WEBVTT 1 00:00:00.440 --> 00:00:05.839 Section four of Safeguarding Children Pediatric Medical Countermeasured Research by 2 00:00:05.960 --> 00:00:10.519 Presidential Commission for the Study of Bioethical Issues. This LibriVox 3 00:00:10.560 --> 00:00:14.720 recording is in the public domain recording by Patrick McAfee, 4 00:00:14.919 --> 00:00:20.519 Merritt Island. Chapter two Current Ethical and Radilatory Framework for 5 00:00:20.640 --> 00:00:27.640 Pediatric Research, Part two. This Bioethics Commission reaffirms its own 6 00:00:27.679 --> 00:00:31.839 commitment to the principle and practice of democratic deliberation and 7 00:00:31.960 --> 00:00:36.960 its importance in shaping pediatric research protections, given the dual 8 00:00:37.000 --> 00:00:41.719 obligations to protect individual research participants and to protect children 9 00:00:41.759 --> 00:00:48.719 as a class. Enhanced transparency and accountability and extensive community engagement, 10 00:00:49.159 --> 00:00:53.039 for example, are essential to informing the review and conduct 11 00:00:53.039 --> 00:00:58.159 of pediatric research by fostering meaningful inclusion of the affected 12 00:00:58.200 --> 00:01:02.960 communities at all stages of their research process. Community engagement 13 00:01:03.079 --> 00:01:08.439 constitutes a component of democratic deliberation that researchers can employ 14 00:01:08.640 --> 00:01:13.200 to incorporate the values of the community into the research process. 15 00:01:14.159 --> 00:01:19.079 The Bioethics Commission includes in its recommendations appropriate provision for 16 00:01:19.280 --> 00:01:25.640 community engagement in both pre and post event research. Moreover, 17 00:01:26.040 --> 00:01:31.120 in all stages of pediatric research, democratic deliberation provides an 18 00:01:31.239 --> 00:01:35.280 essential means of confirming both that the research is consistent 19 00:01:35.439 --> 00:01:40.120 with societal and community values, and also that it achieves 20 00:01:40.319 --> 00:01:46.560 socially valuable and broadly valued goals. Indeed, the Bioethics Commission 21 00:01:46.680 --> 00:01:51.959 has begun the community engagement process, specifically in the democratic 22 00:01:52.000 --> 00:01:58.560 deliberation process more generally through its deliberations, and recognized that 23 00:01:58.640 --> 00:02:02.840 communities are well positioned to contribute to the discussion now 24 00:02:03.319 --> 00:02:08.240 before any research occurs. The significant test of the social 25 00:02:08.319 --> 00:02:13.080 value and importance of pediatric research projects, especially when such 26 00:02:13.159 --> 00:02:18.080 projects subject individual children to some risk for the potential 27 00:02:18.120 --> 00:02:21.719 benefit of children as a class, is that a broad 28 00:02:21.840 --> 00:02:25.800 range of citizens and parents, having been informed and given 29 00:02:25.840 --> 00:02:32.240 the opportunity to comment, value and support those projects. Foundational 30 00:02:32.360 --> 00:02:37.919 ethical principles provide both clarification and guidance in formulating strong 31 00:02:38.000 --> 00:02:42.639 safeguards for children, both as individuals and as a group. 32 00:02:43.639 --> 00:02:48.120 Essential research protections that follow from a principled approach often 33 00:02:48.240 --> 00:02:53.400 involve appeal to more than one ethical principle. One protection 34 00:02:53.639 --> 00:02:59.840 central to this report, a commitment to repudiating exploitation provides 35 00:02:59.879 --> 00:03:04.400 a clear example of such an appeal. The commitment derives 36 00:03:04.439 --> 00:03:09.319 from the principle of respectful persons and its attendant imperative 37 00:03:09.479 --> 00:03:13.719 not to treat others as mere means, as well as 38 00:03:14.120 --> 00:03:19.639 from non maleficence, the duty to do no harm, the 39 00:03:19.719 --> 00:03:24.000 commitment to avoid exploiting the vulnerable is clearly a matter 40 00:03:24.120 --> 00:03:29.360 of justice and deliberty. Democracy helps to assure a just 41 00:03:29.479 --> 00:03:33.879 outcome by promoting dialogue with those who have not yet 42 00:03:33.960 --> 00:03:39.960 had their chance to voice concerns, thereby protecting against exploitation. 43 00:03:41.280 --> 00:03:45.639 Continuing in the tradition of the National Commission, this Bioethics 44 00:03:45.639 --> 00:03:50.919 Commission reaffirmed the view that ethical research is not research 45 00:03:51.080 --> 00:03:56.680 that strikes the appropriate balance or trade off among fundamental 46 00:03:56.800 --> 00:04:02.120 social values, but rather quote that all of these principles 47 00:04:02.280 --> 00:04:07.080 must be taken together as the necessary and sufficient conditions 48 00:04:07.120 --> 00:04:12.199 for the ethical conduct of research regarding children. Unless research 49 00:04:12.319 --> 00:04:16.560 can be designed which reflects all four, it cannot be 50 00:04:16.639 --> 00:04:23.600 called ethical. The recommendations of this report therefore are informed by, 51 00:04:23.920 --> 00:04:28.839 and seek to satisfy all four fundamental principles of respect 52 00:04:28.959 --> 00:04:36.199 for persons, beneficence, justice, and democratic deliberation, which are widely 53 00:04:36.199 --> 00:04:41.079 affirmed by our society and firmly established in the best 54 00:04:41.199 --> 00:04:48.000 practices of scientific research with human subjects. Current regulations for 55 00:04:48.120 --> 00:04:54.079 conducting pediatric research, the three Belmont principles and the principle 56 00:04:54.120 --> 00:04:59.639 of democratic deliberation also informed the National Commission's reasoning and 57 00:04:59.680 --> 00:05:06.439 rect recommendations for additional regulatory protections for pediatric research participants. 58 00:05:07.199 --> 00:05:12.480 The Department of Health and Human Services HHS and later 59 00:05:12.720 --> 00:05:18.879 FDA adopted the National Commission's recommendations almost verbatim, and the 60 00:05:18.959 --> 00:05:25.160 regulations subsequently promulgated concerning research with children remain largely the 61 00:05:25.199 --> 00:05:32.560 same today, comprising Subpart D of HHS Regulations at forty 62 00:05:32.639 --> 00:05:39.839 five CFR Part forty six and FDA Regulations at twenty 63 00:05:39.879 --> 00:05:45.639 one CFR Part fifty. The language of these two sets 64 00:05:45.680 --> 00:05:51.759 of regulations is substantively identical. Although Subpart D makes up 65 00:05:51.879 --> 00:05:57.399 part of these agencies Human Subjects Protections Regulations, it is 66 00:05:57.480 --> 00:06:02.560 separate from and supplementary to iois Subpart A, referred to 67 00:06:02.639 --> 00:06:08.160 as the Common Rule, which governs research with adults. Sub 68 00:06:08.279 --> 00:06:13.519 Part D specifies stringent protections for children in addition to 69 00:06:13.680 --> 00:06:19.040 those provided in the Common Rule. The key impetus for 70 00:06:19.120 --> 00:06:24.399 a separate regulatory subpart addressing additional protections for child participants 71 00:06:24.800 --> 00:06:29.439 in research was the recognition that while adults can consent 72 00:06:29.639 --> 00:06:35.160 to assume research risks, children cannot. More specific to the 73 00:06:35.199 --> 00:06:39.600 content of this report. Adults can consent to participate in 74 00:06:39.680 --> 00:06:44.040 research from which they will accrue no benefit for themselves 75 00:06:44.639 --> 00:06:50.279 but that benefits others. By contrast, children cannot participate in 76 00:06:50.360 --> 00:06:54.600 research that poses higher risks than those of daily life, 77 00:06:55.160 --> 00:06:59.800 except in circumstances where research offers the prospect of benefit 78 00:06:59.839 --> 00:07:04.199 to participants themselves or to those with the same condition. 79 00:07:05.480 --> 00:07:10.160 For the most part, protections for pediatric research participants are 80 00:07:10.199 --> 00:07:15.720 well defined and well implemented. The regulations include special protections 81 00:07:15.759 --> 00:07:20.399 for wards of the state, delineate requirements for parental permission 82 00:07:20.519 --> 00:07:26.680 and child assent, and provide criteria for rbs to use 83 00:07:27.000 --> 00:07:30.439 in reviewing research depending on its level of risk and 84 00:07:30.560 --> 00:07:36.279 potential benefit. Local IRBs can review and approve research with 85 00:07:36.439 --> 00:07:41.079 children that one does not involve greater than minimal risk, 86 00:07:41.519 --> 00:07:46.079 two involves greater than minimal risk but presents the prospect 87 00:07:46.319 --> 00:07:52.240 of direct benefit to individual participants, or three involves a 88 00:07:52.360 --> 00:07:56.879 minor increase over minimal risk and no prospect of direct 89 00:07:56.920 --> 00:08:02.279 benefit to individual research participants, but is likely to yield 90 00:08:02.480 --> 00:08:08.920 generalizable knowledge about the children's disorder or condition. Local IRBs 91 00:08:09.040 --> 00:08:13.319 are not permitted to approve research outside of these categories, 92 00:08:13.759 --> 00:08:18.920 but quote research not otherwise approvable, which presents an opportunity 93 00:08:19.040 --> 00:08:23.519 to understand, prevent, or alleviate a serious problem affecting the 94 00:08:23.560 --> 00:08:28.079 health or welfare of children end quote. Generally, higher risk 95 00:08:28.560 --> 00:08:33.679 non therapeutic research can nonetheless be approved by the Secretary 96 00:08:33.799 --> 00:08:39.039 of HHS in consultation with a panel of national experts. 97 00:08:39.720 --> 00:08:44.000 This report refers to such national level expert review by 98 00:08:44.080 --> 00:08:50.840 its HHS Provision number forty five CFR Section forty six 99 00:08:50.960 --> 00:08:55.600 point four zero seven, Section four zero seven, which is 100 00:08:55.679 --> 00:09:00.840 a common convention in ethics discourse on this subject. Equivalent 101 00:09:00.919 --> 00:09:07.399 substantive requirements are found in FDA Regulations at twenty one CFR, 102 00:09:07.759 --> 00:09:12.559 Section fifty point five four. Whether the review is conducted 103 00:09:12.600 --> 00:09:20.240 by the HHS Office for Human Research Protection OHRP FDA, 104 00:09:20.679 --> 00:09:24.919 or both, the ethical requirements are essentially the same across 105 00:09:25.000 --> 00:09:30.360 both sets of regulations. The regulations governing these review mechanisms 106 00:09:30.480 --> 00:09:35.879 are included in Table two point one. Table two point 107 00:09:35.919 --> 00:09:42.360 one Regulations governing Review of Pediatric Human Subjects Research Protocols. 108 00:09:42.960 --> 00:09:50.759 Local IRB review mechanisms minimal risk. HHS will conduct or 109 00:09:50.840 --> 00:09:54.519 fund research in which the IRB finds that no greater 110 00:09:54.600 --> 00:09:59.039 than minimal risk to children is presented only if THERB 111 00:09:59.240 --> 00:10:03.039 finds that adequate provisions are made for soliciting assent of 112 00:10:03.120 --> 00:10:06.840 the children and the permission of their parents or guardians 113 00:10:07.200 --> 00:10:11.600 as set forth in section forty six point four zero eight. 114 00:10:12.840 --> 00:10:18.519 Prospect of direct benefit to the individual participant. HS will 115 00:10:18.559 --> 00:10:22.399 conduct for fund research in which the IRB finds that 116 00:10:22.679 --> 00:10:26.960 more than minimal risk to children presented by an intervention 117 00:10:27.720 --> 00:10:31.159 or procedure that holds out the prospect of direct benefit 118 00:10:31.320 --> 00:10:35.960 for the individual subject, or by a monitoring procedure that 119 00:10:36.080 --> 00:10:39.679 is likely to contribute to the subjects well being only 120 00:10:39.799 --> 00:10:44.759 if the IRB finds that a the risk is justified 121 00:10:44.799 --> 00:10:49.360 by the anticipated benefit to the subjects, b the relation 122 00:10:49.559 --> 00:10:53.240 of the anticipated benefit to the risk is at least 123 00:10:53.279 --> 00:10:57.639 as favorable to the subjects as that presented by available 124 00:10:57.679 --> 00:11:03.440 alternative approaches, and adequate provisions are made for soliciting the 125 00:11:03.519 --> 00:11:07.200 assent of the children and permission of their parents or 126 00:11:07.279 --> 00:11:10.960 guardians as set forth in section forty six point four 127 00:11:11.159 --> 00:11:17.200 zero eight, likely to yield generalizable knowledge about participants condition 128 00:11:17.799 --> 00:11:23.399 and only minor increase over minimal risk. HHS will conduct 129 00:11:23.559 --> 00:11:27.360 or fund research in which the IRB finds that more 130 00:11:27.399 --> 00:11:32.759 than minimal risk to children is presented by an intervention 131 00:11:32.960 --> 00:11:35.759 or procedure that does not hold out the prospect of 132 00:11:35.840 --> 00:11:40.080 direct benefit for the individual subject, or by a monitoring 133 00:11:40.120 --> 00:11:43.039 procedure which is not likely to contribute to the well 134 00:11:43.080 --> 00:11:47.200 being of the subject. Only if the IRB finds that 135 00:11:47.600 --> 00:11:51.840 a the risk represents a minor increase over minimal risk. 136 00:11:52.399 --> 00:11:57.440 B The intervention or procedure presents experiences to subjects that 137 00:11:57.480 --> 00:12:02.320 are reasonably commensurate with those inherent in their actual or 138 00:12:02.360 --> 00:12:09.720 expected medical, dental, psychological, social, or educational situations. C The 139 00:12:09.759 --> 00:12:14.200 intervention or procedure is likely to yield generalizable knowledge about 140 00:12:14.240 --> 00:12:18.919 the subject's disorder or condition, which is of vital importance 141 00:12:19.000 --> 00:12:24.200 for the understanding or amelioration of the subject's disorder or condition. 142 00:12:24.519 --> 00:12:29.600 And d Adequate provisions are made for soliciting assent of 143 00:12:29.639 --> 00:12:33.279 the children and permission of their parents or guardians, as 144 00:12:33.399 --> 00:12:37.960 set forth in Section forty six point four zero eight 145 00:12:39.200 --> 00:12:44.159 National Level Review mechanisms greater than minimal risk with no 146 00:12:44.320 --> 00:12:50.159 prospect of direct benefit to individual participants or those participants' condition, 147 00:12:51.480 --> 00:12:55.759 HHS will conduct or fund research that the IRB does 148 00:12:55.799 --> 00:13:00.000 not believe meets the requirements of Section forty six point 149 00:13:00.000 --> 00:13:04.320 point four zero four, Section forty six point four zero 150 00:13:04.360 --> 00:13:09.440 five or Section forty six point four zero six only 151 00:13:09.600 --> 00:13:13.879 if a the IRB finds that the research presents a 152 00:13:13.960 --> 00:13:20.120 reasonable opportunity to further the understanding, prevention, or alleviation of 153 00:13:20.159 --> 00:13:23.480 a serious problem affecting the health or welfare of children, 154 00:13:23.960 --> 00:13:28.320 and b the Secretary, after consultation with a panel of 155 00:13:28.360 --> 00:13:36.080 experts impertinent disciplines for example, science, medicine, education, ethics, law, 156 00:13:36.639 --> 00:13:41.360 and following opportunity for public review and comment, has determined 157 00:13:41.559 --> 00:13:46.360 either one that the research in fact satisfies the conditions 158 00:13:46.399 --> 00:13:51.120 of Section forty six point four zero four, Section forty 159 00:13:51.159 --> 00:13:55.559 six point four zero five or Section forty six point 160 00:13:55.600 --> 00:14:01.519 four zero six, as applicable, or two the following one, 161 00:14:02.039 --> 00:14:07.039 the research presents a reasonable opportunity to further the understanding, prevention, 162 00:14:07.320 --> 00:14:10.720 or alleviation of a serious problem affecting the health or 163 00:14:10.759 --> 00:14:15.399 welfare of children. Two, the research will be conducted in 164 00:14:15.480 --> 00:14:21.080 accordance with sound ethical principles, and three adequate provisions are 165 00:14:21.120 --> 00:14:24.720 made for soliciting the ascent of children and the permission 166 00:14:24.759 --> 00:14:28.679 of their parents or guardians, as set forth in Section 167 00:14:28.840 --> 00:14:33.679 forty six point four zero eight. Note in the case 168 00:14:33.720 --> 00:14:37.919 of review by FDA. Under section fifty point five to four, 169 00:14:38.480 --> 00:14:42.320 the Commissioner of Food and Drugs convenes the expert panel 170 00:14:42.720 --> 00:14:46.559 and makes the final determination, which is forwarded to the 171 00:14:46.799 --> 00:14:53.440 HHS Secretary for concurrent review. Under sections forty six point 172 00:14:53.480 --> 00:14:58.360 four zero seven and fifty point five four, the Secretary 173 00:14:58.639 --> 00:15:04.159 makes the final determine end of Table two point one. 174 00:15:04.159 --> 00:15:09.360 This report references research regulated by Section four zero seven 175 00:15:09.559 --> 00:15:13.279 as research with healthy children that poses more than minimal 176 00:15:13.360 --> 00:15:18.039 risk with no prospect of direct benefit. The Bioethics Commission 177 00:15:18.159 --> 00:15:22.440 recognized and considered in its work the full range of 178 00:15:22.519 --> 00:15:26.960 research that is encompassed by Section four zero seven, including 179 00:15:27.320 --> 00:15:31.159 one research with healthy children that poses greater than minimal 180 00:15:31.240 --> 00:15:35.799 risk and that offers no prospect of direct benefit, two 181 00:15:36.399 --> 00:15:39.799 research with children affected by a disease or condition that 182 00:15:39.879 --> 00:15:43.720 poses more than minimal risk and does not yield information 183 00:15:43.799 --> 00:15:48.080 of vital importance about their disease or condition, and three 184 00:15:48.679 --> 00:15:52.600 research with children affected by a disease or condition that 185 00:15:52.720 --> 00:15:58.519 poses greater than a minor increase over minimal risk pediatric 186 00:15:58.639 --> 00:16:04.399 research subject to local IRB approval. The National Commission's most 187 00:16:04.600 --> 00:16:10.600 straightforward recommendations addressed research that poses only minimal risk codified 188 00:16:10.799 --> 00:16:14.759 in section four zero four, or that offers the prospect 189 00:16:15.120 --> 00:16:19.799 of direct benefit to participants codified in section four zero five. 190 00:16:20.720 --> 00:16:26.080 More complicated, but still ethically tractable was research posing greater 191 00:16:26.159 --> 00:16:30.519 than minimal risk but likely to yield generalizable knowledge about 192 00:16:30.519 --> 00:16:36.159 the participant's condition, codified in section four zero six. Research 193 00:16:36.240 --> 00:16:39.120 that is greater than minimal risk with no prospect of 194 00:16:39.200 --> 00:16:43.159 direct benefit to subjects or benefit to others with their 195 00:16:43.159 --> 00:16:51.000 condition was considered decidedly more controversial and ethically problematic section 196 00:16:51.039 --> 00:16:56.799 four zero four minimal risk research. Making its recommendation on 197 00:16:56.919 --> 00:17:02.600 minimal risk research, the National commissionized that quote the scope 198 00:17:02.600 --> 00:17:07.680 of parental responsibility includes the right to choose activities and 199 00:17:07.799 --> 00:17:11.599 to define a manner of life for their children end quote. 200 00:17:12.359 --> 00:17:17.680 Finding that quote many experiences which parents generally allow to 201 00:17:17.799 --> 00:17:22.319 their children are somewhat risky and cannot be said without 202 00:17:22.480 --> 00:17:27.440 forcing the case to involve particular benefits end quote, the 203 00:17:27.559 --> 00:17:31.920 National Commission considered it uncontroversial that parents should have the 204 00:17:31.960 --> 00:17:36.480 opportunity to enroll their children in research where the risks 205 00:17:36.960 --> 00:17:41.839 quote are equivalent to normal risks of childhood end quote. 206 00:17:41.960 --> 00:17:46.519 The National Commission recommended and the regulations allow an IRB 207 00:17:46.680 --> 00:17:51.359 to approve minimal risk research that provides for parental permission 208 00:17:51.799 --> 00:17:57.119 and meaningful assent from child participants, as well as standard 209 00:17:57.160 --> 00:18:05.960 pediatric research safeguards such as risk minimization, privacy and confidentiality protections, 210 00:18:06.000 --> 00:18:11.640 and equitable subject selection. The National Commission defined risk as 211 00:18:11.960 --> 00:18:17.400 quote the probability and magnitude of physical or psychological harm 212 00:18:17.480 --> 00:18:21.319 that is normally encountered in the daily lives or in 213 00:18:21.359 --> 00:18:26.680 the routine medical or psychological examination of healthy children. End 214 00:18:28.000 --> 00:18:32.839 As implemented. Protections for minimal risk research have been subject 215 00:18:32.880 --> 00:18:38.200 to ongoing debate, mostly focused on the regulatory definition of 216 00:18:38.839 --> 00:18:43.920 minimal risk, which omits the National Commission's reference to healthy children. 217 00:18:44.680 --> 00:18:48.480 While disagreement remains as to whether the standard is intended 218 00:18:48.519 --> 00:18:53.720 to be objective or subjective, several national committees studying the 219 00:18:53.799 --> 00:18:58.680 matter have concluded that minimal risk should be interpreted as 220 00:18:58.759 --> 00:19:01.599 the degree of risk in encountered in the daily life 221 00:19:01.960 --> 00:19:05.960 of a healthy child living in a safe environment, or 222 00:19:06.039 --> 00:19:09.599 the risk to which a healthy child is exposed during 223 00:19:09.799 --> 00:19:16.000 a routine examination. The Bioethics Commission accepted this shared understanding 224 00:19:17.160 --> 00:19:21.920 section four zero five. Research presenting the prospect of direct 225 00:19:21.960 --> 00:19:26.599 benefit in considering research that presents greater than minimal risk 226 00:19:26.680 --> 00:19:31.160 but also the prospect of direct benefit to research participants. 227 00:19:31.319 --> 00:19:35.599 The National Commission concluded that risk might be justified by 228 00:19:36.279 --> 00:19:42.640 avoidance of greater harm or provision of important anticipated benefit. 229 00:19:43.640 --> 00:19:47.519 Any risk entailed in research, however, can be justified only 230 00:19:47.599 --> 00:19:52.119 by the potential direct benefits to the individual child participant 231 00:19:52.559 --> 00:19:56.880 that are associated with the intervention itself, not by ancillary 232 00:19:56.960 --> 00:20:02.359 benefits such as a medical examination. The risk benefit ratio 233 00:20:02.680 --> 00:20:06.799 of the experimental intervention must be at least as good 234 00:20:06.960 --> 00:20:12.680 as that of available alternatives. The relevant regulatory language closely 235 00:20:12.759 --> 00:20:17.279 reflects that of the National Commission, stating that an RB 236 00:20:17.559 --> 00:20:20.480 may approve a protocol if it finds that the risk 237 00:20:20.640 --> 00:20:24.000 is greater than minimal, but that the research holds the 238 00:20:24.039 --> 00:20:28.079 prospect of direct benefit to the individual, either through the 239 00:20:28.200 --> 00:20:32.440 intervention or through quote a monitoring procedure that is likely 240 00:20:32.519 --> 00:20:37.599 to contribute to the subject's well being end quote. Beneficial 241 00:20:37.720 --> 00:20:42.799 monitoring procedures might include, for example, obtaining samples of blood 242 00:20:42.920 --> 00:20:45.960 or spinal fluid in order to determine that drug levels 243 00:20:46.000 --> 00:20:51.240 are safe and effective. A reviewing IRB must also find 244 00:20:51.400 --> 00:20:55.720 that a quote the risk is justified by the anticipated 245 00:20:55.759 --> 00:21:00.880 benefit to the subject end quote B. The risk benefit 246 00:21:01.039 --> 00:21:04.839 ratio is at least as good as existing alternatives, and 247 00:21:05.599 --> 00:21:11.079 see all relevant parental permission and meaningful child assent provisions 248 00:21:11.200 --> 00:21:15.359 are observed. There is ongoing debate over the extent to 249 00:21:15.440 --> 00:21:20.960 which benefit should include non medical benefits, but in practice 250 00:21:21.160 --> 00:21:26.160 the scope is most often limited to medical benefits associated 251 00:21:26.200 --> 00:21:31.920 with the intervention being studied Section four zero six more 252 00:21:31.960 --> 00:21:35.200 than minimal risk without the prospect of direct benefit, but 253 00:21:35.440 --> 00:21:39.799 likely to yield knowledge about the participant's condition. The National 254 00:21:39.799 --> 00:21:44.440 Commission recognized that some valuable research involving children will inevitably 255 00:21:44.839 --> 00:21:48.079 present greater than minimal risk with no prospect of direct 256 00:21:48.119 --> 00:21:53.680 benefit to the individual participants. Prohibiting this type of research completely, 257 00:21:54.519 --> 00:21:57.759 as initially supported by some members of the National Commission, 258 00:21:58.359 --> 00:22:02.119 might have come at too great a cost, sacrificing research 259 00:22:02.720 --> 00:22:06.319 of critical importance to child welfare in order to avoid 260 00:22:06.559 --> 00:22:11.839 only a minor increased risk. In developing its recommendations for 261 00:22:11.920 --> 00:22:15.519 approval of a limited class of research entailing greater than 262 00:22:15.559 --> 00:22:20.279 minimal risk and no prospect of direct benefit, the National 263 00:22:20.359 --> 00:22:24.359 Commission kept in mind the proposition that parents are routinely 264 00:22:24.519 --> 00:22:29.720 allowed to authorize their child's involvement in activities such as skiing, 265 00:22:30.319 --> 00:22:33.599 where risk is greater than minimal and the potential for 266 00:22:33.720 --> 00:22:39.559 benefit is debatable. Given that information, the National Commission recommended 267 00:22:39.599 --> 00:22:44.559 that pediatric research with no prospect of direct benefit in 268 00:22:44.640 --> 00:22:49.440 presenting no more than a minor increase over minimal risk 269 00:22:49.960 --> 00:22:54.119 could be ethically permissible and allowed by regulation if the 270 00:22:54.160 --> 00:22:57.519 knowledge likely to be generated by the research was of 271 00:22:58.000 --> 00:23:06.200 vital importance to understand or ameliorate a pediatric disorder or condition. Specifically, 272 00:23:06.400 --> 00:23:11.000 in light of reports that valuable diagnostic, therapeutic and preventive 273 00:23:11.039 --> 00:23:16.400 measures have been discovered in research that entails risk that quote, 274 00:23:16.720 --> 00:23:20.640 while minor, would be considered more than minimal end quote. 275 00:23:21.119 --> 00:23:26.519 The National Commission recommended that local IRBs could approve research 276 00:23:26.640 --> 00:23:31.880 that meets the following conditions. One quote, the risk involved 277 00:23:31.960 --> 00:23:36.720 must be only a minor increment beyond minimal end quote. 278 00:23:36.839 --> 00:23:40.920 Two quote, the procedures to be used must be reasonably 279 00:23:41.000 --> 00:23:46.000 commensurate with similar to those with which prospective subjects have 280 00:23:46.079 --> 00:23:51.000 had experience end quote, and three quote, the research must 281 00:23:51.039 --> 00:23:55.039 be likely to yield generalizable knowledge important for the understanding 282 00:23:55.480 --> 00:24:02.799 or amelioration of the subject's specific disorder or condition. Research 283 00:24:02.960 --> 00:24:07.119 that meets these specifications may be approved because the minor 284 00:24:07.200 --> 00:24:11.440 additional increment of risk to participants is acceptable in light 285 00:24:11.640 --> 00:24:15.480 of the quote foreseeable benefit in the future to an 286 00:24:15.519 --> 00:24:21.200 identifiable class of children quote. In making its recommendation, the 287 00:24:21.279 --> 00:24:27.160 National Commission emphasized that quote minor increase over minimal risk 288 00:24:27.680 --> 00:24:32.079 in quote is only a narrow expansion, and that any 289 00:24:32.160 --> 00:24:37.519 protocol submitted under this provision should quote pose no significant 290 00:24:37.519 --> 00:24:42.720 threat to the child's health or well being. HHS and 291 00:24:43.079 --> 00:24:49.519 FDA adopted the National Commission's recommendation. Taken together, the three 292 00:24:49.599 --> 00:24:52.920 categories of research that can be approved by a local 293 00:24:53.039 --> 00:24:58.720 IRB constitute the majority of pediatric research approved and conducted 294 00:24:58.759 --> 00:25:02.559 in the United States. Where a protocol does not fall 295 00:25:02.720 --> 00:25:07.000 into one of these approvable categories, it is generally adminded 296 00:25:07.160 --> 00:25:11.559 so that it conforms to local review requirements, or else 297 00:25:11.759 --> 00:25:16.039 it is denied approval. Only rarely is such a protocol 298 00:25:16.160 --> 00:25:20.440 elevated for national level review under section four zero seven 299 00:25:21.000 --> 00:25:26.319 see Pediatric Research requiring National level review, higher risk and 300 00:25:26.480 --> 00:25:32.319 no prospect of direct benefit, Chapter two. These regulatory provisions 301 00:25:32.359 --> 00:25:36.559 for local IRB review place strict, ethically sound limits on 302 00:25:36.640 --> 00:25:40.119 the degree of risk to which children can be exposed 303 00:25:40.160 --> 00:25:43.400 in research, and from the time they have been in place, 304 00:25:43.880 --> 00:25:48.240 they have permitted and indeed fostered research lead to interventions 305 00:25:48.279 --> 00:25:54.359 for the most common childhood illnesses and conditions, pediatric research 306 00:25:54.519 --> 00:25:59.200 requiring national level review higher risk and no prospect of 307 00:25:59.279 --> 00:26:03.880 a direct benefit to healthy participants Section four zero seven. 308 00:26:05.079 --> 00:26:09.200 Although the National Commission created a mechanism for local approval 309 00:26:09.319 --> 00:26:12.759 of greater than minimal risk research with children affected by 310 00:26:12.920 --> 00:26:16.519 a disorder or condition, it did not develop a set 311 00:26:16.559 --> 00:26:20.839 of criteria for local IRBs to approve higher risk research 312 00:26:20.960 --> 00:26:24.519 with healthy children, or research where the risk is greater 313 00:26:24.640 --> 00:26:29.839 than a minor increase over minimal risk. This latter type 314 00:26:29.839 --> 00:26:33.720 of research was reserved for evaluation and approval by a 315 00:26:33.839 --> 00:26:38.720 national panel of experts in the Secretary of HHS, later 316 00:26:38.880 --> 00:26:43.960 codified as Section four zero seven. The National Commission struggled 317 00:26:43.960 --> 00:26:47.200 with the idea of involving children in such research with 318 00:26:47.279 --> 00:26:51.200 no prospect of direct benefit to the individual child participant, 319 00:26:51.960 --> 00:26:56.759 but recognized that there might be extraordinary circumstances in which 320 00:26:56.839 --> 00:27:00.279 the dangers to children as a class or the community 321 00:27:00.440 --> 00:27:03.839 as a whole that would result from excluding children from 322 00:27:03.920 --> 00:27:08.359 research would be so great that they might require society 323 00:27:08.400 --> 00:27:13.640 reluctantly to accept a higher level of research risk. For instance, 324 00:27:14.119 --> 00:27:16.880 in the event of a pending epidemic that could be 325 00:27:16.920 --> 00:27:21.880 stemmed by testing a novel vaccine with children. The circumstances 326 00:27:22.039 --> 00:27:26.920 might require this reluctant acceptance of levels of risk otherwise 327 00:27:27.160 --> 00:27:33.240 unacceptable in pediatric research, for example, higher risks involved in 328 00:27:33.359 --> 00:27:39.799 determining dosing specifications for particular age groups. Acknowledging that every 329 00:27:39.839 --> 00:27:44.960 such situation would involve different considerations that could not be 330 00:27:45.000 --> 00:27:50.400 precisely resolved in the abstract, the National Commission concluded that 331 00:27:50.480 --> 00:27:53.640 it would be preferable to debate the matter in an 332 00:27:53.680 --> 00:27:59.359 actual situation, where the quote real issues and the likely 333 00:27:59.519 --> 00:28:04.920 cost of any solution can be more clearly discerned end quote. 334 00:28:05.599 --> 00:28:10.039 In providing the opportunity for considered debate in light of 335 00:28:10.200 --> 00:28:14.920 more specific circumstances, the National Commission went a step further, 336 00:28:15.519 --> 00:28:19.440 calling for public input as well, stating that the moral 337 00:28:19.519 --> 00:28:24.119 obligation to protect the community to the extent ethically and 338 00:28:24.240 --> 00:28:30.759 practically possible, and the prohibition against using unconsenting persons at 339 00:28:30.839 --> 00:28:34.680 considerable risk to their well being for the promotion of 340 00:28:34.720 --> 00:28:38.920 the common good were of such import that debate on 341 00:28:39.160 --> 00:28:44.880 how to reconcile the obligation and prohibition must be held publicly. 342 00:28:45.640 --> 00:28:49.759 The National Commission recommended that research entailing this level of 343 00:28:49.839 --> 00:28:54.799 risk could only be approved as an quote exception to 344 00:28:54.920 --> 00:28:59.240 the general rules end quote. In other words, when quote 345 00:28:59.519 --> 00:29:03.559 the outlome prohibition of such research on grounds of risk 346 00:29:04.119 --> 00:29:10.400 might have consequences which themselves appear unethical end and could 347 00:29:10.480 --> 00:29:15.759 only go forward after one and IRB determines that for 348 00:29:16.359 --> 00:29:21.519 urgent or unique reasons the research should be permitted, and 349 00:29:21.880 --> 00:29:26.079 two the research is reviewed and approved at the national 350 00:29:26.160 --> 00:29:29.640 level to determine that it does not violate the principles 351 00:29:29.680 --> 00:29:35.279 of respect for persons, beneficence and justice, with opportunity for 352 00:29:35.319 --> 00:29:41.640 public comment. Additionally, appropriate parental permission and meaningful child assent 353 00:29:41.799 --> 00:29:46.640 would be required. Now Commission recommended that this national level 354 00:29:46.680 --> 00:29:50.880 review include judgment by the Secretary of the responsible Agency, 355 00:29:51.599 --> 00:29:57.519 and that approved research should be delayed pending congressional notification 356 00:29:58.119 --> 00:30:02.599 and a reasonable opportunity for Congress to take action regarding 357 00:30:02.640 --> 00:30:09.759 the proposed research. As enacted, the regulations provide that research 358 00:30:09.799 --> 00:30:14.680 may be approved if one and IRB determines that the 359 00:30:14.759 --> 00:30:20.440 research quote presents a reasonable opportunity to further the understanding, 360 00:30:20.640 --> 00:30:25.200 prevention or alleviation of a serious problem affecting the health 361 00:30:25.359 --> 00:30:30.960 or welfare of children end quote, but is not approvable 362 00:30:31.119 --> 00:30:37.359 under sections four zero four to Fords zero six and two. 363 00:30:37.640 --> 00:30:42.079 Upon convening a panel of experts and soliciting public comment, 364 00:30:42.720 --> 00:30:49.400 the Secretary of HHS determines that one the quote research 365 00:30:49.559 --> 00:30:53.839 presents a reasonable opportunity to further the understanding, prevention or 366 00:30:53.880 --> 00:30:58.279 alleviation of a serious problem affecting the health or welfare 367 00:30:58.319 --> 00:31:03.759 of children end quote. Two quote the research will be 368 00:31:03.799 --> 00:31:08.519 conducted in accordance with sound ethical principles end quote, and 369 00:31:08.839 --> 00:31:13.400 three Adequate provision is made for permission of parents and 370 00:31:13.480 --> 00:31:20.240 guardians in meaningful assent or affirmative agreement of children. This 371 00:31:20.319 --> 00:31:24.880 structure creates three independent bodies that must review or approve 372 00:31:24.960 --> 00:31:30.200 any protocol submitted for assessment under section four zero seven, 373 00:31:30.960 --> 00:31:37.119 one the LOCALRB, two the National Panel of Experts, and 374 00:31:37.440 --> 00:31:44.480 three the Secretary of HHS. As evidenced by the language 375 00:31:44.480 --> 00:31:51.119 of section four zero seven, HHS and FDA, in its regulations, 376 00:31:51.799 --> 00:31:59.000 modified the National Commission's recommendation. The provision adopted by HHS 377 00:31:59.039 --> 00:32:03.799 and FDA does not provide for notification of Congress and 378 00:32:04.079 --> 00:32:08.640 sufficient delay for Congress to intervene. The reasons for this 379 00:32:08.720 --> 00:32:14.920 omission are unclear. In addition, the regulations depart from the 380 00:32:15.000 --> 00:32:20.640 National Commission's recommendations by providing for an ad hoc panel 381 00:32:20.720 --> 00:32:25.319 of experts to conduct the National level review rather than 382 00:32:25.519 --> 00:32:32.880 a standing quote national Ethical Advisory body end quote. Unlike 383 00:32:32.960 --> 00:32:38.640 the standing committee, a system that HHS expected to prove 384 00:32:39.160 --> 00:32:44.720 quote cumbersome, inflexible, and unadaptable to the variety of different 385 00:32:44.799 --> 00:32:49.240 research problems likely to be encountered within the scope of 386 00:32:49.279 --> 00:32:55.200 the department's activities end quote. The agency hoped that an 387 00:32:55.240 --> 00:33:00.119 ad hoc structure would provide the flexibility necessary to to 388 00:33:00.240 --> 00:33:07.240 convene sufficiently expert individuals in a range of scientific specialties, 389 00:33:08.039 --> 00:33:14.440 ethics concentrations, legal fields, and other relevant disciplines for a 390 00:33:14.480 --> 00:33:21.960 given protocol. Similarly, regulations adopting National level Review, rather than 391 00:33:22.240 --> 00:33:28.000 enumerting the principles in the National Commission's recommendation Respect for Persons, 392 00:33:28.480 --> 00:33:34.799 beneficence and Justice, simply require that research be conducted in 393 00:33:34.880 --> 00:33:42.920 accordance with sound ethical principles. Although the provision permits necessary 394 00:33:43.000 --> 00:33:49.680 flexibility for review of research required by extraordinary circumstances, many 395 00:33:49.920 --> 00:33:55.519 expert panels have reported great uncertainty in determining whether a 396 00:33:55.640 --> 00:34:01.480 protocol was consistent with sound ethical principles, especially in the 397 00:34:01.519 --> 00:34:09.599 context of extraordinary circumstances that would justify approval. National level 398 00:34:09.760 --> 00:34:17.519 review case study driveax smallpox vaccine protocol. In two thousand 399 00:34:17.559 --> 00:34:21.880 and two, an independent panel reviewed a protocol to test 400 00:34:22.000 --> 00:34:28.119 smallpox vaccine in forty children two to five years of age. 401 00:34:28.920 --> 00:34:34.480