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- SUCAN SUTANTO
Singapore Guideline for Good Clinical Practice (SGGCP) is the primary regulatory document which needs to be observed when conducting trials in Singapore. Last revised in 1999 by Ministry of Health (MOH), the SGCCP regulate conduct of clinical trials in Singapore along with The Medicine (Clinical Trials) Regulations and the Medicine Act. For all research studies involving human subjects or their tissues and organs, MOH made it mandatory that ethics committees are established to provide scientific reviews of their study protocols. The establishment of this committee involved all hospitals, both government and restructured. Thus “Institutional review boards” (IRB) was born and its guidelines was designed by The Bioethics Advisory Committee (BAC).
IRB play a central role as the gateway for ethnics review of “all Human Biomedical Research carried out under the auspices of its appointing institution” (MOH 2007 p.04). Individual researcher and institutions bear the ultimate ethical responsibility for governing their research. Based on the IRB’s Operational Guidelines (MOH 2007), three fundamental ethical principles; respect for persons, beneficence and justice must be followed in conducting biomedical research involving human. Potentially vulnerable populations must be given special attention.
The following sections will examine one of the vulnerable population–children. It is primarily challenging for the Ethics committees in assessing pediatric related research as the above principles discussed may conflict with some issues. Vague definitions of principle of equipoise, minimal risk and informed procedures are some contributing factors. The role of ethic committees in evaluation of risk and their impact in pediatric research will be given more focus.
PubMed database is primarily used in the search. Combination of keywords are used including of ‘ethics committees’, ‘research’, ‘children’, ‘pediatric’, ‘risk’, ‘ethics’ and ‘assessment’.
Children as a population sampling
In Singapore, 21 years is the age of majority under the common law. For any individual below the age of 21, Clinical Trial regulation states that parent’s or legal representative’s consent must be obtained for participation in trials. This present an ethical dilemma where the children’s autonomy become their parent or legal guardian, assuming that they have the children’s best interest at heart. The risk-benefit ratio of the research is then left to parents and IRBs to determine.
Risk assessment in pediatric research
According to U.S. Department of Health and Human Services (HHS) and Pediatric Clinic of North America (Laventhal et al., 2012), there are four definable risk in human research. In Singapore, the risk are less definitive, 2012 BAC guidelines describe only “research involving minimal risk such as surveys” and “risks involving more than minimal risks such as those involving invasive procedures”
The first level is minimal risk and it can be defined as probability and magnitude of physical or psychological harm that is normally encountered in the daily lives or in the routine medical, dental, or psychological examination of healthy children (HHS 2009). Studies in this category can be carried out even if they do not offer any direct benefit to the child although consent of at least one parent and the child assent is necessary. However this definition is rather vague and carries an inherent issue when applied to pediatric patient such as in the hospital. A survey was conducted on review board chair regarding skin biopsy on newborn and there is actually a split opinion and classification on whether it should be classified as “minimal risk” (Westra et al., 2011).
The second level of risk involves a “minor increase over minimal risk”. Although there might not be direct benefits to the child, such research might be allowed if it has the potential to yield valuable knowledge. Risks are deemed acceptable if they are comparable to the actual or expected condition of the child, medically or physiologically. In this case, both parents’ consent and child’s assent are required (HHS 2009).
The third level of risk is defined as “greater than minimal or even minor increase over minimal risk” with prospect of direct benefit to the child. Whether the potential benefit justifies the risk must be assessed and determined by IRBs (Laventhal et al., 2012). To determine the risk benefit, IRBs uses component analysis approach. Each intervention or procedure must be evaluated separately. For those components that represent greater than minimal risk, further assessment will be done to determine whether it does or does not hold out the prospect of direct benefit to the enrolled child (Roth-Cline et al., 2011).
The component analysis method however has been critiqued as it is standardized to the norm of clinical equipoise to determine the ethical acceptability of protocols. Definitively, clinical equipoise works on the principles of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each treatment arm of a clinical trial and that no one should receive an inferior treatment (Roth-Cline et al., 2011). A dilemma might present itself in trials where data collected is sufficient to doubt the clinical equipoise but not necessarily enough to justify scientific conclusion. An example could be seen in a review of neonatal hypoxic ischemic encephalopathy (HIE) hypothermia treatment trial published by Laventhal et al in 2012.
It was shown in a number of trials involving more than 600 infants that cooling HIE infants core temperature might help to elevate their condition. These randomized controlled trials managed to show overall improvement in mortality and disability outcomes although some adverse side effects were reported. However, Laventhal et al., 2012 pointed out that current evidence might not be adequate to determine the safety of this therapy and its efficacy. Therefore, whether to make this treatment mandatory for such patients remain to be decided. In this case, there is a dilemma on whether to allow more of such trials. On one hand, given that much evidence already supports the treatment, it would seem unethical to even deny the controlled subjects from such a beneficial treatment. On the other hand, just because a robust scientific conclusion has not been drawn, is it fair to continue to expose the infants to treatments with possible adverse outcomes? For those randomized into non treatment arm, would there be any potential direct benefits? Yet, to answer those questions and to find out long term safety and efficacy questions, the only way might be to conduct more trials.
Even within the IRB chairmen there are variations and application of assessment of risk- benefit potential. Shah et al in 2004(Shah et al., 2004) randomly surveyed 175 chairmen in United for certain intervention on children relative to the prospect risk and direct benefit. Results were surprising. In one intervention, an allergy skin testing, 23% considers it a minimal risk, close to half consider it minor increase above minimal risk and the rest as more than a minor increase over minimal risk. In the case of direct benefit for participants, 60% of those surveyed consider added psychological counselling as a direct benefit, while another 10% consider participant payment as a direct benefit. These divides in opinion indicates that the integrity of risk and benefits analysis by IRBs can be challenged.
The fourth risk level exists for trials where there is no prospect of direct benefit with more than a minor increase over minimal risk for the child. Such studies could be allowed if they have high potential to produce very important knowledge. Such cases are not under approval of IRBs, instead they are referred to an experts panels under the federal government. (Laventhal et al., 2012).
In a review by Wendler and Varma in 2006, they examine 9 studies assessed by IRBs which fall into the fourth level. IRBs classified different levels of harm; negligible, minor, moderate, severe and catastrophic harm relative to the normal probability a healthy child may encounter in day to day situation. Wendler and Varma then assess the proposed interventions for each study and then compare with the classification given by IRBS.They argued that eight of the studies could actually be categorized into minimal risk instead of the fourth level of risk. A primary example was the intravenous glucose tolerance test (IVGTT) on healthy children. Known possible harms include nausea, bruising and hypoglycemia. Very minimal adverse events were recorded in thousands of pediatric studies involving IVGTT. Only 1 in 3000 risk of hypoglycemia, it can be resolved with carbohydrates or glucose injection. It is therefore arguable that the IVGTT risk much more minimal in comparison to the 30 in 1000 chance of “minor” harm in average children in their daily routines used as a base of the classification. As such, the review shows that misclassification could occur and valuable research time may be delayed unnecessarily. There is a lack of empirical database on risks of ordinary activities for reference and this might be a contributing factor for the misclassification. It forces the IRB members to rely on their own individuals life experiences to determine the perceptions of risk therefore causing biased.
To conclude, pediatric studies have been shown to provide an ethical review challenge. In order to improve the risk analysis and reduce bias, empirical data on the risk of research procedures in pediatric studies as well as database on the risk of daily activities should be collected and better established for reference. There should be standardized guidelines for risk analysis with certain flexibility to account for unique feature of each study
Bioethics Advisory Committee (2004) Research involving human subjects. Guidelines for IRBs. Singapore: BAC. Available from: http://www.bioethics-singapore.org/index/publications/reports/172-research-involving-human-subjects-guidelines-for-irbs.html [Accessed 28th Jan 2015]
Bioethics Advisory Committee (2012) Ethics Guidelines for Human Biomedical Research. Singapore: BAC. Available from: http://www.bioethics-singapore.org/images/uploadfile/32914 PM2012-06-20 – BAC Ethics Guidelines (for comments) F.pdf [Accessed 28th Jan 2015]
Ministry of Health (2007) Governance Framework for Human Biomedical Research. Available from : https://www.moh.gov.sg/content/dam/moh_web/Publications/Guidelines/Human Biomedical Research/2007/Governance Frwk for HBR_14-12-07_formatted.pdf [accessed 02 March 2015]
Department of Health and Human Services (2009). US code of Federal Regulations, USA, FDA, Available from: http://www.hhs.gov/ohrp/archive/humansubjects/guidance/45cfr46.html#46.404 [Accessed 28th Jan 2015]
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Ministry of Health (2007) Operational Guidelines for Institutional Review Boards. Singapore: MOH Available from: https://www.moh.gov.sg/content/dam/moh_web/Publications/Guidelines/Human Biomedical Research/2007/IRB Operational Guidelines_14-12-07_formatted.pdf [Accessed 28th Jan 2015]
ROTH-CLINE, M., GERSON, J., BRIGHT, P., LEE, C. S. & NELSON, R. M. 2011. Ethical considerations in conducting pediatric research. Handb Exp Pharmacol, 205, 219-44.
SHAH, S., WHITTLE, A., WILFOND, B., GENSLER, G. & WENDLER, D. 2004. How do institutional review boards apply the federal risk and benefit standards for pediatric research? Jama, 291, 476-82.
Westra AE, Wit, JM; Sukhai, RN. And Beaufort ID. (2011) How to best define the concept of minimal risk. The Journal of Pediatrics 159 (3) 496-500
WENDLER, D. & VARMA, S. 2006. Minimal risk in pediatric research. J Pediatr, 149, 855-61.
Wendler, D. and Glantz L. (2007). A standard for assessing the risks of pediatric research: pro and con. J Pediatr 150, 579-582
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