Law. 2013: University fo Sydney, Faculty of Law.
  16. De Vries MC, et al., Norms versus Practice: Pediatric Oncologists’ Attitudes towards Involving Adolescents in Decision Making concerning Research Participation. Pediatr Blood Cancer 2010. 55(1): p. 12-128.
  17. de Vries, M.C., et al., Ethical issues at the interface of clinical care and research practice in pediatric oncology: a narrative review of parents’ and physicians’ experiences. BMC Med Ethics, 2011. 12: p. 18.
  18. Gillam, L. and J. Sullivan, Ethics at the end of life: Who should make decisions about treatment limitation for young children with life-threatening or life-limiting conditions? Journal of Paediatrics & Child Health, 2011. 47(9): p. 594-598.
  19. Spriggs, M.P. and L.H. Gillam, Consent in paediatric research: an evaluation of the guidance provided in the 2007 NHMRC National statement on ethical conduct in human research. The Medical Journal Of Australia, 2008. 188(6): p. 360-362.
  20. Snowdon, C., J. Garcia, and D. Elbourne, Making sense of randomization: responses of parents of critically ill babies to random allocation of treatment in a clinical trial. Social Science & Medicine, 1997. 45: p. 1337-1355.
  21. Kupst, M., et al., Clinical trials in pediatric cancer: parental perspectives on informed consent. Journal Of Pediatric Hematology/Oncology: Official Journal Of The American Society Of Pediatric Hematology/Oncology, 2003. 25(10): p. 787-790.
  22. Wiley, F., et al., Parents’ perceptions of randomization in pediatric clinical trials. Cancer Practitioner, 1999. 7: p. 248-256.
  23. Appelbaum, P.S. and C. Lidz, Re-evaluating the therapeutic misconception: response to Miller and Joffe. Journal of the Kennedy Institute of Ethics, 2006. 16(4): p. 367-373.
  24. Appelbaum, P.S. and C.W. Lidz, Re-evaluating the therapeutic misconception: response to Miller and Joffe. Kennedy Institute of Ethics Journal, 2006. 16(4): p. 367-373.