WEBVTT 1 00:00:00.680 --> 00:00:07.599 Section three of Safeguarding Children Pediatric Medical Countermeasure Research by 2 00:00:07.719 --> 00:00:13.160 Presidential Commission for the Study of Bioethical Issues. This LibriVox 3 00:00:13.199 --> 00:00:17.800 recording is in the public domain. Recording by Patrick mcaffee, 4 00:00:18.359 --> 00:00:24.719 Merritt Island. Chapter two Current Ethical and Regulatory Framework for 5 00:00:25.000 --> 00:00:31.960 Pediatric Research, Part one. Pediatric research is essential to ensure 6 00:00:32.079 --> 00:00:38.000 that children have access to therapies that are safe and effective. Quote. 7 00:00:38.280 --> 00:00:43.399 Children are not just small adults end They vary substantially 8 00:00:43.479 --> 00:00:47.640 from adults and from other children of different ages in 9 00:00:47.679 --> 00:00:53.719 the ways they process medicines, respond to interventions, interact with 10 00:00:53.759 --> 00:00:59.399 their environment, drug effects and toxicities, as well as immune 11 00:00:59.439 --> 00:01:03.240 responses to vaccines are affected by the rapid growth and 12 00:01:03.280 --> 00:01:08.280 development in body size, weight, and organ function, as well 13 00:01:08.319 --> 00:01:14.480 as the metabolic processes that characterize childhood. Children behave differently 14 00:01:14.560 --> 00:01:18.840 from adults as well. For example, they generally spend more 15 00:01:18.879 --> 00:01:22.879 time outdoors and put objects in their mouths when they 16 00:01:22.879 --> 00:01:29.319 are young, increasing their exposure to some environmental contaminants. Given 17 00:01:29.400 --> 00:01:35.159 these differences, without specific data from pediatric research, health care 18 00:01:35.200 --> 00:01:43.200 providers often have inadequate information to accurately estimate dosages, formulations, 19 00:01:43.239 --> 00:01:48.879 and treatment regimens. The pharmaceutical industry historically has had little 20 00:01:48.959 --> 00:01:54.040 incentive to conduct systematic clinical trials with children, even when 21 00:01:54.120 --> 00:01:57.799 those trials could have been conducted with minimal risk to 22 00:01:57.879 --> 00:02:03.879 individual children. US childhood is relatively short and most children 23 00:02:04.000 --> 00:02:09.680 are healthy. The market for pediatric pharmaceuticals and other medical 24 00:02:09.719 --> 00:02:15.280 products is small and subdivided by stages of development, often 25 00:02:15.360 --> 00:02:20.360 making it difficult to enroll adequate numbers of appropriate participants 26 00:02:20.400 --> 00:02:26.599 necessary for rigorous trials. As of nineteen ninety seven, studies 27 00:02:26.800 --> 00:02:30.599 showed that up to eighty percent of the drugs used 28 00:02:30.639 --> 00:02:37.719 by children had never been studied in pediatric populations for safety, dosing, 29 00:02:38.240 --> 00:02:43.199 or efficacy. Beginning in the late nineteen nineties, out of 30 00:02:43.319 --> 00:02:49.319 concern for protecting children through research rather than from research, 31 00:02:49.960 --> 00:02:54.199 Congress passed a series of laws to remedy the paucity 32 00:02:54.280 --> 00:03:00.000 of pediatric data by creating incentives for ethically sound peddle 33 00:03:00.000 --> 00:03:07.680 theatric clinical research. This legislation, including the Best Pharmaceuticals for 34 00:03:07.840 --> 00:03:14.240 Children Act of two thousand two and the Pediatric Research 35 00:03:14.360 --> 00:03:20.719 Equity Act of two thousand three, provided extended market exclusivity 36 00:03:21.159 --> 00:03:25.400 for products tested with children, and enabled the US Food 37 00:03:25.479 --> 00:03:31.560 and Drug Administration FDA to request drug and biologic testing 38 00:03:32.000 --> 00:03:39.319 with pediatric populations. These incentive programs have spurred pediatric research 39 00:03:39.879 --> 00:03:44.879 and provided data that contributed to an approximately fifty percent 40 00:03:45.080 --> 00:03:51.000 reduction in off label use of drugs for children. This 41 00:03:51.080 --> 00:03:55.159 is a vast improvement from the recent past, although the 42 00:03:55.280 --> 00:04:03.479 rate of off label use still remains high. Historical research abuses, 43 00:04:04.479 --> 00:04:10.400 a convergence of research abuses influenced the move toward regulatory 44 00:04:10.520 --> 00:04:15.319 human subject's research protections, developed in part by the National 45 00:04:15.319 --> 00:04:20.079 Commission in the nineteen seventies and enacted by the Department 46 00:04:20.120 --> 00:04:26.079 of Health, Education and Welfare now HHS in the late 47 00:04:26.199 --> 00:04:33.120 nineteen seventies and early nineteen eighties. Research abuses, including well 48 00:04:33.160 --> 00:04:39.079 known cases such as Willowbrook, Tuskegee, and the Nazi atrocities, 49 00:04:39.680 --> 00:04:46.600 were historically important in moving toward regulation. Henry Beecher's publication 50 00:04:47.160 --> 00:04:50.120 of an article in the New England Journal of Medicine, 51 00:04:50.600 --> 00:04:56.839 which exposed twenty two cases of human experimentation abuses, also 52 00:04:56.879 --> 00:05:02.759 motivated human subject's research regulation. Among the cases included in 53 00:05:02.879 --> 00:05:10.480 Beecher's publication was the Willebrook study, research conducted with institutionalized 54 00:05:10.879 --> 00:05:17.199 and mentally handicapped children. The current ethical and regulatory framework 55 00:05:17.519 --> 00:05:22.000 has proven largely capable of protecting children in the face 56 00:05:22.120 --> 00:05:29.439 of increasing pediatric research, promoting their welfare, and enhancing research quality. 57 00:05:30.439 --> 00:05:38.879 Medical countermeasure MCM. Research, however, presents unique ethical challenges to 58 00:05:38.959 --> 00:05:45.839 the existing regulatory framework. This chapter provides an overview of 59 00:05:45.920 --> 00:05:51.639 the ethical and regulatory framework for pediatric research. It begins 60 00:05:51.759 --> 00:05:55.040 with an overview of the ethical principles that form the 61 00:05:55.079 --> 00:06:01.199 foundation of current federal regulations governing pediatric lias research, and 62 00:06:01.439 --> 00:06:07.319 concludes with a discussion of how those fundamental principles animated 63 00:06:07.560 --> 00:06:14.480 the development and adoption of pediatric research protections. Ethical underpinnings 64 00:06:15.040 --> 00:06:21.199 guiding principles. A core set of ethical principles provides the 65 00:06:21.240 --> 00:06:27.120 foundation for pediatric research protections, reflecting a consensus on the 66 00:06:27.120 --> 00:06:32.519 ethical conduct of human subjects research. These ethical principles are 67 00:06:32.639 --> 00:06:36.240 drawn from the National Commission for the Protection of Human 68 00:06:36.319 --> 00:06:43.759 Subjects of Biomedical and Behavioral Researches, the National Commissions, Belmont 69 00:06:43.839 --> 00:06:50.720 Report and furthered by democratic deliberation which the National Commission 70 00:06:51.240 --> 00:06:56.879 and subsequent commissions practiced in their work, and this Bioethics 71 00:06:56.879 --> 00:07:03.160 Commission explicitly adds as a critical principle for publicly accountable 72 00:07:03.240 --> 00:07:11.240 decision making in research involving children. The National Commission emphasized 73 00:07:11.439 --> 00:07:16.199 the importance of including children in research to interrupt what 74 00:07:16.360 --> 00:07:23.920 had become a long history of untested and harmful pediatric innovations. 75 00:07:24.639 --> 00:07:29.720 The National Commission recognized that, in addition to protecting children 76 00:07:29.800 --> 00:07:36.000 from research risks, society ought to protect children through research. 77 00:07:36.800 --> 00:07:40.639 This need to ensure the safety of children was grounded 78 00:07:40.759 --> 00:07:45.480 in respect for persons and the inability of children to 79 00:07:45.639 --> 00:07:53.160 consent to research related risks. The National Commission's report clarified 80 00:07:53.399 --> 00:07:59.480 what became the United States Central tenet of pediatric research. 81 00:08:00.279 --> 00:08:05.720 Pediatric research generally should be allowed only when such research 82 00:08:06.079 --> 00:08:12.879 exposes children to minimal risk. Minimal risk research entails a 83 00:08:12.959 --> 00:08:17.160 level of risk in which the degree and likelihood of 84 00:08:17.199 --> 00:08:20.959 harm is no greater than that faced by a healthy 85 00:08:21.079 --> 00:08:26.160 child in daily life or at a routine physical or 86 00:08:26.199 --> 00:08:33.639 psychological examination. Research risk can be greater than minimal only 87 00:08:33.720 --> 00:08:38.720 when the research offers the prospect of direct benefit to 88 00:08:38.840 --> 00:08:44.679 participants themselves, or if a minor increase above minimal risk, 89 00:08:45.320 --> 00:08:50.240 when research offers the prospect of benefit to others with 90 00:08:50.360 --> 00:08:57.120 the same condition, except in extraordinary circumstances, asking children to 91 00:08:57.200 --> 00:09:00.799 take on greater risk in research when they do not 92 00:09:00.960 --> 00:09:06.559 stand to benefit directly pushes the bounds of ethical acceptability 93 00:09:07.120 --> 00:09:11.639 because children do not have the legal or ethical capacity 94 00:09:11.759 --> 00:09:17.200 to consent, and society has a duty to protect children 95 00:09:17.279 --> 00:09:22.240 from risk of harm to which they cannot consent. This 96 00:09:22.399 --> 00:09:28.399 view is widely shared, affirmed in leading international guidance documents, 97 00:09:29.000 --> 00:09:34.159 and reflected in US law. It continues to serve as 98 00:09:34.360 --> 00:09:39.200 the first principle of ethically sound pediatric research around the 99 00:09:39.200 --> 00:09:46.720 world today. Development of the central tenet of pediatric research. 100 00:09:47.960 --> 00:09:52.960 The four ethical principles that guided the Bioethics Commission's discussion 101 00:09:53.519 --> 00:10:01.559 of pediatric research protections are respect for persons, benefit and 102 00:10:02.120 --> 00:10:08.399 justice as outlined in the Belmont Report, and democratic deliberation, 103 00:10:09.080 --> 00:10:12.399 which was implicit both in the way the National Commission 104 00:10:12.519 --> 00:10:17.360 carried out its work and also in its recommendations regarding 105 00:10:17.399 --> 00:10:25.039 the process of reviewing and approving pediatric research. Respect for 106 00:10:25.080 --> 00:10:30.960 persons the Belmont Report delineates the principle of respect for persons, 107 00:10:31.399 --> 00:10:37.960 which recognizes persons as autonomous and capable of deliberating about 108 00:10:38.000 --> 00:10:43.399 their personal goals, considering their own choices and opinions, and 109 00:10:43.559 --> 00:10:50.960 determining their own lives. Respect for persons also establishes quote 110 00:10:51.159 --> 00:10:57.879 that persons with diminished autonomy, including children, are entitled to protection. 111 00:11:00.200 --> 00:11:05.679 Some commentators believe that the obligation of protection in the 112 00:11:05.720 --> 00:11:12.600 Belmont Report is really a matter of beneficence. However, disregard 113 00:11:12.679 --> 00:11:16.960 for the well being of children also reflects a lack 114 00:11:17.000 --> 00:11:22.000 of respect owed to them as young persons. This respect 115 00:11:22.240 --> 00:11:26.000 derives in part from the fact that children have and 116 00:11:26.159 --> 00:11:30.679 will further develop personal values and goals, as well as 117 00:11:30.759 --> 00:11:35.919 the capacity for self determination to strive and fulfill them. 118 00:11:37.320 --> 00:11:43.120 Respect for persons requires that research participants with full decision 119 00:11:43.279 --> 00:11:48.559 making capacity be given the information and the opportunity to 120 00:11:48.720 --> 00:11:53.480 consent voluntarily and knowingly to what will happen to them 121 00:11:53.840 --> 00:11:59.039 as a result of their participation. This imperative is often 122 00:11:59.200 --> 00:12:03.960 viewed as deriving from the human capacity for reason and 123 00:12:04.080 --> 00:12:10.080 self determination. Human beings are generally capable of setting their 124 00:12:10.159 --> 00:12:15.679 own ends in accordance with their values and priorities in 125 00:12:15.840 --> 00:12:21.159 rationally pursuing these ends. Treating others in a way that 126 00:12:21.279 --> 00:12:29.120 disregards their human capacity for rationality and self determination constitutes 127 00:12:29.240 --> 00:12:34.000 disrespect for those persons. And when we use people only 128 00:12:34.120 --> 00:12:38.080 to pursue the ends or interests of others, in other words, 129 00:12:38.200 --> 00:12:42.440 using them as mere means we fail to respect their 130 00:12:42.559 --> 00:12:48.480 human dignity. Coercive uses of research participants, as in the 131 00:12:48.559 --> 00:12:54.840 Nazi medical atrocities, provide the most obvious instances of the 132 00:12:54.960 --> 00:13:01.960 impermissible treatment of participants as means only. Coercion of adult 133 00:13:02.039 --> 00:13:07.399 participants in research is a violation of a participant's autonomy. 134 00:13:08.039 --> 00:13:12.279 The rational ability to direct the course of one's own 135 00:13:12.360 --> 00:13:18.320 life to treat people merely as means to exploit them 136 00:13:18.480 --> 00:13:21.759 or use them only to further the interests of others 137 00:13:22.360 --> 00:13:26.320 is not the same as treating people both as means 138 00:13:26.360 --> 00:13:33.399 and as ends in themselves. Ethical human subjects research illustrates 139 00:13:33.559 --> 00:13:39.120 this distinction. Participation in research that offers a prospect of 140 00:13:39.240 --> 00:13:45.879 direct benefit might prove useful to others while simultaneously advancing 141 00:13:45.919 --> 00:13:52.639 the interests of individual research participants. In other instances of 142 00:13:52.799 --> 00:13:59.600 scientifically and ethically sound research, adult research participants are well 143 00:13:59.639 --> 00:14:05.360 informed and willing to bear personal risks with no expectation 144 00:14:05.679 --> 00:14:10.639 of return, in order to benefit others. In these cases, 145 00:14:11.039 --> 00:14:17.759 transparency about risks and benefits allows individuals to make their 146 00:14:17.840 --> 00:14:23.519 own assessment of whether research participation comports with their personal 147 00:14:23.639 --> 00:14:30.600 values and pursuits. Accordingly, adults who provide their informed consent 148 00:14:31.039 --> 00:14:37.720 to participate in otherwise scientifically sound and necessary research are 149 00:14:37.799 --> 00:14:43.559 not treated only as means, but also as ends in themselves. 150 00:14:45.320 --> 00:14:51.399 Ethical safeguards in pediatric research informed by respect for persons. 151 00:14:52.919 --> 00:14:57.039 Research with children differs from that with adults because children 152 00:14:57.120 --> 00:15:02.200 cannot consent in the relevant sense. They are substantially lacking 153 00:15:02.879 --> 00:15:09.039 in the developed capacities necessary for adequately informed, in voluntary 154 00:15:09.159 --> 00:15:16.279 decision making, making them a vulnerable population. Although this incapacity 155 00:15:16.519 --> 00:15:20.559 is most often attributed to their level of cognitive development, 156 00:15:21.200 --> 00:15:26.519 the vulnerability of children can derive from multiple sources, such 157 00:15:26.720 --> 00:15:32.480 as expectations of deference to adult authority, lack of independent 158 00:15:32.559 --> 00:15:40.159 resources for autonomous decision making, and long standing institutionalized relationships 159 00:15:40.159 --> 00:15:46.519 of adult authority and power. For this reason, extra protections 160 00:15:46.960 --> 00:15:50.919 are warranted to ensure that children are not placed at 161 00:15:50.960 --> 00:15:56.399 excessive risk for the benefit of others. These additional safeguards 162 00:15:56.480 --> 00:16:03.679 include parental permission meaning full child assent, and limits on 163 00:16:03.759 --> 00:16:11.240 the degree of permissible research related risk. Applied ethics in 164 00:16:11.480 --> 00:16:18.919 pediatric research, paternalism constitutes those actions that restrict the freedom 165 00:16:19.000 --> 00:16:22.279 of others on the grounds that those actions are the 166 00:16:22.320 --> 00:16:27.000 best way to promote or protect their interests. In the 167 00:16:27.039 --> 00:16:32.399 case of children. Such restrictions are not only justified because 168 00:16:32.519 --> 00:16:37.759 children cannot identify and pursue their own interests, but because 169 00:16:38.279 --> 00:16:44.200 quote such restrictions on a child's freedom guarantee his autonomy 170 00:16:44.639 --> 00:16:49.679 in either or both of two ways. These restrictions protect 171 00:16:49.720 --> 00:16:52.679 the child from harm that would limit his freedom in 172 00:16:52.720 --> 00:16:57.840 the future, being seriously injured or a lack of education, 173 00:16:58.759 --> 00:17:02.559 or These restrictions are what we think the child will 174 00:17:02.759 --> 00:17:07.279 later agree to, what he will later see as something 175 00:17:07.359 --> 00:17:16.599 he would do in his own interest. Parental permission. Parental 176 00:17:16.599 --> 00:17:21.880 permission requires that parents act on their child's behalf, operating 177 00:17:22.079 --> 00:17:25.519 on their understanding of what is in their child's best 178 00:17:25.759 --> 00:17:31.319 or essential interests. With this in mind, parents might allow 179 00:17:31.400 --> 00:17:35.680 a child to participate in research that offers a prospect 180 00:17:35.839 --> 00:17:41.279 of direct benefit, precisely because enrollment appears to promote the 181 00:17:41.400 --> 00:17:46.480 child's interests. In the context of research that poses no 182 00:17:46.640 --> 00:17:51.519 substantial risk to a child's health or well being but 183 00:17:51.680 --> 00:17:56.759 offers no prospect of direct benefit, some parents will compare 184 00:17:57.240 --> 00:18:02.640 short term risks and benefits. For these parents, research that 185 00:18:02.799 --> 00:18:07.079 provides no direct benefit might be out of the question. 186 00:18:08.240 --> 00:18:11.279 Other parents might be willing to take on risk for 187 00:18:11.359 --> 00:18:16.160 themselves but reluctant to subject their child to any research 188 00:18:16.359 --> 00:18:21.680 risk without the prospect of direct benefit, not knowing what 189 00:18:21.720 --> 00:18:26.759 the child will think upon reaching adulthood about having been 190 00:18:26.799 --> 00:18:31.279 subjected to risk for the benefit of others without their consent, 191 00:18:32.799 --> 00:18:37.000 and still other parents will give greater weight to the 192 00:18:37.039 --> 00:18:43.640 study's incremental contribution to long term scientific or societal endeavors, 193 00:18:44.000 --> 00:18:49.039 which might eventually result in medical progress that helps their 194 00:18:49.160 --> 00:18:57.079 child or the child's potential offspring, as well as other children. Alternatively, 195 00:18:57.640 --> 00:19:01.440 parents might enroll their children in react that poses no 196 00:19:01.599 --> 00:19:05.720 substantial risk to their health or well being to teach 197 00:19:05.839 --> 00:19:09.799 them a moral lesson about the value of service to others. 198 00:19:11.079 --> 00:19:15.599 Parents of older children might wish to give effect to 199 00:19:15.720 --> 00:19:20.519 their developing autonomy by including them in projects to which 200 00:19:20.559 --> 00:19:25.240 they assent and which they might later endorse as consistent 201 00:19:25.400 --> 00:19:32.400 with their own ethical perspective and interests. Meaningful child assent. 202 00:19:33.720 --> 00:19:38.440 While children are not fully autonomous, they nevertheless have varying 203 00:19:38.519 --> 00:19:44.039 capacities to make informed self regarding choices and express their 204 00:19:44.079 --> 00:19:50.279 preferences regarding how they will be treated. Children's partial autonomy 205 00:19:50.400 --> 00:19:57.319 affords them a developmentally appropriate ability to participate in decisions 206 00:19:57.359 --> 00:20:02.559 regarding their involvement in research. Out of respect for this 207 00:20:02.720 --> 00:20:08.920 developing ability of children, their assent should be solicited if possible, 208 00:20:09.759 --> 00:20:16.599 and their descent respected if applicable. Obtaining the meaningful ascent 209 00:20:16.759 --> 00:20:20.839 of a capable child is one component of respecting that 210 00:20:21.000 --> 00:20:25.400 child as a person. It must not be interpreted, however, 211 00:20:25.640 --> 00:20:31.599 either as informed consent or as a substitute for parental permission. 212 00:20:32.240 --> 00:20:39.599 Parental permission is absolutely necessary to informed participation in conjunction 213 00:20:40.240 --> 00:20:45.839 with meaningful child assent. The fact that children have a 214 00:20:45.920 --> 00:20:51.519 developing capacity for autonomy lends significance to a child's meaningful 215 00:20:51.599 --> 00:20:57.279 assent or dissent, and also establishes a need to protect 216 00:20:57.680 --> 00:21:03.640 this capacity for self determination. The principle of respect for 217 00:21:03.720 --> 00:21:10.119 persons permits only those research protocols that preserve and sustain 218 00:21:10.279 --> 00:21:14.400 the full development of a child's autonomy, such that the 219 00:21:14.440 --> 00:21:19.640 current and future aspirations of some children are never unduly 220 00:21:19.759 --> 00:21:25.240 compromised merely for the sake of benefiting others. This is 221 00:21:25.279 --> 00:21:29.680 accomplished in important part by the final form of protection 222 00:21:29.960 --> 00:21:34.440 discussed here, which limits the degree of risk to which 223 00:21:34.559 --> 00:21:40.839 children can be exposed in research, limiting the degree of 224 00:21:41.079 --> 00:21:45.880 research related risk, placing strict limits on the level of 225 00:21:46.079 --> 00:21:51.079 risk acceptable in pediatric research is a third and critically 226 00:21:51.200 --> 00:21:55.039 important way to protect children. In light of their incomplete 227 00:21:55.079 --> 00:22:02.519 autonomy and their inability to consent. Child research participants will 228 00:22:02.559 --> 00:22:05.799 one day grow up and reflect on whether they would 229 00:22:05.880 --> 00:22:10.480 have consented to participate in the research had they been capable. 230 00:22:11.480 --> 00:22:16.839 While parents may exercise legitimate discretion when granting permission for 231 00:22:16.960 --> 00:22:20.799 their children to enroll in research, there is no way 232 00:22:21.000 --> 00:22:26.160 to know whether all participants, once adults, will endorse the 233 00:22:26.279 --> 00:22:32.359 decision retrospectively, even if they provided meaningful assent as children. 234 00:22:33.319 --> 00:22:37.319 To reduce the possibility that some participants will look back 235 00:22:37.440 --> 00:22:42.000 and think they were unethically used by their parents or researchers, 236 00:22:42.720 --> 00:22:47.160 protections should be in place to ensure that participants who 237 00:22:47.200 --> 00:22:51.759 reflect on their past research participation will be likely to 238 00:22:52.000 --> 00:22:55.720 endorse the ways in which they were protected, if not 239 00:22:55.920 --> 00:23:02.200 their own participation. On this view, mass participants might later 240 00:23:02.279 --> 00:23:06.920 reflect that even if they would not have consented to participate, 241 00:23:07.559 --> 00:23:12.519 protections were in place that prevented them from being harmed. 242 00:23:14.720 --> 00:23:19.519 Risk limits are essential to combat the potential for exploitation 243 00:23:20.039 --> 00:23:24.960 of both children and adults. However unintended, such exploitation may 244 00:23:25.000 --> 00:23:30.559 be because children cannot make an autonomous decision to participate 245 00:23:30.720 --> 00:23:35.640 in research. From an ethical and legal perspective, great care 246 00:23:35.759 --> 00:23:41.039 must be taken to ensure that research risks are rigorously limited. 247 00:23:41.839 --> 00:23:46.880 In particular because research is in part always justified on 248 00:23:46.960 --> 00:23:51.880 the basis of potential benefit to others, but not necessarily 249 00:23:52.000 --> 00:23:57.119 to the children who are subject to risks as research subjects, 250 00:23:57.839 --> 00:24:01.920 special efforts must be made to sure that children are 251 00:24:01.920 --> 00:24:07.160 not exploited by permitting greater research risks to children when 252 00:24:07.279 --> 00:24:12.839 society stands to benefit in greater measure. The imposition of 253 00:24:12.920 --> 00:24:17.680 a rigorous risk ceiling ensures that, no matter how great 254 00:24:17.720 --> 00:24:22.960 the potential benefit, child research participants are not exposed to 255 00:24:23.279 --> 00:24:29.119 a disrespectful and exploitative level of risk for the interests 256 00:24:29.119 --> 00:24:34.839 of others in society. Another reason why it is important 257 00:24:34.920 --> 00:24:39.319 to limit the research risks to which children are subjected 258 00:24:39.880 --> 00:24:42.759 is that the state does not have the same broad 259 00:24:42.839 --> 00:24:47.920 latitude as parents to make risk laden decisions on behalf 260 00:24:48.000 --> 00:24:52.319 of children. There are public obligations to limit both the 261 00:24:52.359 --> 00:24:57.400 outer bounds of parental authority so as to prevent negligence, 262 00:24:57.960 --> 00:25:02.799 and the outer bounds of govern mental authority over children 263 00:25:03.039 --> 00:25:07.680 so as to prevent the exploitation of individual children. For 264 00:25:07.720 --> 00:25:12.640 public purposes. One way in which the government defines the 265 00:25:12.880 --> 00:25:17.680 outer bounds of its own authority over individual children and 266 00:25:17.839 --> 00:25:22.000 respects the future autonomy of children is by limiting the 267 00:25:22.119 --> 00:25:26.519 levels of research risk that parents may be asked to 268 00:25:26.680 --> 00:25:31.559 accept for their children, especially when that research is above 269 00:25:31.799 --> 00:25:37.079 minimal risk and does not directly benefit the child. These 270 00:25:37.200 --> 00:25:41.440 risk limits are one of the core protections that children receive, 271 00:25:41.720 --> 00:25:45.559 both out of respect for their dignity as persons and 272 00:25:45.759 --> 00:25:49.279 to help ensure that they will be able to exercise 273 00:25:49.799 --> 00:25:56.359 their own autonomy as adults. Interpreting the scope of respect 274 00:25:56.480 --> 00:26:02.079 for persons, given that children are all under clearly delineated 275 00:26:02.119 --> 00:26:07.920 circumstances to participate in research without the prospect of direct benefit, 276 00:26:08.599 --> 00:26:16.119 current regulations implicitly reject one particularly restrictive interpretation of the 277 00:26:16.160 --> 00:26:22.000 principle of respect for persons see Current Regulations for Conducting 278 00:26:22.200 --> 00:26:29.880 Pediatric Research, Chapter two. Under this most restrictive interpretation, due 279 00:26:29.920 --> 00:26:34.359 to their incapacity to consent, the principle of respect for 280 00:26:34.440 --> 00:26:40.319 persons would prohibit all research with children, including even minimal 281 00:26:40.640 --> 00:26:46.799 risk research that offers no prospect of direct benefit. Strong 282 00:26:46.880 --> 00:26:51.880 consensus in the field of bioethics, including the judgment reflected 283 00:26:51.920 --> 00:26:59.000 in the National Commission's position, regards this understanding as overly restrictive. 284 00:27:00.039 --> 00:27:06.079 An alternative, widely accepted interpretation of respectful persons allows for 285 00:27:06.160 --> 00:27:10.319 the participation of children in research that offers no prospect 286 00:27:10.839 --> 00:27:16.039 of direct benefit under certain carefully defined circumstances, even if 287 00:27:16.039 --> 00:27:21.319 the research imposes more than minimal risk on pediatric participants, 288 00:27:21.839 --> 00:27:27.200 stopping short of posing any substantial risk to the fundamental 289 00:27:27.200 --> 00:27:32.400 health or wellbeing of the research participants. On this widely 290 00:27:32.440 --> 00:27:38.400 accepted interpretation, research without the prospect of direct benefit is 291 00:27:38.440 --> 00:27:43.119 permissible if it imposes no greater than minimal risk, a 292 00:27:43.200 --> 00:27:47.000 level of risk comparable to the risks that healthy children 293 00:27:47.119 --> 00:27:52.279 living in a safe environment routinely encounter in everyday life 294 00:27:52.960 --> 00:27:58.839 or during a routine medical examination, and under certain limited circumstances, 295 00:27:59.440 --> 00:28:03.240 a slightly higher but still very limited level of risk 296 00:28:03.799 --> 00:28:08.319 which poses no substantial risk to the participant's health or 297 00:28:08.400 --> 00:28:13.279 well being. The widely accepted interpretation of the principle of 298 00:28:13.400 --> 00:28:17.359 respect for persons should be endorsed on the grounds that 299 00:28:17.480 --> 00:28:22.720 research protections can help to ensure respect for children by 300 00:28:22.799 --> 00:28:29.279 safeguarding their current capacities, guaranteeing their future autonomy by ensuring 301 00:28:29.440 --> 00:28:33.599 they are not treated as mere means and by not 302 00:28:33.680 --> 00:28:39.000 subjecting them to undue risk. In addition, this more inclusive 303 00:28:39.039 --> 00:28:45.599 interpretation receives support from other relevant moral principles. The principle 304 00:28:45.599 --> 00:28:50.440 of beneficence, further addressed in the next section, calls upon 305 00:28:50.599 --> 00:28:56.119 society and the research community to advance biomedical knowledge in 306 00:28:56.200 --> 00:29:01.039 the interest of the public's welfare. The importance of beneficence 307 00:29:01.519 --> 00:29:06.559 in the context of pediatric biomedical research councils against the 308 00:29:06.599 --> 00:29:13.079 most restrictive interpretation of respect for persons and in favor 309 00:29:13.119 --> 00:29:17.640 of the widely accepted approach to pediatric ethics as reflected 310 00:29:17.680 --> 00:29:24.480 in the national commissions, recommendations and current regulations. All pediatric 311 00:29:24.640 --> 00:29:29.680 research must satisfy the ethical principle of respect for persons. 312 00:29:30.400 --> 00:29:34.799 This Bioethics Commission articulated a set of conditions under which 313 00:29:34.960 --> 00:29:41.079 pediatric research without the prospect of direct benefit fully respects 314 00:29:41.160 --> 00:29:46.359 and ethically protects children as individuals and as a group 315 00:29:47.119 --> 00:29:50.559 see pre event studies posing no more than a minor 316 00:29:50.759 --> 00:29:58.640 increase over minimal risk approvable under section four seven, Chapter three. 317 00:29:58.799 --> 00:30:03.720 By treating the int of child participants as a paramount concern, 318 00:30:04.480 --> 00:30:09.759 pediatric research without the prospect of direct benefit, can respect 319 00:30:09.839 --> 00:30:14.839 and uphold the humanity of participants and refuse to view 320 00:30:14.960 --> 00:30:19.720 them as objects merely serving the ends of science or society, 321 00:30:20.440 --> 00:30:25.440 provided that the research risks are strictly limited and parental 322 00:30:25.480 --> 00:30:31.799 permission and meaningful child assent are obtained. This generally entails 323 00:30:31.839 --> 00:30:36.240 permitting research that involves no more than minimal risk, but 324 00:30:36.680 --> 00:30:42.039 under certain strictly limited circumstances, permitting a slightly higher than 325 00:30:42.119 --> 00:30:47.240 minimal but still very limited level of risk, provided that 326 00:30:47.279 --> 00:30:52.839 the protocol poses no substantial risk to the children's health 327 00:30:53.400 --> 00:31:00.920 or well being Beneficence. Beneficence, as described in the Bellport, 328 00:31:01.319 --> 00:31:05.200 is the obligation to undertake efforts to secure the well 329 00:31:05.240 --> 00:31:11.000 being of others. In pediatric research, the duty to safeguard 330 00:31:11.079 --> 00:31:15.519 participants by protecting them from harm and undue risk of 331 00:31:15.640 --> 00:31:22.279 harm is particularly salient because children have reduced autonomy and 332 00:31:22.359 --> 00:31:29.319 cannot legally consent, making them a vulnerable population. Beneficence requires 333 00:31:29.359 --> 00:31:35.359 that special safeguards be employed to protect vulnerable populations, for example, 334 00:31:35.440 --> 00:31:39.880 the requirement of minimal risk or prospect of direct benefit 335 00:31:40.039 --> 00:31:46.079 for most pediatric research. This principle provides additional support for 336 00:31:46.160 --> 00:31:52.079 the conclusion that some proposed pediatric trials impose excessive risks 337 00:31:52.599 --> 00:31:56.720 too high to ask parents to consider having their children 338 00:31:56.759 --> 00:32:01.720 bear These studies would involve potential harm that would threaten 339 00:32:01.799 --> 00:32:05.400 the basic health or well being of children, who, as 340 00:32:05.519 --> 00:32:10.039 research participants, would not stand to directly benefit or be 341 00:32:10.160 --> 00:32:15.559 able to offer their own informed consent. The Belmont Report 342 00:32:15.720 --> 00:32:22.319 includes under beneficence the corollary principle of non maleficence or 343 00:32:22.720 --> 00:32:27.279 do no harm, an obligation not to cause deliberate harm 344 00:32:27.359 --> 00:32:32.000 to others. This obligation to minimize the risk of harm 345 00:32:32.079 --> 00:32:36.440 from research, especially for children, in view of their inability 346 00:32:36.519 --> 00:32:41.440 to consent, provides an additional principled foundation for a firm 347 00:32:41.519 --> 00:32:47.519 limit to acceptable research risks. Notably, however, there might be 348 00:32:47.640 --> 00:32:52.160 cases in which, in order to avoid harm, research is 349 00:32:52.240 --> 00:32:57.359 needed to discover what is harmful. Similarly, to discover what 350 00:32:57.519 --> 00:33:02.599 is beneficial might at times require exposing some persons to 351 00:33:02.640 --> 00:33:07.680 the risk of harm. As stated by the National Commission. Quote, 352 00:33:08.200 --> 00:33:12.119 the problem posed by these imperatives is to decide when 353 00:33:12.359 --> 00:33:18.039 it is justifiable to seek certain benefits despite the risks involved, 354 00:33:18.559 --> 00:33:22.160 and when the benefits should be foregone because of the 355 00:33:22.319 --> 00:33:28.880 risks end quote. Beneficence is directed not only at individual 356 00:33:28.960 --> 00:33:33.960 research participants, but also toward the broader public seeking to 357 00:33:34.039 --> 00:33:39.640 benefit society as a whole. The Belmont Report acknowledged this, 358 00:33:40.200 --> 00:33:46.960 stating quote, the obligations of beneficence affect both individual investigators 359 00:33:47.000 --> 00:33:51.440 and society at large because they extend both to particular 360 00:33:51.599 --> 00:33:57.880 research projects and to the entire enterprise of research. In 361 00:33:57.920 --> 00:34:01.599 the case of scientific research in general, members of the 362 00:34:01.720 --> 00:34:06.720 larger society are obliged to recognize the longer term benefits 363 00:34:06.759 --> 00:34:12.519 and risks that may result from the improvement of knowledge 364 00:34:12.920 --> 00:34:19.480 and from the development of novel medical, psychotherapeutic, and social procedures. 365 00:34:20.119 --> 00:34:25.360 End quote. Those who deliberate and consider whether research should 366 00:34:25.440 --> 00:34:30.840 proceed ought to take into account the duty quote of 367 00:34:30.880 --> 00:34:35.960 a society and its government to promote individual activities and 368 00:34:36.199 --> 00:34:42.679 institutional practices, including scientific and biomedical research, that have great 369 00:34:42.760 --> 00:34:49.400 potential to improve the public's well being end quote. Beneficence 370 00:34:49.480 --> 00:34:55.360 guides the risk benefit assessment in research. While risk indicates 371 00:34:55.480 --> 00:35:01.400 possible harm, benefit refers to the anticipated game means resulting 372 00:35:01.519 --> 00:35:06.880 from the research. The Belmont Report offered five considerations for 373 00:35:07.039 --> 00:35:13.280 assessing risk benefit justification in research with all human participants. 374 00:35:14.119 --> 00:35:19.239 One brutal or inhumane treatment of human subjects is never 375 00:35:19.559 --> 00:35:26.159 morally justified. Two Risks should be reduced to those necessary 376 00:35:26.199 --> 00:35:31.320 to achieve the research objective. Risk can perhaps never be 377 00:35:31.599 --> 00:35:36.400 entirely eliminated, but it can often be reduced by careful 378 00:35:36.440 --> 00:35:43.599 attention to alternative procedures. Three. When research involves significant risk 379 00:35:43.840 --> 00:35:50.400 of serious impairment, review committees should be extraordinarily insistent on 380 00:35:50.519 --> 00:35:55.519 the justification of the risk, looking usually to the likelihood 381 00:35:55.519 --> 00:35:59.599 of benefit to the subject, or, in some rare cases, 382 00:36:00.079 --> 00:36:07.559 to the manifest voluntariness of the participation. Four. When vulnerable 383 00:36:07.760 --> 00:36:13.159 populations are involved in research, the appropriateness of involving them 384 00:36:13.239 --> 00:36:18.800 should itself be demonstrated. A number of variables go into 385 00:36:18.800 --> 00:36:22.840 such judgments, including the nature and degree of risk, the 386 00:36:22.920 --> 00:36:27.280 condition of the particular population involved, and the nature and 387 00:36:27.440 --> 00:36:34.199 level of the anticipated benefits. Five Relevant risks and benefits 388 00:36:34.280 --> 00:36:40.760 must be thoroughly arrayed in the informed consent process. Two 389 00:36:40.800 --> 00:36:44.840 of these considerations are especially applicable to the question before 390 00:36:44.880 --> 00:36:50.320 the Bioethics Commission. Two reducing risk to that necessary to 391 00:36:50.400 --> 00:36:54.760 achieve the research objective and to the lowest possible level 392 00:36:54.840 --> 00:37:01.280 by considering alternative approaches. And four justifying the appropriateness of 393 00:37:01.360 --> 00:37:07.679 including vulnerable populations in this case children. Non maleficence, which 394 00:37:08.440 --> 00:37:13.000 requires us to reduce research risks as far as possible, 395 00:37:13.599 --> 00:37:18.639 becomes especially salient when research is planned with children who 396 00:37:18.679 --> 00:37:23.440 cannot consent to assume risks on the behalf of others. 397 00:37:24.679 --> 00:37:31.400 Beneficence and non maleficence, similar to respect for children as persons, 398 00:37:31.960 --> 00:37:37.360 obligate us to ensure that research risks be necessary and minimized, 399 00:37:37.880 --> 00:37:44.320 and to employ alternative approaches that might avoid exposing children 400 00:37:44.400 --> 00:37:49.559 to risk, for example, using computer and animal models or 401 00:37:49.679 --> 00:37:54.599